WO2008014471A1 - Drug combination pharmaceutical compositions and methods for using them - Google Patents
Drug combination pharmaceutical compositions and methods for using them Download PDFInfo
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- WO2008014471A1 WO2008014471A1 PCT/US2007/074625 US2007074625W WO2008014471A1 WO 2008014471 A1 WO2008014471 A1 WO 2008014471A1 US 2007074625 W US2007074625 W US 2007074625W WO 2008014471 A1 WO2008014471 A1 WO 2008014471A1
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- etodolac
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- propranolol
- cachexia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Definitions
- compositions e.g., preparations, formulations, kits and other products of manufacture, e.g., exemplary drug combinations packaged together or separately in blister packs, lidded blisters or blister cards, or wrapped in paper, plastic or cellophane wrappers (e.g., a shrink wrap), comprising combinations of beneficial ingredients that are serviceable as therapies for treating, preventing or improving conditions, states and disease symptoms involving inflammation, excessive sympathoneural drive, cachexia, anorexia, and anorexia-cachexia, and stress or anxiety related thereto, and method of using them.
- compositions and therapies comprising use of a beta adrenergic antagonist (also called “beta blockers” e.g., propranolol) in combination with an anti-inflammatory agent, e.g., a nonsteroidal anti-inflammatory drug (NSAID), an angiotensin-con verting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), an anabolic steroid, a natural oil or fatty acid or any combination thereof.
- NSAID nonsteroidal anti-inflammatory drug
- ACE angiotensin-con verting enzyme
- ARB angiotensin receptor blocker
- anabolic steroid e.g., a natural oil or fatty acid or any combination thereof.
- Single agent therapies have been used as therapies or suggested for use as therapies for disease symptoms and diseases states such as involving, inflammation, excessive sympathoneural drive, cachexia, anorexia, and anorexia-cachexia, and stress or anxiety related thereto for the purpose of improving one or more undesirable symptoms associated with the disease states or for slowing the progression (worsening) of the symptoms.
- disease symptoms and diseases states such as involving, inflammation, excessive sympathoneural drive, cachexia, anorexia, and anorexia-cachexia, and stress or anxiety related thereto for the purpose of improving one or more undesirable symptoms associated with the disease states or for slowing the progression (worsening) of the symptoms.
- the success achieved with the attempted doses of single agents has been limited, and the obstacles to increasing the doses include legitimate concerns about exceeding the therapeutic windows and/or concerns about the manifestation of undesirable side effects at higher doses.
- Angiotensin II augments norepinephrine release from sympathetic nerve terminals by inhibiting reuptake of norepinephrine into nerve terminals and enhancing the vascular response to norepinephrine.
- Angiotensin II leads to direct vasoconstriction through increased norepinephrine release, decreased reuptake, increased sympathetic activation and release of catecholamines from the adrenal medulla.
- Compounds that inhibit the enzyme that converts angiotensin I to angiotensin II are frequently used for controlling blood pressure.
- ACE inhibitors angiotensin converting enzyme inhibitors
- the renin-angiotensin system has a large degree of overlap with the effects of beta blockers and the beta adrenergic receptor pathway has a direct effect on the regulation of rennin release. Therefore, the use of ACE inhibitors has been suggested as a means to treat cachexia.
- the problem with the use of ACE inhibitors is the same as that for beta blockers, specifically the need to reduce the inflammatory response in addition to autonomic nervous system dysregulation.
- Cancer cachexia is a catastrophic weight-loss disorder associated with more than a 40 percent reduction in life expectancy, which limits chemotherapy efficacy and impairs patient tolerance to life-extending therapies.
- cachexia is one of the most feared disorders of advanced cancer and significantly affects quality of life.
- effective treatments for cancer cachexia are lacking, and no FDA approved treatments are available.
- Cachexia affects 80% of advanced solid- tumor cancer patients and is associated with significant patient morbidity, including weakness, fatigue, gastrointestinal distress, sleep/wake disturbances, pain, listlessness, shortness of breath, lethargy, depression, malaise and fear of being a burden on family and friends. For more than 20% of terminal cancer patients, cachexia results in the direct cause of death.
- Cachexia is a maladaptive nutritional state secondary to a chronic systemic inflammatory response and autonomic nervous system dysregulation. Improved treatment protocols for this complex and devastating disorder are greatly needed.
- a safe and effective treatment that could alleviate suffering and improve outcomes would be a significant medical advance for cancer treatment and potentially for the treatment other end-stage diseases as well.
- Possible intervention points and therapeutics that have been suggested include: aberrant eicosanoid metabolism with nonsteroidal anti -inflammatory agents, omega-3 fatty acids; amino acid deficiencies relevant to need with tailored protein supplements, specific amino acid therapy; altered energy mechanisms in muscle cells with creatine, ATP, angiotensin- converting enzyme (ACEj inhibitors; impaired muscle synthesis and muscle repair with anabolic steroids,
- This invention provides combination preparations and formulations, kits and other products of manufacture (e.g., blister packs, lidded blisters or blister cards, or individual wrapped paper, plastic or cellophane packages or packettes) that can be used for treating, preventing and/or ameliorating conditions, diseases, symptoms and disease states comprising inflammation, excessive sympathoneural drive (sympathetic nerve activity), cachexia, anorexia, and anorexia-cachexia, and stress or anxiety related thereto for the purpose of improving one or more undesirable symptoms associated with the disease states or for slowing the progression (worsening) of one or more symptoms associated with these disease symptoms and disease states.
- products of manufacture e.g., blister packs, lidded blisters or blister cards, or individual wrapped paper, plastic or cellophane packages or packettes
- diseases, symptoms and disease states comprising inflammation, excessive sympathoneural drive (sympathetic nerve activity), cachexia, anorexia, and anorexia-cachexia, and stress or anxiety related thereto for the purpose of improving one or more
- the invention provides therapeutic combinations comprising at least one member of a first group and at least one member of a second group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (beta blockers); and members of the second group are selected from the group consisting of angiotensin-con verting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), non-steroidal anti-inflammatory drugs (NSAID), anabolic steroids, natural oils and fatty acids and a combination thereof.
- ACE angiotensin-con verting enzyme
- ARBs angiotensin receptor blockers
- NSAID non-steroidal anti-inflammatory drugs
- the therapeutic combination comprises: at least one beta adrenergic receptor antagonist (beta blocker) and at least one angiotensin- con verting enzyme (ACE) inhibitors; at least one beta adrenergic receptor antagonist (beta blocker) and at least one non-steroidal anti-inflammatory drug (NSAID); at least one beta adrenergic receptor antagonist (beta blocker) and at least one angiotensin receptor blocker (ARB); at least one beta adrenergic receptor antagonist (beta blocker) and at least one anabolic steroid; or at least one beta adrenergic receptor antagonist (beta blocker) and at least one natural oil or fatty acid.
- ACE angiotensin- con verting enzyme
- the therapeutic combinations further comprise at least one member of a third group, wherein the member of the third group is a different composition than the selected member of the first or second group, and members of the third group are selected from the group consisting of angiotensin-con verting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), non-steroidal anti-inflammatory drugs (NSAIDs), anabolic steroids, natural oils and fatty acids and a combination thereof.
- ACE angiotensin-con verting enzyme
- ARBs angiotensin receptor blockers
- NSAIDs non-steroidal anti-inflammatory drugs
- anabolic steroids natural oils and fatty acids and a combination thereof.
- the therapeutic combination can comprise: at least one beta adrenergic receptor antagonist (beta blocker), at least one angiotensin-converting enzyme (ACE) inhibitor and at least one angiotensin receptor blocker (ARB); at least one beta adrenergic receptor antagonist (beta blocker), at least one angiotensin-converting enzyme (ACE) inhibitor and at least one non-steroidal anti-inflammatory drug (NSAID); at least one beta adrenergic receptor antagonist (beta blocker), at least one angiotensin-converting enzyme (ACE) inhibitor and at least one anabolic steroid; at least one beta adrenergic receptor antagonist (beta blocker), at least one angiotensin-converting enzyme (ACE) inhibitor and at least one natural oil or fatty acid; at least one beta adrenergic receptor antagonist (beta blocker), at least one angiotensin receptor blocker (ARB) and at least one non-steroidal anti-inflammatory drug (NSAID); at least one beta adren
- the therapeutic combinations further comprise at least one member of a fourth group, wherein the member of the fourth group is a different composition than the selected member of the first, second or third group, and members of the fourth group are selected from the group consisting of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), non-steroidal anti-inflammatory drugs (NSAIDs), anabolic steroids, natural oils and fatty acids and a combination thereof.
- ACE angiotensin-converting enzyme
- ARBs angiotensin receptor blockers
- NSAIDs non-steroidal anti-inflammatory drugs
- anabolic steroids natural oils and fatty acids and a combination thereof.
- the therapeutic combinations further comprise at least one member of a fifth group, wherein the member of the fifth group is a different composition than the selected member of the first, second, third or fourth group, and members of the fifth group are selected from the group consisting of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), non-steroidal anti-inflammatory drugs (NSAIDs), anabolic steroids, natural oils and fatty acids and a combination thereof.
- ACE angiotensin-converting enzyme
- ARBs angiotensin receptor blockers
- NSAIDs non-steroidal anti-inflammatory drugs
- anabolic steroids natural oils and fatty acids and a combination thereof.
- the therapeutic combinations further comprise at least one member of a sixth group, wherein the member of the sixth group is a different composition than the selected member of the first, second, third, fourth or fifth group, and members of the sixth group are selected from the group consisting of angiotensin-converting enzyme
- ACE angiotensin receptor blockers
- NSAID non-steroidal anti-inflammatory drugs
- anabolic steroids natural oils and fatty acids and a combination thereof.
- the therapeutic combinations comprise at least one member of the first group and the at least one member of the second group are formulated as separate compositions. In one aspect, the therapeutic combinations comprise at least one member of the first group and the at least one member of the group are formulated in the same composition. In one aspect, each member of each selected group is formulated as a separate composition, or, all selected members are formulated in the same composition, or, a combination thereof. In one aspect, each member of each selected group is manufactured in a separate package or container, e.g., a blister package or plurality of packettes, lidded blister or blister card, or, all selected members are manufactured in the same package or container, or, any combination thereof.
- the blister package is a "high barrier" blister package, e.g., a foil to foil package, or a polyvinyl chloride (PVC) plastic or an aluminium foil (alufoil) blister packaging material.
- the invention provides pharmaceutical compositions comprising a therapeutic combination of the invention; or, therapeutic combination of the invention can be singly or multiply formulated or packaged as one or more pharmaceutical compositions.
- the pharmaceutical compositions can further comprise any pharmaceutically acceptable excipient.
- compositions used in the therapeutic combinations of the invention can be formulated in or as a feed, a food, a liquid, an elixir, an aerosol, a spray, a powder, a tablet, a pill, a capsule, a gel, a geltab, a nanosuspension, a nanoparticle, a microgel or a suppository.
- the invention provides therapeutic combinations, e.g., pharmaceutical compositions of the invention, comprising at least one beta adrenergic receptor antagonist (beta blocker), which can comprise at least one atenolol, nadolol, metoprolol, propranolol, carteolol, carvedolol, labetalol, oxprenolol, penbutolol, pindolol, sotalol, timolol or a combination thereof.
- beta adrenergic receptor antagonist beta blocker
- invention provides therapeutic combinations, e.g., pharmaceutical compositions of the invention, comprising at least one angiotensin-converting enzyme (ACE) inhibitor, and the angiotensin-converting enzyme (ACE) inhibitor can comprise benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril or a combination thereof.
- ACE angiotensin-converting enzyme
- invention provides therapeutic combinations, e.g., pharmaceutical compositions of the invention, comprising an angiotensin receptor blocker, e.g., comprising candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, or a combination thereof.
- an angiotensin receptor blocker e.g., comprising candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, or a combination thereof.
- invention provides therapeutic combinations, e.g., pharmaceutical compositions of the invention, comprising non-steroidal anti-inflammatory drugs (NSAIDs), e.g., comprising aspirin, diclofenac; diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen; ketorolac, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, a COX-2 inhibitor (e.g., a COX-2-selective inhibitor) or a combination thereof, wherein optionally the COX-2-selective inhibitor comprises celecoxib rofecoxib, etoricoxib, valdecoxib, parecoxib, meloxicam or lumiracoxib.
- NSAIDs non-ster
- invention provides therapeutic combinations, e.g., pharmaceutical compositions of the invention, comprising steroids, e.g., anabolic steroids, such as andarine, ethylestrenol, mesterolone, methandrostenolone, methenolone, methyltestosterone, oxandrolone, oxymetholone stanozolol, boldenone, hexoxymestrolum, methandrostenolone, methenolone enanthate, nandrolone decanoate, nandrolone phenproprionate, stanozolol, stenbolone, testosterone cypionate, testosterone enanthate, testosteron, testosterone nicotinate, therobolin, trenbolone, trenbolone, trophobolene or a combination thereof.
- steroids e.g., anabolic steroids, such as andarine, ethylestrenol, mesterolone, methandrostenolone, metheno
- invention provides therapeutic combinations, e.g., pharmaceutical compositions of the invention, comprising a natural oil or fatty acid, e.g., comprising an omega-3 fatty acid, a fish oil, a long-chain polyunsaturated fatty acid, an n-3 and/or n-6 highly unsaturated fatty acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or a combination thereof.
- EPA eicosapentaenoic acid
- DHA docosahexaenoic acid
- invention provides therapeutic combinations, e.g., pharmaceutical compositions of the invention, and methods using these therapeutic combinations, wherein the therapeutic combinations are formulated for use as a medicament in the treatment of chronic systemic inflammatory stress; burns, chronic obstructive pulmonary disease; congestive heart failure; chronic kidney disease; surgery; cancer; sepsis; ageing; acute respiratory distress syndrome; acute lung injury; infection; a CNS disorder or injury; anemia; immunosuppression; insulin resistance; anorexia; anxiety; sleep disturbances; weakness; fatigue; gastrointestinal distress; sleep disturbances; wake disturbances; pain; listlessness; shortness of breath; lethargy; depression; malaise; or, a combination thereof.
- the therapeutic combinations can be formulated for use in the treatment or amelioration of a condition or disease comprising a chronic Systemic Inflammatory Response State
- the therapeutic combinations can be formulated for or used in the manufacture of a medicament or pharmaceutical composition for treating or ameliorating a trauma, condition or disease comprising: a chronic Systemic Inflammatory Response State (SIRS); chronic systemic inflammatory stress; burns, chronic obstructive pulmonary disease; congestive heart failure; chronic kidney disease; surgery; cancer; sepsis; ageing; acute respiratory distress syndrome; acute lung injury; infection; a CNS disorder or injury; anemia; immunosuppression; insulin resistance; anorexia; anxiety; sleep disturbances; weakness; fatigue; gastrointestinal distress; sleep disturbances; wake disturbances; pain; listlessness; shortness of breath; lethargy; depression; malaise; or, a combination thereof.
- SIRS Systemic Inflammatory Response State
- chronic systemic inflammatory stress burns, chronic obstructive pulmonary disease
- congestive heart failure chronic kidney disease
- surgery cancer
- sepsis ageing
- acute respiratory distress syndrome acute lung injury
- infection a CNS disorder or injury
- anemia immuno
- the trauma, condition or disease comprises a maladaptive nutritional state secondary to the SIRS.
- the maladaptive nutritional state comprises cachexia, and optionally the cachexia comprises cachexia secondary to cancer.
- the CNS disorder comprises
- Parkinson's disease or Alzheimer's disease are Parkinson's disease or Alzheimer's disease.
- the invention provides methods for treating or ameliorating a trauma, condition or disease comprising a chronic Systemic Inflammatory Response State (SIRS), chronic systemic inflammatory stress; burns, chronic obstructive pulmonary disease; congestive heart failure; chronic kidney disease; surgery; cancer; sepsis; ageing; acute respiratory distress syndrome; acute lung injury; infection; a CNS disorder or injury; anemia; immunosuppression; insulin resistance; anorexia; anxiety; sleep disturbances; weakness; fatigue; gastrointestinal distress; sleep disturbances; wake disturbances; pain; listlessness; shortness of breath; lethargy; depression; malaise; or, a combination thereof, the method comprising the steps of: (a) providing the therapeutic combination of the invention, or the pharmaceutical composition of the invention; and (b) administering a therapeutically effective amount of the therapeutic combination of step (a), thereby treating or ameliorating the trauma, condition or disease.
- the condition or disease comprises a maladaptive nutritional state secondary to the SIRS, or the maladaptive nutritional state comprises cachexia
- the therapeutic combination of the invention, or the pharmaceutical composition of the invention is administered in single or multiple doses, and optionally the pharmaceutical compositions are packaged in a single or a plurality of packages or packets.
- the therapeutic combination of the invention, or the pharmaceutical composition of the invention is administered intravenously, topically, orally, by inhalation, by infusion, by injection, intraperitoneally, intramuscularly, subcutaneously, intra-aurally, by intra-articular administration, by intra-mammary administration, by topical administration or by absorption through epithelial or mucocutaneous linings.
- kits comprising the therapeutic combination of the invention, or the pharmaceutical composition of the invention.
- the kit can comprise at least one package, e.g., a blister pack or plurality of packettes, lidded blister or blister card, containing any one or more of a therapeutic combination of any of the invention, or the pharmaceutical composition of the invention.
- the therapeutic combination of the invention, or the pharmaceutical composition of the invention is formulated for administration intravenously, topically, orally, by inhalation, by infusion, by injection, intraperitoneally, intramuscularly, subcutaneously, intra-aurally, for intra-articular administration, for intra- mammary administration, for topical administration or for absorption through epithelial or mucocutaneous linings.
- the therapeutic combination of the invention, or the pharmaceutical composition of the invention can be packaged for administration intravenously, topically, orally, by inhalation, by infusion, by injection, intraperitoneally, intramuscularly, subcutaneously, intra-aurally, for intra-articular administration, for intra-mammary administration, for topical administration or for absorption through epithelial or mucocutaneous linings.
- therapeutic combinations of the invention, or pharmaceutical compositions of the invention e.g., the multi-ingredient combinations of drugs of the invention
- are formulated for chrono-dosing, or the methods of the invention comprise use of chrono-dosing or escalating dosage regimens.
- the therapeutic combinations of the invention, or pharmaceutical compositions of the invention are formulated for administration once a day, b.i.d. or t.i.d or more often, or for continuous administration.
- therapeutic combinations of the invention, or pharmaceutical compositions of the invention are formulated and dosaged as set forth in any one of exemplary ingredient combinations 1 to 90.
- the invention provides preparations therapeutic combinations comprising at least one member of a first group and at least one member of a second group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); and members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors).
- the invention provides preparations therapeutic combinations comprising at least one member of a first group and at least one member of a second group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); and members of the second group are selected from the group consisting of angiotensin receptor blockers (or ARB 's).
- the invention provides preparations therapeutic combinations comprising at least one member of a first group and at least one member of a second group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); and members of the second group are selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAID 's).
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAID 's).
- the invention provides preparations therapeutic combinations comprising at least one member of a first group and at least one member of a second group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); and members of the second group are selected from the group consisting of a steroid, e.g., an anabolic steroid, such as a steroid as described in Table 1, below.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of a steroid, e.g., an anabolic steroid, such as a steroid as described in Table 1, below.
- the invention provides preparations therapeutic combinations comprising at least one member of a first group and at least one member of a second group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); and members of the second group are selected from the group consisting of natural oils and fatty acids.
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, and at least one member of a third group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors); and members of the third group are selected from the group consisting of angiotensin receptor blockers (or ARB 's).
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors)
- members of the third group are selected from the group consisting of angiotensin receptor blockers (or ARB 's).
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, and at least one member of a third group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors); and members of the third group are selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAID's).
- NSAID's non-steroidal anti-inflammatory drugs
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, and at least one member of a third group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors); and members of the third group comprising a steroid, e.g., an anabolic steroid, such as a steroid as described in Table 1 , below.
- a steroid e.g., an anabolic steroid, such as a steroid as described in Table 1 , below.
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, and at least one member of a third group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors); and members of the third group are selected from the group consisting of natural oils and fatty acids.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors)
- members of the third group are selected from the group consisting of natural oils and fatty acids.
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, and at least one member of a third group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin receptor blockers (or ARB 's); and members of the third group are selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAID 's).
- NSAID nonsteroidal anti-inflammatory drugs
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, and at least one member of a third group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin receptor blockers (or ARB 's); and members of the third group comprising steroids, e.g., an anabolic steroid, such as a steroid as described in Table 1, below.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of angiotensin receptor blockers (or ARB 's)
- members of the third group comprising steroids, e.g., an anabolic steroid, such as a steroid as described in Table 1, below.
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, and at least one member of a third group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin receptor blockers (or ARB 's); and members of the third group are selected from the group consisting of natural oils and fatty acids.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of angiotensin receptor blockers (or ARB 's)
- members of the third group are selected from the group consisting of natural oils and fatty acids.
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, and at least one member of a third group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAID's); and members of the third group comprising steroids, e.g., an anabolic steroid, such as a steroid as described in Table 1, below.
- NSAID's non-steroidal anti-inflammatory drugs
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, and at least one member of a third group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAID's); and members of the third group are selected from the group consisting of natural oils and fatty acids.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAID's)
- members of the third group are selected from the group consisting of natural oils and fatty acids.
