WO2007047351A2 - Methods for treating hypertension in overweight and obese individuals - Google Patents

Abstract

Disclosed are novel compositions for treating hypertension and conditions associated with hypertension comprising a first ingredient and a second ingredient, wherein the first ingredient comprises at least one anti-hypertensive agent and the second ingredient comprises at least one anti-obesity agent. Also disclosed are methods of treating hypertension and conditions associated with hypertension comprising administering a first ingredient and a second ingredient, wherein the first ingredient comprises at least one anti-hypertensive agent and the second ingredient comprises at least one anti-obesity agent. In various embodiments, the combinations act synergistically to alleviate symptoms and/or risk factors associated with hypertension. In preferred embodiments, the anti-obesity agent does not substantially affect blood pressure, and thereby decreases the risk and/or unpredictability associated with concurrent administration of the anti-hypertensive agent.

Description

METHODS FOR TREATING HYPERTENSION IN OVERWEIGHT AND OBESE

INDIVIDUALS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 60/726,425, filed October 13, 2005, which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION Field of the Invention

[0002] The present invention relates to improved methods and pharmaceutical compositions for the treatment of hypertension and the reduction of cardiovascular risk factors in overweight and obese patients

Description of the Related Art

[0003] Obese individuals (BMI > 30) are twice as likely to suffer from hypertension compared to normal weight individuals (BMI < 25) (Stamler et al., JAMA, 1978). Sodium retention, and increases in vascular resistance, blood volume, and cardiac output are thought to be underlying causes for development of hypertension in obese individuals. Obesity and hypertension, when co-existent, greatly increase the risk for development of cardiovascular disease, possibly due to alterations in the renin-angiotensin system and insulin resistance.

[0004] Weight loss leads to reductions in vascular resistance and cardiac output, suppression of the renin-angiotensin-aldosterone system, and improved insulin resistance (Resin et al., Ann Intern Med, 1983; Tuck et al., N Eng J Med, 1981). Whereas even a modest degree of weight loss results in lowered blood pressure in obese individuals (NIH Publication 98-4083, 1998), management of hypertension in obese individuals is often extremely difficult in clinical practice. In most cases, currently available anti-hypertensive drugs poorly control hypertension without weight reduction. Moreover, many anti-obesity drugs (e.g., sibutramine, phentermine) do not lower blood pressure, even when weight loss is achieved. Indeed, the prescribing information for sibutramine and phentermine both contain warnings against use of these products with even mild hypertension since these products can unpredictably result in an increase in blood pressure.

[0005] In addition to those individuals who satisfy a strict definition of medical obesity, a significant portion of the adult population is overweight. These obese and overweight individuals would benefit from the availability of an effective treatment that ', targets weight loss without causing a substantial or unpredictable blood pressure increase. A practitioner treating hypertension in an obese patient would have difficulty ascertaining the anti-hypertensive effect of an anti-hypertension treatment if the co-administered anti-obesity medication itself causes an unpredictable blood pressure increase.

[0006] Thus, there is a need for pharmaceutical compositions and methods of treatment that allow simultaneous treatment of hypertension and weight loss without complication or interference from the anti-obesity agent.

SUMMARY OF THE INVENTION

[0007] Disclosed are compositions for the treatment of hypertension in obese or overweight patients comprising a first ingredient and a second ingredient, wherein the first ingredient comprises at least one anti-hypertensive agent and the second ingredient comprises at least one anti-obesity agent. Also disclosed are methods of treating hypertension comprising administering a first ingredient and a second ingredient, wherein the first ingredient comprises at least one anti-hypertensive agent and the second ingredient comprises at least one anti-obesity agent.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT [0008] When used herein, the following terms and their grammatical equivalents have the definitions given below, in addition to their ordinary and customary meanings.

[0009] The term "treating" or its grammatical equivalents does not necessarily mean total cure. Any alleviation of any undesired signs or symptoms of the disease to any extent or the slowing down of the progress of the disease can be considered treatment. Furthermore, treatment may include acts that may worsen the patient's overall feeling of well being or appearance. Treatment may also include lengthening the life of the patient, even if the symptoms are not alleviated, the disease conditions are not ameliorated, or the patient's overall feeling of well being is not improved.

[0010] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting a compound of the invention with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Pharmaceutical salts can also be obtained by reacting a compound of the invention with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl) methylamine, and salts thereof with amino acids such as arginine, lysine, and the like.

[0011] The term "ester" refers to a chemical moiety with formula -(R)_n-COOR', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.

[0012] An "amide" is a chemical moiety with the formula -(R)_n-C(O)NHR' or -(R)_n-NHC(O)R', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1. An amide may be an amino acid or a peptide molecule attached to a molecule of the present invention, thereby forming a prodrug.

[0013] Any amine, hydroxy, or carboxyl side chain on the metabolites, esters, or amides of the compounds described herein can be esterified or amidified. The procedures and specific groups to be used to achieve this end are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley & Sons, New York, NY, 1999, which is herein incorporated by reference in its entirety.

[0014] The term "metabolite" refers to a compound to which an active compound is converted within the cells of a mammal. The pharmaceutical compositions described herein may include one or more metabolites of the compounds described herein. The scope of the methods described herein includes those instances where a compound is administered to the patient, yet the metabolite of the compound is the bioactive entity.

[0015] A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug, or may demonstrate increased palatability or be easier to formulate. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to provide the active moiety.

[0016] Throughout the present disclosure, when a particular compound is mentioned by name, for example, bupropion, it is understood that the scope of the present disclosure encompasses pharmaceutically acceptable salts, esters, amides, metabolites, or prodrugs of the named compound. Also, if the named compound comprises a chiral center, the scope of the present disclosure also includes compositions comprising the racemic mixture of the two enantiomers, as well as compositions comprising each enantiomer individually, substantially free of the other enantiomer. Thus, for example, contemplated herein is a composition comprising the S enantiomer substantially free of the R enantiomer, or a composition comprising the R enantiomer substantially free of the S enantiomer. By "substantially free" it is meant that the composition comprises less than 10%, or less than 8%, or less than 5%, or less than 3%, or less than 1% of the minor enantiomer. If the named compound comprises more than one chiral center, the scope of the present disclosure also includes compositions comprising a mixture of the various diastereomers, as well as compositions comprising each diastereomer substantially free of the other diastereomers. Thus, for example, commercially available bupropion is a racemic mixture comprising two separate enantiomers. The recitation of "bupropion" throughout this disclosure includes compositions that comprise the racemic mixture of bupropion, compositions that comprise the (+) enantiomer substantially free of the (-) enantiomer, and compositions that comprise the (-) enantiomer substantially free of the (+) enantiomer.

[0017] The term "pharmaceutical composition" refers to a mixture of a compound with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

[0018] The term "carrier" defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example dimethyl sulfoxide (DMSO) is a commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or tissues of an organism.

[0019] The term "diluent" defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.

[0020] The term "physiologically acceptable" defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.

[0021] In one aspect, a composition is provided for the treatment of hypertension comprising a first ingredient and a second ingredient, wherein the first ingredient comprises at least one anti-hypertensive agent and the second ingredient comprises at least one anti- obesity agent. In various embodiments, the combination of the first ingredient and the second ingredient has an enhanced efficacy in the treatment of hypertension and/or one or more symptoms and/or risk factors associated with hypertension. In some embodiments, the first ingredient exerts a synergistic effect with the second ingredient with regard to the treatment of hypertension and/or one or more symptoms and/or risk factors associated with hypertension.

[0022] In some aspects, compositions provided herein reduce cardiovascular risk factors and/or overall mortality risk. In additional aspects, compositions of the invention are effective in treating cardiovascular diseases, including but not limited to, congestive heart failure, asymptomatic left ventricular dysfunction, and coronary artery disease.

[0023] In an additional aspect, a method is provided for treating hypertension comprising administering a first ingredient and a second ingredient, wherein the first ingredient comprises at least one anti-hypertensive agent and the second ingredient comprises at least one anti-obesity agent, hi various embodiments, the first ingredient and second ingredient are administered more or less simultaneously, hi other embodiments the first ingredient is administered prior to the second ingredient, hi yet other embodiments, the first ingredient is administered subsequent to the second ingredient.

[0024] hi another aspect, a method is provided for treating or preventing cardiovascular diseases or conditions, including but not limited to, congestive heart failure, myocardial infarction, asymptomatic left ventricular dysfunction, or coronary artery disease, wherein the method comprises administering a first ingredient and a second ingredient, where the first ingredient comprises at least one anti-hypertensive agent and the second ingredient comprises at least one anti-obesity agent. Further aspects relate to methods of treating other conditions associated with hypertension, including but not limited to, diabetes, nephrotic disease, liver disease, and vision disorders, such as retinal macroaneurysm and hollenhorst plaque, wherein the method comprises administering a first ingredient and a second ingredient, and the first ingredient comprises at least one anti-hypertensive agent and the second ingredient comprises at least one anti-obesity agent.

[0025] hi some embodiments, the methods provided herein comprise administering a composition as described above, hi other embodiments, the methods comprise administering at least one anti-hypertensive agent and at least one anti-obesity agent separately or in various combinations.

[0026] hi certain embodiments, the individual has a body mass index (BMI) greater than 25. In other embodiments, the individual has a BMI greater than 30. hi still other embodiments, the individual has a BMI greater than 40. However, in some embodiments, the individual may have a BMI less than 25 (e.g., BMI >23 defines "overweight" in some Asian countries).

