WO2008070308A2

WO2008070308A2 - Method and composition of a carminative herb or natural supplement to decrease the adverse effects of orlistat, an oral lipase inhibitor, and a method with formulations to concurrently reduce fracture risk and insure appropriate fatsoluble vitamin supplementation when using orlistat, an oral lipase inhibitor, and a method o

Info

Publication number: WO2008070308A2
Application number: PCT/US2007/082062
Authority: WO
Inventors: Md Ronald J. Thompson
Original assignee: Thompson Md Ronald J
Priority date: 2006-10-24
Filing date: 2007-10-22
Publication date: 2008-06-12
Also published as: WO2008070308A3

Abstract

A medicament to decrease the adverse events of Orlistat, an oral lipase inhibitor, arranged to be taken in combination with Orlistat, comprising: an admixture of carminative herbs and one or more chelating agents to absorb and mechanically agitate non-digested fats. Orlistat, being an oral lipase inhibitor, blocks the absorption of ingested fats from the small intestines, to enable proven weight loss. Fat-soluble vitamin deficiencies can be a consequence of orlistat use, especially if used for a long time without medical supervision. The present invention comprises a fat-soluble-only vitamin complex, specifically for use with orlistat, which vitamin complex contains a significantly increased amount of vitamin D, to prevent osteoporosis and to reduce fracture risk. A method of using orlistat for reducing ghrelin levels in a human body to facilitate weight reduction and to permanently reduce appetite and eliminate weight regain by the step of orally ingesting tetrahydrolipstatin - THL (Orlistat) on a regular basis for a period of at least one to two years.

Description

METHOD AND COMPOSITION OF A CARMINATIVE HERB OR NATURAL SUPPLEMENT TO DECREASE THE ADVERSE EFFECTS OF ORLISTAT. AN ORAL LIPASE INHIBITOR. AND A METHOD WITH FORMULATIONS TO CONCURRENTLY REDUCE FRACTURE RISK AND INSURE APPROPRIATE FAT- SOLUBLE VITAMIN SUPPLEMENTATION WHEN USING ORLISTAT. AN ORAL LIPASE INHIBITOR. AND A METHOD OF USING ORAL LIPASE INHIBITORS TO REDUCE PLASMA GHRELIN AND TO PREVENT WEIGHT REGAIN

Field of the Invention

This invention relates to medicaments and more particularly to herbs and nutritional supplements for use in weight loss programs and further for improvements in the use of a pharmaceutical known as orlistat, and this invention also relates to improving the use of Orlistat in human consumption, and help vitamin absorption during such use thereof, and also includes a method of reducing ghrelin levels in a human body for weight reduction and to permanently reduce appetite and eliminate weight regain by the step of orally ingesting tetrahydrolipstatin - THL (Orlistat) on a regular basis for a period of at least one to two years. Background of the Invention and Prior Art

Orlistat is the generic name for Xenical® (Roche), a prescription lipase inhibitor, FDA approved for weight loss and obesity management. Lipase is the pancreatic enzyme that breaks down ingested fats into small chain fatty acids in the lower lumen of the stomach, and the small intestine. By inhibiting the actions of the lipase enzyme, ingested fats cannot be absorbed, and weight loss naturally occurs. The problem with Olistat treatment is, the most undesirable side effects are caused by the passage of the undigested fats through the gastrointestinal tract! The Physicians Desk Reference lists the adverse events (side effects) of Olistat clinical trials on over 2800 patients for one or two years as: Upper gastrointestinal adverse events

Abdominal pain/discomfort 25.5%

Nausea 8.1% Lower gastrointestinal adverse events

Oily spotting 26.6%

Flatus - with discharge 23.9%

Fecal urgency 22.1%

Fatty/oily stool 26.0% Oily evacuation 11.9%

Increased defecation 10.8%

Fecal incontinence 7.7%

Orlistat, as a lipase inhibitor, creates a mal-absorption state, where ingested fats are not absorbed by the intestine, and therefore must be eliminated through the lower intestine and rectum. All of the adverse events are directly caused by the elimination of large sized fat globules.

The chemical name for Orlistat is tetrahydrolipstatin. U.S. Patent 4,598,089 issued July 1, 1986, incorporated herein by reference in its entirety, defines tetrahydrolipstatin, and teaches its unique lipase inhibitor actions. These actions are further defined in U.S. Patents 5,245,056 and 5,399,720, (both incorporated herein by reference), to treat obesity and various medical conditions associated with obesity, specifically diabetes and hypertension. U.S. Patent 6,696,467, (incorporated herein by reference) further teaches and defines the specific benefits of the lipase inhibitor tetrahydrolipstatin for the treatment of obesity by weight reduction and appetite suppression. U.S. Patent 6,004,996 (incorporated herein by reference), describes the production of tetahydrolipstatin into microspheres for optimal therapeutic delivery into the lumen of the stomach. These microspheres have a very efficient action as a lipase inhibitor, because of the large surface area to bind to the lipase enzyme.