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, and at least one member of a third group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group comprising steroids, e.g., an anabolic steroid, such as a steroid as described in Table 1 , below, and members of the third group are selected from the group consisting of natural oils and fatty acids.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group comprising steroids, e.g., an anabolic steroid, such as a steroid as described in Table 1 , below
- members of the third group are selected from the group consisting of natural oils and fatty acids.
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, at least one member of a third group, and at least one member of a fourth group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors); members of the third group are selected from the group consisting of angiotensin receptor blockers (or ARB 's); and members of the fourth group are selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAID 's).
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors)
- members of the third group are selected from the group consisting of angiotensin receptor block
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, at least one member of a third group, and at least one member of a fourth group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors); members of the third group are selected from the group consisting of angiotensin receptor blockers (or ARB 's); and members of the fourth group comprising steroids, e.g., an anabolic steroid, such as a steroid as described in Table 1 , below.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors)
- members of the third group are selected from the
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, at least one member of a third group, and at least one member of a fourth group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors); members of the third group are selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAID's); and members of the fourth group comprising steroids, e.g., an anabolic steroid, such as a steroid as described in Table 1, below.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors)
- members of the third group are selected from the group consisting of
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, at least one member of a third group, and at least one member of a fourth group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin receptor blockers (or ARB 's); members of the third group are selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAID 's); and members of the fourth group comprising steroids, e.g., an anabolic steroid, such as a steroid as described in Table 1, below.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of angiotensin receptor blockers (or ARB 's)
- members of the third group are selected from the group consisting of non
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, at least one member of a third group, and at least one member of a fourth group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors); members of the third group are selected from the group consisting of angiotensin receptor blockers (or ARB 's); and members of the fourth group are selected from the group consisting natural oils and fatty acids.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors)
- members of the third group are selected from the group consisting of angiotensin receptor blockers (or ARB 's)
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, at least one member of a third group, and at least one member of a fourth group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors); members of the third group are selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAID 's); and members of the fourth group are selected from the group consisting natural oils and fatty acids.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors)
- members of the third group are selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAID 's)
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, at least one member of a third group, and at least one member of a fourth group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin receptor blockers (or ARB 's); members of the third group are selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAID's); and members of the fourth group are selected from the group consisting natural oils and fatty acids.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of angiotensin receptor blockers (or ARB 's)
- members of the third group are selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAID's)
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, at least one member of a third group, and at least one member of a fourth group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors); members of the third group comprising steroids, e.g., an anabolic steroid, such as a steroid as described in Table 1, below; and members of the fourth group are selected from the group consisting natural oils and fatty acids.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors)
- members of the third group comprising steroids, e.g., an anabolic ste
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, at least one member of a third group, and at least one member of a fourth group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin receptor blockers (or ARB 's); members of the third group comprising steroids, e.g., an anabolic steroid, such as a steroid as described in Table 1, below; and members of the fourth group are selected from the group consisting natural oils and fatty acids.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of angiotensin receptor blockers (or ARB 's)
- members of the third group comprising steroids, e.g., an anabolic steroid,
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, at least one member of a third group, and at least one member of a fourth group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAID 's); members of the third group comprising steroids, e.g., an anabolic steroid, such as a steroid as described in Table 1, below; and members of the fourth group are selected from the group consisting natural oils and fatty acids.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAID 's)
- members of the third group comprising steroids, e.g., an anabolic steroid, such as
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, at least one member of a third group, at least one member of a fourth group, and at least one member of a fifth group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors); and members of the third group are selected from the group consisting of angiotensin receptor blockers (or ARB 's); members of the fourth group are selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAID's); and members of the fifth group comprising steroids, e.g., an anabolic steroid, such as a steroid as described in Table 1 , below.
- steroids e.g., an anabolic steroid, such as a steroid as described in Table 1 , below.
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, at least one member of a third group, at least one member of a fourth group, and at least one member of a fifth group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors); and members of the third group are selected from the group consisting of angiotensin receptor blockers (or ARB 's); members of the fourth group are selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAID's); and members of the fifth group are selected from the group consisting of natural oils and fatty acids.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitor
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, at least one member of a third group, at least one member of a fourth group, and at least one member of a fifth group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors); and members of the third group are selected from the group consisting of angiotensin receptor blockers (or ARB 's); members of the fourth group comprising steroids, e.g., an anabolic steroid, such as a steroid as described in Table 1, below; and members of the fifth group are selected from the group consisting of natural oils and fatty acids.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, at least one member of a third group, at least one member of a fourth group, and at least one member of a fifth group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors); and members of the third group are selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAID's); members of the fourth group comprising steroids, e.g., an anabolic steroid, such as a steroid as described in Table 1, below; and members of the fifth group are selected from the group consisting of natural oils and fatty acids.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of angio
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, at least one member of a third group, at least one member of a fourth group, and at least one member of a fifth group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin receptor blockers (or ARB 's); and members of the third group are selected from the group consisting of non-steroidal antiinflammatory drugs (NSAID 's); members of the fourth group are selected from the group consisting of anabolic steroids; and members of the fifth group are selected from the group consisting of natural oils and fatty acids.
- members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers)
- members of the second group are selected from the group consisting of angiotensin receptor blockers (or ARB 's)
- the invention provides preparations therapeutic combinations comprising at least one member of a first group, at least one member of a second group, at least one member of a third group, at least one member of a fourth group, at least one member of a fifth group, and at least one member of a sixth group; wherein members of the first group are selected from the group consisting of beta adrenergic receptor antagonists (or beta blockers); members of the second group are selected from the group consisting of angiotensin converting enzyme inhibitors (or ACE inhibitors); and members of the third group are selected from the group consisting of angiotensin receptor blockers (or ARB 's); members of the fourth group are selected from the group consisting of non-steroidal anti- inflammatory drugs (NSAID's); members of the fifth group comprising steroids, e.g., an anabolic steroid, such as a steroid as described in Table 1 , below; and members of the sixth group are selected from the group consisting of natural oils and fatty acids.
- the invention provides solids, liquids or emulsions comprising drug preparation of the invention, a drug combination of the invention, or a formulation of the invention, or use of any of these compositions to practice a method of the invention.
- the invention provides capsules, "caplets”, sprays, inhalants, powders, lotions, patches - or any transdermal delivery system, implants, suppositories, geltabs, tablets or pills comprising (or, for use in) a preparation, formulation, kit or any product of manufacture of the invention.
- a drug preparation of the invention, a drug combination of the invention can be formulated for enteral or parenteral administration, and in practicing the combinations or methods of the invention they can be administered enterally or parenterally.
- the invention provides foods or food supplements comprising a drug preparation of the invention, a drug combination of the invention, or a formulation of the invention.
- the food or food supplement can comprise a drink, a flavored drink, a powder, a concentrate, a flavored bar, a power bar, a diet bar, an energy bar or a nutritional bar.
- the invention provides methods for maintaining the health of a tissue comprising administering an effective amount of a preparation of the invention or a formulation of the invention.
- the tissue can be skeletal muscle tissue, fat tissue, or more than one body tissue type, including the majority of the body.
- the invention provides methods for ameliorating a disease or condition in an individual comprising administering an effective amount of a preparation of the invention or a formulation of the invention.
- the disease or condition can affect skeletal muscle tissue or fat tissue.
- the product this invention provides different products that comprise (contain at least) all the combinations and permutations of any ingredients provided herein by specific mention.
- This invention also provides different products that comprise (contain at least) all the combinations and permutations of any ingredients provided herein, if not by specific mention of said ingredients, then by knowledge in the art that said ingredients are part of one or more category or group of ingredients provided herein.
- this invention provides each of the products herein for use as therapies for improving states and disease symptoms such as involving inflammation, excessive sympathoneural drive, cachexia, anorexia, and anorexia-cachexia, and stress or anxiety related thereto.
- this invention provides the use of each the products herein as therapies for improving states and disease symptoms such as involving inflammation, excessive sympathoneural drive, cachexia, anorexia, and anorexia-cachexia, and stress or anxiety related thereto.
- this invention provides different products that comprise (contain at least) all the combinations and permutations of ingredients selected from members of Group 1 (e.g. in Table 1), members of Group 2 (e.g. in Table 1), members of Group 3 (e.g. in Table 1), members of Group 4 (e.g. in Table 1), members of Group 5 (e.g. in Table 1), members of Group 6 (e.g. in Table 1), members of Group 7 (e.g. in Table 1), members of Group 8 (e.g. in Table 1), members of Group 9 (e.g. in Table 1), members of Group 10 (e.g. in Table 1), members of Group 6 (e.g. in Table 1), members of Group 11 (e.g.
- this invention provides kits and packages containing therapeutic preparations, which therapeutic preparations that comprise (contain at least) all the combinations and permutations of from any one ingredient to any 100 ingredients selected from members of Group 1 (e.g. in Table 1), members of Group 2 (e.g. in Table 1), members of Group 3 (e.g. in Table 1), members of Group 4 (e.g. in Table 1), members of Group 5 (e.g. in Table 1), members of Group 6 (e.g. in Table 1), members of Group 7 (e.g. in Table 1), members of Group 8 (e.g. in Table 1), members of Group 9 (e.g. in Table 1), members of Group 10 (e.g.
- the invention provides novel preparations comprising the following components, for which non- limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); and b) one or more members selected from Group 2 (e.g. captopril or enalapril).
- Group 1 e.g. carvedolol or propanolol
- Group 2 e.g. captopril or enalapril
- this invention provides novel preparations comprising the following components, for which non- limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); and b) one or more members selected from Group 3 (e.g. losartan).
- Group 1 e.g. carvedolol or propanolol
- Group 3 e.g. losartan
- this invention provides novel preparations comprising the following components, for which non- limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); and b) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen).
- Group 1 e.g. carvedolol or propanolol
- Group 4 e.g. aspirin or ibuprofen or naproxen.
- this invention provides novel preparations comprising the following components, for which non- limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); and b) one or more members selected from Group 5 (e.g. oxandrolone or testosterone). In one embodiment, this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); and b) one or more members selected from Group 6 (e.g. EPA or DHA).
- Table 1 a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); and b) one or more members selected from Group 6 (e.g. EPA or DHA).
- this invention provides novel preparations comprising the following components, for which non- limiting examples are listed in Table 1: a) one or more members selected from Group 2 (e.g. captopril or enalapril); and b) one or more members selected from Group 3 (e.g. losartan).
- this invention provides novel preparations comprising the following components, for which non- limiting examples are listed in Table 1: a) one or more members selected from Group 2 (e.g. captopril or enalapril); and b) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen).
- Group 2 e.g. captopril or enalapril
- Group 4 e.g. aspirin or ibuprofen or naproxen.
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 2 (e.g. captopril or enalapril); and b) one or more members selected from Group 5 (e.g. oxandrolone or testosterone).
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 3 (e.g. losartan); and b) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen).
- Group 3 e.g. losartan
- Group 4 e.g. aspirin or ibuprofen or naproxen
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 3 (e.g. losartan); and b) one or more members selected from Group 5 (e.g. oxandrolone or testosterone). In one embodiment, this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 2 (e.g. captopril or enalapril); and b) one or more members selected from Group 6 (e.g. EPA or DHA).
- Table 1 a) one or more members selected from Group 3 (e.g. losartan); and b) one or more members selected from Group 5 (e.g. oxandrolone or testosterone).
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 2 (e.g. captopril or enalapril); and
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen); and b) one or more members selected from Group 5 (e.g. oxandrolone or testosterone).
- Group 4 e.g. aspirin or ibuprofen or naproxen
- Group 5 e.g. oxandrolone or testosterone
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 3 (e.g. losartan); and b) one or more members selected from Group 6 (e.g. EPA or DHA).
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); b) one or more members selected from Group 2 (e.g. captopril or enalapril); and c) one or more members selected from Group 3 (e.g. losartan).
- Group 1 e.g. carvedolol or propanolol
- Group 2 e.g. captopril or enalapril
- Group 3 e.g. losartan
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); b) one or more members selected from Group 2 (e.g. captopril or enalapril); and c) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen).
- Group 1 e.g. carvedolol or propanolol
- Group 2 e.g. captopril or enalapril
- Group 4 e.g. aspirin or ibuprofen or naproxen
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); b) one or more members selected from Group 2 (e.g. captopril or enalapril); and c) one or more members selected from Group 5 (e.g. oxandrolone or testosterone).
- Group 1 e.g. carvedolol or propanolol
- Group 2 e.g. captopril or enalapril
- Group 5 e.g. oxandrolone or testosterone
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen); and b) one or more members selected from Group 6 (e.g. EPA or DHA).
- Group 4 e.g. aspirin or ibuprofen or naproxen
- Group 6 e.g. EPA or DHA
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); b) one or more members selected from Group 3 (e.g. losartan); and c) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen).
- Group 1 e.g. carvedolol or propanolol
- Group 3 e.g. losartan
- Group 4 e.g. aspirin or ibuprofen or naproxen
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g., carvedolol or propanolol); b) one or more members selected from Group 3 (e.g. losartan); and c) one or more members selected from Group 5 (e.g. oxandrolone or testosterone).
- Group 1 e.g., carvedolol or propanolol
- Group 3 e.g. losartan
- Group 5 e.g. oxandrolone or testosterone
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g., carvedolol or propanolol); b) one or more members selected from Group 2 (e.g., captopril or enalapril); and c) one or more members selected from Group 6 (e.g. EPA or DHA).
- Group 1 e.g., carvedolol or propanolol
- Group 2 e.g., captopril or enalapril
- Group 6 e.g. EPA or DHA
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); b) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen); and c) one or more members selected from Group 5 (e.g. oxandrolone or testosterone).
- Group 1 e.g. carvedolol or propanolol
- Group 4 e.g. aspirin or ibuprofen or naproxen
- Group 5 e.g. oxandrolone or testosterone
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); b) one or more members selected from Group 3 (e.g. losartan); and c) one or more members selected from Group 6 (e.g. EPA or DHA).
- Group 1 e.g. carvedolol or propanolol
- Group 3 e.g. losartan
- Group 6 e.g. EPA or DHA
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 2 (e.g. captopril or enalapril); b) one or more members selected from Group 3 (e.g. losartan); and c) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen).
- Group 2 e.g. captopril or enalapril
- Group 3 e.g. losartan
- Group 4 e.g. aspirin or ibuprofen or naproxen
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 2 (e.g. captopril or enalapril); b) one or more members selected from Group 3 (e.g. losartan); and c) one or more members selected from Group 5 (e.g. oxandrolone or testosterone).
- Group 2 e.g. captopril or enalapril
- Group 3 e.g. losartan
- Group 5 e.g. oxandrolone or testosterone
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); b) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen); and c) one or more members selected from Group 6 (e.g. EPA or DHA).
- Group 1 e.g. carvedolol or propanolol
- Group 4 e.g. aspirin or ibuprofen or naproxen
- Group 6 e.g. EPA or DHA
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 2 (e.g. captopril or enalapril); b) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen); and c) one or more members selected from Group 5 (e.g. oxandrolone or testosterone).
- Group 2 e.g. captopril or enalapril
- Group 4 e.g. aspirin or ibuprofen or naproxen
- Group 5 e.g. oxandrolone or testosterone
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 2 (e.g. captopril or enalapril); b) one or more members selected from Group 3 (e.g. losartan); and c) one or more members selected from Group 6 (e.g. EPA or DHA).
- Group 2 e.g. captopril or enalapril
- Group 3 e.g. losartan
- Group 6 e.g. EPA or DHA
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 3 (e.g. losartan); b) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen); and c) one or more members selected from Group 5 (e.g. oxandrolone or testosterone).
- Group 3 e.g. losartan
- Group 4 e.g. aspirin or ibuprofen or naproxen
- Group 5 e.g. oxandrolone or testosterone
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 2 (e.g. captopril or enalapril); b) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen); and c) one or more members selected from Group 6 (e.g. EPA or DHA).
- Group 2 e.g. captopril or enalapril
- Group 4 e.g. aspirin or ibuprofen or naproxen
- Group 6 e.g. EPA or DHA
- this invention provides novel preparations comprising the following components, for which non- limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); b) one or more members selected from Group 2 (e.g. captopril or enalapril); c) one or more members selected from Group 3 (e.g. losartan); and d) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen).
- this invention provides novel preparations comprising the following components, for which non- limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g.
- carvedolol or propanolol b) one or more members selected from Group 2 (e.g. captopril or enalapril); c) one or more members selected from Group 3 (e.g. losartan); and d) one or more members selected from Group 5 (e.g. oxandrolone or testosterone).
- Group 2 e.g. captopril or enalapril
- Group 3 e.g. losartan
- Group 5 e.g. oxandrolone or testosterone
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 3 (e.g. losartan); b) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen); and c) one or more members selected from Group 6 (e.g. EPA or DHA).
- Group 3 e.g. losartan
- Group 4 e.g. aspirin or ibuprofen or naproxen
- Group 6 e.g. EPA or DHA
- this invention provides novel preparations comprising the following components, for which non- limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); b) one or more members selected from Group 2 (e.g. captopril or enalapril); c) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen); and d) one or more members selected from Group 5 (e.g. oxandrolone or testosterone).
- Group 1 e.g. carvedolol or propanolol
- Group 2 e.g. captopril or enalapril
- c) one or more members selected from Group 4 e.g. aspirin or ibuprofen or naproxen
- Group 5 e.g. oxandrolone or testosterone
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); b) one or more members selected from Group 2 (e.g. captopril or enalapril); c) one or more members selected from Group 3 (e.g. losartan); and d) one or more members selected from Group 6 (e.g. EPA or DHA).
- Group 1 e.g. carvedolol or propanolol
- Group 2 e.g. captopril or enalapril
- Group 3 e.g. losartan
- Group 6 e.g. EPA or DHA
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); b) one or more members selected from Group 3 (e.g. losartan); c) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen); and d) one or more members selected from Group 5 (e.g. oxandrolone or testosterone).
- this invention provides novel preparations comprising the following components, for which non- limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g.
- carvedolol or propanolol b) one or more members selected from Group 2 (e.g. captopril or enalapril); c) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen); and d) one or more members selected from Group 6 (e.g. EPA or DHA).
- Group 2 e.g. captopril or enalapril
- members selected from Group 4 e.g. aspirin or ibuprofen or naproxen
- Group 6 e.g. EPA or DHA
- this invention provides novel preparations comprising the following components, for which non- limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); b) one or more members selected from Group 2 (e.g. captopril or enalapril); c) one or more members selected from Group 3 (e.g. losartan); d) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen); and e) one or more members selected from Group 5 (e.g. oxandrolone or testosterone).
- Group 1 e.g. carvedolol or propanolol
- Group 2 e.g. captopril or enalapril
- Group 3 e.g. losartan
- d one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen)
- Group 5 e.g
- this invention provides novel preparations comprising the following components, for which non- limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); b) one or more members selected from Group 3 (e.g. losartan); c) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen); and d) one or more members selected from Group 6 (e.g. EPA or DHA).
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g.
- carvedolol or propanolol b) one or more members selected from Group 3 (e.g. losartan); c) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen); and d) one or more members selected from Group 6 (e.g. EPA or DHA).
- Group 3 e.g. losartan
- Group 4 e.g. aspirin or ibuprofen or naproxen
- Group 6 e.g. EPA or DHA
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); b) one or more members selected from Group 2 (e.g. captopril or enalapril); c) one or more members selected from Group 3 (e.g. losartan); d) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen); and e) one or more members selected from Group 6 (e.g. EPA or DHA).
- Group 1 e.g. carvedolol or propanolol
- Group 2 e.g. captopril or enalapril
- Group 3 e.g. losartan
- d one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen)
- Group 6 e.g. EPA or
- this invention provides novel preparations comprising the following components, for which non-limiting examples are listed in Table 1: a) one or more members selected from Group 1 (e.g. carvedolol or propanolol); b) one or more members selected from Group 2 (e.g. captopril or enalapril); c) one or more members selected from Group 3 (e.g. losartan); d) one or more members selected from Group 4 (e.g. aspirin or ibuprofen or naproxen); e) one or more members selected from Group 5 (e.g. oxandrolone or testosterone); and f) one or more members selected from Group 6 (e.g. EPA or DHA).
- Group 1 e.g. carvedolol or propanolol
- Group 2 e.g. captopril or enalapril
- Group 3 e.g. losartan
- d) one or more members selected from Group 4 e.g. as
- the term "at least one member” in reference to exemplary alternative embodiments comprises minimally every integer value from one to about 20 or more, inclusive; i.e. in one aspect it means at least one member, in another aspect it means at least two members, in another aspect it means at least three members, ..., etc, and in another aspect it means at least 20 members.
- Alternative embodiments can comprise more than 20 members.
- this invention provides every combination and permutation of ingredients exemplified in Table 1 (i.e. Groups 1-20).
- Examples of such combinations and permutations provided herein include the possibilities where ingredients are selected from at least 1 group, where the at least 1 group is selected from any of Groups 1-20.
- Examples of such combinations and permutations provided herein include the possibilities where ingredients are selected from at least 2 groups, where the at least 2 groups are selected from any of Groups 1-20. In alternative embodiments there may be at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, and at least 20 different members selected from any to each of Groups 1-20. Examples of such combinations and permutations provided herein include the possibilities where ingredients are selected from at least 3 groups, where the at least 3 groups are selected from any of Groups 1-20.