First ingredient

[0027] In various embodiments, the anti-hypertensive agent comprises a diuretic, a beta-blocker, an adrenergic antagonist, a rauwolfia alkaloid, a central-acting alpha- adrenergic receptor agonist, a calcium-channel blocker, a vasodilator, a diuretic, an ACE (angiotensin converting enzyme) inhibitor, an angiotensin II receptor antagonist (ARB), and/or another anti-hypertensive compound or combination of anti-hypertensive compounds.

[0028] In some embodiments, the anti-hypertensive agent comprises a beta- blocker (beta-adrenergic receptor antagonist). Beta-blockers are known to have antihypertensive effects. Various clinical studies have shown that administration of beta- blockers to patients with hypertension results in a decrease in blood pressure and a reduction in cardiac output. Without being bound by any particular theory, it is believed that the antihypertensive effect of beta-blockers is related to several mechanisms, including a central nervous system sympatholytic action and a marked reduction in plasma renin activity. A reduction in plasma renin activity has an inhibitory action on the renin-angiotensin system, thus decreasing after-load and allowing for more efficient forward function of the heart. The use of beta-blockers increases survival rates among patients suffering from CHF and/or hypertension, and beta-blockers are now part of the standard of care for these conditions.

[0029] A number of beta-blockers are commercially available. These compounds include, but are not limited to, acebutolol, alprenolol, atenolol, betaxolol, bisoprolol, bupranolol, carteolol, celiprolol, epanolol, esmolol, landiolil, levabetaxolol, levobunolol, metipranolol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, pindolol, practolol, propranolol, sotalol, and timolol. Beta-blockers are typically beta_! and/or beta₂ adrenergic receptor blocking agents, which decrease the positive chronotropic, positive inotropic, bronchodilator, and/or vasodilator responses caused by beta-adrenergic receptor agonists. In some embodiments, the beta-blocker is selected from the group consisting of atenolol, metoprolol, propranolol, timolol, nadolol, and bisoprolol. In some embodiments, the antihypertensive agent comprises a combination of a beta-blocker and a diuretic, for example timolol in combination with hydrochlorothiazide, bisoprolol in combination with hydrochlorothiazide, nadolol in combination with bendroflumethiazide, or atenolol in combination with chlorthalidone.

[0030] In some embodiments, the anti-hypertensive agent comprises an alpha- blocker (alpha-adrenergic receptor antagonist). Alpha-blockers include, but are not limited to, doxazosin, fuzosin, dapiprazole, indoramin, isometheptene, metazosin, moxisylyte, phenoxybenzamine, phentolamine, piperoxan, pilmenidine, prazosin, tamsulosin, terazosin, and urapidil. Without being bound by any particular theory, it is believed that the antihypertensive effect of alpha-blockers is related to their inhibitory effect on alpharreceptors of vascular smooth muscle, which prevents the uptake of catecholamines by smooth muscle cells. In some embodiments, the alpha-blocker is selected from the group consisting of doxazosin, terazosin, and prazosin. In certain embodiments, the alpha-blocker is in combination with a diuretic, for example prazosin plus polythiazide.

[0031] In some embodiments, the anti-hypertensive agent comprises an alpha- and beta-blocker, such as carvedilol or labetolol. Without being bound by any particular theory, it is believed that the anti-hypertensive effect of alpha- and beta-blockers is related to the mechanisms of alpha-blockers and/or beta-blockers, as described above.

[0032] In some embodiments, the anti-hypertensive agent comprises a central acting alpha-adrenergic agonist, such as methyldopa, clonidine, guanfacine, or guanabenz. Without being bound by any particular theory, it is believed that the anti-hypertensive effect of central acting alpha-adrenergic agonists is related to their ability to stimulate central alpha- 2 adrenergic receptors, thereby reducing sympathetic nerve impulses to the heart and/or blood vessels, resulting in a decrease in peripheral vascular resistance and/or heart rate. In some embodiments, the antihypertensive agent comprises a combination of an alpha-adrenergic agonist and a diuretic, for example methyldopa in combination with chlorothiazide, or clonidine in combination with chlorthalidone.

[0033] In some embodiments, the anti-hypertensive agent comprises a calcium- channel blocker (CCB), such as amlodipine, barnidipine, bepridil, diltiazem, efonidipine, etafenone, felodipine, flunarizine, gallopamil, isradipine, lacidipine, lercanidipine, mibefradil, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil. Without being bound by any particular theory, it is believed that the anti-hypertensive effect of calcium-channel blockers is related to their ability to inhibit excitatory Ca²⁺ currents in vascular smooth muscle and/or cardiac muscle, resulting in a decrease in peripheral vascular resistance and/or cardiac output. In certain embodiments, the calcium-channel blocker is selected from the group consisting of amlodipine, diltiazem, felodipine, isradipine, nifedipine, and verapamil. In some embodiments, the calcium-channel blocker is in combination with another antihypertensive compound, for example amlodipine in combination with benazepril, or felodipine in combination with enalapril.

[0034] In some embodiments, the anti-hypertensive agent comprises a vasodilator, such as hydralazine, minoxidil, nitroprusside, and diazoxide. Without being bound by any particular theory, it is believed that the anti-hypertensive effect of vasodilators is related to their ability to relax vascular smooth muscle, resulting in a decrease in peripheral vascular resistance. In some embociments, the vasodilator is diazoxide.

[0035] In some embodiments, the anti-hypertensive agent comprises a diuretic. Without being bound by any particular theory, it is believed that the anti-hypertensive effect of various diuretics is related to their effect on the absorption and/or excretion of electrolytes and/or water by the kidneys, causing a reduction of plasma volume. Useful diuretics include adenosine A₁ receptor antagonists (AAiRAs), as well as related compounds described, for example, in U.S. Patent Nos. 5,290,782, 5,395,836, 5,446,046, 5,631,260, 5,736,528, 6,210,687, and 6,254,889, the entire disclosures of all of which are hereby incorporated by reference herein, including any drawings. In some embodiments, the AAiRA is selected from the group consisting of CVT-124, KW-3902, and FK-838.

[0036] Diuretics typically act on a specific segment of nephrons, e.g., proximal tubule, loop of Henle, or distal tubule. In some embodiments, the diuretic is a proximal diuretic, i.e., a diuretic that principally acts on the proximal tubule. Examples of proximal diuretics include, but are not limited to, acetazolamide, methazolamide, and dichlorphenamide. Carbonic anhydrase inhibitors are known to be diuretics that act on the proximal tubule, and are therefore, proximal diuretics. In some embodiments, the diuretic is a loop diuretic, i.e., a diuretic that principally acts on the loop of Henle. Examples of loop diuretics include, but are not limited to, ethacrynic acid, piretanide, ticrynafen, furosemide (LASIX^®), bumetanide (BUMEX^®), and torsemide (DEMADEX^® or TOREM). In some embodiments, the diuretic is a distal diuretic, i.e., a diuretic that principally acts on the distal nephron. Examples of distal diuretics include, but are not limited to, metolazone and thiazides, such as methylclothiazide, hydroflumethiazide, hydrochlorothiazide, chlorthalidone, trichlormethiazide, bendroflumethiazide, and polythiazide. Collecting duct diuretics are used with the purpose of avoiding the hypokalemia that is associated with promixal and loop diuretics. These include spiranolactone, triamterene and amiloride. In some embodiments, the antihypertensive agent comprises the combination of diuretics acting at different sites, for example triamterene in combination with hydrochlorothiazide, amiloride in combination with hydrochlorothiazide.

[0037] Useful diuretics include adenosine A₁ receptor antagonists (AA₁RAs), as well as related compounds described, for example, in U.S. Patent Nos. 5,290,782, 5,395,836, 5,446,046, 5,631,260, 5,736,528, 6,210,687, and 6,254,889, the entire disclosures of all of which are hereby incorporated by reference herein, including any drawings. A number of other diuretics may also be used, including amiloride, chlortalidone, indapamide, furosemide, torsemide, bumetanide, ethacrynic acid, piretanide, norsemide, spironolactone, triamterene, ticrynafen, metolazone, amiloridethiazides, and thiazides, such as bendrofiuazide, benzthiazide, chlorothiazide, cyclopenthiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, metolazone, polythiazide, quinethazone, trichlormethiazide, xipamide.

[0038] In some embodiments, the anti-hypertensive agent comprises an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB). Each of these classes of compounds have been shown to be effective in the treatment of cardiac disease, such as congestive heart failure, hypertension, asymptomatic left ventricular dysfunction, and acute myocardial infarction.

[0039] Useful ACE inhibitors include lisinopril, cilazapril, delapril, imidapril, zofenapril, enalaprilat, enalapril, quinapril, ramipril, benazepril, captopril, fosinopril, moexipril, trandolapril, and perindopril. Without being bound by any particular theory, it is believed that the anti-hypertensive effect of ACE inhibitors is related to their ability to inhibit the action of angiotensin converting enzyme, which converts angiotensin I to angiotensin II, which normally causes vasoconstriction. In some embodiments, the ACE inhibitor is selected from the group consisting of lisinopril, enalapril, quinapril, ramipril, benazepril, captopril and fosinopril. In some embodiments, the antihypertensive agent comprises the combination of an ACE inhibitor and a diuretic, for example quinapril in combination with hydrochlorothiazide, benazepril in combination with hydrochlorothiazide, lisinopril in combination with hydrochlorothiazide, moexipril in combination with hydrochlorothiazide, or lisinopril in combination with hydrochlorothiazide. hi other embodiments, the antihypertensive agent comprises the combination of an ACE inhibitor and a calcium channel blocker, for example enalapril in combination with felodipine, benazepril in combination with amlodipine, and trandolapril in combination with verapamil.

