| Orlistat Pellets |
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| Introduction |
| Orlistat (marketed as a prescription under the trade name Xenical by Roche in most countries, or over-the-counter as Alli by GlaxoSmithKline in the United States), also known as tetrahydrolipstatin, is a drug designed to treat obesity. Its primary function is preventing the absorption of fats from the human diet, thereby reducing caloric intake. It is intended for use in conjunction with a physician-supervised reduced-calorie diet. Orlistat is the saturated derivative of lipstatin, a potent natural inhibitor of pancreatic lipases isolated from the bacterium Streptomyces toxytricini. However, due to simplicity and stability, orlistat rather than lipstatin was developed into an anti-obesity drug.
The effectiveness of orlistat in promoting weight loss is definite, though modest. Pooled data from clinical trials suggest that people given orlistat in addition to lifestyle modifications, such as diet and exercise, lose about 2–3 kilograms (4.4–6.6 lb) more than those not taking the drug over the course of a year. Orlistat also modestly reduces blood pressure, and appears to prevent the onset of type 2 diabetes, whether due to weight loss itself or to other effects; in a large randomized controlled trial, orlistat was found to reduce the incidence of diabetes by nearly 40% in obese people. Orlistat is notorious for its gastrointestinal side effects (sometimes referred to as treatment effects), which can include steatorrhea (oily, loose stools). These decrease with time, however, and are the only significant adverse effects of the drug, which appears to be safe for long-term use. In the United States, the European Union, and Australia, orlistat is available for sale without a prescription. Over-the-counter approval was controversial in the United States, with consumer advocacy group Public Citizen repeatedly opposing it on safety and efficacy grounds. Generics of orlistat are available in India. |
| Pharmacology: |
| Orlistat works by inhibiting gastric and pancreatic lipases, the enzymes that break down triglycerides in the intestine. When lipase activity is blocked, triglycerides from the diet are not hydrolyzed into absorbable free fatty acids, and are excreted undigested instead. Only trace amounts of orlistat are absorbed systemically; the primary effect is local lipase inhibition within the GI tract after an oral dose. The primary route of elimination is through the feces.
At the standard prescription dose of 120 mg three times daily before meals, orlistat prevents approximately 30% of dietary fat from being absorbed,[9] and about 25% at the standard over-the-counter dose of 60 mg. Higher doses do not produce more potent effects. |
| Efficacy: |
| The amount of weight loss achieved with orlistat varies. In one-year clinical trials, between 35.5% and 54.8% of subjects achieved a 5% or greater decrease in body mass, although not all of this mass was necessarily fat. Between 16.4% and 24.8% achieved at least a 10% decrease in body mass. After orlistat was stopped, a significant number of subjects regained weight—up to 35% of the weight they had lost.
The incidence of type 2 diabetes in an obese population over four years is decreased with orlistat (6.2%) compared to placebo (9.0%). Long-term use of orlistat also leads to a modest reduction in blood pressure (mean reductions of 2.5 and 1.9 mmHg in systolic and diastolic blood pressure respectively). |
| Side effects: |
| The primary side effects of the drug are gastrointestinal-related, and include steatorrhea (oily, loose stools with excessive flatus due to unabsorbed fats reaching the large intestine), fecal incontinence and frequent or urgent bowel movements. GlaxoSmithKline recommends that all users be cautious of the possible side effects until they "have a sense of any treatment effects". To minimize these effects, foods with high fat content should be avoided; the manufacturer advises consumers to follow a low-fat, reduced-calorie diet. Oily stools and flatulence can be controlled by reducing the dietary fat content to somewhere in the region of 15 grams per meal. The manual for Alli makes it clear that orlistat treatment involves aversion therapy, encouraging the user to associate eating fat with unpleasant treatment effects.