- Examples of such combinations and permutations provided herein include the possibilities where ingredients are selected from at least 4 groups, where the at least 4 groups are selected from any of Groups 1-20. In alternative embodiments there may be at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, and at least 20 different members selected from any to each of Groups 1-20.
- Examples of such combinations and permutations provided herein include the possibilities where ingredients are selected from at least 5 groups, where the at least 5 groups are selected from any of Groups 1-20. In alternative embodiments there may be at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, and at least 20 different members selected from any to each of Groups 1-20.
- Examples of such combinations and permutations provided herein include the possibilities where ingredients are selected from at least 6 groups, where the at least 6 groups are selected from any of Groups 1-20. In alternative embodiments there may be at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, and at least 20 different members selected from any to each of Groups 1-20.
- Examples of such combinations and permutations provided herein include the possibilities where ingredients are selected from at least 7 groups, where the at least 7 groups are selected from any of Groups 1-20. In alternative embodiments there may be at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, and at least 20 different members selected from any to each of Groups 1-20.
- Examples of such combinations and permutations provided herein include the possibilities where ingredients are selected from at least 8 groups, where the at least 8 groups are selected from any of Groups 1-20. In alternative embodiments there may be at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, and at least 20 different members selected from any to each of Groups 1-20.
- Examples of such combinations and permutations provided herein include the possibilities where ingredients are selected from at least 9 groups, where the at least 9 groups are selected from any of Groups 1-20. In alternative embodiments there may be at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, and at least 20 different members selected from any to each of Groups 1-20. Examples of such combinations and permutations provided herein include the possibilities where ingredients are selected from at least 10 groups, where the at least 10 groups are selected from any of Groups 1-20.
- Examples of such combinations and permutations provided herein include the possibilities where ingredients are selected from at least 11 groups, where the at least 11 groups are selected from any of Groups 1-20. In alternative embodiments there may be at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, and at least 20 different members selected from any to each of Groups 1-20. Examples of such combinations and permutations provided herein include all possibilities where ingredients are selected from at least 12 groups, where the at least 12 groups are selected from any of Groups 1-20.
- Examples of such combinations and permutations provided herein include all possibilities where ingredients are selected from at least 13 groups, where the at least 13 groups are selected from any of Groups 1-20. In alternative embodiments there may be at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, and at least 20 different members selected from any to each of Groups 1-20.
- Examples of such combinations and permutations provided herein include all possibilities where ingredients are selected from at least 14 groups, where the at least 14 groups are selected from any of Groups 1-20. In alternative embodiments there may be at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, and at least 20 different members selected from any to each of Groups 1-20.
- Examples of such combinations and permutations provided herein include all possibilities where ingredients are selected from at least 15 groups, where the at least 15 groups are selected from any of Groups 1-20. In alternative embodiments there may be at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, and at least 20 different members selected from any to each of Groups 1-20.
- Examples of such combinations and permutations provided herein include all possibilities where ingredients are selected from at least 16 groups, where the at least 16 groups are selected from any of Groups 1-20. In alternative embodiments there may be at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, and at least 20 different members selected from any to each of Groups 1-20.
- Examples of such combinations and permutations provided herein include all possibilities where ingredients are selected from at least 17 groups, where the at least 17 groups are selected from any of Groups 1-20. In alternative embodiments there may be at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, and at least 20 different members selected from any to each of Groups 1-20.
- Examples of such combinations and permutations provided herein include all possibilities where ingredients are selected from at least 18 groups, where the at least 18 groups are selected from any of Groups 1-20. In alternative embodiments there may be at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, and at least 20 different members selected from any to each of Groups 1-20. Examples of such combinations and permutations provided herein include all possibilities where ingredients are selected from at least 19 groups, where the at least 19 groups are selected from any of Groups 1-20.
- Examples of such combinations and permutations provided herein include all possibilities where ingredients are selected from at least 20 groups, where the at least 20 groups are selected from Groups 1-20. In alternative embodiments there may be at least one, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, and at least 20 different members selected from any to each of Groups 1-20.
- the invention provides product of manufactures comprising a blister package, lidded blisters or blister cards, a clamshell, a tray or a shrink wrap comprising a therapeutic combination of the invention, or a pharmaceutical composition of the invention, e.g., a pills, tabs, geltabs, capsules and the like.
- the product of manufacture comprises at least one beta adrenergic receptor antagonist (a beta blocker) and an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a non-steroidal anti-inflammatory drug (a NSAID), an anabolic steroid, a natural oil, a fatty acid or a combination thereof.
- the product of manufacture comprises at least one beta adrenergic receptor antagonist (a beta blocker) and at least one non-steroidal anti-inflammatory drug (a NSAID).
- the at least one non-steroidal antiinflammatory drug (a NSAID) can comprise an aspirin, dichlofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen; ketorolac, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, a COX-2 inhibitor (e.g., a COX-2-selective inhibitor) or a combination thereof.
- a COX-2 inhibitor e.g., a COX-2-selective inhibitor
- the COX-2 inhibitor (e.g., a COX-2-selective inhibitor) comprises celecoxib rofecoxib, etoricoxib, valdecoxib, parecoxib, meloxicam and/or lumiracoxib.
- the invention also provides products of manufacture comprising a blister package or plurality of packettes, a lidded blister, a blister card, a clamshell, a tray or a shrink wrap comprising a therapeutic combination comprising an atenolol, nadolol, metoprolol, propranolol, carteolol, carvedolol, labetalol, oxprenolol, penbutolol, pindolol, sotalol, timolol or a combination thereof, and at least one non-steroidal anti-inflammatory drug (a NSAID).
- a NSAID non-steroidal anti-inflammatory drug
- the invention provides therapeutic combinations of the invention for use as a medicament, e.g., for use in the treatment of cachexia.
- the cachexia is defined as at least two of the symptoms selected from the group consisting of: 1) a hyper- inflammatory state, 2) altered hormone levels and/or cytokine levels (over normal); 3) sustained heart rate or rhythm variability (over normal); 4) weight loss, and 5) sustained increased heart rate (over normal), wherein optionally the sustained increased heart rate is having a sustained elevated heart rate of at least about 6 bpm over normal (over what is considered normal for a particular healthy individual).
- the cachexia is defined by an individual having at least a sustained elevated heart rate of at least about 6 bpm (over what is considered normal for a particular healthy individual) and weight loss.
- sustained heart rate or rhythm variability over normal is measured over a period of at least 10, 20, 30, 40, 50, 60 or more minutes, or, alternatively, over a 24 hour period, or alternatively over a period of 200, 300, 400 or 500 or more beats, or a combination thereof; or alternatively, where the heart rate (or rhythm) variability is statistically significant with a p value of at least 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09 or 1.0, or more, or a p value of less than 0.1.
- the "normalcy" or "abnormalcy” of heart rate or rhythm - the variability of heart rate or rhythm - is determined by comparing a patient suspected of having SIRS, e.g., cachexia, with what would be considered normal values for a similar individual (e.g., an individual of similar age, health, weight, sex, race and the like) (in other words, it is not necessary that the individual's heart rate be evaluated in a healthy state).
- practicing the invention e.g., administering the therapeutic combinations of the invention, or practicing the methods of the invention
- the variability of heart rate or rhythm is measured using R to R variability, QRS patterns, or a combination thereof, or any method known in the art to determine heart rate or rhythm variability; see, e.g., U.S. Patent Nos. 7,009,492;
- Normal versus abnormal heart rate or rhythm are determined by comparing values from similar individuals, e.g., individuals of the same age, weight, sex, race and the like.
- the invention provides uses of the therapeutic combinations of the invention in the manufacture of a medicament or pharmaceutical composition for treating, ameliorating or preventing a trauma, condition or disease comprising: a chronic Systemic Inflammatory Response State (SIRS); chronic systemic inflammatory stress; burns, chronic obstructive pulmonary disease; congestive heart failure; chronic kidney disease; surgery; cancer; sepsis; ageing; acute respiratory distress syndrome; acute lung injury; infection; a CNS disorder or injury; anemia; immunosuppression; insulin resistance; anorexia; anxiety; sleep disturbances; weakness; fatigue; gastrointestinal distress; sleep disturbances; wake disturbances; pain; listlessness; shortness of breath; lethargy; depression; malaise; or, a combination thereof.
- SIRS Systemic Inflammatory Response State
- chronic systemic inflammatory stress burns, chronic obstructive pulmonary disease
- congestive heart failure chronic kidney disease
- surgery cancer
- sepsis ageing
- acute respiratory distress syndrome acute lung injury
- infection a CNS disorder or injury
- the trauma, condition or disease comprises a maladaptive nutritional state secondary to the SIRS.
- the maladaptive nutritional state comprises cachexia
- optionally the cachexia comprises cachexia secondary to cancer.
- the cachexia is defined as at least two of the symptoms selected from the group consisting of: 1) a hyper-inflammatory state, 2) altered hormone levels and/or cytokine levels; 3) sustained heart rate variability (more variability than normal); 4) weight loss, and 5) sustained increased heart rate, wherein optionally the sustained increased heart rate is having a sustained elevated heart rate of at least about 6 bpm (over what would be considered normal for a particular individual).
- the cachexia is defined by an individual having at least a sustained elevated heart rate of at least about 6 bpm (over what would be considered normal for a particular individual) and weight loss.
- kits comprising a therapeutic combination of the invention, or a pharmaceutical composition of the invention.
- the kit comprises at least one blister pack comprising a therapeutic combination of the invention, or a pharmaceutical composition of the invention.
- the invention provides kits for the treatment, amelioration or prevention of a chronic Systemic Inflammatory Response State (SIRS) or a maladaptive nutritional state in a patient population, the kit comprising a therapeutic combination of the invention, or a pharmaceutical composition of the invention, and instructions for use of the therapeutic combination or pharmaceutical composition.
- SIRS Systemic Inflammatory Response State
- the maladaptive nutritional state comprises cachexia
- the cachexia comprises cachexia secondary to cancer
- the instructions for use indicate that the patient population for practicing the methods and compositions of the invention are individuals having a chronic Systemic Inflammatory Response State (SIRS) or a maladaptive nutritional state, wherein optionally the cachexia is defined as at least two of the symptoms selected from the group consisting of: 1) a hyper-inflammatory state, 2) altered hormone levels and/or cytokine levels; 3) sustained increased heart rate variability (more variability than normal); 4) weight loss, and 5) sustained increased heart rate, wherein optionally the increased heart rate is having a sustained elevated heart rate of at least about 6 bpm over what would be considered normal for that particular individual.
- the cachexia is defined by an individual having at least a sustained elevated heart rate of at least about 6 bpm (over what would be considered normal for that particular individual) and weight loss.
- kits for the treatment, amelioration or prevention of a CNS disorder wherein the kit comprises a therapeutic combination of the invention, or a pharmaceutical composition of the invention.
- the CNS disorder comprises Parkinson's disease or Alzheimer's disease.
- the invention provides computer implemented methods for diagnosing cachexia, wherein the computer implemented method comprises analysis of data representing measurements of at least two of symptoms selected from the group consisting of: 1) a hyper-inflammatory state, 2) hormone levels and/or cytokine levels; 3) heart rate variability over normal; 4) weight loss, and 5) sustained increased heart rate over normal are analyzed and the presence of at least two of the symptoms indicates a readout of a diagnosis of cachexia.
- the cachexia diagnosis comprises diagnosis of early onset cachexia or early stage of cachexia.
- the invention also provides computer program products for implementing the computer implemented methods of the invention, and computers comprising the computer program products of the invention.
- One exemplary therapeutic combination of drugs of the invention comprises a member of the first drug group comprises a beta adrenergic receptor antagonist (a beta blocker) comprising a propranolol or equivalent; and a member of the second drug group comprises a non-steroidal anti-inflammatory drug (a NSAID) comprising an etodolac or equivalent; e.g., the non-steroidal anti-inflammatory drug (a NSAID) comprises etodolac (such as LODINETM, or other equivalents, as listed below), or the beta adrenergic receptor antagonist (a beta blocker) comprises propranolol (such as INDERALTM, or other equivalents, as listed below); thus, in one aspect, the beta adrenergic receptor antagonist (a beta blocker) comprises propranolol or other equivalents and the nonsteroidal anti-inflammatory drug (a NSAID) comprises etodolac or other equivalents.
- a NSAID non-steroidal anti-inflammatory drug
- the etodolac or equivalent and the propranolol or other equivalents are formulated as separate compositions or product of manufacture, or, they are formulated in the same composition or product of manufacture; which can be, e.g., a single package, a packette, a plurality of packages, a blister packet, packettes or packets, a cellophane, paper or plastic wrapper(s), or a package or blister pack comprising a polyvinyl chloride (PVC) plastic and/or an aluminium foil (alufoil) material, and the like.
- PVC polyvinyl chloride
- alufoil aluminium foil
- the therapeutic combination comprises a first and a second group drug packaged together in a single package, a plurality of packages or a blister packet, packettes or packets or other equivalents.
- the first and second group drugs are packaged together in a single package, a plurality of packages or blister packets or packettes, and with both drugs released upon opening of the single package, packettes or packet.
- Any material can be used for these products of manufacture (kits, packages, packettes or packets or other equivalents) e.g., cellophane, paper or plastic, or a package or blister pack comprising a polyvinyl chloride (PVC) plastic and/or an aluminium foil (alufoil) material, or other equivalents.
- PVC polyvinyl chloride
- alufoil aluminium foil
- each of the first and second group drugs are packaged together in a single package, a plurality of packages or blister packets, and with both drugs are formulated as a tablet, a pill, a lozenge, a capsule, a caplet, a patch, a spray, an inhalant, a gel, a geltab, a nanosuspension, a nanoparticle, a microgel and/or a pellet, and the tablet, pill, lozenge, capsule, gel, geltab, nanosuspension, nanoparticle, microgel and/or a pellet, or other equivalents, are released upon opening of the single package or packet.
- the therapeutic combinations of the invention are formulated or manufactured as a feed, a food, a pellet, a lozenge, a liquid, an elixir, an aerosol, an inhalant, a spray, a powder, a tablet, a pill, a capsule, a gel, a geltab, a nanosuspension, a nanoparticle, a microgel or a suppository.
- the single package or a plurality of packages is a blister pack, package or plurality of blister packettes.
- the therapeutic combinations of the invention comprise formulations having the dosage of etodolac ranges from about 200 mg to 400 mg a day, or, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 mg or more; and the dosage of propranolol can range from 10 to 320 mg per day based on heart rate and blood pressure of the individual; or, can be about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 mg or more; wherein the invention includes all combinations of these exemplary dosages.
- the methods of the invention comprise administration of these therapeutic combinations of the invention; wherein practicing the methods of the invention can include use of any or all combinations of these exemplary dosages.
- therapeutic combinations of the invention can be packaged in dosages that match a chrono-dosing regimen to match an optimal dose for the time of day, or the day or month (as any therapeutic drug combination of the invention can be applied once, twice, three or four times, or more, a day or a week or a month, depending on the patient and the indication the for which the drugs are being administered).
- the drugs are packaged in dosages that match a chrono-dosing regimen comprising: (a) in the AM, 20 mg propranolol, 200mg etodolac; in the afternoon, 10 mg propranolol, 200 mg etodolac; in the PM, 10 mg propranolol, 400 mg etodolac; (b) in the AM 40 mg propranolol, 200 mg etodolac; in the afternoon 20 mg propranolol, 200 mg etodolac; in the evening, 20 mg propranolol, 400 mg etodolac; (c) in the AM 80 mg propranolol, 200 mg etodolac; in the afternoon 40 mg propranolol, 200 mg etodolac, in the evening 40 mg, etodolac; or (d) a dose escalation comprising a regimen of (a) to (b) to (c); or any equivalents.
- AM 20 mg propranolol, 200mg etodolac; afternoon, 10 mg propranolol, 200 mg etodolac; PM 5 mg propranolol, 400 mg etodolac; Dose Escalation 1: AM 40 mg propranolol, 200 mg etodolac; afternoon 20 mg propranolol, 200 mg etodolac; evening, 10 mg propranolol, 400 mg etodolac;
- Dose escalation 2 AM 80 mg propranolol, 200 mg etodolac; afternoon 40 mg propranolol, 200 mg etodolac, evening 20 mg, etodolac.
- the drugs are formulated for administration once a day, b.i.d. or t.i.d, or four times a day, or more, or for weekly, or biweekly, or monthly administration (in any combination, as described herein, particularly to accommodate chronodosaging).
- the drugs are dosaged as set forth in any one of exemplary ingredient combinations 1 to 90.
- the drugs are formulated for administration intravenously, topically, orally, by inhalation, by infusion, by injection, by inhalation, intraperitoneally, intramuscularly, subcutaneously, intra- aurally, for intra-articular administration, for intra-mammary administration, for topical administration or for absorption through epithelial or mucocutaneous linings.
- the therapeutic combinations of the invention including the compositions and products of manufacture of the invention, further comprise instructions for use, e.g., in the treatment of cachexia, the treatment of anorexia or anorexia-cachexia, and stress or anxiety related thereto.
- the cachexia is defined as at least two of the symptoms selected from the group consisting of: 1) a hyper- inflammatory state, 2) altered hormone levels and cytokine levels; 3) increased heart rate variability; 4) weight loss, and 5) increased heart rate, wherein optionally the increased heart rate is having a sustained elevated heart rate of at least about 6 bpm; or, the cachexia is defined by an individual having at least a sustained elevated heart rate of at least about 6 bpm and weight loss.
- the invention also provides pharmaceutical compositions or kits comprising one or more therapeutic drug combinations of the invention.
- the pharmaceutical compositions or kits of the invention can further comprise a pharmaceutically acceptable excipient.
- compositions or kits of the invention can be formulated or manufactured as a feed, a food, a food or feed concentrate, a pellet, a lozenge, a liquid, a lotion, an implant, a nanoparticle, an elixir, an aerosol, a spray, an aerosol, an inhalant, a powder, a tablet, a pill, a capsule, a gel, a geltab, a nanosuspension, a nanoparticle, a patch, a microgel or a suppository.
- the invention also provides uses of the therapeutic combinations, pharmaceutical compositions or kits, in the manufacture of a medicament or pharmaceutical composition for treating, ameliorating or preventing a trauma, condition or disease comprising: a chronic Systemic Inflammatory Response State (SIRS); chronic systemic inflammatory stress; burns, chronic obstructive pulmonary disease; congestive heart failure; chronic kidney disease; surgery; cancer; sepsis; ageing; acute respiratory distress syndrome; acute lung injury; infection; a CNS disorder or injury; anemia; immunosuppression; insulin resistance; anorexia; anxiety; sleep disturbances; weakness; fatigue; gastrointestinal distress; sleep disturbances; wake disturbances; pain; listlessness; shortness of breath; lethargy; depression; malaise; or, a combination thereof.
- SIRS Systemic Inflammatory Response State
- the trauma, condition or disease comprises a maladaptive nutritional state secondary to the SIRS; and the maladaptive nutritional state can comprise cachexia, and optionally the cachexia comprises cachexia secondary to cancer.
- the cachexia is defined as at least two of the symptoms selected from the group consisting of: 1) a hyper-inflammatory state, 2) altered hormone levels and cytokine levels; 3) increased heart rate variability; 4) weight loss, and 5) increased heart rate, wherein optionally the increased heart rate is having a sustained elevated heart rate of at least about 6 bpm.
- the cachexia is defined by an individual having at least a sustained elevated heart rate of at least about 6 bpm and weight loss.
- the CNS disorder comprises Parkinson's disease or Alzheimer's disease.
- the invention also provides methods for treating or ameliorating a trauma, condition or disease comprising a chronic Systemic Inflammatory Response State (SIRS), chronic systemic inflammatory stress; burns, chronic obstructive pulmonary disease; congestive heart failure; chronic kidney disease; surgery; cancer; sepsis; ageing; acute respiratory distress syndrome; acute lung injury; infection; a CNS disorder or injury; anemia; immunosuppression; insulin resistance; anorexia; anxiety; sleep disturbances; weakness; fatigue; gastrointestinal distress; sleep disturbances; wake disturbances; pain; listlessness; shortness of breath; lethargy; depression; malaise; or, a combination thereof, the method comprising the steps of: (a) providing a therapeutic combination of the invention, or a pharmaceutical composition, kit or any product of manufacture of the invention; and, (b) administering a therapeutically effective amount of the therapeutic combination, or pharmaceutical composition, kit or product of manufacture, of step (a), thereby treating or ameliorating the trauma, condition or disease.
- SIRS Systemic Inflammatory Response State
- the condition or disease comprises a maladaptive nutritional state secondary to the SIRS; and the maladaptive nutritional state can comprise cachexia and/or anorexia, e.g., the cachexia can comprise cachexia secondary to any chronic disease or condition, e.g., a cancer.
- the cachexia is defined as at least two of the symptoms selected from the group consisting of: 1) a hyper-inflammatory state, 2) altered hormone levels and cytokine levels; 3) increased heart rate variability; 4) weight loss, and 5) increased heart rate, wherein optionally the increased heart rate is having a sustained elevated heart rate of at least about 6 bpm.
- the cachexia is defined by an individual having at least a sustained elevated heart rate of at least about 6 bpm and weight loss.
- kits and other products of manufacture comprising a therapeutic combination, formulation or pharmaceutical composition of the invention.