[0040] A number of ARBs are also commercially available or known in the art. These compounds include losartan, irbesartan, candesartan, telmisartan, olmesartan, eprosartan, tasosartan, valsartan, saralasin, olmesartan, saralasin, and tasosartan. ARBs reduce blood pressure by relaxing blood vessels, allowing better blood flow. Without being bound by any particular theory, it is believed that the anti-hypertensive effect of ARBs stems from their ability to block the binding of angiotensin II, which normally causes vasoconstriction, hi some embodiments, the ARB is selected from the group consisting of losartan, irbesartan, valsartan, candesartan, and valsartan. In some embodiments, the antihypertensive agent comprises a combination of an ARB and a diuretic, for example candesartan in combination with hydrochlorothiazide, irbesartan in combination with hydrochlorothiazide, olmesartan in combination with hydrochlorothiazide, valsartan in combination with hydrochlorothiazide, losartan in combination with hydrochlorothiazide, telmisartan in combination with hydrochlorothiazide, and eprosartan in combination with hydrochlorothiazide.

[0041] hi some embodiments, the antihypertensive agent is an aldosterone receptor antagonist, for example eplerenone. hi some embodiments, it is a renin inhibitor, such as aliskiren. hi some embodiments, it is an advanced glycation end product (AGE) crosslink breaker, such as alagebrium. hi some embodiments, it is an endothelin receptor antagonists, such as ambrisentan or sitaxsentan. [0042] In some embodiments, the anti-hypertensive agent is a rauwolfia alkaloid, such as reserpine, yohimbine, rauwolfia serpentina, deserpidine, or ajmaline, or an adrenergic neuron antagonist, such as guanadrel, guanethidine, or bethanidine. Without being bound by any particular theory, it is believed that the anti-hypertensive effects of adrenergic neuron antagonists and rauwolfia alkaloids are related to their ability to modulate adrenergic signaling by various mechanisms.

[0043] hi some embodiments, the anti-hypertensive agent is a ganglion blocker, such as trimethaphan or mecamylamine.

Second ingredient

[0044] In some embodiments, the anti-obesity agent comprises an anticonvulsant effective in promoting weight loss. In some embodiments, the anticonvulsant is selected from the group including, but not limited to, zonisamide, topiramate, nembutal, lorazepam, clonazepam, clorazepate, tiagabine, gabapentin, fosphenytoin, phenytoin, carbamazepine, valproate, felbamate, levetiracetam, oxcarbazepine, lamotrigine, methsuximide, ethosuxmide, and other weight-loss promoting anticonvulsants (including agents that block kainate/AMPA (D,L-α-amino-3-hydroxy-5-methyl-isoxazole propionic acid) subtype glutamate receptors, and agents that inhibit glutamate release and activity via other mechanisms).

[0045] In certain embodiments, the anti-obesity agent is effective in promoting weight loss in a mammal. The mammal may be selected from the group consisting of mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, primates, such as monkeys, chimpanzees, and apes, and humans. ^■

[0046] hi some embodiments, the anticonvulsant comprises a compound of structural formula (IV):

wherein R₁ is hydrogen or a halogen atom, R₂ and R₃ are the same or different and are each hydrogen or an alkyl having 1 to 3 carbon atoms, and one of X and Y is a carbon atom and another is a nitrogen atom, provided that the group -CH₂SO₂NR₂R₃ is bonded to the carbon atom of either of X and Y.

[0047] In some embodiments, the compound of structural formula (I) comprises zonisamide. Zonisamide is a marketed anticonvulsant indicated as adjunctive therapy for adults with partial onset seizures. Without being bound by any particular theory, it is believed that the mechanism of antiepileptic activity appears to be: 1) sodium-channel blocking; and, 2) reduction of inward T-type calcium currents, hi addition, zonisamide binds to the GABA/benzodiazepine receptor complex without producing change in chloride flux. Further, zonisamide facilitates serotonergic and dopaminergic neurotransmission. For example, there is evidence that zonisamide increases serotonin and dopamine synthesis rates (Hashiguti et al, J Neural Transm Gen Sect. 1993;93:213-223; Okada et al, Epilepsy Res. 1992; 13: 113-119, both of which are incorporated by reference herein in their entirety), and stimulates dopamine D₂ receptors (Okada et al, Epilepsy Res. 1995;22: 193-205, incorporated by reference herein in its entirety). Zonisamide is also thought to possess a weak inhibitory effect on carbonic anhydrase.

[0048] Zonisamide has been shown to cause significant weight loss (comparable to marketed weight loss medications) in patients presenting with primary obesity (Gadde et al, JAMA 289:1820-1825 (2003), incorporated by reference herein in its entirety). Gadde et al reported that in addition to 9.4% weight loss, obese patients treated with zonisamide had a mean systolic blood pressure decrease of 6.8 mm Hg. Without being bound by any particular theory, it has been postulated that the effect of zonisamide on the CNS concentration of serotonin, dopamine and/or carbonic anhydrase is responsible for this effect. Zonisamide was well tolerated, fatigue being the only side effect that occurred more frequently than with placebo treatment.

[0049] With regard to the pharmacokinetics of zonisamide, its renal excretion and minimal potential for inhibition or induction of hepatic microsomal enzymes, are favorable qualities for combination use with anti-hypertensives. [0050] In some embodiments, the anticonvulsant comprises a compound of structural formula (V):

wherein X is CH₂ or oxygen,

R₁ is hydrogen or alkyl,

R₂, R₃, R₄ and R₅ are independently hydrogen or lower alkyl, and when X is CH₂, R₄ and R₅ can be alkene groups joined to form a benzene ring and when X is oxygen, R₂ and R₃ and/or R₄ and R₅ together can be a methylenedioxy group of the following formula (VI):

_R/\- wherein

R₆ and R₇ are the same or different and are hydrogen, lower alkyl or are alkyl and are joined to form a cyclopentyl or cyclohexyl ring.

[0051] In some embodiments, the anticonvulsant of structural formula II comprises topiramate. In other embodiments, other methane-sulfonamide derivatives, in addition to zonisamide and topiramate, such as those described in U.S. Patent 4,172,896, or other sulfamates (including sulfamate-substituted monosaccharides), such as those described in U.S. Patent 4,513,006, incorporated by reference herein in its entirety, are used.

[0052] In some embodiments, the at least one anti-obesity agent comprises bupropion. In other embodiments, compounds disclosed in U.S. Patent Nos. 3,819,706 and 3,885,046, both of which are incorporated by reference herein in their entirety, are used, hi additional embodiments, the at least one anti-obesity agent comprises a compound that enhances the activity of norepinephrine and/or dopamine, such as a norepinephrine reuptake inhibitor, for example, atomoxetine, thionisoxetine, radafaxine, or reboxetine, or a mixed dopamine/norepinephrine reuptake inhibitor, for example, bupropion. In further embodiments, the at least one anti-obesity agent comprises a norepinephrine releaser, for example diethylpropion and phentermine.

[0053] In some embodiments, the compound that enhances the activity of norepinephrine and/or dopamine via uptake inhibition or other mechanism is a metabolite of bupropion. The metabolites of bupropion suitable for inclusion in the methods and compositions disclosed herein include the erythro- and threo-amino alcohols of bupropion, the erythro-amino diol of bupropion, and morpholinol metabolites of bupropion. In some embodiments, the metabolite of bupropion is (±)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5- triniethyl-2-morpholinol. m some embodiments the metabolite is (-)-(2R*,3R*)-2-(3- chlorophenyl)-3,5,5-trimethyl-2-morpholinol, while in other embodiments, the metabolite is (+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol. Preferably, the metabolite of bupropion is (+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol, which is known by its common name of radafaxine, which is described in U.S. Patent No. 6,274,579, issued on August 14, 2001 to Morgan et al., which is hereby incorporated by reference herein in its entirety, including any drawings.

[0054] In some embodiments, the at least one anti-obesity agent comprises an opioid receptor antagonist. The opioid receptor antagonist may be a MOP (mu-opioid) receptor antagonist. In some embodiments the opioid antagonist is selected from the group consisting of alvimopan, norbinaltoφhimine, nalmefene, naloxone, naltrexone, methylnaltrexone, and nalorphine.

[0055] In certain embodiments the opioid antagonist antagonizes an opioid receptor in a mammal. The mammal may be selected from the group consisting of mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, primates, such as monkeys, chimpanzees, and apes, and humans.

[0056] hi other embodiments, the opioid antagonist is a partial opioid agonist. Compounds of this class have some agonist activity at opioid receptors. However, because they are weak agonists, they function as de-facto antagonists. Examples of partial opioid agonists include pentacozine, buprenorphine, nalorphine, propiram, and lofexidine.

[0057] hi some embodiments, the anti-obesity agent comprises orlistat, sibutramine, or rimonobant. [0058] In some embodiments, the anti-obesity agent comprises a combination of one or more of the above compounds. For example, in some embodiments, the anti-obesity agent comprises a combination of zonisamide, topiramate, or other weight-loss promoting anticonvulsant, and bupropion or other compound that enhances the activity of norepinephrine and/or dopamine via uptake inhibition or other mechanism. In other embodiments, the anti-obesity agent comprises a combination of zonisamide, topiramate, or other weight-loss promoting anticonvulsant, and an opioid antagonist, such as naltrexone, naloxone, or nalmefene. In other embodiments, the anti-obesity agent comprises a combination of bupropion and zonisamide, topiramate, or other weight-loss promoting anticonvulsant. Various methods of treating obesity and related conditions involve administering certain drugs or combinations thereof. For example, a number of references disclose the administration of certain weight loss formulations that include an anticonvulsant, an opioid antagonist and/or a norepinephrine reuptake inhibitor (NRI) to a patient in need thereof to affect weight loss. See, for example, U.S. Patent Application Publication Nos. 2004/0033965; 2004/0198668; 2004/0254208; 2005/0137144; 2005/0143322; 2005/0181070; 2005/0215552; 2005/0277579; 2006/0009514; 2006/0142290; 2006/0160750 and 2006/0079501, all of which are hereby incorporated by reference in their entireties, and particularly for the purpose of describing anti-obesity agents.