Detailed Description of the Present Invention The present invention comprises a medicament arrangement to decrease the adverse effects caused by the pharmaceutical agent Orlistat in weight loss therapy. A carminative herb is an herb or nutritional supplement that is utilized to improve digestion or to treat dyspepsia or irritable bowel symptoms of ulcerative colitis. These carminative herbs, usually in a combination with other carminative herbs have heretofore been used to improve digestion and to treat maladies of specific organs in the digestive system, such as gall bladder, pancreas, liver, stomach or intestines both large and small. Carminative herbs however, have not been employed or utilized to treat the side effects or adverse events of specific weight loss medications. Such surprising results when used in combination with the use of the weight loss drug Orlistat, offers the consumer an opportunity to avoid such problems realized when Orlistat is used by itself.

A list of "carminative" herbs, used as herbs or admixed with other herbs to prepare an herbal or nutritional supplement medicament is: Mentha Spicata (peppermint); Zingiber Offinate (ginger); Foeniculum Vulgare (fennel); Pimpinella Anisum (anise); Melissa Officinalis (lemon balm); Taraxacum Officinale (dandelion);Aloe Vera (aloe); Iberis Amara (candy tuft); Valeriana Officinaus (valerian); Carbo Vegetabilius; Nux Vomica; Chamomilla; Fennel Seed; Caraway Seed; Clove Oil; Wormwood Oil; Dill Oil; Turmeric Oil; Barberry; Bitter Orange; Blessed Thistle; Cardamom; Centaury; Chicory; Cinnamon; Coriander; Denil's Claw; Gentian; Horehound; Juniper; Linden; Milk Thistle; Radish; Rosemary; Sage; St John's Wort; Varrom; Capsaicin; Artichoke Leaf Extract; Boldo; Cayenne and Banana Powder.

It is certain that several of the carminative herbs have a surfactant-like action to emulsify fats. The emulsification of fats to prevent the formation of large globules is the method to treat or even prevent some of the listed adverse events of Orlistat therapy.

A method of decreasing the adverse effects of orlistat uses naturalized bowel relaxation in addition to specific emulsifier simethicone and chelating/mechanical agitator agents, activated charcoal and methyl cellulose. Chelating Agents as Mechanical Activators

Once in a small enough physical state by the actions of the emulsifying agent, the chelating agent will absorb the undigested unabs orbed fat from the stomach and small intestine to decrease Orlistat related adverse events. The hallmark chelating agent in treatment of toxic poisoning is activated carbon (activated charcoal). Activated carbon is not absorbed, but remains in the gastrointestinal tract and eliminated with bowel movements. The activated carbon will chelate free fats in the gastrointestinal lumens. A second chelating agent is cellulose or methylcellulose, a non-fermentable fiber that will, like activated carbon, chelate the small emulsified fats that result from orlistat therapy. Any chelating agent could be utilized, but for example, activated carbon and methylcellulose are the most effective and are thus the preferred substances here.

A second mode of action of the chelating agents, activated charcoal, is to physically and mechanically decrease the surface tension of undigested fats. This is a mechanism which have the inert granules and methylcellulose fibers are kept in a churning motion in the small intestine by the inherent peristalsis of the circular smooth muscles of the small intestines. This churning motion mechanically disrupts the formation of large fat globules. The two mechanisms to decrease surface tension, chemical and mechanical, synergistically function to prevent the formation of large fat globules, the pathogenesis of the adverse effects of Orlistat.