- the kits, product of manufacture, therapeutic combination, formulation or pharmaceutical composition comprises at least one blister pack or a plurality of blister packettes, or a plurality of individual or clustered packages (e.g., as paper, cellophane, plastic, polyvinyl chloride (PVC) plastic and/or an aluminium foil (alufoil) material, and the like) comprising the therapeutic combination, formulation or pharmaceutical composition of the invention.
- PVC polyvinyl chloride
- alufoil aluminium foil
- the invention provides kits and other products of manufacture for the treatment, amelioration or prevention of a chronic Systemic Inflammatory Response State (SIRS) or a maladaptive nutritional state in a patient population, the kit comprising a therapeutic combination, formulation or pharmaceutical composition of the invention, and instructions for use.
- the maladaptive nutritional state comprises cachexia, or the cachexia comprises cachexia secondary to cancer.
- the cachexia is defined as at least two of the symptoms selected from the group consisting of: 1) a hyper- inflammatory state, 2) altered hormone levels and/or cytokine levels; 3) increased heart rate variability; 4) weight loss, and 5) sustained increased heart rate, wherein optionally the sustained increased heart rate is having a sustained elevated heart rate of at least about 6 bpm.
- the cachexia is defined by an individual having at least a sustained elevated heart rate of at least about 6 bpm and weight loss.
- kits and other products of manufacture for the treatment, amelioration or prevention of a CNS disorder
- the kit comprises a therapeutic combination, formulation or pharmaceutical composition of the invention
- the CNS disorder can comprise Parkinson's disease or Alzheimer's disease.
- the invention provides products of manufacture comprising a blister package, a clamshell, a tray or a shrink wrap comprising a therapeutic combination, formulation or pharmaceutical composition of the invention.
- the product of manufacture can comprise a blister package, a clamshell, a tray or a shrink wrap.
- the product of manufacture comprises therapeutic combinations or pharmaceutical compositions of the invention, wherein the therapeutic combination or pharmaceutical composition are formulated for at least one, two, three, four, five, six, seven or more dosage administrations, including comprising bid or tid, or weekly, biweekly or monthly dosage administrations, or a combination thereof.
- the therapeutic combination or pharmaceutical composition are formulated as one dosage administration in the morning and one dosage administration in the evening.
- the dosage schedule provides a relatively higher dose of one drug in the morning (the AM) than in the evening, and a relatively higher dose of another medication in the evening than in the morning.
- a therapeutic combination or pharmaceutical composition of the invention further comprises a nutritional supplement (e.g., a mineral, an electrolyte, a vitamin, a fat, a sugar and the like).
- a nutritional supplement e.g., a mineral, an electrolyte, a vitamin, a fat, a sugar and the like.
- SIRS Systemic Inflammatory Response State
- a therapeutic combination or pharmaceutical composition of the invention are administered to an individual in need thereof, and the therapeutic combination or the pharmaceutical composition are formulated for at least two administrations, one in the morning and one in the evening, wherein the dosage schedule provides a relatively higher dose of beta blocker in the morning (the AM) than in the evening, and a relatively higher dose of an antiinflammatory medication in the evening than in the morning.
- the administration regimen comprises at least two dosages of beta adrenergic receptor antagonist (a beta blocker) drug and at least two dosages of non-steroidal anti- inflammatory drug (a NSAID), and further comprising administration of an anti-anxiety drug
- the drugs are organized or labeled in the blister package, clamshell, tray or shrink wrap for usage by an individual for at least two administrations, one in the morning and one in the evening, wherein the dosage schedule provides a relatively higher dose of beta blocker in the morning (the AM) than in the evening, and a relatively higher dose of an anti-anxiety and/or an anti-inflammatory medication in the evening than in the morning.
- the administration regimen comprises doses of propranolol given in 20 or 40 mg tablets immediate release on a bid basis, and in the first dose week the doses for propranolol are
- the dosage is adjusted to 20 mg of the immediate release product in the morning and 60 mg of the extended release at bedtime, and optionally if after an additional week the subject shows no improvement or has not obtained a 20% reduction in heart rate, without decreasing heart rate below 60 bpm or blood pressure below 90/60, the dose is adjusted to 40 mg of the immediate release propranolol in the morning and 120 mg of the extended release propranolol at bedtime.
- the administration regimen comprises doses of etodolac are given in 200 mg capsules or 500 mg tablets on a bid basis, and doses for etodolac are started at 200 mg in the morning and at bedtime, and after 1 week the dosage are adjusted to 200 mg in the morning and 500 mg at bedtime.
- the invention provides blister packs or a plurality of blister packettes comprising a therapeutic combination of or pharmaceutical composition of the invention, wherein the propranolol or equivalent and etodolac or equivalent are arranged or clustered in the blister pack or a plurality of blister packettes: (a) in a chrono-dosing arrangement or pattern; or (b) individually.
- the invention provides paper, plastic, cellophane package, polyvinyl chloride
- PVC polyvinyl
- alufoil aluminium foil
- compositions e.g., pharmaceutical compounds, preparations, formulations, kits and products of manufacture (e.g., blister packages, shrink wraps, etc.), comprising combinations of beneficial ingredients that are serviceable as therapies for improving, treating, ameliorating and/or preventing conditions, states and/or disease symptoms involving inflammation, excessive sympathoneural drive, cachexia, anorexia, and anorexia-cachexia, and stress or anxiety related thereto, and method of using them.
- compositions and methods of the invention are exemplified by, e.g., wasting and/or atrophy, such as muscle atrophy, or anorexia-cachexia, e.g., as cachexia related to chronic and/or wasting diseases, such as cancer.
- Table 1 provides serviceable components, i.e., exemplary combinations of drugs and/or pharmaceuticals of the invention. These components (e.g., exemplary combinations of drugs) are presented as members of groups with non-limiting examples provided that can be used in the compositions (e.g., pharmaceutical compounds, preparations, formulations, kits and products of manufacture) and methods of the invention.
- compositions and therapies comprising use of a beta adrenergic antagonist (also called “beta blockers”) in combination with an anti- inflammatory agent, e.g., a nonsteroidal anti-inflammatory drug (NSAID), an angiotensin-con verting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), an anabolic steroid, a natural oil or fatty acid or any combination thereof.
- NSAID nonsteroidal anti-inflammatory drug
- ACE angiotensin-con verting enzyme
- ARB angiotensin receptor blocker
- anabolic steroid e.g., an anabolic steroid, a natural oil or fatty acid or any combination thereof.
- an exemplary drug combination of the invention comprises an etodolac or equivalent and a propranolol or equivalent, which can be formulated together (e.g., as a pill, geltab, tablet, liquid, intravenous formulation, spray, etc.) or separately (e.g., as separate pill, geltab, tablet and the like in a product of manufacture, e.g., a blister pack, or simple paper, plastic or cellophane wrapper).
- the beta blocker comprises acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedolol, esmolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol or timolol or equivalents.
- Table 1 Exemplary ingredients used in the methods and compositions of the invention.
- Group I Table 1 Group Members (The examples are listed for each group are non- limiting examples. The sub-groups are not necessarily mutually exclusive.) Group Table 1. Group Members (The examples are listed for each group are non- limiting examples. The sub-groups are not necessarily mutually exclusive.)
- Immunomodulators Rapamycin, lenalidomide.
- Antidepressant Agents and Mood Altering Drugs include: alternative and herbal antidepressants (AHAs) monoamine oxidase inhibitors (MAOIs)
- NARIs noradrenaline reuptake inhibitors
- RMAOIs reversible monoamine oxidase inhibitors
- SNRIs serotonin and noradrenaline reuptake inhibitors
- SRIs serotonin reuptake inhibitors
- SSRIs selective serotonin reuptake inhibitors
- TCAs tricyclic antidepressants
- TTCAs tetracyclic antidepressants
- AHAs include St John's Wort (Hypericum), Valerian root (Valerian officinalis), Damiana (Turnera diffusa), Ginkgo (Ginkgo biloba) Ginseng (Panax ginseng).
- MAOIs include phenelzine, tranylcypromine
- NARIs include reboxetine
- RMAOIs include moclobemide
- SNRIs include duloxetine, milnacipran, nefazodone, venlafaxine.
- SRIs &/or SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline.
- TCAs include amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortryptyline, pro tripty line, trimipramine
- TTCAs include maprotiline, mianserin, and mirtazapine
- Cannabinoid receptor ligands including plant-derived cannabinoids, endogenous cannabinoids (endocannabinoids), synthetic cannabinoids, compounds that have cannabinoid receptor agonist activity (agonist activity includes direct, modulating, and potentiating), compounds that have cannabinoid receptor antagonist activity, and compounds that have both cannabinoid receptor agonist activity and cannabinoid receptor antagonist activity, compounds that have CBl receptor-selective activity, compounds that have CB2 receptor-selective activity, and compounds that have selectivity for cannabinoid receptors that are not CBl or CB2.
- Group Table 1 Group Members (The examples are listed for each group are non- limiting examples.
- the sub-groups are not necessarily mutually exclusive.
- idebenone lutein, lycopenes, MDL 29311, melatonin, N 2 - Mercaptopropionylglycine(N 2 -MPG), N-acetyl-L-cysteine (NAC), NADH (Q- 1), N-acetylserotonin (NAS), nifedipine, nimodipine, oligomeric proanthocyanidins (OPCs), omeprazole, OPC-14117, organogermanium compounds, pangamic acid (sometimes called vitamin B15), pentoxifylline, phenolic compounds, phloretin, phloridzin, phytosterols, piracetam, plants and plant extracts (e.g.
- vitamin A e.g. retinal, retinol, retinoic acid
- vitamin B e.g.
- vitamin C including provitamin C or ascorbign, vitamin Cl or ascorbic acid, vitamin C2 or dehydroascorbic acid,vitamin C3 or ascorbyl palmitate, vitamin C4 or calcium ascorbate, vitamin C5 or isoascorbic acid, vitamin C6 or calcium isoascorbate
- vitamin E e.g. tocotrienols and tocopherols, including alpha-, gamma-, and delta- versions thereof
- vitamin P citrin
- xanthones zeaxanthin.
- the eight "essential" amino acids isoleucine, leucine, lysine, methionine, phenylalanine, threonine,tryptophan and valine.
- the "non-essential” amino acids alanine, arginine, asparagin, aspartic acid, carnitine, citrulline, cysteine, cystine, gamma- aminobutyric acid (gaba), glutamic acid, glutamine, glycine, ornithine, proline, serine, taurine, and tyrosine.
- All amino acids based on the compositions of proteins e.g. fibrinogen
- SAPRs acute phase protein responses
- alanine e.g., alanine, arginine, cysteine, glutamine, glycine, phenylalanine, proline, serine, and tryptophan.
- Atorvastatin fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin.
- subgroups (categories within each Group) in Table 1 are not necessarily mutually exclusive.
- desipramine is listed as a tricyclic antidepressant, and is chemically categorized as such; however, it works on both serotonin and norepinephrine, so it can also be considered an SNRI.
- this invention provides protection for each subgroup, and each subgroup may include members of another subgroup; thus, using this non-limiting example, the subgroup of SNRIs includes desipramine.
- ingredients of the invention can be administered by more than one route.
- a number of steroids see, for example, Table 1, Group 5
- a common route of administration e.g. oral administration
- this invention provides that, for each ingredient provided herein, that all possible routes of administration are provided herein and intended for protection herein; likewise, intended for protection herein are kits containing each ingredient provided including ingredient forms suitable for different modes of administration (e.g.
- this invention provides protection for each subgroup, and each subgroup may include members of another subgroup; thus, using this non-limiting illustration, the subgroup of steroids that can be administered orally, include members of the subgroup of steroids that can be administered by intramuscular injection.
- the preparations of the invention comprise ingredients of the invention (e.g., exemplary combinations of drugs of the invention) as exemplified in Table 1, and, in one aspect, are orally ingestible.
- these preparations can be liquids (e.g. that can be orally ingested with the help of a spoon, injectables such as intravenous injections or subcutaneous formulations), sprays, inhalants, gels, patches, powders, capsules, geltabs, tablets and/or pills.
- they can also be formed into flavored bars (e.g. similar to what bars that are marketed as “power bars”, “diet bars”, “energy bars”, and “nutritional bars”) or flavored liquids, including concentrates.
- ingredients of the invention e.g., exemplary combinations of drugs of the invention
- ingredients exemplified in Table 1 for making the preparations of the invention
- the exemplary combinations of drugs of the invention can use any known antioxidant; thus, specifically provided herein are the thousands of antioxidants currently known.
- a measurable antioxidant value may be determined by test such as ORAC (see discussion, below), HORAC, NORAC, as well as by other tests or methods including the trolox equivalent antioxidant capacity (TEAC) method, the 2,2-azinobis-3-ethylbenzothiazoline-6-sulphonate (ABTS) method, the total radical- trapping antioxidant (TRAP) method, the 2,2-diphenyyl-l-picrylhydrazl (DPPH) method, the dichlorofluorescin-diacetate (DCFH-DA) method and the N,N-dimethyl-p- phenylenediamine (DMPD) method, to name just a few.
- ORAC trolox equivalent antioxidant capacity
- ABTS 2,2-azinobis-3-ethylbenzothiazoline-6-sulphonate
- TRIP total radical- trapping antioxidant
- DPPH 2,2-
- compositions provided herein include the aforementioned members listed in Table 1 as well as analogs and derivatives thereof that have antioxidant activity, specifically a measurable positive antioxidant activity or value.
- ingredients used to practice this invention include any single known or groups of ingredients that have a measurable positive ORAC value (or similar value using another comparable test) (ORAC assays and ORAC value discussed in detail, below) of at least about 1 ORAC unit/gram, or, at least about 5 ORAC units/gram, or, at least about 10 ORAC units/gram, or, at least about 20 ORAC units/gram, or, at least about 30 ORAC units/gram, or, at least about 40 ORAC units/gram, or, at least about 50 ORAC units/gram, or, at least about 60 ORAC units/gram, or, at least about 70 ORAC units/gram, or, at least about 80 ORAC units
- Beta Blocker (Absolute amount, mg)
- Beta Blocker (Absolute amount, mg)
- Anti-TNF (Absolute amount, mg)
- TCA (other unit of measure, e.g. RDA)
- Exemplary ingredient combination 80 Exemplary ingredient combination 81
- compositions e.g., for use in the exemplary combinations of drugs of the invention
- pharmaceutical compositions, preparations and kits that can be administered by several routes, including intravenous, topical and oral.
- this invention provides forms of compositions, preparations and kits that can be administered by inhalation, infusion or injection, (e.g., intraperitoneal, intramuscular, subcutaneous, intra-aural, intra- articular, intra-mammary, etc.), topical application (e.g., on areas, such as eyes, ears, skin or on afflictions such as wounds, burns, etc.), and by absorption through epithelial or mucocutaneous linings (e.g.
- compositions, preparations and kits containing the present components that are suitable for each of these methods of administration as well as other methods of administration that are know in the art.
- this invention provides compositions, preparations and kits in liquid forms that can be administered orally.
- the compositions, preparations and kits can be also prepared as capsules, gels, geltabs, tablets, powders, sprays, aerosols, pellets (e.g. for animal consumption), suppositories, or creams and ointments.
- the compositions, preparations and kits can be also prepared as physiological solutions suitable for I. V. administration or other parenteral administration.
- a multi-ingredient kit may contain two or more ingredients in approximately equal amounts. An amount may be determined, e.g. by mass or by weight or by molar amount.
- a multi-ingredient kit, as provided herein may contain two or more ingredients in unequal amounts.
- a multi-ingredient kit, as provided herein may contain two or more ingredients in approximately equal amounts as well as one or more ingredients that are not in unequal amounts.
- a multi-ingredient kit may contain two or more ingredients in approximately equimolar amounts.
- a multi- ingredient kit may contain two or more ingredients that are not in equimolar amounts.
- a multi-ingredient kit may contain two or more ingredients that are in approximately equimolar amounts as well as one or more ingredients that are not in equimolar amounts.
- said multi-ingredient kit may contain two or more ingredients that are admixed. In another aspect, said multi-ingredient kit, as provided herein, may contain two or more ingredients that are not admixed. In another aspect, said multi-ingredient kit, as provided herein, may contain two or more ingredients that are partially admixed. In another aspect, said multi-ingredient kit, as provided herein, may contain two or more ingredients that are at least partially admixed, as well as one or more ingredients that are not admixed. An ingredient in a multi-ingredient kit, as provided herein, may be liquid forms that can be administered orally.
- An ingredient in a multi-ingredient kit may also be in delivery forms such as capsules, tablets, powders, sprays, aerosols, pellets (e.g. for animal consumption), suppositories, or creams and ointments.
- An ingredient in a multi- ingredient kit, as provided herein may also be in delivery forms such as physiological solutions suitable for I. V. administration or other parenteral administration.
- a multi-ingredient kit may be separated by physically compartmentalization (e.g. in separate compartments that are part of said kit, where said kit is a multi-compartment kit).
- the ingredients may be admixed or not admixed.
- a single pill or capsule may contain more than one key ingredient (e.g. a BB and an NSAID).
- separate compartments as may be found in a "blister pack" type of packaging, may contain different ingredients.
- the invention provides methods for treating or ameliorating a condition or disease comprising a chronic Systemic Inflammatory Response State (SIRS) comprising the steps of administering a therapeutically effective amount of a therapeutic combination of the invention or a pharmaceutical composition of the invention, thereby treating or ameliorating the condition or disease.
- SIRS Systemic Inflammatory Response State
- the invention provides combination pharmaceutical compositions, preparations, formulations, kits and products of manufacture that can be used for treating or ameliorating disease symptoms and diseases states comprising inflammation, excessive sympathoneural drive (sympathetic nerve activity), cachexia, anorexia, and anorexia-cachexia, and stress or anxiety related thereto for the purpose of improving one or more undesirable symptoms associated with the disease states or for slowing the progression (worsening) of one or more symptoms associated with these disease symptoms and disease states.
- the invention provides combination compositions (products of manufacture), e.g., pharmaceutical compositions, preparations, formulations, kits, for treating or ameliorating the symptoms and/or effects of cachexia, which is a severe and debilitating muscle wasting disorder that affects many terminal cancer patients.
- compositions and methods of the invention by treating or ameliorating the symptoms and/or effects of cachexia, can decrease the significant patient morbidity seen in cachexia, and ameliorate or abrogate the weakness, fatigue, gastrointestinal distress, sleep/wake disturbances, pain, listlessness, shortness of breath, lethargy, depression and/or malaise associated with cachexia.
- compositions of the invention have additional psychological effects on the individual, e.g., by ameliorating the fear of being a burden on family and friends.
- administration of compositions of the invention ameliorate the condition where cachectic patients have substantially poorer tolerance to therapy and higher mortality.
- Cachectic cancer patients have a 50% reduction in life expectancy relative to non-cachectic cancer patients.
- Cachexia results in the direct cause of death in more than 20% of terminal cancer patients.
- compositions and methods of the invention by treating or ameliorating the symptoms and/or effects of the complex syndrome of cachexia, including treating or ameliorating the weight loss, lipolysis, loss of muscle and visceral protein, anorexia, chronic nausea and weakness associated with cachexia.
- compositions and methods of the invention can treat or ameliorate the anemia, immunosuppression, insulin resistance, anxiety and sleep disturbances associated with cachexia.
- the syndromes, conditions and diseases that can be treated or ameliorated by administering the compositions of the invention, or practicing the methods of the invention include syndromes, conditions and diseases characterized as Chronic Systemic Inflammatory Response Syndrome (SIRS) or Chronic SIRS, or associated with Chronic SIRS.
- SIRS Systemic Inflammatory Response Syndrome
- Chronic SIRS Chronic SIRS
- severe cachexia occurs in most patients with advanced cancer, AIDS and end-stage chronic diseases
- administering the compositions of the invention, or practicing the methods of the invention can treat or ameliorate advanced cancer (e.g., tumors of the pancreas, stomach, upper gastrointestinal system, and lung), AIDS and end- stage chronic diseases and their symptoms. More than 80% of patients with cancer (particularly those with tumors of the pancreas, stomach, upper gastrointestinal system, and lung) or AIDS develop cachexia before death.
- any clinically acceptable protocols can be used, e.g., for diagnosing cachexia, e.g., cancer cachexia,
- AIDS or other end-stage chronic diseases congestive heart failure (CHF), severe injuries (e.g., burns) can be used.
- CHF congestive heart failure
- severe injuries e.g., burns
- the methods and compositions of the invention are used on a patient population suffering from cachexia, e.g., cancer cachexia, as diagnosed by symptoms comprising having a sustained elevated heart rate of at least about 6 beats per minute (BPM) (over what would be considered normal for that particular individual) and having weight loss.
- cachexia e.g., cancer cachexia
- BPM beats per minute
- diagnosis of severe inflammation also provides an indication to administer the compositions of the invention or practice the methods of the invention.
- diagnosis of any conditions (physical or psychological) or diseases comprising an escalating stress response, a maladaptive immune system feedback and/or a severe dysregulated psycho-neuroendocrine-immune state also provide an indication to administer the compositions of the invention or practice the methods of the invention.
- the invention provides specific criteria for diagnosing a patient population for practicing this invention, including specific criteria for identifying individuals having cachexia, e.g., cancer cachexia (versus anorexia), who are appropriate recipients of the treatments and compositions of this invention.