[0059] m some embodiments, the combination of, for example, zonisamide or topiramate with bupropion is more effective for use in combination with an anti-hypertensive agent for treating hypertension and minimizing cardiovascular risks associated with weight gain. The combination of zonisamide or topiramate with bupropion can be more effective than, for example, zonisamide or topiramate alone and with fewer side effects. Bupropion has synergistic effects with both zonisamide and topiramate in treating obesity. In addition, side effects associated with zonisamide or topiramate (e.g., somnolence, psychomotor slowing, cognitive impairment, fatigue and depression) can be offset by effects associated with bupropion (e.g., insomnia, activation, psychomotor agitation and antidepressant effects). On the other hand, zonisamide or topiramate can reduce the seizure risk associated with bupropion. Lower doses of both types of medication can thus be used in combination treatments, thereby further reducing the overall side effect burden. [0060] It is known that some weight loss compounds such as phentermine or sibutramine can cause substantial increases in blood pressure, in at least some patients. As a result, one of the hurdles of treating hypertensive overweight or obese patients for their weight problem(s) is that the weight loss drug can cause an unpredictable and/or unsafe increase in blood pressure. At the same time, treatment of patients with anti-hypertensive agents is somewhat unpredictable, and requires the physician to monitor blood pressure until the proper dose and/or combination of antihypertensives is found. Combining an antihypertensive drug with anti-obesity drug which presents a risk of substantially and unpredictably increasing blood pressure adds an extra layer of complexity to successfully treating high blood pressure. It is for these reasons that drugs like phentermine and sibutramine contain warnings in their package inserts cautioning about their use in patients with hypertension.

[0061] Applicants have discovered that certain anti-obesity agents do not substantially affect blood pressure, and are therefore substantially blood pressure neutral. These anti-obesity agents are advantageous in combinations with antihypertensives because they do not have the safety concerns associated with anti-obesity agents that present an unpredictable and/or substantial risk of increasing blood pressure, and they simplify the management of blood pressure with antihypertensive agents by not substantially affecting blood pressure. Thus, a physician treating an obese or overweight patient with hypertension can simultaneously treat the hypertension and obesity with a combination of agents without substantial risk of an unpredictable and/or unsafe increase in blood pressure, or the additional complication of a second factor affecting blood pressure while trying to determine the proper dose and/or combination of antihypertensive agents. Anti-obesity agents that are substantially blood pressure neutral include, for example, compositions containing bupropion, preferably combinations of bupropion and naltrexone, or combinations of bupropion and zonisamide.

Compositions:

[0062] In another aspect, pharmaceutical compositions are provided comprising the first and second ingredients described above in combination with a physiologically acceptable carrier, diluent, excipient, or combination thereof. In some embodiments, the first ingredient and/or the second ingredient comprises two or more compounds joined together by a chemical linkage, such as a covalent bond, so that the two different compounds form separate parts of the same molecule. The chemical linkage is preferably selected such that after entry into the body, the linkage is broken, such as by enzymatic action, acid hydrolysis, base hydrolysis, or the like, and the two separate compounds are then formed. Any of the combinations of anti-hypertensive agents and anti-obesity agents discussed herein can be used in the preparation of a medicament to treat hypertension and/or obesity.

[0063] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds of the instant application maybe found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.

[0064] Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.

[0065] Alternately, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly in the renal or cardiac area, often in a depot or sustained release formulation. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ.

[0066] The pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabeleting processes.

[0067] Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.

[0068] For injection, the agents of the invention may be formulated in aqueous solutions or lipid emulsions, preferably in physiologically compatible buffers such as Hanks 's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0069] For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination of the invention, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0070] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. [0071] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers maybe added. Furthermore, the formulations of the present invention may be coated with enteric polymers. AU formulations for oral administration should be in dosages suitable for such administration.

[0072] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0073] For administration by inhalation, compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifiuoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0074] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

[0075] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0076] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0077] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0078] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0079] A pharmaceutical carrier for the hydrophobic compounds of the invention is a co-solvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A common co-solvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™ , and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of POLYSORBATE 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides -may substitute for dextrose.

[0080] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

[0081] Some emulsions used in solubilizing and delivering the xanthine derivatives described above are discussed in U.S. Patent 6,210,687, which is incorporated by reference herein in its entirety, including any drawings.

[0082] Many of the compounds used in the pharmaceutical combinations of the invention may be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acid or base forms.

[0083] Pharmaceutical compositions suitable for use in the present invention include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0084] The exact formulation, route of administration and dosage for the pharmaceutical compositions of the present invention can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1). Typically, the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. Note that for almost all of the specific compounds mentioned in the present disclosure, human dosages for treatment of at least some condition have been established. Thus, in most instances, the present invention will use those same dosages, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage. Where no human dosage is established, as will be the case for newly-discovered pharmaceutical compounds, a suitable human dosage can be inferred from ED₅₀ or ID₅₀ values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.

[0085] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 500 mg, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of the pharmaceutical compositions of the present invention or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day. Alternatively the compositions of the invention may be administered by continuous intravenous infusion, preferably at a dose of up to 400 mg per day. Thus, the total daily dosage by oral administration will be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will be in the range 0.1 to 400 mg. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.

[0086] For example, in some embodiments, the dosage range for zonisamide, for an oral dose, is in the range of about 25 to about 800 mg per day. Preferably the dose is from about 100 mg to 600 mg per day, more preferably from about 200 mg to 400 mg per day. In yet other embodiments, the dosage is 25 mg per day, 50 mg per day, or 100 mg per day. The daily dosage range for topiramate can be from about 25 mg to 1600 mg, preferably from about 50 mg to 600 mg, and more preferably from about 100 mg to 400 mg. The daily dosage range for bupropion can be from about 25 mg to 600 mg, preferably from about 50 mg or about 150 mg to 450 mg. The above doses generally are given once per day or divided (e.g., equally) into multiple doses. When zonisamide or topiramate are used in combination with bupropion, the ratio of zonisamide or topiramate to bupropion can range, for example, from about 2:1 to 1:2. The above ranges are given as non-limiting examples, and it may be necessary in some embodiments to use doses outside of the recited ranges.

[0087] In another example, the diuretic furosemide may administered in a dose of 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg, or higher, either orally or intravenously. When furosemide is administered intravenously, it may be administered as a single injection or as a continuous infusion. When the administration is through a continuous infusion, the dosage of furosemide may be less than 1 mg per hour, 1 mg per hour, 3 mg per hour, 5 mg per hour, 10 mg per hour, 15 mg per hour, 20 mg per hour, 40 mg per hour, 60 mg per hour, 80 mg per hour, 100 mg per hour, 120 mg per hour, 140 mg per hour, or 160 mg per hour, or higher. The above ranges are given as non-limiting examples, and it may be necessary in some embodiments to use doses outside of the recited ranges.

[0088] In another example, the diuretic hydrochlorothiazide may be administered in a dose of 12.5 mg, 15 mg, 25 mg, 30 mg, 50 mg or higher.

[0089] In another example, the calcium channel blocker amlodipine may be administered in a dose of 1.25 mg, 2.5 mg, 5 mg, 10 mg or higher.

[0090] In another example, the ACE inhibitor benazepril may be administered in a dose of 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, or higher. Another ACE inhibitor ramipril may be administered in a dose of 1.25 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, or higher. Another ACE inhibitor lisinopril may be administered in a dose of 5 mg, 10 mg, 20 mg, 40 mg or higher.

[0091] In another example, the ARB losartan may be administered in a dose of 25 mg, 50 mg, 75 mg, 100 mg, or higher. Another ARB irbesartan may be administered in a dose of 75 mg, 150 mg, 225 mg, 300 mg, or higher. Another ARB valsartan may be administered in a dose of 40 mg, 80 mg, 120 mg, 160 mg, 200 mg, 240 mg, 280 mg, 320 mg, or higher.

[0092] In another example, an antiobesity drug, preferably zonisamide or topiramate, may be added to an antihypertensive drug combination such as valsartan plus hydrochlorothiazide, in which case the doses of the latter two drugs may be 40 mg, 80 mg, 120 mg, 160 mg, 200 mg, 240 mg, 280 mg, 320 mg, or higher for valsartan, and 12.5 mg, 15 mg, 25 mg, 30 mg, 50 mg, or higher for hydrochlorothiazide.

[0093] In another example, an antiobesity drug, preferably zonisamide or topiramate, may be added to an antihypertensive drug combination such as amlodipine and benazepril, in which case the doses of the latter two drugs may be 1.25 mg, 2.5 mg, 5 mg, 10 mg, or higher for amlodipine, and 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, or higher.

[0094] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.

[0095] Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.