The present invention is also represented through the figures 1, 2 and 3. In figure 1, the Lipase enzyme is released and breaks down the fat in the stomach, allowing that fat to be absorbed in the bloodstream in a normal manner. In figure 2, Olistat, the chemical name for products such as Xenical® and Alii™ are shown blocking the Lipase enzyme which prevents the absorption of fat. This also allows the formation of large fat globules. Figure 3 represents the blocking of the Lipase enzyme by Xenical or AlIi, preventing the absorption of fat, with the present invention, a carminative herb admixture and chelating agent/mechanical agitator preventing the formation of large fat globules. The invention thus comprises a medicament to decrease the adverse events of Olistat, an oral lipase inhibitor, in combination with Olistat, comprising: a carminative herb; a surfactant, and one or more chelating agents to absorb non-digested fats. The surfactant preferably comprises for example, at least one of the following: Simethicone, Stearoxy dimethicone, Dimethicone, Methicone, Amino bispropyl dimethicine, Amino propyl dimethicine, Amodimethicone, Amodimethicine hydroxysterate, Dehyroxy dimethricine, C24-28 alkyl methicine, C30-45 alkyl methicine, C30-45 alkyl dimethicine, Certearyl methicine and Cetyl Dimethicine. The carminative agent preferably comprises for example, at least one of the following: Mentha Spicata (peppermint), Zingiber Offinate (ginger), Foeni-culum Vulgare (fennel), Pimpinella Anisum (anise), Melissa Officinalis (lemon balm), Taraxacum Officinale (dandelion), Aloe Vera (aloe), Iberis Amara (candy tuft), Valeriana Officinaus (valerian), Carbo Vegetabilius, Nux Vomica, Chamomilla, Fennel Seed, Caraway Seed, Clove Oil, and Wormwood Oil. The carminative agent preferably comprises for example, at least one of the following: Dill Oil, Turmeric Oil, Barberry, Bitter Orange, Blessed Thistle, Cardamom, Centaury, Chicory, Cinnamon, Coriander, Denil's Claw, Gentian, Horehound, Juniper, Linden, Milk Thistle, Radish, Rosemary, Sage, St John's Wort, Varrom, Capsaicin, Artichoke Leaf Extract, Boldo, Cayenne or Banana Powder. The chelating agents preferably comprise at least one of the following: Peppermint, Activated Carbon and Methyl cellulose. The chelating agents are for example, taken in the following ranges, said Peppermint 90 mg/capsule 50 - 200 mg; said Activated Carbon 300 mg/capsule 100-500 mg, and said Methyl cellulose 200 mg/ capsule 100-400 mg,

The invention also comprises a medicament to decrease the adverse events of Olistat, an oral lipase inhibitor, in combination with Olistat, comprising for example: a carminative agent comprising at least one of: Mentha Spicata (peppermint), Zingiber Offinate (ginger); Foeniculum Vulgare (fennel); Pimpinella Anisum (anise), Melissa Officinalis (lemon balm), Taraxacum Officinale (dandelion), Aloe Vera (aloe), Iberis Amara (candy tuft), Valeriana Officinaus (valerian), Carbo Vegetabilius, Nux Vomica, Chamomilla, Fennel Seed, Caraway Seed, Clove Oil, Wormwood Oil, and an emulsifier comprised of at least one of the following: Simethicone, Stearoxy dimethicone, Dimethicone, Methicone, Amino bispropyl dimethicine, Amino propyl dimethicine, Amodimethicone, Amodimethicine hydroxysterate, Dehyroxy dimethricine, C24-28 alkyl methicine, C30-45 alkyl methicine, C30-45 alkyl dimethicine, Certearyl methicine and Cetyl Dimethicine; and one or more chelating agents to absorb non-digested fats, wherein said chelating agent comprises at least one of the following: Activated Carbon and Methyl cellulose.

The invention also comprises a method to decrease the adverse events of Olistat, an oral lipase inhibitor, comprising one or more of the following steps: taking orally Olistat and a compound of an emulsifier, a carminative agent and at least one chelating agent to absorb non-digested fats; and mechanically agitate said fats by said chelating agent. The agent is preferably for example, one or more of the following: Simethicine, Peppermint, Activated Carbon and Methyl cellulose. Olistat is tetrahydrolipstatin. The carminative agent is selected for example from one or more of the following: Mentha Spicata (peppermint), Zingiber Offinate (ginger); Foeniculum Vulgare (fennel); Pimpinella Anisum (anise), Melissa Officinalis, (lemon balm), Taraxacum Officinale (dandelion), Aloe Vera (aloe), Iberis Amara, (candy tuft), Valeriana Officinaus (valerian), Carbo Vegetabilius, Nux Vomica, Chamomilla, Fennel Seed, Caraway Seed, Clove Oil and Wormwood Oil. The carminative agent comprises for example, at least one of the following: Dill Oil, Turmeric Oil, Barberry, Bitter Orange, Blessed Thistle, Cardamom, Centaury, Chicory, Cinnamon, Coriander, Denil's Claw, Gentian, Horehound, Juniper, Linden, Milk Thistle, Radish, Rosemary, Sage, St John's Wort, Varrom, Capsaicin, Artichoke Leaf Extract, Boldo, Cayenne and Banana Powder.

Further improvements to the use of orlistat (#2A) Three factors in the use of Orlistat, which are inter-related but their relative associations are not understood or appreciated by the medical and scientific community. Orlistat, an oral lipase inhibitor can induce vitamin deficiency; Overweight, or obesity, is itself a risk factor for the developing osteoporosis and increasing fracture risk; Current recommendations for vitamin supplementation are inadequate to prevent fracture risk and fractures.

Orlistat an oral lipase inhibitor, can induce a vitamin deficiency

Webster defines a vitamin as "any group of organic substances essential in small quantities to normal metabolism, found in minute amounts in natural foodstuffs, and also produced synthetically: deficiencies of vitamins produce specific disorders".