- this invention provides a) signature markers to distinguish cachexia from anorexia (e.g., symptoms comprising having an elevated sustained heart rate (over what would be considered normal for that particular individual) of at least about 6 beats per minute (BPM) and having weight loss), and b) effective therapies for treating cachexia.
- cachexia is defined as a "maladaptive nutritional state characterized by hyper-catabolism and deficient or impaired protein-sparing mechanisms" (normally, in starvation or nutritionally-deprived states the body spares protein over fat; this "protein sparing" is lost when an individual is in a "cachexic” state).
- cachexia is distinguished (e.g.
- sustained increased heart rate over what would be considered normal for a particular individual, e.g., having an elevated heart rate of at least about 6 bpm.
- a sustained (i.e. not an acute exercise-induced short term change) heart rate increase of about 6 bpm or more is one easily measurable parameter that is used to determine a patient population to practice this invention, e.g., to distinguish cachexia from anorexia.
- NCTG North Central Cancer Treatment Group
- the invention provides specific easily defined and measurable criteria for diagnosing cachexia, including cancer cachexia, to identify individuals to which it is appropriate to administer the compositions of the invention, or practice the methods of the invention.
- compositions and methods (and uses) of the invention are used to treat, ameliorate or prevent anorexia.
- the invention's methods for distinguishing between anorexia and cachexia allows for a differential diagnosis of (identifying the distinction between) anorexia and cachexia.
- the invention provides methods for ameliorating cachexia, anorexia, anorexia-cachexia, stress and/or anxiety related to a cancer comprising administering to an individual in need thereof a pharmaceutically effective amount of the therapeutic combination of the invention, or the pharmaceutical composition of the invention.
- cachexia is identified as a maladaptive nutritional state secondary to a chronic systemic inflammatory response and autonomic dysregulation. While the invention is not limited by any particular mechanism of action, in one aspect, the natural history of a healthy inflammatory response is characterized by a sequence of feedback responses beginning with tissue breakdown leading to a stress response of inflammation and immune activation, and finally restoration of tissue integrity. If the sequence of events is within normal adaptive range, both in terms of the extent of trauma and duration of the response, then tissue integrity is restored.
- compositions of the invention or practicing the methods of the invention can effectively help address the complexity of the treatment and management of these diseases, e.g., cachexia in its many forms and many causes; practicing the invention will make these easier to manage.
- the invention is not limited by any particular mechanism of action, in one aspect the autonomic nervous system (ANS) and the inflammatory response are underlying causes of diseases treated by this invention.
- the invention comprises use of compounds that regulate the autonomic nervous system, in one aspect the adrenergic system, with beta blockers and in combination with other drugs, e.g., anti-inflammatory drugs, such as non-steroidal anti-inflammatory drugs (NSAID) and eicosapentaenoic acid (EPA).
- NSAID non-steroidal anti-inflammatory drugs
- EPA eicosapentaenoic acid
- compositions of the invention or practicing the methods of the invention are a treatment for chronic SIRS, e.g., cachexia.
- cachexia syndrome may be associated with malign patterns of eicosanoid production and the presence of a chaotic population of cytokines with consequent aberrations in neuroendocrine-immune control systems, hypothalamic control of appetite, and intermediary metabolism.
- detection or diagnosis of aberrations in neuroendocrine-immune control systems, hypothalamic control of appetite, and intermediary metabolism can be used as an indication for administration of compositions of the invention, or to practice the methods of the invention.
- Metabolic changes also may be associated with changes in autonomic control and an increase in body energy consumption, with further mismatches of food intake with need.
- the systemic aberrations are similar to the acute stress reaction commonly observed in patients with life-threatening infections or major trauma. When this potentially life-saving "switch" is left on, over time the chronic stress inflammatory reaction may enhance tumor growth while inducing a devastating effect on a variety of organs and tissues.
- chronic stress, life-threatening infections or major trauma can be used as an indication for administration of compositions of the invention, or to practice the methods of the invention.
- Wasting cancer patients, or individuals diagnosed with "wasting syndrome" are also a patient population for administration of compositions of the invention, or to practice the methods of the invention.
- muscle synthesis and repair decline, whereas increased muscle proteolysis occurs, possibly due to tumor- produced proteolysis factors.
- the wasting syndrome commonly noted at the time of diagnosis in many forms of cancer, notably those of the upper gastrointestinal tract and lung, progresses through the course of illness, finally leaving the patient in a severe state of malnutrition.
- a recent review details current concepts of this pathophysiology and the relevance of these concepts to anorexia-cachexia research.
- C reactive protein e.g., C reactive protein, or CRP
- CRP C reactive protein
- cytokines notably interleukin (IL)-6, TNF ⁇ and interferon (IFN ⁇ -y correlate with both cachexia and with poor prognosis in cancer patients and other illnesses
- IL-6 interleukin-6
- IFN ⁇ -y interferon
- non-normal levels of these markers can be used to determine whether an individual would benefit from administration of compositions of the invention, or to practice the methods of the invention.
- evidence has been presented for circulatory levels of tumor catabolic products in humans, there is less evidence for circulating cytokines.
- the autonomic nervous system helps to control arterial pressure, gastrointestinal motility, urinary bladder emptying, sweating, body temperature, and many other activities.
- the autonomic nervous system is primarily activated by centers in the spinal cord, brain stem, and hypothalamus. The efferent autonomic signals are transmitted to the various organs of the body through either the sympathetic nervous system or the parasympathetic nervous system.
- the neurotransmitter of all preganglionic autonomic fibers, all postganglionic parasympathetic fibers, and a few postganglionic sympathetic fibers is acetylcholine. These are referred to as cholinergic fibers.
- the adrenergic fibers compose the majority of the postganglionic sympathetic fibers and use the neurotransmitter norepinephrine (noradrenaline).
- the elevated resting energy expenditure is not likely due to tumor metabolism, but more likely it is due to an interaction between the cancer and the neuroendocrine-immune system. While the invention is not limited by any particular mechanism of action, the elevated resting energy metabolism secondary to tumor metabolism is primarily due to the increased adrenergic activity in cancer patients, and this increased adrenergic activity is ameliorated by administration of compositions of the invention, or to practice the methods of the invention.
- compositions of the invention can be in conjunction with other treatments for cachexia, e.g., a variety of interventions including hormones and steroids, cytokines, nutritional supplementation, and appetite stimulation.
- cytokines, nutritional supplementation, and appetite stimulation are useful in treating aspects of the disease, but should be administered in the correct sequence or combination. For example, adding an anabolic steroid while there is degradation of fat and muscle will cause increased cycling and more energy use since the protein is being rapidly broken down to supply other processes. Likewise, adding only nutritional supplementation will be difficult, since the patient has no appetite and will be ineffective since the use of body energy reserves and nutrients is imbalanced.
- compositions of the invention or practicing the methods of the invention, addresses this problem.
- Administration of compositions of the invention, or practicing the methods of the invention can be used in conjunction with diagnoses using the following diagnostic markers (intervention points), and therapeutics: ⁇ aberrant eicosanoid metabolism with nonsteroidal anti-inflammatory agents [NSAlDs], omega-3 fatty acids; ⁇ amino acid deficiencies relevant to need with tailored protein supplements, specific amino acid therapy; a altered energy mechanisms in muscle cells with creatine, ATP, angiotensin- converting enzyme (ACE) inhibitors; ⁇ impaired muscle synthesis and muscle repair with anabolic steroids;
- NSAlDs nonsteroidal anti-inflammatory agents
- ACE angiotensin- converting enzyme
- compositions of the invention can be used to treat or ameliorate conditions or symptoms associated with maladaptive immune responses, maladaptive infection responses (e.g., those dominated by gamma interferon), maladaptive trauma response (e.g., dominated by IL-6) or maladaptive wound healing response (e.g., dominated by TNF or IL-I), for example, including cancer cachexia as a maladaptive nutritional state secondary to a chronic Systemic Inflammatory Response State (SIRS).
- SIRS Systemic Inflammatory Response State
- the sequence proceeds with (1) a breakdown in tissue integrity due to trauma, infection, cancer, etc.; (2) stress, with associated imbalanced metabolic and signaling fluxes; (3) a stress response characterized by a cycle of immune activation, inflammation and healing, and (4) ultimate restoration of tissue integrity, balanced fluxes (homeostasis), and immune inactivation.
- tissue integrity due to trauma, infection, cancer, etc.
- stress with associated imbalanced metabolic and signaling fluxes
- a stress response characterized by a cycle of immune activation, inflammation and healing
- (4) ultimate restoration of tissue integrity, balanced fluxes (homeostasis), and immune inactivation As long as the trauma is within the adaptive range and the immune system correctly partitions, escalates and de-escalates its immune response, the process is adaptive and restores tissue integrity.
- the immune response is maladaptive and does not restore tissue homeostasis. Instead, the cancer progresses, leading to a positive feedback cycle of escalating cancer induced flux imbalances and escalating maladaptive immune system feedback responses.
- the escalating flux imbalances and maladaptive feedback responses leads to a severe dysregulated neuroendocrine-immune state.
- the specific pattern of neuroendocrine-immune imbalances appears to partition into three broad classes of maladaptive infection response (dominated by gamma interferon), maladaptive trauma response (dominated by IL-6) or maladaptive wound healing response (dominated by TNF or IL-I).
- the overall state is characterized by a chronic SIRS.
- compositions of the invention can be used to treat or ameliorate dysregulation associated with a stressed state, e.g., cachexia.
- the autonomic nervous system is central to regulation of the immune and nutritional systems and throughout the body.
- Antagonists of ⁇ -adrenergic receptors (beta- blockers) address the underlying autonomic disorder. These drugs also reduce the inflammatory cytokines, but the additions of NSAIDS or EPA are needed to effectively reduce this response.
- Beta blockers also reduce the signaling pathway to lipolysis and muscle degradation. Beta blockade has reduced REE in cardiac and burn cachexia and has demonstrated short term effects in cancer cachexia. Since the underlying imbalances are the same for cachexia due to cancer, HIV/ AIDS, CHF, burn, COPD and others, as indicated by similar inflammatory and autonomic nervous system dysregulation, they should all respond well to treatment that targets both systems.
- NSAIDs tend to increase blood pressure and therefore provide synergistic effects with beta-blockers by offsetting the potentially adverse hypotensive effect of beta-blockers.
- Many NSAIDS and EPA also show a direct effect on the cancer itself by regulating angiogenesis, apoptosis, metastasis and energy utilization. Therefore, these agents will be particularly beneficial for cancer patients.
- beta-blockers are to reduce overall flux and the energy demand of the system so it is not beyond normal adaptive ranges.
- the body is able to resolve residual signal and will return to a normal state. Once this state is reached, the process of building muscle can begin. This process can be enhanced by drugs such as anabolic steroids and beta2 agonists.
- the embodiments of the invention comprising a combination treatment, or a therapeutic combination, or a pharmaceutical composition, comprising a non-selective beta blocker and an NSAID will provide the reduction in energy use and the activity of the autonomic nervous system while also providing a means to reduce inflammatory response by reducing prostaglandin biosynthesis.
- etodolac demonstrated the lowest GI complications rate among non-specific Cox inhibitors without the reported increase in cardiovascular events associated with specific cox2 inhibitors.
- etodolac is currently in an investigator- lead Phase I/II clinical trial adjunct to standard chemotherapy for breast cancer and the R(-) isomer of etodolac is in a commercial Phase II clinical trial for treatment of Chronic Lymphocytic Leukemia.
- this combination of the invention a non-selective beta blocker and an NSAID
- the relative activity against the different receptor subtypes is balanced, thereby providing the broadest therapeutic effect.
- the presence of the etodolac can serve to maintain blood pressure and to reduce the inflammatory response caused by the disease.
- this combination of the invention will provide for reduced anxiety which will help deal with the social aspects of cachexia and in combination with etodolac will allow the patient to sleep easier. Therefore, this aspect of the invention, including methods and compositions for treating and ameliorating cachexia, addresses both the neuroendocrine-immune and the inflammatory disorder underlying the disease.
- the following table provides guidelines to practice the compositions and methods of the invention: it gives highlights some of the key features of various beta blockers including primary receptor subtype targeted and pharmacokinetic and pharmacodynamic properties. This table is not meant to include all beta blockers that can be used in practicing the compositions and methods of the invention, including the treatment of cachexia, but represents some exemplary drugs, which are some of the more common drugs, and their important characteristics.
- beta blocker Although several beta blockers have been used to examine the effect on REE in cachexia associated with CHF, and a few have been used on patients with cancer, any beta blocker can be used to practice the combination therapy of the invention, and it is important to identify the best beta blocker and exemplary combination for each patient. Specific considerations as guidelines include:
- Pulmonary - The cardioselective beta blockers are advised to patients who have pulmonary or respiratory complications. Agents such as acebutolol, atenolol, bisoprolol or metoprolol would be preferred for these patients. In addition, these patients must be advised of the potential for pulmonary constriction and doses will be lower than for patients without these complications.
- Non-selective (traditional) NSAIDS Non-selective (traditional) NSAIDS
- Omega-3 (omega-3) fatty acids e.g., eicosapentaenoic acid, or EPA
- FAs Omega-3 fatty acids
- EPA is a well-known agent for reducing an inflammatory response; it is a direct inhibitor of adipocyte lipid mobilization and has been used with varying success in the treatment of cachexia. Variability in success appears to be driven by ability to tolerate an effective dose and high rate of metabolism by the liver.
- EPA is generally administered orally and is in combination with DHA in fish oil in about a 2: 1 ratio. Large doses of fish oil are known to cause unpleasant side effects and patients are often unable to tolerate a therapeutic dose.
- Oral EPA must be absorbed by the gut, which may be impaired in cachexia patients. Once EPA enters the blood stream it goes to the liver where it is cleared as much as 90% in the first pass, making adequate dosing problematic. Recent formulations of EPA may make dosing less of a problem.
- the invention comprises use of cytokine and/or hormone levels as well as heart rate variability (over what would be considered normal for a particular individual) as key factors in the diagnostics of early cachexia.
- HRV heart rate variation
- ANS autonomic nervous system
- Heart rate variation can be used to identify patients that have cachexia or are trending towards cachexia, as well as patients with more generally described chronic and acute SIRS. By first screening patients for HRV through a simple measurement of heart rate, then profiling the blood markers, it will be possible to identify patients at risk for cachexia, or in the early stages of cachexia, with a high degree of certainty.
- the invention provides compositions that have the ideal profile of a drug to treat the patient with cachexia, e.g., a composition that is easy to take, such as a once a day pill or liquid formulation.
- the drug is effective but does not cause depression, tiredness, bradycardia or hypotension.
- the impact is to reduce the metabolic flux rate, balance the muscle and fat utilization, and to reduce inflammation.
- the instant invention recognizes that simply supplying nutrients or providing signals to encourage increase of lean muscle mass is not beneficial until the high metabolic and energy flux through the muscle tissue is brought into normal range.
- agents such as beta2 adrenergic agonists and anabolic hormones to start adding muscle mass.
- beta blockers it is important to monitor blood pressure, heart rate and fatigue.
- Administration and Dosing Since patients with cachexia are often taking many other medications it is important that the therapy for cachexia not interfere with, and ideally should benefit, ongoing therapy.
- Frequency of dosing It is important to minimize the frequency and number of medications a patient must take. Patients who are required to take a medication only once or twice a day will have much higher compliance compared to a those who require medication of multiple pills three or more times a day. Formulation to a once a day dose is an advantage for all reformulations of the product.
- Dose Form In some aspects, unless there is a highly significant therapeutic reason, medication should be administered orally in pill or tablet form, or as a liquid that can be combined with a drink so taking the medication is not unpleasant. Since the patients with cachexia are frequently on a number of other medications it is important to make administration uncomplicated.
- the invention provides two pills in a single package, e.g., a single blister-pack, to assure that the both drugs are taken and at the correct time.
- a product is provided as an oral liquid formulation that will be desired by many patients.
- dugs can be provided in a single cartridge that is easily opened and which then allows both drugs to be administered at the same time.
- ingredients used to practice this invention include any single known or groups of ingredients that have a measurable positive ORAC "Oxygen Radical Absorbance Capacity" (ORAC) value (or similar value using another comparable test) of at least about 1 ORAC unit/gram, or, at least about 5 ORAC units/gram, etc. as set forth, above.
- ORAC assays are well known in the art, e.g., the Total Antioxidant Capacity Assay, or "Oxygen Radical Absorbance Capacity" (ORAC/NORAC), from Brunswick Laboratories, Wareham, MA; thus, the one of skill in the art would understand how to practice an ORAC assay and understand how to interpret a positive, or negative, ORAC assay in the context of this invention.
- the ORAC assay depends on the free radical damage to a fluorescent probe through the change in its fluorescence intensity. The change of fluorescence intensity is an index of the degree of free radical damage.
- the inhibition of free radical damage by an antioxidant which is reflected in the protection against the change of probe fluorescence in the ORAC assay, is a measure of its antioxidant capacity against the free radical.
- the ORAC assays can be performed in vitro, and if performed in vitro, do not determine the bioavailability within the body. A high ORAC value indicates that the tested sample possesses a high potency of antioxidant activity chemically.
- the "improved" ORAC assay of Brunswick Laboratories, Wareham, MA, used in one aspect of this invention is exactly the same as the "original” ORAC assay in terms of experimental conditions, AUC technique and chemical principles.
- the "original” assay's fluorescent probe, beta-phycoerythrin (PE) is replaced with fluorescein (FL)4. FL as compared to PE does not interact with antioxidants, shows excellent photostability and reduces the cost of experiments.
- the ORAC value obtained by this "improved" ORAC is higher than that obtained by the original ORAC assay.
- ingredients used to practice this invention include any single known or groups of ingredients that measure positive as antioxidants on the Trolox Equivalent Antioxidant Capacity (TEAC) assay.
- TEAC Trolox Equivalent Antioxidant Capacity
- BIOTM spectrophotometric analyzer Hoffmann-La Roche Inc., Nutley,. NJ. This assay is based on the observation that when 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) is incubated in the presence of a peroxidase and hydrogen peroxide or in the presence of hydroxyl, peroxyl, alkoxyl, and inorganic radicals, the slightly more stable ABTS + radical cation is generated. From the time the ABTS, metmyoglobin, buffer, and hydrogen peroxide are added together, the absorbance of infra red radiation is measured at a wavelength of 734nm with respect to time.
- ABTS 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonic acid)
- the unit of measure in this assay is the TEAC, which is the concentration (mmol/1) of Trolox with the equivalent antioxidant capacity to a 1.0 mmol/1 solution of the substance being tested.
- the TEAC assay can detect the antioxidant capacity of water-soluble drugs or drugs that can be solubilized. Also, due to the ability of the TEAC assay to detect the contribution of other components, the TEAC assay can be used to measure the antioxidant capacity of the system.
- the TEAC method can be used for pharmacological and nutritional studies.
- ingredients used to practice this invention include any single known or groups of ingredients that measure positive as antioxidants on the Total Radical-Trapping Antioxidant Parameter, TRAP, method.
- Aqueous dispersions of oxidizable organic compounds that can be readily and reproducibly initiated at a constant rate, Ri, by peroxidation using the water-soluble azo compound 2,2'-azo-bis-(2-amidipropropane hydrochloride), ABAP is the basis of the Total Radical-Trapping Antioxidant Parameter, TRAP, method.
- the TRAP method was developed by Wayner et al. and published in 1985.
- the TRAP Upon addition of the ABAP to the plasma, the length of time that oxygen uptake by peroxidizable plasma is inhibited is measured with an oxygen probe, and this value is referred to as the TRAP.
- Trolox is used in this method by creating a second induction period after the natural antioxidants have been depleted.
- This second induction period is used to calculate an Ri value, which is used to calculate the TRAP value.
- the TRAP value is reported as the number of moles of peroxyl radicals trapped per liter of fluid.
- the duration of time is the only thing measured in the TRAP method, which is a limiting factor in its analysis.
- the time taken to prevent maximum oxygen uptake cannot be measured easily and precisely, and the total radical trapping capability per mole of some antioxidants is dependent on their initial concentration. This leaves out the extent of inhibition.
- the TRAP method shows the contribution of the serum components to the total radical-trapping antioxidant content, which is a problem if the antioxidant contribution of a specific chemical is the desired information.
- the TRAP method is more specific than the TEAC method due to the involvement of a number of different radical species in the TEAC method as opposed to just the chain-carrying peroxyl species in the TRAP method.
- the TRAP method requires high levels of dilution of plasma to produce the required lag phase, and the process to accomplish this shortens the lipid chain length necessary for a rapid chain reaction.
- compositions including preparations, formulations and/or kits, comprising combinations of ingredients, as described above (including the multi- ingredient combinations of drugs of the invention), that are serviceable as therapies for treating, preventing or improving conditions, states and disease symptoms involving inflammation, excessive sympathoneural drive, cachexia, anorexia, and anorexia-cachexia, and stress or anxiety related thereto.
- each member of the combination of ingredients is manufactured in a separate package, kit or container; or, all or a subset of the combinations of ingredients are manufactured in a separate package or container.
- the package, kit or container comprises a blister package, a clamshell, a tray, a shrink wrap and the like.
- the package, kit or container comprises a "blister package” (also called a blister pack, or bubble pack).
- the blister package is made up of two separate elements: a transparent plastic cavity shaped to the product and its blister board backing. These two elements are then joined together with a heat sealing process which allows the product to be hung or displayed.