[0096] hi cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0097] The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

[0098] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0099] In a preferred embodiment, the anti-obesity agent is a bupropion containing compound, more preferably a combination of bupropion and naltrexone, or a combination of bupropion and zonisamide. Controlled release formulations of bupropion are commercially available. Controlled release formulations of zonisamide are described in U.S. Provisional Application Serial No. 60/835,564, filed August 4, 2006, which is hereby incorporated by reference in its entirety and particularly for the purpose of describing such controlled release zonisamide formulations and methods of making them. The combination of bupropion plus naltrexone or zonisamide is preferably a controlled release formulation, wherein at least one or both of the active ingredients are released in a controlled manner. Controlled release formulations of naltrexone are described in U.S. Provisional Application Serial No. 60//811,251, filed June 5, 2006, which is hereby incorporated by reference in its entirety and particularly for the purpose of describing controlled release naltrexone formulations and methods for making them. In some embodiments, the controlled release formulation is a sustained release formulation. For example, in some embodiments, the combination of the invention comprises an antihypertensive, a sustained release formulation of bupropion, and naltrexone. In some embodiments, the antihypertensive agent and the anti- obesity agent are in separate dosage forms, while in others they are combined in a single dosage form. In some embodiments, where the anti-obesity agent is a combination of two or more compounds, the two or more compounds are combined in a single dosage form. Where a single dosage form of two or more anti-obesity compounds is used, one or more of the compounds can be in a controlled or sustained release formulation.

Methods of treatment

[0100] In another aspect, methods for treating hypertension are provided comprising administering a first ingredient and a second ingredient, wherein the first ingredient comprises at least one anti-hypertensive agent and the second ingredient comprises at least one anti-obesity agent. In various embodiments, the first ingredient and second ingredient are administered more or less simultaneously. In other embodiments the first ingredient is administered prior to the second ingredient. In yet other embodiments, the first ingredient is administered subsequent to the second ingredient.

[0101] In various embodiments, a patient in need of treatment for hypertension has a systolic blood pressure greater than 160, 150, 140, 130, or 120 mmHg and/or a diastolic blood pressure greater than 110, 100, 90, or 80 mmHg, although prescription medications are generally considered for patients with stage 1 hypertension (systolic 140-159 mmHg, diastolic 90-99 mmHg) and stage 2 hypertension (systolic >160 mmHg, diastolic >100 mmHg). In some embodiments, a patient in need of treatment for hypertension has elevated blood pressure over an extended period. In some embodiments, the patient in need of treatment for hypertension suffers from diabetes, left ventricular hypertrophy, high cholesterol, high triglycerides, metabolic syndrome, family history of premature cardiovascular disease, microalbuminurea, or obesity, or has a history of smoking.

[0102] In another aspect, methods are provided for treating diseases or conditions associated with hypertension, including but not limited to, congestive heart failure, myocardial infarction, asymptomatic left ventricular dysfunction, atrial fibrillation, arrhythmia, recurrent ventricular tachycardia, recurrent ventricular fibrillation, coronary artery disease, nephrotic disease, liver disease, and vision disorders, such as retinal macroaneurysm and hollenhorst plaque, wherein the method comprises administering a first ingredient and a second ingredient, and the first ingredient comprises at least one antihypertensive agent and the second ingredient comprises at least one anti-obesity agent. In some instances, patients suffering from a cardiovascular disease are in need of after-load reduction. The methods of the present invention are suitable to provide treatment for these patients as well.

[0103] In a further aspect, methods are provided for improving overall health outcomes, decreasing morbidity rates, and/or decreasing mortality rates comprising identifying a patient in need thereof, and administering a first ingredient and a second ingredient, and the first ingredient comprises at least one anti-hypertensive agent and the second ingredient comprises at least one anti-obesity agent.

[0104] Overall health outcomes are determined by various means in the art. For example, improvements in morbidity and/or mortality rates, improvements in the patient's general feelings, improvements in the quality of life, improvements in the level of comfort at the end of life, and the like, are considered when overall health outcome are determined. Mortality rate is the number of patients who die while undergoing a particular treatment for a period of time compared to the overall number of patients undergoing the same or similar treatment over the same period of time. Morbidity rates are determined using various criteria, such as the frequency of hospital stays, the length of hospital stays, the frequency of visits to the doctor's office, the dosage of the medication being administered, and the like.

[0105] hi some embodiments, methods described herein comprise administering one or more compositions, as described above, hi other embodiments, the methods comprise administering at least one anti-hypertensive agent and at least one anti-obesity agent separately or in various combinations, hi some embodiments, the anti-obesity agent does not substantially increase blood pressure.

[0106] In certain embodiments, the individual has a body mass index (BMI) greater than 25. hi other embodiments, the individual has a BMI greater than 30. hi still other embodiments, the individual has a BMI greater than 40. However, in some embodiments, the individual may have a BMI less than 25.

[0107] hi some embodiments the first ingredient and the second ingredient are administered more or less simultaneously. In other embodiments the first ingredient is administered prior to the second ingredient, hi yet other embodiments, the first ingredient is administered subsequent to the second ingredient.

[0108] In certain embodiments, the first ingredient and the second ingredient are administered individually, hi some embodiments, the first ingredient and the second ingredient are in separate administrable compositions, but the patient is directed to take the separate compositions nearly simultaneously, i.e., one pill is taken right after the other or one injection of one compound is made right after the injection of another compound, etc. hi other embodiments the administering step comprises administering either the first ingredient or the second ingredient first and then administering the other one of either the first ingredient or the second ingredient. In these embodiments, the patient may be administered a composition comprising one of the compounds and then at some time, e.g., a few minutes or a few hours later, be administered another composition comprising the other one of the compounds. Also included in these embodiments are those in which the patient is administered a composition comprising one of the compounds on a routine or continuous basis while receiving a composition comprising the other compound occasionally, hi further embodiments, the patient may receive both compounds on a routine or continuous basis, such a continuous infusion of the compound through an IV line.

[0109] hi other embodiments, the first ingredient and the second ingredient are in the same administrable composition, i.e., a single tablet, pill, or capsule, or a single solution for intravenous injection, or a single drinkable solution, or a single dragee formulation or patch, containing both ingredients, hi some embodiments, the first ingredient and the second ingredient are covalently linked to each other such that they form a single chemical entity. The single chemical entity is then digested and is metabolized, such as by enzymatic action, acid hydrolysis, base hydrolysis, or the like, into two or more separate, physiologically active chemical entities, one or more of which is the first ingredient and one or more of which is the second ingredient.

[0110] hi certain embodiments, the patient may be a mammal. The mammal may be selected from the group consisting of mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, primates, such as monkeys, chimpanzees, and apes, and humans, hi some embodiments, the patient is a human.

[0111] In some embodiments, pharmacological methods of treating hypertension comprising administering an anti-hypertensive agent and an anti-obesity agent are combined with one or more behavioral methods, such as dieting (e.g., reductions in intake of sodium, calories, fat/cholesterol, alcohol), exercise, and smoking cessation.

[0112] It will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present invention. Therefore, it should be clearly understood that the forms of the present invention are illustrative only and are not intended to limit the scope of the present invention.

[0113] All documents and other information sources cited above are hereby incorporated by reference in their entirety, as are Gadde et al, Obesity Res. 9:544-551 (2001) and Gadde et al, JAMA 289:1820-1825 (2003). Some Embodiments of the Invention

[0114] Some of the embodiments of the present invention are as follows:

[0115] In the 1^st embodiment, the invention relates to a composition for treating hypertension comprising a first ingredient and a second ingredient, wherein the first ingredient comprises at least one anti-hypertensive agent and the second ingredient comprises at least one anti-obesity agent.

[0116] In the 2^nd embodiment, the invention relates to the composition of the 1^st embodiment, wherein the anti-hypertensive agent is a beta-blocker.

[0117] In the, 3^rd embodiment, the invention relates to the composition of the 2^nd embodiment, wherein the beta-blocker is selected from the group consisting of: acebutolol, alprenolol, atenolol, betaxolol, bisoprolol, bupranolol, carteolol, celiprolol, epanolol, esmolol, landiolil, levabetaxolol, levobunolol, metipranolol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, pindolol, practolol, propranolol, succinate, and timolol.

[0118] In the 4^th embodiment, the invention relates to the composition of the 1^st embodiment, wherein the anti-hypertensive agent is an alpha-adrenergic receptor antagonist.

[0119] In the 5^th embodiment, the invention relates to the composition of the 4^th embodiment, wherein the alpha-adrenergic receptor antagonist is selected from the group consisting of: doxazosin, fuzosin, dapiprazole, indoramin, isometheptene, metazosin, moxisylyte, phenoxybenzamine, phentolamine, piperoxan, pilmenidine, prazosin, tamsulosin, terazosin, and urapidil.

[0120] hi the 6^th embodiment, the invention relates to the composition of the 1^st embodiment, wherein the anti-hypertensive agent is an alpha and beta-blocker.

[0121] In the 7^th embodiment, the invention relates to the composition of the 6^th embodiment, wherein the alpha and beta-blocker is selected from the group consisting of: carvedilol and labetolol.

[0122] m the 8^th embodiment, the invention relates to the composition of the 1^st embodiment, wherein the anti-hypertensive agent is an adrenergic neuron antagonist.

[0123] In the 9^th embodiment, the invention relates to the composition of the 8^th embodiment, wherein the adrenergic neuron antagonist is selected from the group consisting of: bethanidine, debrisoquine, guanadrel, guanfacine, and guanethidine. [0124] In the 10^th embodiment, the invention relates to the composition of the 1^st embodiment, wherein the anti-hypertensive agent is rauwolfia alkaloid.

[0125] hi the 11^th embodiment, the invention relates to the composition of the 10^th embodiment, wherein the rauwolfia alkaloid is selected from the group consisting of: ajmaline, deserpidine, reserpine, rauwolfia serpentina, and yohimbine.

[0126] hi the 12^th embodiment, the invention relates to the composition of the 1^st embodiment, wherein the anti-hypertensive agent is a centrally acting alpha-adrenergic agonist.

[0127] hi the 13^th embodiment, the invention relates to the composition of the 12^th embodiment, wherein the centrally acting alpha-adrenergic agonist is selected from the group consisting of: methyldopa, clonidine, guanfacine, and guanabenz.