According to Roche, side effects are most severe when beginning therapy and may decrease in frequency with time; this is supported by the results of the XENDOS study, which found that only 36% of people had gastrointestinal adverse effects during their fourth year of taking orlistat, whereas 91% of study subjects had experienced at least one GI-related side effect during the first year of treatment. It has also been suggested that the decrease in side effects over time may be associated with long-term compliance with a low-fat diet. The side effect profile of orlistat led US consumer group Prescription Access Litigation (PAL) to award its first 2007 "Bitter Pill Award" to GlaxoSmithKline-the 'With Allies Like This, Who Needs Enemas?' Award. |
| Precautions: |
| Absorption of fat-soluble vitamins and other fat-soluble nutrients is inhibited by the use of orlistat. A multivitamin tablet containing vitamins A, D, E, K, and beta-carotene should be taken once a day, at bedtime, when using orlistat.
On June 4, 2009, the U.S. Food and Drug Administration released its quarterly list of drugs that are under investigation for potential safety issues or new safety information. Orlistat was included in the list as having a "Potential Signal of Serious Risk" of liver toxicity, meaning that a potential risk of liver toxicity was identified based on reports to the FDA Adverse Event Reporting System between October and December 2008. Isolated cases of orlistat-associated liver problems have been reported before. On August 24, the FDA reported that it would investigate 30 cases of liver damage reported between 1999 and October 2008 in patients taking orlistat, including six cases of liver failure. |
| Interactions: |
| Orlistat may reduce plasma levels of ciclosporin (also known as "cyclosporin" or "cyclosporine", trade names Sandimmune, Gengraf, Neoral, etc.), an immunosuppressive drug frequently used to prevent transplant rejection; the two drugs should therefore not be administered concomitantly. Orlistat can also impair absorption of the antiarrhythmic amiodarone. |
| Contraindications: |
Orlistat is contraindicated in:
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| Chemistry: |
The structure of this agent in essence comprises a propiolactone that bears two long fatty acid-like side chains. Construction of one of the side chains in this somewhat lengthy synthesis begins with the cyclohexanone acetal of L-malic acid. The carboxylic acid is first reduced to the carbinol by means of diborane, and that is then protected as its tert-butyldimethylsilyl ether. The acetal ring is then opened by means of sodium methoxide in methanol. The resulting ester is then reduced, and the resulting hydroxyl is converted to a leaving group by reaction with naphthylsulfonyl chloride. Treatment with a strong base leads to internal displacement and thus the formation of the oxirane. The ring is then opened with the lithium reagent from the exchange of n-bromodecane with butyllithium to afford the long chain product.
Addition of the second part of the molecule starts by first protecting the free hydroxyl group as its benzyl ether by exchange with O-benzyliminitrifloroacetamide. The silyl protecting group on the other hydroxyl is then removed by means of hydrogen fluoride. Swern oxidation then converts that to an aldehyde group. The titanium tetrachloride catalyzed addition of a carbocation to the aldehyde group serves to add the second fatty side chain. Thus the addition of the ambident carbocation from the allylic silyl reagent in the presence of bis-cyclopentyldienyltitanium dichloride gives the condensation product. Asymmetric induction by the adjacent chiral ether leads to the stereoselective formation of the new chiral center. Ozonization of the terminal olefin followed by an oxidative workup leads to the loss of the two terminal carbon atoms and the formation of the carboxylic acid. Treatment of the hydroxyl acid with benzenesulfonyl chloride in pyridine leads those functional groups to cyclize to the propiolactone, likely though the intermediacy of the sulfonate. The configuration of the hexyl side chain is next inverted to match that of the natural product via its enolate by treatment with a strong base. Hydrogenolysis of the benzyl ether affords the intermediate. The last fragment, formyl leucine, is added by means of a version of the Mitsonobu reaction. Thus the reaction of with the acid in the presence of diethyldiazo dicarboxylate (DEAD) and triphenyl phosphine leads to the ester and thus orlistat. The inversion of configuration at oxygen indicates that this last reaction involves SN2-like displacement rather than esterification. |