- Exemplary types of "blister packages” include: Face seal blister packages, gang run blister packages, mock blister packages, interactive blister packages, slide blister packages.
- Blister packs, clamshells or trays are forms of packaging used for goods; thus, the invention provides for blister packs, clamshells or trays comprising a composition (e.g., a (the multi-ingredient combination of drugs of the invention) combination of active ingredients) of the invention.
- Blister packs, clamshells or trays can be designed to be non-reclosable, so consumers can tell if a package has already opened. They are used to package for sale goods where product tampering is a consideration, such as the pharmaceuticals of the invention.
- a blister pack of the invention comprises a moulded PVC base, with raised areas (the "blisters") to contain the tablets, pills, etc.
- a specialized form of a blister pack is a strip pack.
- blister packs adhere to British Standard 8404.
- a blister packs also comprise a method of packaging where the compositions comprising combinations of ingredients of the invention are contained in- between a card and a clear PVC.
- the PVC can be transparent so the item (pill, tablet, geltab, etc.) can be seen and examined easily; and in one aspect, can be vacuum-formed around a mould so it can contain the item snugly and have room to be opened upon purchase.
- the card is brightly coloured and designed depending on the item (pill, tablet, geltab, etc.) inside, and the PVC is affixed to the card using pre-formed tabs where the adhesive is placed.
- the adhesive can be stong enough so that the pack may hang on a peg, but weak enough so that this way one can tear open the join and access the item.
- the card has a perforated window for access.
- more secure blister packs e.g., for items such as pills, tablets, geltabs, etc. of the invention are used, and they can comprise of two vacuum-formed PVC sheets meshed together at the edges, with the informative card inside. These can be hard to open by hand, so a pair of scissors or a sharp knife may be required to open.
- blister packaging comprises at least two components (e.g., is a multi-ingredient combination of drugs of the invention): a thermoformed "blister" which houses the product (e.g., a pharmaceutical combination of the invention), and then a
- thermoformed PVG blister and the printed blister card can be as small or as large as you would like, but there are limitations and cost considerations in going to an oversized blister card.
- Conventional blister packs can also be sealed (e.g., using an AERGO 8 DUOTM, SCA Consumer Packaging, Inc., DeKaIb IL) using regular heat seal tooling. This alternative aspect, using heat seal tooling, can seal common types of thermoformed packaging.
- the invention provides a blister package, a clamshell, a tray or a shrink wrap comprising at least one beta adrenergic receptor antagonist (a beta blocker) and an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a non-steroidal anti-inflammatory drug (a NSAID), an anabolic steroid, a natural oil, a fatty acid or a combination thereof.
- a beta blocker beta adrenergic receptor antagonist
- ACE an angiotensin-converting enzyme
- ARB angiotensin receptor blocker
- a non-steroidal anti-inflammatory drug a non-steroidal anti-inflammatory drug
- anabolic steroid a natural oil, a fatty acid or a combination thereof.
- the therapeutic combination in the blister package, clamshell, tray or shrink wrap comprises at least one beta adrenergic receptor antagonist (a beta blocker) and at least one non-steroidal antiinflammatory drug (a NSAID), such as an aspirin, dichlofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen; ketorolac, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, a COX-2 inhibitor (e.g., a COX-2-selective inhibitor) inhibitor or a combination thereof.
- a COX-2 inhibitor e.g., a COX-2-selective inhibitor
- the therapeutic combination in the blister package, clamshell, tray or shrink wrap comprises at least one beta adrenergic receptor antagonist (a beta blocker) and a COX-2 inhibitor (e.g., a COX-2-selective inhibitor), such as celecoxib rofecoxib, etoricoxib, valdecoxib, parecoxib, meloxicam and/or lumiracoxib.
- a beta blocker e.g., a COX-2-selective inhibitor
- a COX-2 inhibitor e.g., a COX-2-selective inhibitor
- the therapeutic combination in the blister package, clamshell, tray or shrink wrap comprises an atenolol, nadolol, metoprolol, propranolol, carteolol, carvedolol, labetalol, oxprenolol, penbutolol, pindolol, sotalol, timolol or a combination thereof, and at least one non-steroidal anti-inflammatory drug (a NSAID).
- a NSAID non-steroidal anti-inflammatory drug
- the products of manufacture of the invention can comprise the packaging of the therapeutic drug combinations of the invention, alone or in combination, as "blister packages” or as a plurality of packettes, including as lidded blister packages, lidded blister or blister card or packets, or a shrink wrap.
- laminated aluminium foil blister packs are used, e.g., for the preparation of drugs designed to dissolve immediately in the mouth of a patient.
- This exemplary process comprises having the drug combinations of the invention prepared as an aqueous solution(s) which are dispensed (e.g., by measured dose) into an aluminum (e.g., alufoil) laminated tray portion of a blister pack.
- This tray is then freeze-dried to form tablets which take the shape of the blister pockets.
- the alufoil laminate of both the tray and lid fully protects any highly hygroscopic and/or sensitive individual doses.
- the pack incorporates a child-proof peel open security laminate.
- the system give tablets an identification mark by embossing a design into the alufoil pocket that is taken up by the tablets when they change from aqueous to solid state.
- individual 'push-through' blister packs/ packettes are used, e.g., using hard temper aluminum (e.g., alufoil) lidding material.
- hermetically- sealed high barrier aluminum (e.g., alufoil) laminates are used.
- any of the invention's products of manufacture including kits or blister packs, use foil laminations and strip packs, stick packs, sachets and pouches, peelable and non-peelable laminations combining foil, paper, and film for high barrier packaging.
- any of the invention's products of manufacture including kits or blister packs, include memory aids to help remind patients when and how to take the drug. This safeguards the drug's efficacy by protecting each pill until it's taken; gives the product or kit portability, makes it easy to take a dose anytime or anywhere.
- Example 1 Exemplary treatment for non-lung, non-hematological metastatic cancer
- Beta Adrenergic Antagonist (beta blocker) and Non-steroidal anti- inflammatory (NSAID).
- NSAID Non-steroidal anti- inflammatory
- VB 122 Specific Drugs (this combination designated "VB 122"): Propranolol (e.g., INDERALTM), a non selective antagonist that inhibits betal, beta2 and beta3 subclasses of beta adrenergic receptors (the drug is contraindicated for patients with bronchospastic disease, e.g., chronic bronchitis, emphysema, asthma); and, etodolac (e.g., LODINETM), an NSAID that inhibits both Cox-1 and Cox-2 enzymes with some preference towards Cox-2 causing less gastrointestinal problems.
- Propranolol e.g., INDERALTM
- a non selective antagonist that inhibits betal, beta2 and beta3 subclasses of beta adrenergic receptors (the drug is contraindicated for patients with bronchospastic disease, e.g., chronic bronchitis, emphysema, asthma
- Dosing Route multiple including intravenous, topical, and oral by inhalation, infusion or injection, (e.g., intraperitoneal, intramuscular, subcutaneous, intra-aural, intraarticular, intra-mammary, etc.), topical application (e.g., on areas, such as eyes, ears, skin or on afflictions such as wounds, burns, etc.), and by absorption through epithelial or mucocutaneous linings (e.g. vaginal and other epithelial linings, gastrointestinal mucosa, etc.).
- infusion or injection e.g., intraperitoneal, intramuscular, subcutaneous, intra-aural, intraarticular, intra-mammary, etc.
- topical application e.g., on areas, such as eyes, ears, skin or on afflictions such as wounds, burns, etc.
- epithelial or mucocutaneous linings e.g. vaginal and other epithelial linings, gastrointestinal
- Dosing Dose for propranolol is individualized. Doses include from 10 to 320 mg per day based on heart rate and blood pressure. Since the effect of propranolol and etodolac are opposite on blood pressure it is very important that patient compliance be maintained for safety. Therefore, in one aspect, the drugs are supplied in a single package or a plurality of packages, e.g., a blister pack, with one of each pill released upon opening.
- An exemplary protocol comprising an individualized course of dose escalation is: Start: AM, 10 mg propranolol, 400 mg etodolac PM, 10 mg propranolol, 400 mg etodolac
- Dose Escalation 3 AM, 80 mg propranolol, 400 mg etodolac PM, 80 mg propranolol, 400 mg etodolac
- Dose is increased to obtain a heart rate of approximately 60 bpm with blood pressure maintained above 90/60.
- chrono-dosing to match the optimal dose for the time of day is used.
- a high dose of propranolol in the morning will provide the best dose for typical high morning blood pressure and to provide a good bolus dose to start the day.
- Afternoon dosing is lower and evening dose is lower again, or the same as afternoon.
- Propranolol has been linked to unusual and vivid dreams so a low dose in the evening is preferred.
- Etodolac is provided at a modest dose twice during the day and is increased in the evening to provide additional pain management for good rest in the night.
- An exemplary protocol comprising an individualized chrono-dosing is: Start: AM, 20 mg propranolol, 200mg etodolac; afternoon, 10 mg propranolol, 200 mg etodolac; PM 10 mg propranolol, 400 mg etodolac.
- Dose Escalation 1 AM 40 mg propranolol, 200 mg etodolac; afternoon 20 mg propranolol, 200 mg etodolac; evening, 20 mg propranolol, 400 mg etodolac
- Dose escalation 2 AM 80 mg propranolol, 200 mg etodolac; afternoon 40 mg propranolol, 200 mg etodolac, evening 40 mg, etodolac.
- this release profile is obtained by reformulating the active ingredient such that one or two pills are taken per day.
- Another exemplary protocol is:
- AM 20 mg propranolol, 200mg etodolac; afternoon, 10 mg propranolol, 200 mg etodolac; PM 5 mg propranolol, 400 mg etodolac.
- Dose Escalation 1 AM 40 mg propranolol, 200 mg etodolac; afternoon 20 mg propranolol, 200 mg etodolac; evening, 10 mg propranolol, 400 mg etodolac
- Dose escalation 2 AM 80 mg propranolol, 200 mg etodolac; afternoon 40 mg propranolol, 200 mg etodolac, evening 20 mg, etodolac.
- this release profile is obtained by reformulating the active ingredient such that one or two pills are taken per day.
- Example 2 An exemplary non-hematological metastatic cancer treatment
- the following example describes an exemplary treatment protocol of the invention, using an exemplary composition of the invention.
- Population Patients with advanced cancer, Stage III or IV, with evidence of weight loss. Exclude patients with hematological cancer.
- Beta Adrenergic Antagonist beta blocker
- NSAID Non-steroidal antiinflammatory
- Atenolol e.g., TENORMINTM
- selective antagonist that inhibits betal subclass of receptors over beta2 and beta3 receptors
- the drug is useful for patients with bronchospastic disease, e.g., chronic bronchitis, emphysema, asthma (atenolol is eliminated primarily by the kidneys through the urine; patients with impaired renal function (creatinine clearance 10-50) may be better to use the VB- 142 combination, see below
- Etodolac e.g., LODINETM
- an NSAID that inhibits both Cox-1 and Cox-2 enzymes with some preference towards Cox-2 causing less gastrointestinal problems.
- Dosing Route multiple including intravenous, topical, and oral by inhalation, infusion or injection, (e.g., intraperitoneal, intramuscular, subcutaneous, intra-aural, intraarticular, intra-mammary, etc.), topical application (e.g., on areas, such as eyes, ears, skin or on afflictions such as wounds, burns, etc.), and by absorption through epithelial or mucocutaneous linings (e.g. vaginal and other epithelial linings, gastrointestinal mucosa, etc.).
- infusion or injection e.g., intraperitoneal, intramuscular, subcutaneous, intra-aural, intraarticular, intra-mammary, etc.
- topical application e.g., on areas, such as eyes, ears, skin or on afflictions such as wounds, burns, etc.
- epithelial or mucocutaneous linings e.g. vaginal and other epithelial linings, gastrointestinal
- Dosing Dose for atenolol is individualized. Doses include from 12.5 to 100 mg per day based on heart rate and blood pressure Since the effect of atenolol and etodolac are opposite on blood pressure it is very important that patient compliance be maintained for safety. Therefore, the drugs may be supplied in a blister pack with one of each pill released upon opening.
- An exemplary protocol comprising an individualized course of dose escalation is:
- Dose Escalation 1 AM, 25 mg atenolol, 400 mg etodolac PM, 25 mg atenolol, 400 mg etodolac
- Dose Escalation 2 AM, 25 mg atenolol, 400 mg etodolac PM, 50 mg atenolol, 400 mg etodolac
- Dose is increased to obtain a heart rate of approximately 60 bpm with blood pressure maintained above 90/60.
- chrono-dosing to match the optimal dose for the time of day is used.
- a high dose of atenolol in the morning will provide the best dose for typical high morning blood pressure and to provide a good bolus dose to start the day.
- Afternoon dosing is lower and evening dose is lower again, or the same as afternoon.
- Etodolac is provided at a modest dose twice during the day and is increased in the evening to provide additional pain management for good rest in the night.
- An exemplary protocol comprising individualized chrono-dosing is:
- Dose escalation 2 AM 50 mg atenolol, 200 mg etodolac; afternoon 25 mg atenolol, 200 mg etodolac, evening 25 mg atenolol, 400 mg etodolac.
- this release profile is obtained by reformulating the active ingredient such that one or two pills are taken per day.
- Another exemplary protocol is:
- Dose Escalation 1 AM 25 mg atenolol, 200 mg etodolac; afternoon 12.5 mg atenolol, 200 mg etodolac; evening, 6.25mg atenolol, 400 mg etodolac
- Dose escalation 2 AM 50 mg atenolol, 200 mg etodolac; afternoon 25 mg atenolol, 200 mg etodolac, evening 12.5 mg, etodolac.
- Dose escalation 3 AM 50 mg atenolol, 200 mg etodolac; afternoon 25 mg atenolol, 200 mg etodolac, evening 25 mg, etodolac.
- this release profile, or a substantially similar profile is obtained by reformulating the active ingredient such that one or two pills are taken per day.
- Example 3 An exemplary treatment for non-hematological metastatic cancer
- Beta Adrenergic Antagonist beta blocker
- NSAID Non-steroidal antiinflammatory
- Metoprolol e.g., TOPROL-XLTM, metoprolol succinate
- VB-142 Metoprolol
- Metoprolol is a selective antagonist that inhibits betal subclass of receptors over beta2 and beta3 receptors (the drug is useful for patients with bronchospastic disease, e.g., chronic bronchitis, emphysema, asthma); and, metoprolol.
- Metoprolol is extensively metabolized so patients with impaired renal function may be put on this rather than the VB-132 combination (see above).
- Etodolac e.g., LODINETM
- an NSAID that inhibits both Cox-1 and Cox-2 enzymes with some preference towards Cox-2 causing less gastrointestinal problems.
- Dosing Route multiple including intravenous, topical, and oral by inhalation, infusion or injection, (e.g., intraperitoneal, intramuscular, subcutaneous, intra-aural, intraarticular, intra-mammary, etc.), topical application (e.g., on areas, such as eyes, ears, skin or on afflictions such as wounds, burns, etc.), and by absorption through epithelial or mucocutaneous linings (e.g. vaginal and other epithelial linings, gastrointestinal mucosa, etc.).
- infusion or injection e.g., intraperitoneal, intramuscular, subcutaneous, intra-aural, intraarticular, intra-mammary, etc.
- topical application e.g., on areas, such as eyes, ears, skin or on afflictions such as wounds, burns, etc.
- epithelial or mucocutaneous linings e.g. vaginal and other epithelial linings, gastrointestinal
- Dosing Dose for metoprolol is individualized. Doses include from 12.5 to 100 mg per day based on heart rate and blood pressure Since the effect of metoprolol and etodolac are opposite on blood pressure it is very important that patient compliance be maintained for safety. Therefore, the drugs may be supplied in a blister pack with one of each pill released upon opening.
- An exemplary protocol including a simple individualized course of dose escalation, comprises:
- Dose is increased to obtain a heart rate of approximately 60 bpm with blood pressure maintained above 90/60.
- chrono-dosing to match the optimal dose for the time of day is used.
- a high dose of metoprolol in the morning will provide the best dose for typical high morning blood pressure and to provide a good bolus dose to start the day.
- Afternoon dosing is lower and evening dose is lower again, or the same as afternoon.
- Etodolac is provided at a modest dose twice during the day and is increased in the evening to provide additional pain management for good rest in the night.
- An exemplary protocol of individualized chrono-dosing is:
- Dose Escalation 1 AM 25 mg metoprolol, 200 mg etodolac; afternoon 12.5 mg metoprolol, 200 mg etodolac; evening, 20 mg metoprolol, 400 mg etodolac
- Dose escalation 2 AM 50 mg metoprolol, 200 mg etodolac; afternoon 25 mg metoprolol, 200 mg etodolac, evening 25 mg metoprolol, 400 mg etodolac.
- this release profile is obtained by reformulating the active ingredient such that one or two pills are taken per day.
- Another exemplary protocol is: Start: AM, 12.5 mg metoprolol, 200mg etodolac; afternoon, 12.5 mg metoprolol, 200 mg etodolac; PM 6.25 mg metoprolol, 400 mg etodolac.
- Dose escalation 2 AM 50 mg metoprolol, 200 mg etodolac; afternoon 25 mg metoprolol, 200 mg etodolac, evening 12.5 mg, etodolac.
- Dose escalation 3 AM 50 mg metoprolol, 200 mg etodolac; afternoon 25 mg metoprolol, 200 mg etodolac, evening 25 mg, etodolac.
- this release profile is obtained by reformulating the active ingredient such that one or two pills are taken per day.
- a beta blocker and an NSAID are used in combination to treat cachexia.
- the beta blocker antagonizes the beta receptors resulting in normalization of energy metabolism as well as lipid and protein metabolism.
- the NSAID provides additional anti-inflammatory capacity to work in synergy with the beta blocker reducing inflammation and has offsetting activity blood pressure to attenuate any drop in blood pressure that may result from the beta blocker therapy.
- the use of beta blocker alone is inadequate because it primarily affects the autonomic system.
- the NSAID alone has its primary impact on the inflammatory system and needs the beta blocker to attenuate the adrenergic dysfunction.
- the dose of the NSAID is fixed and the dose of the beta blocker is increased periodically at approximately intervals: a) In one aspect, the beta blocker is non-selective and the NSAID is non-selective b) In one aspect, the beta blocker is non-selective and the NSAID is cox2 selective c) In one aspect, the beta blocker is cardio-selective (betal selective) and the
- the NSAID is non-selective d)
- the beta blocker is cardio-selective (betal selective) and the NSAID is cox2 selective
- a beta blocker and an NSAID are used in combination to treat cachexia.
- the dose of the NSAID is fixed and the dose of the beta blocker is increased periodically at approximately weekly intervals. Since the patient with cachexia is often overwhelmed with medications and may have difficulty swallowing pills and keeping track of medication dose and times the medication is provided in a convenient format for administration: a) Any beta blocker and NSAID combination, e.g., as described herein. b) In one aspect, the pills are provided in a blister pack in which the appropriate dose of each drug can be dispensed together. c) The medications are provided in liquid formulation in separate compartments that are released by removing a single cap.
- the medication is provided in liquid or solid form in a multi-dose blister pack where the dose of the beta blocker is available at increasing levels to provide the doses needed to reach target dose.
- the packages are also provided with a fixed dose beta blocker and NSAID for administration once the best dose for the patient is identified using the multi-dose pack.
- the medications are provided at 1 A and 80% of standard available doses of beta blocker to provide a broader range and reduced level of beta blockers for the cachexia patients that have reduced body mass.
- the medication is provided in an extended release solid formulation such that medication must be taken only once daily.
- the medication is provided as an extended release liquid formulation such that medication must be taken only once daily.
- a dose pack is provided that provides a constant level of NSAID in two daily doses whereas the beta blocker is provided at a lower dose for the morning administration and a higher dose for the evening administration.
- a beta blocker and eicosapentaenoic acid are used in combination to treat cachexia.
- the beta blocker antagonizes the beta receptors resulting in normalization of energy metabolism as well as lipid and protein metabolism.
- the EPA provides additional anti-inflammatory capacity to work in synergy with the beta blocker reducing inflammation and has offsetting activity blood pressure to attenuate any drop in blood pressure that may result from the beta blocker therapy.
- the use of beta blocker alone is inadequate because it primarily affects the autonomic system. The EPA alone has its primary impact on the inflammatory system and needs the beta blocker to attenuate the adrenergic dysfunction.
- the dose of the EPA is fixed and the dose of the beta blocker is increased periodically at approximately intervals: a) In one aspect, the beta blocker is non- selective and the EPA is as a capsule b) In one aspect, the beta blocker is non-selective and the EPA is administered as an intravenous infusion. c) In one aspect, the beta blocker is cardio-selective (betal selective) and the EPA a capsule. d) In one aspect, the beta-blocker is cardioselective (betal selective) and the EPA is administered as an intravenous infusion.
- a selective betal blocker and a COX 1/2 inhibitor are used in combination to treat cachexia.
- the beta blocker antagonizes the beta receptors in the heart resulting in reduced energy expenditure, normalization of energy metabolism as well as lipid and protein metabolism.
- the NSAID provides additional anti-inflammatory capacity to work in synergy with the beta blocker reducing inflammation and has offsetting activity blood pressure to attenuate any drop in blood pressure that may result from the beta blocker therapy.
- the use of beta blocker alone is inadequate because it primarily affects the autonomic system.
