Use of orlistat

Use of orlistat could interfere with the body s absorption of fat-soluble vitamins and beta carotene. Long-term use could result in deficiencies of vitamins A, D, E, and K, and beta carotene. Patients are advised to take supplements. Another possible side effect is calcium deficiency. 

A single case report suggests that the concurrent use of orlistat and sucrose polyesters (Olestra - used in some foods as a fat substitute) can result in additive gastrointestinal adverse effects (soft, fatty/oily stools, increased flatus and abdominal pain). In the case in question, symptoms resolved when the patient stopped eating Ofesfra-containing food while continuing to take orlistat. ... 

Orlistat may reduce the absorption of fat soluble vitamins including vitamin and a change to a lower fat diet associated with the use of orlistat may also contribute to changes in the balance between vitamin K and warfarin. ... 

The safety and efficacy of orlistat have not been determined beyond 4 years of use. Minimal systemic effects exist because orlistat acts locally in the GI tract. Thus, common side effects reported include oily spotting, flatus with discharge, fecal urgency, fatty/oily stools, oily evacuation, increased defecation, and fecal incontinence.31 Other adverse events include bloating, abdominal pain, dyspepsia, nausea, vomiting, diarrhea, and headache.37... 

For a detailed description of orlistat and its approved uses (or for any other prescription medication approved for sale in the United States), see The Physicians Desk Reference. 

Xenical is a proprietary preparation of orlistat, which is used as an adjunct to diet in the treatment of obesity. 

One of the early syntheses of orlistat (1) by Hoffmann-La Roche utilized the Mukaiyama aldol reaction as the key convergent step. Therefore, in the presence of TiCU, aldehyde 7 was condensed with ketene silyl acetal 8 containing a chiral auxiliary to assemble ester 9 as the major diastereomer in a 3 1 ratio. After removal of the amino alcohol chiral auxiliary via hydrolysis, the a-hydroxyl acid 10 was converted to P-lactone 11 through the intermediacy of the mixed anhydride. The benzyl ether on 11 was unmasked via hydrogenation and the (5)-7V-formylleucine side-chain was installed using the Mitsunobu conditions to fashion orlistat (1). 

Most recently in 2003, McLeod s group obtained the 3-lactone motif of orlistat (1) using a bromolactonization reaction.3,Y-Unsaturated acid 38 was prepared from a diene-ester, hexadeca-2,4-dienoic acid methyl ester. McLeod et al discovered that conducting the bromolactonization in methanol and 10% aqueous sodium bicarbonate solution afforded predominantly rrany-39, which was then transformed to orlistat (1). 

Most prescription diet pills are prescribed for shortterm use of not more than several months. Sibutramine and orlistat have been prescribed for longer use in the treatment of significantly obese people. For both medications, this treatment ranged from six months to one year. The safety and effectiveness of use for longer than one year have not been determined. 

The inhibition effects of orlistat on HPL activity were studied in the absence or in the presence of NaTDC, using tributyrin or PSO as substrate (Tiss et ah, manuscript in preparation). In the absence of bile salts, as shown in Fig. 9.18 B, the rate of tributyrin hydrolysis by HPL decreased rapidly according to a similar pattern, with increasing orlistat concentration and fhe I50 value was found to be around 2.2 pM. When using PSO as substrate, orhstat was found to be more efficient in inhibiting HPL activity (l5o=0.4 pM). 

In the particular case of PPL and HGL, using pure dicaprin films, it was found that around 1.5% of the total amount of injected enzyme was recovered after film aspiration [115, 116]. As judged by this percentage of hpid-bound enzyme, the effective surface molar excesses of orlistat to film-bound hpase, inducing a 50% reduction in catalytic activity, were estimated as 10- to 20-fold with PPL, RGL and HGL. The stoichiometry at the interface can be described as follows one hpase molecule embedded within 105 substrate molecules wiU be inactivated to half its initial rate by the presence of 10 orhstat molecules. 

With HPL, the kinetic studies were carried out at 12 mN rn, using mixed films of orlistat/dicaprin, orlistat/diolein and orlistat/PSO. At this surface pressure, which was below the collapse pressure of ah the components (35, 29, 25 and 13 mN rri for diClO, diolein, orhstat and PSO, respectively), all the above films were stable with time, i.e., no significant decrease in the surface pressure was observed within 20 min. Under these conditions, the 050 values, leading to half inhibition of HPL activity on dicaprin, diolein and PSO were found to be 0.0002%... 

The efficacy of orlistat in inhibiting HPL acting on PSO was found to be higher when using the monomolecular film technique as compared to the single oil drop technique. 

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