[0128] hi the 14^th embodiment, the invention relates to the composition of the 1^st embodiment, wherein the anti-hypertensive agent is a calcium-channel blocker.

[0129] hi the 15^th embodiment, the invention relates to the composition of the 14^th embodiment, wherein the calcium-channel blocker is selected from the group consisting of: amlodipine, barnidipine, bepridil, diltiazem, efonidipine, etafenone, felodipine, flunarizine, gallopamil, isradipine, lacidipine, lercanidipine, mibefradil, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil.

[0130] In the 16^th embodiment, the invention relates to the composition of the 1^st embodiment, wherein the anti-hypertensive agent is an angiotensin converting enzyme (ACE) inhibitor.

[0131] In the 17^th embodiment, the invention relates to the composition of the 16^th embodiment, wherein the angiotensin converting enzyme (ACE) inhibitor is selected from the group consisting of: lisinopril, cilazapril, delapril, imidapril, zofenapril, enalaprilat, enalapril, quinapril, ramipril, benazepril, captopril, fosinopril, moexipril, trandolapril, and perindopril.

[0132] In the 18^th embodiment, the invention relates to the composition of the 13^th embodiment, wherein the anti-hypertensive agent is a vasodilator. [0133] In the 19^th embodiment, the invention relates to the composition of the 18^th embodiment, wherein the vasodilator is selected from the group consisting of: hydralazine, minoxidil, nitroprusside, and diazoxide.

[0134] In the 20^th embodiment, the invention relates to the composition of the 1^st embodiment, wherein the anti-hypertensive agent is a gangion blocker selected from the group consisting of: mecamylamine and trimethaphan.

[0135] In the 21^st embodiment, the invention relates to the composition of the 13^th embodiment, wherein the anti-hypertensive agent is an angiotensin II receptor blocker (ARB).

[0136] In the 22^nd embodiment, the invention relates to the composition of the 21^st embodiment, wherein the angiotensin II receptor blocker (ARJB) is selected from the group consisting of: losartan, irbesartan, candesartan, telmisartan, olmesartan, eprosartan, tasosartan, valsartan, saralasin, olmesartan, saralasin, and tasosartan.

[0137] In the 23^rd embodiment, the invention relates to the composition of the 1^st embodiment, wherein the anti-hypertensive agent is a diuretic.

[0138] In the 24^th embodiment, the invention relates to the composition of the 23^rd embodiment, wherein the diuretic is an adenosine A₁ receptor antagonist (AA₁RA).

[0139] In the 25^th embodiment, the invention relates to the compositions of any of the 2^nd through 24^th embodiments wherein the anti-obesity agent is a weight-loss promoting anticonvulsant.

[0140] In the 26^th embodiment, the invention relates to the composition of the 25^th embodiment, wherein the weight-loss promoting anticonvulsant is a compound of structural formula (IV):

wherein R₁ is hydrogen or a halogen atom, R₂ and R₃ are the same or different and are each hydrogen or an alkyl having 1 to 3 carbon atoms, and one of X and Y is a carbon atom and another is a nitrogen atom, provided that the group -CH₂SO₂NR₂R₃ is bonded to the carbon atom of either of X and Y.

[0141] In the 27^th embodiment, the invention relates to the composition of the 26^th embodiment, wherein the compound of structural formula (IV) is zonisamide.

[0142] In the 28^th embodiment, the invention relates to the composition of the 25^th embodiment wherein the weight loss-promoting anticonvulsant is a compound of structural formula (V):

wherein X is CH₂ or oxygen,

R₁ is hydrogen or alkyl,

R₂, R₃, R₄ and R₅ are independently hydrogen or lower alkyl, and when X is CH₂, R₄ and R₅ can be alkene groups joined to form a benzene ring and when X is oxygen, R₂ and R₃ and/or R₄ and R₅ together can be a methylenedioxy group of the following formula (VI):

wherein

R₆ and R₇ are the same or different and are hydrogen, lower alkyl or are alkyl and are joined to form a cyclopentyl or cyclohexyl ring.

[0143] In the 29^th embodiment, the invention relates to the composition of the 28^th embodiment, wherein the compound of structural formula (V) is topiramate.

[0144] In the 30^th embodiment, the invention relates to the composition of the 25^th embodiment wherein the weight loss-promoting anticonvulsant is selected from the group consisting of: nembutal, lorazepam, clonazepam, clorazepate, tiagabine, gabapentin, fosphenytoin, phenytoin, carbamazepine, valproate, felbamate, levetiracetam, oxcarbazepine, lamotrigine, methsuximide, and ethosuxmide. [0145] In the 31^st embodiment, the invention relates to the compositions of any of the 2^nd through 24^th embodiments wherein the anti-obesity agent is a compound that enhances the activity of norepinephrine and/or dopamine.

[0146] hi the 32^nd embodiment, the invention relates to the compositions of the 31^st embodiment, wherein the compound that enhances the activity of norepinephrine and/or dopamine is selected from the group consisting of: atomoxetine, bupropion, thionisoxetine, diethylpropion, phentermine, radafaxine, and reboxetine.

[0147] In the 33^rd embodiment, the invention relates to the compositions of the 31^st embodiment wherein the compound that enhances the activity of norepinephrine and/or dopamine is selected from the group consisting of: (±)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5- trimethyl-2-morphoϊinol, (-)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-moφholinol, and (+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol .

[0148] In the 34^th embodiment, the invention relates to the compositions of any of the 2^nd through 24^th embodiments wherein the anti-obesity agent comprises a first component and a second component, wherein the first component is selected from the group consisting of zonisamide and topiramate, and the second component is selected from the group consisting of bupropion, atomoxetine, and reboxetine.

[0149] hi the 35^th embodiment, the invention relates to the compositions of any of the 2^nd through 24^th embodiments wherein the anti-obesity agent is an opioid receptor antagonist. . ,

[0150] hi the 36^th embodiment, the invention relates to the compositions of the 35^th embodiment wherein the opioid receptor antagonist is a mu-opioid receptor (MOP) antagonist.

[0151] In the 37^th embodiment, the invention relates to the compositions of the 35^th embodiment wherein the opioid receptor antagonist is selected from the group consisting of alvimopan, norbinaltorphimine, nalmefene, naloxone, naltrexone, methylnaltrexone, and nalorphine.

[0152] In the 38^th embodiment, the invention relates to the compositions of the

35 cth embodiment wherein the opioid receptor antagonist is a partial opioid agonist. [0153] In the 39^th embodiment, the invention relates to the compositions of the 38^th embodiment wherein the partial opioid agonist is selected from the group consisting of: pentacozine, buprenorphine, nalorphine, propiram, and lofexidine.

[0154] In the 40^th embodiment, the invention relates to the compositions of any of the 2^nd through 24^th embodiments wherein the anti-obesity agent is selected from the group consisting of orlistat, sibutramine, and rimonobant.

[0155] In the 41^st embodiment, the invention relates to a method for treating hypertension comprising administering a first ingredient and a second ingredient, wherein the first ingredient comprises at least one anti-hypertensive agent and the second ingredient comprises at least one anti-obesity agent.

[0156] In the 42^nd embodiment, the invention relates to a method for treating a condition associated with hypertension comprising administering a first ingredient and a second ingredient, wherein the first ingredient comprises at least one anti-hypertensive agent and the second ingredient comprises at least one anti-obesity agent.

[0157] In the 43^rd embodiment, the invention relates to the method of the 42^nd embodiment, wherein the condition associated with hypertension is selected from the group consisting of: congestive heart failure, myocardial infarction, asymptomatic left ventricular dysfunction, atrial fibrillation, arrhythmia, recurrent ventricular tachycardia, recurrent ventricular fibrillation, coronary artery disease, nephrotic disease, liver disease, diabetes and vision disorders.

[0158] In the 44^th embodiment, the invention relates to a method of improving overall health outcomes, decreasing morbidity rates, or decreasing mortality rates comprising identifying a patient in need thereof, and administering a first ingredient and a second ingredient, and the first ingredient comprises at least one anti-hypertensive agent and the second ingredient comprises at least one anti-obesity agent.

[0159] In the 45^th embodiment, the invention relates to any of the methods of the 41^st through 44^th embodiments wherein the patient has a BMI greater than 25.

[0160] In the 46^th embodiment, the invention relates to any of the methods of the 41^st through 44^th embodiments wherein the patient has a BMI greater than 30. [0161] In the 47^th embodiment, the invention relates to any of the methods of the 41^st through 44^th embodiments wherein the first ingredient and second ingredient are administered substantially simultaneously.

[0162] In the 48^th embodiment, the invention relates to any of the methods of the 41^st through 44^th embodiments wherein the first ingredient is administered prior to the second ingredient.

[0163] In the 49^th embodiment, the invention relates to any of the methods of the 41^st through 44^th embodiments wherein the second ingredient is administered prior to the first ingredient.

[0164] In the 50^th embodiment, the invention relates to any of the methods of the 41^st through 47^th embodiments wherein the first ingredient and second ingredient are administered as any of the compositions of the 1^st through the 24^th embodiments.

[0165] In the 51^st embodiment, the invention relates to any of the methods of the 41^st through 50^th embodiments wherein the plasma concentration levels of the first and second ingredients follow a similar time profile.

Examples

[0166] The examples below are non-limiting and are merely representative of various aspects of the invention.