There are two different classifications for vitamins, fat-soluble and water-soluble vitamins. The fat-soluble vitamins are A, D, E, K and beta carotene. The water-soluble vitamins are Bl, B2, B3, B6, B 12, C, G, H, Kl, K2, K3, M and P. Because orlistat is an oral lipase inhibitor and can prevent the absorption of 25 to 35

% of ingested fats, the U.S. FDA recommends multivitamin supplements while using orlistat, to prevent a vitamin deficiency of the fat soluble vitamins. In the April 26, 1999 press release by the U.S. FDA, "FDA approves Orlistat for obesity", the final paragraph of the press release states, "Because orlistat reduces the absorption of some fat-soluble vitamins and beta-carotene, patients should take a supplement that contains fat-soluble (A,D, E and K) vitamins and beta carotene".

In product labeling for XENICAL® (120 mg orlistat) the directions for use state to ingest a multi-vitamin supplement two hours before or after ingesting XENICAL®. All currently marketed multi-vitamin supplements contain both fat-soluble and water soluble vitamins. There is currently no fat-soluble-only vitamin complex marketed.

Overweight, or obesity is itself a risk factor for developing osteoporosis and increasing fracture risk.

In the medical publication "Risk factors for vitamin D inadequacy among women with osteoporosis: an international epidemiological study "reported in the August 2006 International Journal of Clinical Practice, Dr. Rozzoli et al concluded, "Amongst 2589 women with osteoporosis... recruited to determine risk factors for vitamin D inadequacy, 64% had vitamin D inadequacy. Asian ethnicity, BMI greater than or equal to 30 Kg/M2, (The definition of overweight or obesity), living in non-equitorial countries, inadequate vitamin D supplementation, poor/fair health, no education about vitamin D, skin reactivity and no recent travel to sunny areas were significant predictors."

To better understand the defined risk factors for vitamin D inadequacy as documented by Dr. Rozzoli et al, it is first necessary to define vitamin D. Vitamin D is "any of the several fat-soluble, antirackitic (anti-ricketts) vitamins D 1, D 2, D 3, occurring in milk and fish-liver oils, especially cod and halibut; essential for the formation of normal bones and teeth."

Vitamin D l : a form of vitamin D obtained by ultraviolet irradiation of ergosterol; ultraviolet irradiation - exposure to sunlight - cutaneous (skin) conversion of ergosterol into vitamin D; ergosterol - a synthesized result of cholesterol ingestion of dietary fats.

Vitamin D 2 - the fat soluble predominant form of vitamin D absorbed from dietary fats - calciferol.

Vitamin D 3 - a form of vitamin D occurring in fish-liver oils that differs slightly in structure from vitamin D 2. Being overweight, or obese, with a BMI (Body Mass Index) of greater than or equal to 30 (Kg/m2) is itself a risk factor for vitamin D inadequacy. Therefore, a person on Orlistat therapy has two risk factors for vitamin D inadequacy, the inherent risk of being overweight or obese, and the imposed risk of decreased absorption of both vitamin D 2 and D 3, and the decreased absorption or ergosterol, the substrate necessary to synthesize vitamin D 1.

Current recommendations for vitamin D supplementations are inadequate to prevent fracture risk and fractures.

The current US FDA recommendation for vitamin D intake/supplementation is 400 IU per day. Multiple recently published medical articles have recommended 800 to 1000 IU of daily vitamin D intake/supplementation to reduce osteoporosis and fracture risk.

Dr. Bischoff-Ferrori et al in the May 2005 JAMA article "Fracture prevention with vitamin D supplementation "a meta-analysis of randomized controlled trials" concluded "an oral vitamin D dose of 400 IU/day is not sufficient for fracture prevention." This conclusion was powered by multiple double blind, placebo controlled studies of almost ten thousand participants over thirty years of evaluation. Dr. R Vieth reported that four randomized, placebo controlled clinical trials demonstrated that this dose (800 IU/day of vitamin D) prevents approximately 30% of hip or on-vertebral fractures compared to placebo. "This was reported in the 2005 (37-4) Annals of Medicine article, "The role of vitamin D in the prevention of osteoporosis."

In the journal Current Osteoporosis Research, Sept. 2006, De MF Holick states, "Vitamin D inadequacy is pandemic in adults. Vitamin D deficiency causes osteopenia, precipitates and exacerbates osteoporosis, causes painful bone disease osteomalacia, and increases muscle weakness, which worsens the risk of falls and fractures." In "The role of vitamin D for bone health and fracture prevention." Dr. S. Boonen et al in "calcium and vitamin D in the prevention and treatment of osteoporosis - a clinical update" from June 2006 Journal of Internal Medicine reports "evidence based benefits are most apparent when 800 IU/day of vitamin D is complimented with a dose of 1000-1200 mg per day of elemental calcium." Dr. Boonen also writes, "The types of individuals who should receive vitamin D supplements are: (i) patients with documented osteoporosis receiving antiresorptive or anabolic treatment; (ii) patients receiving gluco corticoids; and (iii) individuals with or at high risk of calcium and or vitamin D insufficiencies in particular older men and women."