- the NSAID alone has its primary impact on the inflammatory system and needs the beta blocker to attenuate the adrenergic dysfunction.
- the dose of the NSAID is fixed and the dose of the beta blocker is increased periodically at approximately intervals to obtain a desired reduction in heart rate.
- any beta blocker that is not considered betal selective is combined with any NSAID that is not considered a cox-2 inhibitor.
- the pills are provided in one package, e.g., a blister pack, in which the appropriate dose of each drug can be dispensed together.
- the medications are provided in liquid formulation in separate compartments that are released by removing a single cap.
- the medication is provided in liquid or solid form in a multi-dose blister pack where the dose of the beta blocker is available at increasing levels to provide the doses needed to reach target dose.
- the packages are also provided with a fixed dose beta blocker and NSAID for administration once the best dose for the patient is identified using the multi-dose pack.
- the medications are provided at 1 A and 80% of standard available doses of beta blocker to provide a broader range and reduced level of beta blockers for the cachexia patients that have reduced body mass.
- the medication is provided in an extended release solid formulation such that medication must be taken only once daily
- the medication is provided as an extended release liquid formulation such that medication must be taken only once daily.
- a dose pack is provided that provides a constant level of NSAID in two daily doses whereas the beta blocker is provided at a lower dose for the morning administration and a higher dose for the evening administration.
- a non-selective beta blocker and a COX 2 inhibitor are used in combination to treat cachexia.
- the beta blocker antagonizes the beta receptors resulting in normalization of energy metabolism as well as lipid and protein metabolism.
- the NSAID provides additional anti-inflammatory capacity to work in synergy with the beta blocker reducing inflammation and has offsetting activity blood pressure to attenuate any drop in blood pressure that may result from the beta blocker therapy.
- the use of beta blocker alone is inadequate because it primarily affects the autonomic system.
- the NSAID alone has its primary impact on the inflammatory system and needs the beta blocker to attenuate the adrenergic dysfunction.
- the dose of the NSAID is fixed and the dose of the beta blocker is increased periodically at approximately intervals a) In one aspect, any beta blocker that is not considered betal selective is combined with any NSAID that is not considered a cox-2 inhibitor. b) The medication is provided in any of the formats described herein.
- a selective betal blocker and a COX 2 inhibitor are used in combination to treat cachexia.
- the beta blocker antagonizes the beta receptors resulting in normalization of energy metabolism as well as lipid and protein metabolism.
- the NSAID provides additional anti-inflammatory capacity to work in synergy with the beta blocker reducing inflammation and has offsetting activity blood pressure to attenuate any drop in blood pressure that may result from the beta blocker therapy.
- beta blocker alone is inadequate because it primarily affects the autonomic system.
- the NSAID alone has its primary impact on the inflammatory system and needs the beta blocker to attenuate the adrenergic dysfunction.
- the dose of the NSAID is fixed and the dose of the beta blocker is increased periodically at approximately intervals: a) In one aspect, any beta blocker that is not considered betal selective is combined with any NSAID that is not considered a cox-2 inhibitor. b) In one aspect, the medication is provided in any of the formats described herein.
- the nonselective beta blocker propranolol and the non selective NSAID ibuprofen are used in combination to treat cachexia.
- the beta blocker antagonizes the beta receptors resulting in normalization of energy metabolism as well as lipid and protein metabolism.
- the NSAID provides additional anti-inflammatory capacity to work in synergy with the beta blocker reducing inflammation and has offsetting activity blood pressure to attenuate any drop in blood pressure that may result from the beta blocker therapy.
- the use of beta blocker alone is inadequate because it primarily affects the autonomic system.
- the NSAID alone has its primary impact on the inflammatory system and needs the beta blocker to attenuate the adrenergic dysfunction.
- the dose of the NSAID is fixed and the dose of the beta blocker is increased periodically at approximately intervals: a)
- the propranolol and ibuprofen are provided in any of the formats described herein.
- the selective betal blocker atenolol and the nonselective NSAID ibuprofen are used in combination to treat cachexia.
- the beta blocker antagonizes the beta receptors resulting in normalization of energy metabolism as well as lipid and protein metabolism.
- the NSAID provides additional anti-inflammatory capacity to work in synergy with the beta blocker reducing inflammation and has offsetting activity blood pressure to attenuate any drop in blood pressure that may result from the beta blocker therapy.
- the use of beta blocker alone is inadequate because it primarily affects the autonomic system.
- the NSAID alone has its primary impact on the inflammatory system and needs the beta blocker to attenuate the adrenergic dysfunction.
- the dose of the NSAID is fixed and the dose of the beta blocker is increased periodically at approximately intervals a)
- the atenolol and ibuprofen are provided in any of the formats described herein.
- the nonselective beta blocker propranolol and the COX 2 preferential NSAID etodolac are used in combination to treat cachexia.
- the beta blocker antagonizes the beta receptors resulting in normalization of energy metabolism as well as lipid and protein metabolism.
- the NSAID provides additional anti-inflammatory capacity to work in synergy with the beta blocker reducing inflammation and has offsetting activity blood pressure to attenuate any drop in blood pressure that may result from the beta blocker therapy.
- the use of beta blocker alone is inadequate because it primarily affects the autonomic system.
- the NSAID alone has its primary impact on the inflammatory system and needs the beta blocker to attenuate the adrenergic dysfunction.
- the dose of the NSAID is fixed and the dose of the beta blocker is increased periodically at approximately intervals a) In one aspect, the propranolol and etodolac are provided in any of the formats described herein. b) In one aspect, the beta blocker propranolol is provided at a starting dosage of 40 mg and etodolac at 500 mg twice daily. The patient receives both medications at the same time. In one aspect, the dose of the propranolol is increased weekly to obtain a reduction in heart rate of 20% as long as the blood pressure does not go below 90/60.
- the selective betal blocker atenolol and cox-2 preferential NSAID etodolac are used in combination to treat cachexia.
- the beta blocker antagonizes the beta receptors resulting in normalization of energy metabolism as well as lipid and protein metabolism.
- the NSAID provides additional anti-inflammatory capacity to work in synergy with the beta blocker reducing inflammation and has offsetting activity blood pressure to attenuate any drop in blood pressure that may result from the beta blocker therapy.
- the use of beta blocker alone is inadequate because it primarily affects the autonomic system.
- the NSAID alone has its primary impact on the inflammatory system and needs the beta blocker to attenuate the adrenergic dysfunction.
- the dose of the NSAID is fixed and the dose of the beta blocker is increased periodically at approximately intervals a) In one aspect, the atenolol and etodolac are provided in any of the formats described herein. b) In one aspect, the atenolol is provided at a starting dosage of 25mg once per day. The NSAID etodolac is provided at 500 mg once daily. The patient receives both medications at the same time. In one aspect, the dose of the atenolol is increased weekly to obtain a reduction in heart rate of 20% as long as the blood pressure does not go below 90/60. In one aspect, a second dose of etodolac is taken after 12 hour s .
- the invention provides a therapeutic combination, e.g., a pharmaceutical composition, comprising a drug comprising a betal blocker that is useful in the treatment of patients with pulmonary stress (e.g., asthma, COPD).
- pulmonary stress e.g., asthma, COPD
- a beta blocker in a patient with asthma or COPD or respiratory impairment is generally contraindicated.
- the betal selective blockers such as atenolol, acebuterol, bisoprolol or metoprolol may be used more safely in cachexia patients with pulmonary complications.
- the cardioselective beta blockers including atenolol, acebutolol, bisoprolol, or metoprolol, are used in this embodiment of a composition of the invention.
- the drugs are prescribed initially at 1 A the lowest recommended dose and the dose is gradually increased.
- the medication is provided in any of the formats described herein.
- a dose-pack is provided of atenolol at increasing dose levels sufficient to obtain an optimal dose. The pack contains a seven day supply of the medication at each set dose so the patient's therapeutic dose can be obtained.
- the pack contains 7 doses of 10 mg of atenolol, 7 doses of 20mg atenolol, 7 doses of 40 mg atenolol , 7 doses of 70 mg atenolol and 7 doses of 100 mg atenolol.
- the doses are selected to provide a lower minimal dose than is now available and provides additional incremental dosage increases than is available. After taking one dose for 5-7 days the patient is recommended to increase to the next dose upon monitoring by the physician. The dose can be increased if there is no adverse effect on the respiratory system and if the blood pressure is not below 90/60 and the heart rate is not 60 bpm or lower.
- the invention provides a long acting cardioselective beta blocker that needs to be taken once per day.
- the beta blocker bisoprolol has a half- life of
- the drug is provided at 2mg, 4 mg and 10 mg for the cachexia patient.
- the problem of cachexia patients taking medication is a serious hurdle in their treatment.
- Therapeutic combinations e.g., pharmaceutical compositions comprising various formulations, and accommodations for this problem, as provided by the instant invention, will help the patient take medication as needed and therefore increase the likelihood of a positive response.
- the beta blocker nadolol, a non-selective, kidney excreted product has a half-life of 10-24 hours and is taken once per day at 40 mg.
- the invention provides this product for cachexia as an easy to swallow pill or in a liquid formulation.
- the liquid formulation of nadolol is also provided with a high calorie nutritional drink with high amino acid content and additional tryptophan, leucine and glutamine but with low sugar and added vitamins.
- the liquid nadolol is combined with the nutrient drink which is immediately taken by the patient.
- a second dose is administered with a second nutritional drink to provide additional calories, nutrients and drug effect.
- the combination of pindolol and ibuprofen is used; this combination formulation of the invention has additional benefits for patients with low blood pressure. Since pindolol has intrinsic sympathomimetic activity it has less of an effect on blood pressure and resting heart rate. Pindolol does not suppress the heart rate increase during exercise which may allow for more comfortable physical activity. The use of ibuprofen has been shown to reduce inflammation and may be useful in maintaining blood pressure as described above. a) In one aspect, the beta blocker pindolol is provided at a starting dosage of 10 mg and ibuprofen at 400 mg twice daily. In one aspect, the patient receives both medications at the same time. In one aspect, the dose of the pindolol is increased weekly to obtain a reduction in heart rate of 20% as long as the blood pressure does not go below 90/60. b) The medication is provided in any of the formats described herein.
- the invention provides a therapeutic combination, e.g., a pharmaceutical composition, comprising a beta blocker with approximately equal activity against beta2 and betal and approximate 25% of the relative activity against beta3 in combination with a non-steroidal anti-inflammatory drug that is not metabolized by the liver.
- the beta blocker has a long half- life in the patient so dosing is required only once per day.
- the NSAID is selected that is not liver metabolized. Both the beta blocker and the NSAID are excreted through the kidneys and do not induce metabolizing enzymes.
- the beta blocker nadolol is provided at a starting dosage of 40mg.
- the NSAID naproxen is provided at 500 mg once daily.
- the patient receives both medications at the same time.
- the dose of the nadolol is increased weekly to obtain a reduction in heart rate of 20% as long as the blood pressure does not go below 90/60.
- a second dose of naproxen may be taken after 12 hours.
- the active ingredients are excreted through the kidney. This provides more reliable dosing between patients and prevents induction of metabolizing enzymes. The relative activity against the different receptor subtypes is balanced, thereby providing the most likely chance of obtaining a therapeutic effect.
- the presence of the naproxen serves to also maintain blood pressure and to reduce the inflammatory response caused by the disease.
- both these drugs are long acting so dosing can be reduced to a single dose of nadolol and naproxen per day. This reduced frequency of dosing may be particularly attractive to patients who are unable or unwilling to take medications on a frequent basis and will promote patient compliance.
- the medication is provided in any of the formats described herein.
- the invention provides a therapeutic combination, e.g., a pharmaceutical composition, comprising a combination product that is useful in patients with impaired pulmonary function for which beta-blockers would be ordinarily contraindicated. Since beta blockers that impact the beta 2 receptor subtype are particularly susceptible to pulmonary constriction a selective beta-blocker, with more activity against beta- 1 subtype, is selected.
- the invention provides a therapeutic combination comprising the betal blocker atenolol, which has low pulmonary activity and is more cardiac selective (more activity against beta-1 subtype receptors than beta-2 receptors), and the NSAID etodolac.
- Atenolol has approximately 16 fold higher relative activity against beta 1 receptor subtypes as compared to a nonselective beta blocker such as propranolol. This reduced activity against the pulmonary associated subtype is responsible for the reduced chance of negative effect in patients with pulmonary disease.
- the atenolol is provided at a starting dosage of 25mg once per day.
- the NSAID etodolac is provided at 500 mg once daily. The patient receives both medications at the same time.
- the dose of the atenolol is increased weekly to obtain a reduction in heart rate of 20% as long as the blood pressure does not go below 90/60.
- a second dose of etodolac may be taken after 12 hours.
- an extended release formulation of etodolac is taken once per day with the atenolol to make it easier for the patient. The adjustment of the dose needs to occur stepwise as described above.
- the invention provides a therapeutic combination, e.g., a pharmaceutical composition, that is a combination product comprising a cardioselective beta blocker with an NSAID to target the heart more directly.
- the beta blocker metoprolol (6:1 betal:beta2 selectivity) is used in combination with the NSAID ibuprofen.
- This combination provides a beta blocker that is cardioselective to reduce high blood pressure and reduce high heart rate.
- the presence of the additional beta blocker activity against beta2 and beta3 provides additional reduction in energy expenditure.
- the ibuprofen is used as an anti-inflammatory to reduce the counter-productive effects of the inflammatory response in these patients.
- the metoprolol is provided at an initial dose of 25 mg twice daily.
- the dose is increased weekly to obtain at least a 20% reduction in heart rate but the blood pressure is maintained above 90/60.
- the invention provides a therapeutic combination, e.g., a pharmaceutical composition, for hospitalized patients that is a combination product comprising a non- selective beta blocker in combination with the natural anti-inflammatory compound eicosapentaneoic acid (EPA, from fish oil).
- EPA natural anti-inflammatory compound
- This therapeutic combination of the invention provides a very strong anti-inflammatory delivered directly into the blood stream. This alleviates the usual problem with EPA in that it is metabolized by the liver and is rapidly metabolized, so the actual dose is relatively low.
- the relative activity of the beta blocker against the different receptor subtypes is balanced, thereby providing the most likely chance of obtaining a therapeutic effect.
- the presence of the EPA serves to reduce inflammation and is know to have the side-benefit of being beneficial to the treatment of cancer.
- the propranolol is administered intravenously (e.g., 2 micrograms/kg/min infusion following 80 microgram/kg infusion).
- the beta blocker propranolol is provided through a nasogastric tube at a starting dosage of 40 mg.
- the EPA is provided as a daily parenteral infusion for one week followed by oral EPA.
- the patient receives daily dosing of intravenous EPA (100mg/day).
- the dose of the propranolol is adjusted daily to obtain a reduction in heart rate of 20% as long as the blood pressure does not go below 90/60.
- the invention provides a therapeutic combination, e.g., a pharmaceutical composition, that is a combination product of a non-selective beta blocker with an NSAID at a dosing schedule that will provide a higher dose of beta blocker in the night and a lower dose during the day.
- a therapeutic combination e.g., a pharmaceutical composition
- the same level of beta blocker is provided at both times.
- the beta blocker metoprolol is provided in a dose-pack that is color coded (e.g., yellow) containing a low dose of the beta blocker in combination with the NSAID etodolac to indicate daytime administration and a high dose that is color coded (another color, e.g., navy blue) containing a higher dose of metoprolol with etodolac for bedtime administration.
- the dose pack is provided for a month supply with an increasing dose of metoprolol in the evening combination.
- exemplary dose pack is in the following table.
- the patient after completing the initial dose pack the patient continues ongoing treatment with the maximum tolerated dose.
- the invention provides a therapeutic combination comprising a beta blocker and an NSAID in a single pill wherein the two components are physically separated. Combining both products into one pill relieves the patient of needing to take multiple pills at multiple times during the day.
- the beta blocker can be any of those listed in Table, below, and the NSAID can be any of those from Table, below. a) In one aspect, combining the non-specific beta-blocker propranolol with the NSAID etodolac, both supplied as extended release formulations, provides a single pill that can be taken just once per 24 hour period thereby easing the burden on the patient.
- a series of pills are provided that will allow increased dosing of the beta blocker to achieve a 20% reduction in heart rate and blood pressure above 90/60 while keeping a constant amount of NSAID.
- the two components of the pill are provided in a dual chamber capsule that does not allow intermixing of the two active ingredients.
- the invention provides methods and compositions for making therapeutic combinations and methods for the taking of medicine in a more user friendly manner, e.g., the invention provides compositions in a form that is easier to take, such as in a liquid.
- the invention provides a product comprising a beta blocker and an NSAID in liquid form.
- the packaging is configured such that the beta blocker and NSAID are supplied in two compartments on a single unit. Removing the seal allows for easy dispensing of both drugs at the same time in a convenient format.
- the dose-packs are provided in multiple colors to indicate different doses of beta blocker (to allow increased dosing to achieve a 20% reduction in heart rate and maintain blood pressure over 90/60) with a constant amount of NSAID.
- combining both products in an easy to use and easy to recognize dose format provides a user-friendly way to provide proper doses while increasing patient compliance.
- the liquid format facilitates delivery to a patient who is experiencing difficulty in swallowing or in complying with taking more than one pill at more than one time per day.
- beta blockers are administered in this way are any of the beta blockers listed in the Tables shown herein, and in combination with any of NSAIDs, as described herein.
- the cachectic patient has special needs with regards to dosing considering their weakened state and low body weight.
- the standard commercial doses available for beta blockers are based on patients of normal size, metabolism and physiology.
- the cachectic patient is underweight, has altered metabolic rate and dysregulated physiology.
- the invention provides doses which are below the standard doses supplied.
- One exemplary dose is obtained by providing a dose that is 50% of the current minimum and providing increased doses that are each 20% less than the available dose.
- the following table provides an example of exemplary (e.g., recommended, depending on the condition and the individual) doses for select beta blockers useful in the treatment of cachexia.
- a similar dose range could be provided for any beta blocker, e.g., as listed in Tables described herein.
- the doses are provided in an economical form so the physician can adjust dose on a regular basis as needed without the patient being required to obtain and fill a new prescription for each dose.
- a dose pack is provided with 10 pills of each dose.
- the patient is prescribed the initial dose pack and starts at the first week dose. After approximately 7 days (5-9) the patient is checked by the doctor and the next dose is administered as warranted. When the proper dose is obtained the patient receives a monthly dose-pack with a constant level of the required dose sufficient to last one month.
- the invention provides for the administration of beta blockers in a dose that restores the 1// scaling in heart rate.
- the healthy human heart rate has been known to exhibit l//-type fluctuations to demonstrate multifractal scaling properties.
- the healthy 1// scaling in heart rate requires the balance between the antagonistic activity of the parasympathetic nervous system (PNS) and the sympathetic nervous system (SNS).
- PNS parasympathetic nervous system
- SNS sympathetic nervous system
- the invention provides for the administration of beta blockers at the appropriate dose to restore the 1// scaling in heart rate.
- the proper dose also maintains a heart rate that is 60 beats per minute (bpm) or above and blood pressure that is over 90/60.
- Example 5 Exemplary Therapeutic Combination Protocols of the Invention
- the dosing schedule is designed to provide a higher dose of beta blocker, e.g., propranolol, in the morning (the AM) when sympathetic activity is high, with a lower long lasting beta blocker dose in the evening to reduce the impact on CNS such as "vivid dreams"; and, in the evening, a relatively higher dose of an anti-anxiety and/or an anti-inflammatory medication, such as an NSAID.
- beta blocker e.g., propranolol
- etodolac or any other NSAID, e.g., aspirin, diclofenac; diflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen; ketorolac, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, a COX-2 inhibitor, such as a C0X-2- selective inhibitor (e.g., celecoxib rofecoxib, etoricoxib, valdecoxib, parecoxib, meloxicam or lumiracoxib) or a combination thereof, is given higher in the evening to provide pain relief and foster better sleep as well as the effect on systemic inflammatory response.
- NSAID e.g., aspirin, diclofenac; diflunisal,
- the invention provides a product of manufacture comprising, e.g., a blister package, clamshell, tray or shrink wrap comprising at least two dosages of beta adrenergic receptor antagonist (a beta blocker) drug and at least two dosages of nonsteroidal anti-inflammatory drug (a NSAID) and/or anti-anxiety drug, and the drugs are organized or labeled in the blister package, clamshell, tray or shrink wrap for usage by an individual for at least two administrations (e.g., clearly labeled for being taken by a patient at different times in the day), at least one of each (beta blocker and non-steroidal anti-inflammatory drug (a NSAID) and/or anti-anxiety drug) in the morning and at least one of each in the evening, wherein the dosage schedule provides a relatively higher dose of beta blocker in the morning (the AM) than in the evening, and a relatively higher dose of an anti-anxiety and/or an anti-inflammatory medication in the evening than in the morning.
- a beta blocker beta
- the packaging and/or labeling can have a higher dosage pill, tablet, geltab and the like, of beta blocker in the morning "section” of the blister package, clamshell, tray or shrink wrap, than the dosage of pill, tablet, geltab and the like, of beta blocker in the evening "section".
- two tablets can be provided in the morning "section” versus the evening "section”. The reverse would be the case for the non-steroidal anti-inflammatory drug (a NSAID) and/or anti-anxiety drug.