Example 1:

[0167] Patients having a BMI of greater than 25 and in need of treatment for hypertension are identified. Regular measurements giving a systolic blood pressure of greater than 140 mmHg and/or a diastolic blood pressure of greater than 90 mmHg indicate a need for pharmacological treatment for hypertension. For patients having additional risk factors, such as diabetes, lower values can indicate the need for pharmacological treatment, for example a systolic blood pressure of greater than 130 mmHg and/or a diastolic blood pressure of greater than 80 mmHg.

[0168] The patient is instructed to take one 25 mg tablet of zonisamide or topiramate on a daily basis. In addition, the patient is instructed to take one 50 mg tablet of the beta-blocker atenolol on a daily basis. Alternatively, the patient may be instructed to take another antihypertensive agent, such as an ACE inhibitor, an ARB, or a diuretic, or combination antihypertensive product. The patient may also be prescribed behavioral treatments, such as a low calorie diet and exercise, in addition to pharmacological therapies.

[0169] Blood pressure and weight are monitored regularly over a period of one to several months. A target blood pressure is typically selected based on the patient's history, for example, a systolic blood pressure equal or less than 120 mmHg and a diastolic blood pressure equal to or less than 80 mmHg. A target weight and/or BMI may also be selected. Changes in obesity-associated cardiovascular risk factors may also be monitored, for example total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, glucose and/or insulin.

[0170] If blood pressure exceeds the target levels after one to several weeks, the dosage of atenolol is increased to 100 mg daily. If blood pressure remains elevated after an additional one to several weeks, an additional anti-hypertensive agent is added to the treatment regimen, preferably belonging to a different functional class than the initial antihypertensive agent. For example, the patient is instructed to take one tablet of 12.5 mg of hydrochlorothiazide (HCTZ) per day in addition to the zonisamide/topiramate and atenolol. If blood pressure remains elevated after one to several weeks of therapy, the dosage of HCTZ can be increased up to 25 mg daily.

[0171] The dosage of the anti-obesity agent (topiramate/zonisamide) is typically titrated such that the patient loses weight at a rate of approximately 10% of initial weight every 6 months. However, the desired rate of weight loss for each individual maybe adjusted by the treating physician based on the individual's particular needs. If the rate of weight loss exceeds the desired rate, the dose zonisamide/topiramate is decreased (e.g., halved), followed by monitoring for one to several months until the desired rate is achieved. If the rate of weight loss is less than the desired rate and blood pressure remains elevated after one to several months of treatment, the daily dose of zonisamide or topiramate can be adjusted up to several hundred milligrams. In addition, the patient may be instructed to take one 200 mg tablet of bupropion per day, or a dose such that the ratio of bupropion: zonisamide/topiramate is between about 1:2 to 2: 1. [0172] If blood pressure remains elevated after several months, the patient may be instructed to make further adjustments in dosages and/or take additional medications until the blood pressure target is reached.

Example 2:

[0173] Patients having a BMI of greater than 25 and in need of treatment for hypertension are identified. Regular measurements giving a systolic blood pressure of greater than 140 mmHg and/or a diastolic blood pressure of greater than 90 mmHg indicate a need for pharmacological treatment for hypertension. For patients having additional risk factors, such as diabetes, lower values can indicate the need for pharmacological treatment, for example a systolic blood pressure of greater than 130 mmHg and/or a diastolic blood pressure of greater than 80 mmHg.

[0174] The patient is instructed to take 50 mg tablet of naltrexone on a daily basis. In addition, the patient is instructed to take one 10 mg tablet of the ACE inhibitor quinapril on a daily basis. Alternatively, the patient may be instructed to take another antihypertensive agent, such as an ARB, a beta-blocker, or a diuretic. The patient may also be prescribed behavioral treatments, such as a low calorie diet and exercise, in addition to pharmacological therapies.

[0175] Blood pressure and weight are monitored regularly over a period of one to several months. A target blood pressure is typically selected based on the patient's history, for example, a systolic blood pressure equal or less than 120 mmHg and a diastolic blood pressure equal to or less than 80 mmHg. A target weight and/or BMI may also be selected. Changes in obesity-associated cardiovascular risk factors may also be monitored, for example total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, glucose and/or insulin.

[0176] If blood pressure remains higher than the target levels after one to several weeks, the dosage of quinapril is increased to 20 mg daily. If blood pressure remains elevated after an additional one to several weeks, an additional anti-hypertensive agent is added to the treatment regimen, preferably belonging to a different functional class than the initial anti-hypertensive agent. [0177] The dosage of the anti-obesity agent (naltrexone) is typically titrated such that the patient loses weight at a rate of approximately 10% of initial weight every 6 months. However, the desired rate of weigh loss for each individual may be adjusted by the treating physician based on the individual's particular needs. If the rate of weight loss exceeds the desired rate, the dose naltrexone is decreased (e.g., halved), followed by monitoring for one to several months until the desired rate is achieved. If the rate of weight loss is less than the desired rate and blood pressure remains elevated after one to several months of treatment, the daily dose of naltrexone can be adjusted up to several hundred milligrams. In addition, the patient may be instructed to take one 200 mg tablet of bupropion per day, or a dose such that the ratio of bupropion:naltrexone is between about 1:25 to 2:1.

[0178] If blood pressure remains elevated after several months, the patient may be instructed to make further adjustments in dosages and/or take additional medications until the blood pressure target is reached.

Example 3:

[0179] Overweight or obese patients in need of treatment for hypertension are identified and treated as described in Examples 1-2, except that the initial anti-hypertensive agent is the alpha-blocker doxazosin. The patient is initially instructed to take a 1 mg tablet of doxazosin daily. If blood pressure remains elevated after one to several weeks, the dose of doxazosin is adjusted to 2 mg, 4 mg, 8mg, or 16 mg daily, until the desired response is achieved.

Example 4:

[0180] Overweight or obese patients in need of treatment for hypertension are identified and treated as described in Examples 1-2, except that the initial anti-hypertensive agent is the alpha and beta-blocker carvedilol. The patient is initially instructed to take a 6.25 mg tablet of carvedilol twice daily. If blood pressure remains elevated after one to several weeks, the dose of carvedilol is adjusted to 25 mg or 50 mg, twice daily, until the desired response is achieved. Example 5:

[0181] Overweight or obese patients in need of treatment for hypertension are identified and treated as described in Examples 1-2, except that the initial anti-hypertensive agent is the central alpha-adrenergic agonist clonidine. The patient is initially instructed to take a 0.1 mg tablet of clonidine twice daily. If blood pressure remains elevated after one to several weeks, the twice daily doses of clonidine are adjusted upwards in 0.1 mg increments until the desired response is achieved, not to exceed about 1 mg per day.

Example 6:

[0182] Overweight or obese patients in need of treatment for hypertension are identified and treated as described in Examples 1-2, except that the initial anti-hypertensive agent is the calcium-channel blocker diltiazem. The patient is initially instructed to take a 120 mg tablet of diltiazem once daily. If blood pressure remains elevated after one to several weeks, the daily dose of diltiazem is adjusted to 180 mg, 240 mg, 300 mg, 360 mg, 440 mg, or 540 mg, until the desired response is achieved.

Example 7:

[0183] Overweight or obese patients in need of treatment for hypertension are identified and treated as described in Examples 1-2, except that the initial anti-hypertensive agent is the vasodilator hydralazine. The patient is initially instructed to take a 10 mg tablet of hydralazine four times daily. If blood pressure remains elevated after one to several weeks, the daily dose of hydralazine is adjusted to 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg, divided into several equal doses, until the desired response is achieved.

Example 8:

[0184] Overweight or obese patients in need of treatment for hypertension are identified and treated as described in Examples 1-2, except that the initial anti-hypertensive agent is the ARB valsartan. The patient is initially instructed to take a 80 mg tablet of valsartan once daily. If blood pressure remains elevated after one to several weeks, the daily dose of valsartan is adjusted to 160 mg, 240 mg, or 320 mg, taken once daily, until the desired response is achieved.

Example 9:

[0185] Overweight or obese patients in need of treatment for hypertension are identified and treated as described in Examples 1-2, except that the initial anti-hypertensive agent is the ganglion blocker mecamylamine. The patient is initially instructed to take a 2.5 mg tablet of mecamylamine twice daily. If blood pressure remains elevated after one to several weeks, the daily dose of mecamylamine is adjusted to 10 mg, 15 mg, 20 mg, or 25 mg until the desired response is achieved.

Example 10:

[0186] Overweight or obese patients in need of treatment for hypertension are identified and treated as described in Examples 1-2, except that the initial anti-hypertensive agent is the neuron antagonist guanadrel. The patient is initially instructed to take a 5 mg tablet of guanadrel, three times daily. If blood pressure remains elevated after one to several weeks, the daily dose of valsartan is adjusted to 30 mg, 45 mg, 60 mg, or 75 mg, taken in several divided doses.

Example 11:

[0187] Normotensive obese patients were enrolled in a clinical trial to test the effectiveness of a combination of bupropion and naltrexone on weight loss. Patients were divided into four treatment groups: bupropion SR 150 mg po BID + naltrexone 50 mg po QD (Group 1 (Bup + NaI)); bupropion SR 150 mg po BID + naltrexone-placebo po QD (Group 2 (Bup + P)); bupropion-placebo po BID + naltrexone 50 mg po QD (Group 3 (P + NaI)); and antidepressant-placebo po BID + naltrexone-placebo po QD (Group 4 (P + P)).