In this statement, Dr. Boonen defines the high risk groups for vitamin D inadequacy and osteoporosis, but does not include individuals on Orlistat therapy. Orlistat therapy and the generalized recommendation of a multivitamin supplementation including fat-soluble vitamins by the FDA, does not recognize the specific risks of inadequate vitamin D supplementation, osteoporosis, fracture risk and fractures. To document the specific risks of orlistat, relative to osteoporosis and vitamin D deficiency, a search was accomplished in the National Library of Medicine and the National Institutes of Health data bases, (www.PIJBMED.com). The specific searches: "osteoporosis risk factor for Orlistat" - No items found; "vitamin D deficiency risk factor for Orlistat" - No items found.

Therefore, the medical community and the medical literature does not identify Orlistat therapy as a specific risk factor for vitamin D deficiency or osteoporosis. This is particularly important because of two future occurrences. One, Orlistat therapy is available as an over-the-counter product, and two, long term Orlistat therapy, of greater than two or three years duration, will be marketed to prevent weight regain, after the discontinuance of Orlistat. Both of these facts will amplify the increased risks of vitamin D deficiency on Orlistat therapy, and the associated increased fracture risks and fractures.

Further Description of the Present Invention (#2)

The invention also comprises a fat-soluble-only vitamin complex containing vitamin A, D, E, K, and beta carotene, without water soluble vitamins, to be orally ingested during Orlistat therapy for weight loss. The fat-soluble vitamin complex will be ingested two hours before or two hours after Orlistat dosing as is currently recommended for a multivitamin with water-soluble vitamins included. In addition, the vitamin D component of the fat-soluble-only vitamin complex, would reflect a dosage of vitamin D that the recent medical literature has documented to prevent vitamin D inadequacy/insufficiency, osteoporosis risks and fracture risks.

Proposed fat-soluble vitamin complex

Component % FDA recommended of daily need Vitamin A 5000 IU 100% 41% as beta carotene Prevents night blindness

Vitamin D 1000 IU to 1500 IU 250-375%

Prevents osteoporosis

Decreases fracture risks

Vitamin E 45 IU 150%

Anti-oxidant

Prevents premature cell death Vitamin K 80 micrograms 100%

Allows normal coagulation

The invention thus comprises a method of treating fat-soluble vitamin deficiencies in a being under Orlistat treatment therapy, comprising the steps of: ingesting a "fat-soluble- only" vitamin supplement during the period in which the orlistat treatment occurs. The "fat- soluble-vitamin" supplement comprises vitamins A, D, E, K and beta carotene. The "fat- soluble-only" vitamin supplement is preferably taken two hours before or after Orlistat ingestion. The invention also comprises a "fat-soluble-only" vitamin complex for the treatment of vitamin D deficiency effected by ingestion of the lipase-inhibitor treatment Orlistat, including: between 1000 IU and 1500 IU of vitamin D, 5000 IU of vitamin A, 45 IU of vitamin E and 80 micrograms of vitamin K.

Yet further improvements in the use of orlistat (#3) Lipase Inhibitors: Ingested fats are long chain fatty acids that cannot be absorbed in the gastrointestinal system. The presence of food in the stomach signals the release of the lipase enzyme from the pancreas. The lipase enzyme breaks down the long chain fatty acids into short chain fats. The short chain fats are then absorbed from the small intestines into the blood stream. Lipase inhibitors such as orlistat (XENICAL®) (tetrahydrolipstatin - THL) bind to the lipase enzyme and prevent the breakdown of long chain fatty acids. Therefore the fats are not absorbed and passed through the gastrointestinal system as long chain fatty acids.

Ghrelin: Ghrelin is a recently discovered endocrine hormone produced in the stomach and released into the circulatory blood. Ghrelin, in the circulating blood, stimulates Ghrelin- specified receptors in the brain (hypothalamus) that creates a sensation of hunger. Conversely, a reduced ghrelin level in blood level creates the sensation of satiety, therefore creates appetite reduction. Endocrine verses Exocrine Endocrine hormones like thyroid, insulin, estrogen, testosterone, progesterone and ghrelin are produced in specific endocrine cells. These hormone-specific cells produce a single type of hormone. The hormone is released into the circulating blood and therefore available to all cells of the body, but only exerts an effect on tissues that are target-specific for that hormone. The ghrelin-specific target tissue is the (brain) hypothalamus. In the hypothalamus, a high concentration of ghrelin stimulates hunger and appetite. Conversely, a low concentration of ghrelin is perceived as satiety, or the lack of hunger and appetite. Exocrine, or secretory cells, line the digestive and respiratory systems. In the digestive tract, these secretory cells release their secretions into the lumen of the hollow viscus to admix with food to accomplish digestion. After digestion of food occurs, the blood vessels absorb the nutrients and circulate these nutrients, including short chain fats and carbohydrates to all cells of the body.