- a NSAID non-steroidal anti-inflammatory drug
- Beta-adrenergic antagonists can reduce the level of inflammatory cytokines, epinephrine, acute phase proteins response, as well as normalize EKG patterns and attenuate weight loss in severely ill subjects.
- beta-blockers and NSAIDs have offsetting hypotensive and hypertensive side effects. Using this convergence of activities, the invention provides use of beta-blockers and NSAIDs together to modulate the dysregulated psycho- neuroendocrine-immune systems and the associated clinical manifestations of cachexia. Prior clinical trials have shown that these drugs (alone) support positive outcomes in cachectic patients.
- This open pilot clinical trial is designed to evaluate the safety of a beta blocker (propranolol or metoprolol) in combination with a non-steroidal anti-inflammatory drug (etodolac) in cachectic metastatic cancer patients. In addition, to determine whether a twelve week treatment with this drug combination will decrease their weight loss, inflammatory markers and improve quality of life. Propranolol, metoprolol and etodolac have been selected for this clinical trial based on their well known safety records and previous positive clinical trials in cachexia related indications.
- the primary goal is to evaluate the safety of this drug combination, which has been utilized clinically, but not previously assessed in a clinical trial.
- individual subjects will be analyzed to determine the comparison differences in measurements of blood and urine analysis, C reactive protein (CRP), heart rate, blood pressure, weight, lean body mass, and quality of life before, during and at the conclusion of the combination drug treatment.
- CRP C reactive protein
- the invention provides compositions and methods for ameliorating and/or preventing cachexia, a complex syndrome that combines weight loss, loss of muscle and visceral protein, lipolysis, anorexia, chronic nausea, and weakness.
- the invention provides compositions and methods for ameliorating and/or preventing cachexia is associated with anemia, immunosuppression, insulin resistance, anxiety, and sleep disturbances.
- These syndromes treated by the compositions and methods of the invention can be broadly characterized as Chronic Systemic Inflammatory Response Syndrome or Chronic SIRS.
- the compositions and methods can also be used to treat and/or prevent severe cachexia occurring in most patients with advanced cancer, AIDS and other end-stage chronic diseases. At the moment of diagnosis, about 80% of patients with upper gastrointestinal cancers and 60% of patients with lung cancer have substantial weight loss.
- compositions and methods can also be used to treat and/or prevent cachexia in children and elderly patients, addressing a cachexia that becomes more pronounced as disease progresses.
- CRP cytokines
- Patient selection can be an important criteria for selection of patient for this protocol. All cachexia studies to date have used weight as the only criteria. By using heart rate (greater than 80 beats per minute (bpm) or 6 bpm increase over two months) with weight loss (5 lbs over 2 months) a population with cachexia as opposed to anorexia or just malnourished (due to treatment, depression or whatever) can be selected.
- heart rate greater than 80 beats per minute (bpm) or 6 bpm increase over two months
- weight loss 5 lbs over 2 months
- anorexia is distinguished from cachexia driven weight loss.
- anorexia is identified as an adaptive nutritional state secondary to lack of nutrition. Anorexia is responsive to increased nutrition.
- cachexia is identified as a maladaptive nutritional state secondary to a maladaptive severe chronic systemic inflammatory response and autonomic dysregulation. Cachexia is non-responsive to increased nutrition.
- the natural history of a healthy inflammatory response is characterized by a sequence of feedback responses beginning with tissue breakdown leading to a stress response of inflammation and immune activation and finally restoration of tissue integrity. If the sequence of events is within normal adaptive range, both in terms of the extent of trauma and duration of the response, then tissue integrity is restored.
- tissue integrity is restored.
- some trauma e.g., cancer, congestive heart failure (CHF), AIDS, burn, etc
- CHF congestive heart failure
- AIDS AIDS
- burn etc
- a positive feedback cycle of escalating stress response and maladaptive immune system feedback leads to a severe dysregulated psycho- neuroendocrine-immune state.
- this invention utilizes compounds that regulate the autonomic nervous system, in particular the adrenergic system, with the beta blocker in combination with the non-steroidal anti- inflammatory drug (NSAID), for treatment of chronic SIRS, and specifically cancer cachexia.
- ANS maladaptive autonomic nervous system
- NSAID non-steroidal anti- inflammatory drug
- the cachexia syndrome appears to be associated with malign patterns of eicosanoid production and the presence of a chaotic population of cytokines with consequent aberrations in neuro-endocrine-immune control systems, hypothalamic control of appetite, and intermediary metabolism. Metabolic changes may be associated with changes in autonomic control and an increase in body energy consumption, with further mismatches of food intake with need.
- the systemic aberrations are similar to the acute stress reaction commonly observed in patients with life-threatening infections or major trauma. When this potentially life-saving "switch" is left on, over time the chronic stress inflammatory reaction may enhance tumor growth while inducing a devastating effect on a variety of organs and tissues.
- the wasting in cancer patients is slowed or reversed - the process where muscle synthesis and repair decline is slowed or reversed, and the increased muscle proteolysis (possibly due to tumor-produced proteolysis factors) is slowed or reversed.
- the wasting syndrome is commonly noted at the time of diagnosis in many forms of cancer, notably those of the upper gastrointestinal tract and lung, progresses through the course of illness, finally leaving the patient in a severe state of malnutrition.
- a recent review details current concepts of this pathophysiology and the relevance of these concepts to anorexia-cachexia research (e.g., see MacDonald (2003) J. Am. Coll. Surg. 197:143-61.
- C reactive protein [CRP] C reactive protein [CRP]
- cytokines notably IL-6, TNF ⁇ and (IFN)- ⁇
- CRP C reactive protein
- the autonomic nervous system helps to control arterial pressure, gastrointestinal motility, urinary bladder emptying, sweating, body temperature, and many other activities.
- the autonomic nervous system is primarily activated by centers in the spinal cord, brain stem, and hypothalamus.
- the efferent autonomic signals are transmitted to the various organs of the body through either the sympathetic nervous system or the parasympathetic nervous system.
- the neurotransmitter of all preganglionic autonomic fibers, all postganglionic parasympathetic fibers, and a few post-ganglionic sympathetic fibers is acetylcholine. These are referred to as cholinergic fibers.
- the adrenergic fibers compose the majority of the postganglionic sympathetic fibers and use the norepinephrine (noradrenaline) as the neurotransmitter.
- norepinephrine norepinephrine
- elevated resting energy expenditure is not likely due to tumor metabolism, but more likely it is due to an interaction between the cancer and the neuroendocrine-immune system.
- the elevated resting energy metabolism is primarily due to the increased adrenergic activity in cancer patients.
- the normal adaptive nutritional states control of the use of energy stores is by a number of factors including insulin/glucagon, catecholamines, ghrelin and related orexigenic and anorectic peptide signals from the neuroendocrine- immune system.
- the result of this regulation is the use of carbohydrates first, followed by mobilization and oxidation of fatty acids and finally degradation of protein and release of gluconeogenic amino acids.
- cachexia stressed state
- this system there is a dysregulation of this system such that protein is not spared at the expense of carbohydrates or fat and there is no reduction in metabolic rate.
- the natural history of healthy inflammation is characterized by a sequence of flux imbalances and positive feedback responses.
- the compositions and methods of the invention address - treat, ameliorate and/or prevent - a breakdown in tissue integrity due to trauma, infection, cancer, etc.; stress, with associated imbalanced metabolic and signaling fluxes; a stress response characterized by a cycle of immune activation, inflammation and healing, and practicing the invention results in the ultimate restoration of tissue integrity, balanced fluxes (homeostasis), and immune inactivation.
- the trauma is within the adaptive range and the immune system correctly partitions, escalates and de-escalates its immune response, the process is adaptive and restores tissue integrity.
- compositions and methods of the invention treat, ameliorate and/or prevent a maladaptive immune response in cancer. If not treated, the cancer progresses, leading to a positive feedback cycle of escalating cancer induced flux imbalances and escalating maladaptive immune system feedback responses.
- the escalating flux imbalances and maladaptive feedback responses leads to a severe dysregulated neuroendocrine-immune state.
- the specific pattern of neuroendocrine-immune imbalances appears to partition into three broad classes of maladaptive infection response (dominated by gamma interferon), maladaptive trauma response (dominated by IL-6) or maladaptive wound healing response (dominated by TNF or IL-I).
- the overall state is characterized by a chronic SIRS.
- a weight- stable adult takes in energy that matches the amount used by the body. If energy supply is too low (fasting state) the body compensates by releasing orexigenic hormones to stimulate feeding and reducing total energy expenditure through the sympathetic nervous system, or more generally the neuroendocrine-immune system. If energy supply is in excess (overfed state) the body stores the excess primarily as fat. In normal adaptive nutritional states control of the use of energy stores (protein, fat and carbohydrates) is by a number of factors including insulin/glucagon, catecholamines, ghrelin and related orexigenic and anorectic peptide signals from the neuroendocrine-immune system.
- NCTG North Central Cancer Treatment Group
- beta blocker propranolol or metoprolol
- NSAID etodolac
- Trial sample A total of 80 subjects will participate in this trial. Recruitment period for the trial is 12 months. The overall duration should not exceed 18 months. Forty (40) subjects will be treated and 40 will be followed for case controls.
- Propranolol Inderal, Inderal LA
- etodolac Lidine
- metoprolol Lipressor, Toprol XL
- Propranolol is a synthetic beta-adrenergic receptor blocking agent chemically described as 2-Propanol, l-[(l-methylethyl)amino]-3-(l-naphthalenyloxy)-, hydrochloride, (+)-.
- Propranolol is a stable, white, crystalline solid which is readily soluble in water and ethanol.
- the immediate release product is available as 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg tablets for oral administration.
- the inactive ingredients contained in each tablet are: lactose, magnesium stearate, microcrystalline cellulose, and stearic acid.
- 10 mg and 80 mg tablets contain FD&C Yellow No. 6 and D&C Yellow No. 10; 20 mg tablets contain FD&C Blue No.l; 40 mg tablets contain FD&C Blue No. 1, FD&C Yellow No. 6, and D&C Yellow No. 10; 60 mg tablets contain D&C Red No. 30.
- the LA product is available on 60 mg, 80 mg, 120 mg and 160 mg capsules.
- Inactive ingredients include: cellulose, ethylcellulose, gelatin capsules, hypromellose, and titanium dioxide.
- Inderal LA 60 mg, 80 mg, and 120 mg capsules contain D&C Red No. 28 and FD&C Blue No. 1;
- Inderal LA 160 mg capsules contain FD&C Blue No. 1.
- Subjects will be prescribed propranolol from 80 mg/per day to a maximum of 160 mg/per day in divided daily dosages.
- Metoprolol The immediate release tablet, metoprolol tartrate, is a selective betal- adrenergic receptor blocking agent, chemically described as (+)-l-(isopropylamino)-3-(p- (2-(methoxyethyl) phenoxy)-2-propanol (2:1) dextrotartrate salt.
- Metoprolol tartrate is a white, practically odorless, crystalline powder which is very soluble in water; freely soluble in methylene chloride, in chloroform, and in alcohol; slightly soluble in acetone; and insoluble in ether. It is available as 25 mg, 50 mg, and 100 mg tablets for oral administration.
- the inactive ingredients in the tablets include cellulose compounds, colloidal silicon dioxide, D&C red no. 30 aluminum lake (50-mg tablets), FD&C blue no. 2 aluminum lake (100-mg tablets), lactose, magnesium stearate, polyethylene glycol, propylene glycol, povidone, sodium starch glycolate, talc, and titanium dioxide.
- the extended release tablet metoprolol succinate is a beta 1- selective
- TOPROL-XL (cardioselective) adrenoceptor blocking agent, for oral administration, available as extended release tablets.
- TOPROL-XL has been formulated to provide a controlled and predictable release of metoprolol for once-daily administration.
- the tablets comprise a multiple unit system containing metoprolol succinate in a multitude of controlled release pellets. Each pellet acts as a separate drug delivery unit and is designed to deliver metoprolol continuously over the dosage interval.
- the tablets contain 23.75, 47.5, 95 and 190 mg of metoprolol succinate equivalent to 25, 50, 100 and 200 mg of metoprolol tartrate, USP, respectively.
- Metoprolol succinate is a white crystalline powder. It is freely soluble in water; soluble in methanol; sparingly soluble in ethanol; slightly soluble in dichloromethane and 2-propanol; practically insoluble in ethyl-acetate, acetone, diethylether and heptane. Inactive ingredients: silicon dioxide, cellulose compounds, sodium stearyl fumarate, polyethylene glycol, titanium dioxide, paraffin. Subjects will be prescribed metoprolol from 50 mg/per day to a maximum of 150 mg/per day in divided daily dosages.
- Etodolac is a pyranocarboxylic acid chemically designated as (+) 1, 8- diethyl-l,3,4,9-tetrahydropyrano-[3,4-b]indole-l-acetic acid. It is a white crystalline compound, insoluble in water but soluble in alcohols, chloroform, dimethyl sulfoxide, and aqueous polyethylene glycol. It will be provided as 200 mg capsule and 500 mg tablet. The inactive ingredients contained in each tablet are: cellulase, hydroxypropyl, methylcellulose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, sodium starch glycolate, and titanium dioxide. Subjects will be prescribed 400 to 700 mg/per day of Etodolac in divided daily dosages. Exemplary Dosage Administrations of the invention (see also table below)
- doses of propranolol are given in 20 or 40 mg tablets immediate release on a bid basis.
- the first dose week the doses for propranolol will be started 20 mg in the morning and 20 mg at bedtime. After 1 week the dosage should be adjusted to 20 mg of the immediate release product in the morning and 60 mg of the extended release at bedtime. If after an additional week the subject shows no improvement or has not obtained a 20% reduction in heart rate, without decreasing heart rate below 60 bpm or blood pressure below 90/60, the dose may be adjusted to 40 mg of the immediate release product in the morning and 120 mg of the extended release product at bedtime.
- doses of metoprolol are given in 25 or 50 mg tablets on a bid basis. Doses for metoprolol will be started at 25 mg of the immediate release product in the morning and at bedtime. After 1 week the dosage should be adjusted to 25 mg of the immediate release product in the morning and 50 mg of the extended release product at bedtime. If after an additional week the subject shows no improvement or has not obtained a 20% reduction in heart rate, without decreasing heart rate below 60 bpm or blood pressure below 90/60, the dose may be adjusted to 50 mg of the immediate release product in the morning and 100 mg of the extended release product at bedtime.
- doses of etodolac are given in 200 mg capsules or 500 mg tablets on a bid basis. Doses for etodolac will be started at 200 mg in the morning and at bedtime. After 1 week the dosage should be adjusted to 200 mg in the morning and 500 mg at bedtime. No additional change in the dosage of etodolac is made.
- Treatment will be given for a maximum of 12 weeks.
- This study is an open pilot clinical trial to evaluate the safety of propranolol in combination with etodolac in subjects diagnosed with metastatic cancer and secondary outcomes of weight, inflammatory markers and quality of life. Another goal of the study is to determine the effects of a 6-week treatment of combination therapy with a beta- blocker and an NSAID on weight due to lack of appetite, inflammatory markers and quality of life.
- Propranolol is a synthetic beta-adrenergic receptor blocking agent chemically described as 2-Propanol, l-[(l-methylethyl)amino]-3-(l- naphthalenyloxy)-, hydrochloride, (+)-. It is a stable, white, crystalline solid which is readily soluble in water and ethanol. It is available as 20 mg, 40 mg, 60 mg, and 80 mg tablets for oral administration. The inactive ingredients contained in each tablet are: lactose, magnesium stearate, microcrystalline cellulose, and stearic acid. In addition, 10 mg and 80 mg tablets contain FD&C Yellow No. 6 and D&C Yellow No. 10; 20 mg tablets contain FD&C Blue No.l ; 40 mg tablets contain FD&C Blue No. 1, FD&C Yellow No. 6, and D&C Yellow No. 10; 60 mg tablets contain D&C Red No. 30.
- Subjects will be prescribed Propranolol from 80 mg/per day to a maximum of 160 mg/per day in divided daily dosages.
- Etodolac is a pyranocarboxylic acid chemically designated as (+) 1, 8-diethyl-l,3,4,9-tetrahydropyrano-[3,4-b]indole-l-acetic acid. It is a white crystalline compound, insoluble in water but soluble in alcohols, chloroform, dimethyl sulfoxide, and aqueous polyethylene glycol. It will be provided as 200 mg tablets. The inactive ingredients contained in each tablet are: cellulase, hydroxypropyl, methylcellulose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, sodium starch glycolate, and titanium dioxide. Subjects will be prescribed 800 mg/per day of etodolac in divided daily dosages.
- doses are given in 20, 40 or 80 mg tablets on a tid basis (an exemplary protocol of the invention).
- doses for propranolol will be started at 40 mg at 8 am, 20 mg at 2 pm, and 20 mg at bedtime (an exemplary protocol of the invention).
- doses should be adjusted to 80 mg at 8 am, 40 mg at 2 pm, and 40 mg at bedtime.
- doses of etodolac are given at 200 mg at 8 am, 200 mg at 2 pm, and 400 mg at bedtime. These dosage regimens are governed by the investigators observations noted in the metabolic changes occurring in the cardiovascular and neuroendocrine systems.
- This study is an open pilot clinical trial to evaluate the effect of propranolol in combination with etodolac to evaluate the influence of these compounds on weight and quality of life in subjects diagnosed with metastatic cancer. Another goal of this study is to determine the effect of 6- week treatment of combination therapy of a beta-blocker with an NSAID on resting energy expenditure (REE), weight, inflammatory markers and quality of life.
- REE resting energy expenditure
- Trial sample A total of 20 subjects will participate in this trial. Recruitment period for the trial is 6 months. The overall duration should not exceed 10 months. Inclusion Criteria
- Unstable angina • Present history of pulmonary edema, Chronic Obstructive Pulmonary Disease (COPD), asthma or bronchospastic diseases
- Propranolol in combination with Etodolac, an exemplary therapeutic combination of the invention.
- propranolol is prescribed starting with doses of 40 mg per day up to 160 mg per day.
- doses are given in 20, 40 or 80 mg tablets on a bid basis.
- doses for propranolol are adjusted up to three times to a maximum of 160 mg per day in order to obtain a 20% reduction in heart rate without decreasing heart rate below 60 bpm or blood pressure below 90/60.
- Doses of Etodolac will be fixed at 400 mg bid.
- Bosaeus I., P. Daneryd, et al. (2001). "Dietary intake and resting energy expenditure in relation to weight loss in unselected cancer patients.” Int J Cancer 93(3): 380-3.
Abstract
Description
Claims
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Cited By (4)
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WO2009111648A1 (en) * | 2008-03-05 | 2009-09-11 | Vicus Therapeutics, Llc | Compositions and methods for mucositis and oncology therapies |
US9839644B2 (en) | 2014-09-09 | 2017-12-12 | ARKAY Therapeutics, LLC | Formulations and methods for treatment of metabolic syndrome |
US9889120B2 (en) | 2016-01-14 | 2018-02-13 | Vicus Therapeutics, Llc | Combination drug therapies for cancer and methods of making and using them |
EP3164121A4 (en) * | 2014-07-01 | 2018-06-13 | Vicus Therapeutics, LLC | Combination drug therapies for cancer and methods of making and using them |
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US5668117A (en) * | 1991-02-22 | 1997-09-16 | Shapiro; Howard K. | Methods of treating neurological diseases and etiologically related symptomology using carbonyl trapping agents in combination with previously known medicaments |
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2007
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US5668117A (en) * | 1991-02-22 | 1997-09-16 | Shapiro; Howard K. | Methods of treating neurological diseases and etiologically related symptomology using carbonyl trapping agents in combination with previously known medicaments |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2009111648A1 (en) * | 2008-03-05 | 2009-09-11 | Vicus Therapeutics, Llc | Compositions and methods for mucositis and oncology therapies |
JP2014101377A (en) * | 2008-03-05 | 2014-06-05 | Vicus Therapeutics Llc | Composition and method for treatment of cancers and mucositis |
AU2009221765B2 (en) * | 2008-03-05 | 2015-05-07 | Vicus Therapeutics, Llc | Compositions and methods for mucositis and oncology therapies |
JP2015193667A (en) * | 2008-03-05 | 2015-11-05 | ビカス セラピューティクス,エルエルシー | Composition and method for treatment of cancers and mucositis |
JP2016196509A (en) * | 2008-03-05 | 2016-11-24 | ビカス セラピューティクス,エルエルシー | Composition and method for treatment of cancers and mucositis |
EP3028743A3 (en) * | 2008-03-05 | 2017-01-25 | Vicus Therapeutics, LLC | Compositions for mucositis and oncology therapies |
AU2015207837B2 (en) * | 2008-03-05 | 2017-05-11 | Vicus Therapeutics, Llc | Compositions and methods for mucositis and oncology therapies |
AU2015207835B2 (en) * | 2008-03-05 | 2017-05-11 | Vicus Therapeutics, Llc | Compositions and methods for mucositis and oncology therapies |
EP3164121A4 (en) * | 2014-07-01 | 2018-06-13 | Vicus Therapeutics, LLC | Combination drug therapies for cancer and methods of making and using them |
US9839644B2 (en) | 2014-09-09 | 2017-12-12 | ARKAY Therapeutics, LLC | Formulations and methods for treatment of metabolic syndrome |
US9889120B2 (en) | 2016-01-14 | 2018-02-13 | Vicus Therapeutics, Llc | Combination drug therapies for cancer and methods of making and using them |
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