[0188] After 16 and 24 weeks of treatment, patients treated with the combination of bupropion and naltrexone (Group 1) lost more weight than the other groups. Surprisingly, the combination of bupropion and naltrexone did not substantially increase blood pressure at either the 16 week or 24 week time point. Table 1: Percenta e Chan e from Baseline to Week 16 and Week 24 in Blood Pressure

*Least squares (LS) means (and 95% CIs) are estimated from a linear fixed effects model, adjusted for sex, baseline BMI, and waist circumference. **Pairwise comparisons vs. Group 1 (Bup + NaI) ***Subjects in Groups 3 and 4 were not followed past Week 16. #Comparison vs. Group 1 (Bup + NaI)

[0189] The combination of bupropion and naltrexone used in Example 11 is an example of a preferred anti-obesity agent for use in combination with an antihypertensive agent for compositions and for the treatment of hypertension in overweight or obese patients that are hypertensive.

Example 12:

[0190] In a second clinical trial to test the effectiveness of a combination of bupropion and naltrexone (NB) on weight loss, normotensive obese patients were divided into six groups and received either bupropion matched placebo and naltrexone matched placebo, bupropion SR (400 mg/day) plus naltrexone matched placebo, bupropion matched placebo plus naltrexone (48 mg/day), or a combination of bupropion SR (400 mg/day) plus one of three doses of naltrexone (48 mg/day, 32 mg/day, or 16 mg/day). [0191] After 24 weeks of treatment, patients treated with the combination of bupropion and naltrexone (all doses) lost more weight than the placebo, bupropion alone, or naltrexone alone groups. The data show that the combinations of bupropion plus naltrexone did not cause a substantial increase in blood pressure from baseline (see Table T).

Table 2: Percent Chan e in Diastolic Blood Pressure from Baseline. Week 24

* Unadjusted least square mean.

[0192] The combinations of bupropion and naltrexone used in Example 12 are examples of preferred anti-obesity agents for use in combination with an antihypertensive agent for compositions and for the treatment of hypertension in overweight or obese patients that are hypertensive.

Example 13:

[0193] Normotensive obese patients were enrolled in a clinical trial to test the effectiveness of a combination of bupropion and zonisamide on weight loss. Patients were divided into four treatment groups: bupropion SR 150 mg po BID + zonisamide 400 mg po QD (Group 1 (Bup + Zon)); bupropion SR 150 mg po BID + zonisamide-placebo po QD (Group 2 (Bup + P)); bupropion-placebo po BID + zonisamide 400 mg po QD (Group 3 (P + Zon)); and bupropion-placebo po BID + zonisamide-placebo po QD (Group 4 (P + P)).

[0194] After 24 weeks of treatment, patients treated with the combination of bupropion and zonisamide (Group 1) lost more weight than the other groups. Surprisingly, the combination of bupropion and zonisamide did not substantially increase blood pressure at the 16 or 24 week time point as evaluated by systolic or diastolic blood pressure change from baseline as shown in Table 3.

*Subjects in Group 4 were not followed past Week 16.

[0195] The combination of bupropion and zonisamide used in Example 13 is an example of a preferred anti-obesity agent for use in combination with an antihypertensive agent for compositions and for the treatment of hypertension in overweight or obese patients that are hypertensive.

Example 14:

[0196] Overweight or obese patients in need of treatment for hypertension are identified and treated as described in Examples 1-2, except that the initial anti-obesity agent is the combination of bupropion and naltrexone. The patient is initially instructed to take bupropion SR 150 mg po BID + naltrexone 50 mg po QD. If the target rate of weight loss is not achieved, the amount of bupropion can be increased to 200 mg BID.

Example 15:

[0197] Overweight or obese patients in need of treatment for hypertension are identified and treated as described in Examples 1-2, except that the initial anti-obesity agent is the combination of bupropion and naltrexone. The patient is initially instructed to take bupropion SR 200 mg po BID + naltrexone 16 mg po QD. If the target rate of weight loss is not achieved, the amount of naltrexone can be increased to 32 mg. If the targeted rate of weight loss is still not achieved, the amount of naltrexone can be increased to 48 mg.

Example 16:

[0198] Overweight or obese patients in need of treatment for hypertension are identified and treated as described in Examples 1-2, except that the initial anti-obesity agent is the combination of bupropion and zonisamide. The patient is initially instructed to take bupropion SR 150 mg po BID + zonisamide 300 mg po QD. If the target rate of weight loss is not achieved, the amount of zonisamide can be increased to 400 mg. If the targeted rate of weight loss is still not achieved, the amount of zonisamide can be increased to 500 mg. hi addition, or alternatively, the amount of bupropion can also be adjusted to 400 mg/day.

Claims

WHAT IS CLAIMED IS:

1. A composition comprising a first ingredient and a second ingredient, wherein the first ingredient comprises at least one anti-hypertensive agent and the second ingredient comprises at least one anti-obesity agent, and wherein said anti-obesity agent comprises bupropion, or a prodrug, metabolite or pharmaceutically acceptable salt thereof.

2. The composition of claim 1, wherein said anti-hypertensive agent is selected from a beta-blocker, an alpha-adrenergic receptor antagonist, an alpha and beta-blocker, an adrenergic neuron antagonist, rauwolfia alkaloid, a centrally acting alpha-adrenergic agonist, a calcium-channel blocker, an angiotensin converting enzyme (ACE) inhibitor, a vasodilator, a gangion blocker, an angiotensin II receptor blocker (ARB), a renin inhibitor, an advanced glycation end product crosslink breaker, an endothelin receptor antagonists, and a diuretic.

3. The composition of claim 1, wherein said anti-obesity agent does not substantially increase blood pressure.

4. The composition of claim 1, wherein said anti-obesity agent further comprises a mu-opioid receptor antagonist, or a metabolite, prodrug or pharmaceutically acceptable salt thereof.

5. The composition of claim 4, wherein the mu-opioid receptor antagonist is selected from alvimopan, norbinaltorphimine, nalmefene, naloxone, naltrexone, methylnaltrexone, and nalorphine.

6. The composition of claim 1, wherein said bupropion is a prodrug, metabolite, or pharmaceutically acceptable salt thereof.

7. The composition of claim 5, wherein the mu-opioid receptor antagonist is naltrexone.

8. The composition of claim 7, wherein at least one of said bupropion and said naltrexone is a controlled release formulation.

9. The composition of claim 8, wherein said bupropion and said naltrexone are in a single dosage form.

10. The composition of claim 7, wherein said composition is a single dosage form, and at least one of said anti-hypertensive agent, said bupropion, and said naltrexone is a controlled release formulation.

11. The composition of claim 7, wherein said naltrexone is a metabolite, prodrug, or pharmaceutically acceptable salt thereof.

12. The composition of claim 1, wherein said anti-obesity agent further comprises at least one of zonisamide and topiramate.

13. The composition of claim 12, wherein said anti-obesity agent comprises zonisamide.

14. The composition of claim 13, wherein at least one of said bupropion and said zonisamide is a controlled release formulation.

15. The composition of claim 14, wherein said bupropion and said zonisamide are in a single dosage form.

16. The composition of claim 13, wherein said zonisamide is a metabolite, prodrug, or pharmaceutically acceptable salt thereof.

17. The composition of claim 13, wherein said composition is a single dosage form, and at least one of said anti-hypertensive agent, said bupropion, and said zonisamide is a controlled release formulation.

18. A method of treating hypertension in an overweight or obese patient, comprising: identifying a patient that is hypertensive and overweight or obese; and administering to said patient a composition comprising a first ingredient and a second ingredient, wherein the first ingredient comprises at least one antihypertensive agent and the second ingredient comprises at least one anti-obesity agent, and wherein said anti-obesity agent comprises bupropion.

19. The method of claim 18, wherein said anti-hypertensive agent is selected from the group comprising a beta-blocker, an alpha-adrenergic receptor antagonist, an alpha and beta-blocker, an adrenergic neuron antagonist, rauwolfia alkaloid, a centrally acting alpha- adrenergic agonist, a calcium-channel blocker, an angiotensin converting enzyme (ACE) inhibitor, a vasodilator, a gangion blocker, an angiotensin II receptor blocker (ARB), and a diuretic.

20. The method of claim 18, wherein said anti-obesity agent does not substantially increase blood pressure.

21. The method of claim 18, wherein said bupropion is a prodrug, metabolite, or pharmaceutically acceptable salt thereof.

22. The method of claim 18, wherein said anti-obesity agent further comprises a mu-opioid receptor (MOP) antagonist, or a metabolite, prodrug or pharmaceutically acceptable salt thereof.

23. The method of claim 22, wherein the mu-opioid receptor antagonist is selected from alvimopan, norbinaltorphimine, nalmefene, naloxone, naltrexone, methylnaltrexone, and nalorphine.

24. The method of claim 23, wherein the mu-opioid receptor antagonist is naltrexone.

25. The method of claim 24, wherein at least one of said bupropion and said naltrexone is a controlled release formulation.

26. The method of claim 25, wherein said bupropion and said naltrexone are in a single dosage form.

27. The method of claim 24, wherein said composition is a single dosage form, and at least one of said anti-hypertensive agent, said bupropion, and said naltrexone is a controlled release formulation.

28. The method of claim 24, wherein said naltrexone is a metabolite, prodrug or pharmaceutically acceptable salt thereof.

29. The method of claim 18, wherein said anti-obesity agent further comprises at least one of zonisamide and topiramate.

30. The method of claim 29, wherein said anti-obesity agent comprises zonisamide.

31. The method of claim 30, wherein at least one of said bupropion and said zonisamide is a controlled release formulation.

32. The method of claim 31, wherein said bupropion and said zonisamide are in a single dosage form.

33. The method of claim 30, wherein said composition is a single dosage form, and at least one of said anti-hypertensive agent, said bupropion, and said zonisamide is a controlled release formulation.

34. The method of claim 30, wherein said zonisamide is a metabolite, prodrug or pharmaceutically acceptable salt thereof.