The stomach as well as part of the small intestines contain both endocrine and exocrine cells. Exocrine cells produce digestive enzymes. Stomach endocrine cells produce ghrelin, cholecystokenin, PPY, pancreatic peptide (PP) and other hormones that help in digestion of food. Cholecystokenin for example, is produced in stomach wall specified endocrine cells, released into the circulating blood, and has a targeted effect on the gallbladder to contract and therefore release the bile stored in the gallbladder into the stomach. The bile aids in digestion of fats, and a high fat content meal is associated with an abundant release of cholecystokenin and bile. Ghrelin production, stimulation of ghrelin release and down regulation are not yet well understood by medical science.

Dr. KL Gettinn, in the article entitled "Effect of fatty acid chain length on suppression of ghrelin and stimulation of PYY, GLP -2 and PP Secretion in Healthy Men," published in the July 2006 journal PEPTIDES, states "We conclude that the effects of intraduodenal fatty acids on ghrelin,

PYY and GLP -2 secretion are dependent on their chain length." Each article cited hereinabove incorporated herein by reference.

Therefore, the increased percentage of long chain fatty acids reduces the serum ghrelin level, and since Orlistat increases the percentage of long chain fatty acids, Orlistat can be expected to reduce the serum ghrelin. With continuous "long-term" use of Orlistat, the endocrine cells that produce ghrelin in the stomach and small intestines can be now, under the current invention, be expected to atrophy. With atrophied ghrelin cells, appetite would be decreased because of the decreased serum ghrelin. With long-term Orlistat use, the atrophied ghrelin cells, decreased appetite because of the decreased ability to produce ghrelin post orlistat therapy, all would translate to decreased weight regain after such Orlistat therapy for at least about two years. Indeed, the "package insert" documents the lack of weight regain after Orlistat therapy, but fails to recognize, anticipate, expect or appreciate the present invention which requires the need to stay on the Orlistat therapy for the long term, which in this invention is at least about two years, so as to permanently atrophy the endocrine cells which would otherwise generate more ghrelin!

XENICAL® (2005 Physician's Desk Reference) Effect on Weight Regain, and incorporated herein by reference, recites as follows: "In study 14119C patients treated with placebo regained 52% of the weight they had previously lost while the patients treated with XENICAL® regained 26% of the weight they had lost (pO.001)." "In study 14185, patients treated with placebo regained 63% of the weight they had previously lost while patients treated with XENICAL® regained 35% of the weight they had lost (p<0.001)." "In study 14302, patients treated with placebo regained 53% of the weight they had previously lost while the patients treated with XENICAL® regained 32% of the weight that they had lost (p<0.001)."

Serum ghrelin determinations were not preformed in any of the XENICAL® weight regain studies referenced above, which cited studies are incorporated herein by reference. Ghrelin was not even discovered until several years after these studies were published. Therefore, we inventively stipulate that the "mechanism of action" of the long term use (at least about two years) of Orlistat for associated prevention of weight regain is the actual "atrophy of the ghrelin-producing cells". Description of the Drawings

The objects and advantages of the present invention relative to Grehlin concerns will become more apparent when viewed in conjunction with the following drawings in which: Figure 1 represents a cross-sectional view of a normal human stomach before any

Orlistat therapy;

Figure 2 represents a cross-sectional view of that normal human stomach after six months of Orlistat therapy, displaying a shrinkage thereof;

Figure 3 represents a cross-sectional view of that normal human stomach after twelve months of Orlistat therapy, displaying a further shrinkage thereof;

Figure 4 represents a cross-sectional view of normal human stomach in a "pre- prandial" state, with a circle placed thereon to designate a subsequently viewed enlarged portion thereof;

Figure 5 represents the enlarged portion shown within the drawing of figure 4, with large plump ghrelin cells, showing abundant ghrelin hormone production released into the bloodstream from ghrelin cells, the ghrelin circulating towards the hydrothalmus to stimulate an appetite;

Figure 6 represents a cross-sectional view of a pre-prandial stomach after six months of Orlistat therapy, with a circle placed thereon to designate a subsequently viewed enlarged portion thereof;

Figure 7 represents a cross-sectional view of a pre-prandial stomach shown after twelve months of Orlistat therapy, and the Orlistat therapy has been discontinued after such a minimum portion of the inventive period, with a circle placed thereon to designate a subsequently viewed enlarged portion thereof; and Figure 8 represents the enlarged portion of figure 7 within the circle, showing ghrelin cells with some atrophied to a very small state, and most ghrelin cells completely atrophic which cannot now produce ghrelin, and showing very little ghrelin hormones circulating in the bloodstream, thereby decreasing appetite, all of which comprises the etiology of reduced weight regain after such inventive prolonged Orlistat therapy. Description of the Present Invention relative to Grehlin production

The present invention relative to Grehlin production comprises the use of long-term orlistat therapy (of several years duration) to: depress the serum ghrelin level by presenting long chain fatty acids to the stomach and duodenum; induce ghrelin cell atrophy; reduce post-Orlistat therapy ghrelin production, to reduce post-orlistat ghrelin associated appetite so as to prevent post Orlistat weight regain. The present invention covers a method of depressing serum ghrelin levels in a body and thereby atrophying ghrelin cells by the oral intake of Orlistat over a minimum time period. Such methodology is represented in the drawings in figures 1 through 8, wherein Figure 1 represents a cross-sectional view of a normal human stomach before any Orlistat therapy; Figure 2 represents a cross-sectional view of that normal human stomach shown in figure 1, after six months of Orlistat therapy, displaying a shrinkage thereof; Figure 3 represents a cross-sectional view of that normal human stomach shown in figure 1 after twelve months of Orlistat therapy, displaying a further shrinkage thereof; Figure 4 represents a cross-sectional view of normal human stomach in a "pre-prandial" or "pre-meal" state, with a circle placed thereon to designate a subsequently viewed enlarged portion thereof; Figure 5 represents the enlarged portion shown within the drawing of figure 4, with large plump ghrelin cells, with abundant ghrelin hormone production released into the bloodstream from the ghrelin cells, the ghrelin circulating towards the hydrothalmus to stimulate an appetite; Figure 6 represents a cross- sectional view of a pre-prandial stomach after six months of Orlistat therapy, with a circle placed thereon to designate a subsequently viewed enlarged portion thereof; Figure 7 representing a cross-sectional view of a pre-prandial stomach shown after twelve months of Orlistat therapy, and the Orlistat therapy has been discontinued after such a minimum inventive period, with a circle placed thereon to designate a subsequently viewed enlarged portion thereof; and wherein Figure 8 representing the enlarged portion of figure 7 within the circle, showing ghrelin cells with some atrophied to a very small state, and most ghrelin cells completely atrophic, thereby now failing to produce ghrelin, and showing very little ghrelin hormones circulating in the bloodstream, thereby decreasing appetite, all of which comprises the etiology of reduced weight regain after such inventive prolonged Orlistat therapy. The invention is thus a method of depressing serum ghrelin levels in a body by the step of: ingesting daily a compound of tetrahydrolipstatin (THL) for a period of at least one and preferably about two years. The invention includes a method of atrophying ghrelin levels in a human body for weight reduction and to permanently reduce appetite and eliminate weight regain by the step of: orally ingesting an admixture of tetrahydrolipstatin - THL on a regular basis for a period of at least eighteen months. The trahydrolipstatin comprises Orlistat. The invention also comprises a method of reducing post Orlistat therapy ghrelin production and eliminating associated weight regain by: maintaining an Orlistat therapy program for a period of at least about two years.

Claims

Claims:

1. A medicament to decrease the adverse events of Olistat, an oral lipase inhibitor, in combination with Olistat, comprising: a carminative herb; an surfactant, and one or more chelating agents to absorb non- digested fats.

2. The medicament as recited in claim 1, wherein said surfactant comprises at least one of the following: Simethicone, Stearoxy dimethicone, Dimethicone, Methicone, Amino bispropyl dimethicine, Amino propyl dimethicine, Amodimethicone, Amodimethicine hydroxysterate, Dehyroxy dimethricine, C24-28 alkyl methicine, C30-45 alkyl methicine, C30-45 alkyl dimethicine, Certearyl methicine and Cetyl Dimethicine.

3. The medicament as recited in claim 2, wherein said carminative agent comprises at least one of the following: Mentha Spicata (peppermint); Zingiber Offinate (ginger); Foeniculum Vulgare (fennel); Pimpinella Anisum (anise); Melissa Officinalis (lemon balm); Taraxacum Officinale (dandelion); Aloe Vera (aloe); Iberis Amara (candy tuft); Valeriana Officinaus (valerian); Carbo Vegetabilius; Nux Vomica; Chamomilla; Fennel Seed; Caraway Seed;

Clove Oil and Wormwood Oil.

4. The medicament as recited in claim 2, wherein said carminative agent comprises at least one of the following: Dill Oil; Turmeric Oil; Barberry Bitter Orange; Blessed Thistle; Cardamom; Centaury; Chicory; Cinnamon;

Coriander; Denil's Claw; Gentian; Horehound; Juniper; Linden; Milk Thistle; Radish; Rosemary; Sage; St John's Wort; Varrom; Capsaicin; Artichoke Leaf Extract; Boldo; Cayenne and Banana Powder.

5. The medicament as recited in claim 1, wherein said chelating agents comprises at least one of the following: Peppermint, Activated Carbon and Methyl cellulose.

6. The medicament as recited in claim 5, wherein said agents are in the following ranges, said Peppermint 90 mg/capsule 50 - 200 mg; said Activated Carbon 300 mg/capsule 100-500 mg, and said Methyl cellulose 200 mg/ capsule 100-400 mg.

7. A medicament to decrease the adverse events of Olistat, an oral lipase inhibitor, in combination with Olistat, comprising: a carminative agent comprising at least one of: Mentha Spicata (peppermint), Zingiber Offinate (ginger); Foeniculum Vulgare (fennel); Pimpinella Anisum (anise), Melissa Officinalis (lemon balm), Taraxacum Officinale (dandelion), Aloe Vera (aloe), Iberis Amara (candy tuft), Valeriana Officinaus (valerian), Carbo Vegetabilius, Nux Vomica, Chamomilla, Fennel Seed, Caraway Seed, Clove Oil,

Wormwood Oil, and an emulsifier comprised of at least one of the following: Simethicone, Stearoxy dimethicone, Dimethicone, Methicone, Amino bispropyl dimethicine, Amino propyl dimethicine, Amodimethicone, Amodimethicine hydroxysterate, Dehyroxy dimethricine, C24-28 alkyl methicine, C30-45 alkyl methicine, C30-45 alkyl dimethicine, Certearyl methicine and Cetyl Dimethicine; and one or more chelating agents to absorb non-digested fats, wherein said chelating agent comprises at least one of the following: Activated Carbon and Methyl cellulose.

8. A method to decrease the adverse events of Olistat, an oral lipase inhibitor, comprising: taking orally Olistat and a compound of an emulsifier, a carminative agent and at least one chelating agent to absorb non-digested fats; and mechanically agitate said fats by said chelating agent.

9. The method as recited in claim 8, wherein said agent is one or more of the following: Simethicine, Peppermint, Activated Carbon and Methyl cellulose.

10. The method of claim 8, wherein Olistat is tetrahydrolipstatin.

11. The method of claim 8, wherein said carminative agent is selected from one or more of the following: Mentha Spicata (peppermint), Zingiber Offinate (ginger); Foeniculum Vulgare (fennel); Pimpinella Anisum (anise), Melissa Officinalis (lemon balm), Taraxacum Officinale (dandelion), Aloe Vera (aloe), Iberis Amara

(candy tuft), Valeriana Officinaus (valerian), Carbo Vegetabilius, Nux Vomica, Chamomilla, Fennel Seed, Caraway Seed, Clove Oil and Wormwood Oil.

12. The method of claim 8, wherein said carminative agent comprises at least one of the following: Dill Oil, Turmeric Oil, Barberry, Bitter Orange, Blessed Thistle,

Cardamom, Centaury, Chicory, Cinnamon, Coriander, Denil's Claw, Gentian, Horehound, Juniper, Linden, Milk Thistle, Radish, Rosemary, Sage, St John's Wort, Varrom, Capsaicin, Artichoke Leaf Extract, Boldo, Cayenne and Banana Powder.

13. A method of treating fat-soluble vitamin deficiencies in a being under Orlistat treatment therapy, comprising: ingesting a "fat-soluble-only" vitamin supplement during the period in which the orlistat treatment occurs.

14.The method as recited in claim 13, wherein said "fat-soluble-vitamin" supplement comprises vitamins A, D, E, K and beta carotene.

15. The method as recited in claim 13, wherein said "fat-soluble-only" vitamin supplement is taken two hours before or after Orlistat ingestion.

16. A "fat-soluble-only" vitamin complex for the treatment of vitamin D deficiency effected by ingestion of the lipase-inhibitor treatment Orlistat, including: between 1000 IU and 1500 IU of vitamin D, 5000 IU of vitamin A and 45 IU of vitamin E, and 80 micrograms of vitamin K.

17. A method of depressing serum ghrelin levels in a body by the step of: ingesting daily a compound of tetrahydrolipstatin (THL) for a period of at least two years.

18. A method of atrophying ghrelin levels in a human body for weight reduction and to permanently reduce appetite and eliminate weight regain by the step of: orally ingesting an admixture of tetrahydrolipstatin - THL on a regular basis for a period of at least eighteen months.

19. The method of claim 18, wherein said tetrahydrolipstatin comprises orlistat.

20. A method of reducing post Orlistat therapy ghrelin production and eliminating associated weight regain by: maintaining an Orlistat therapy program for a period of at least two years.

21. The method as recited in claim 20, wherein said Orlistat is ingested daily during or immediately subsequent to a meal.