Orlistat: its current status as an anti-obesity drug

Ballinger, Anne; Peikin, Steven R.

doi:10.1016/s0014-2999(02)01422-x

Cited by 232 publications

(163 citation statements)

References 30 publications

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“…Clinical trials in adults lasting up to 2 years have not reported serious side effects. 48 Recent studies in obese adolescents 49 and prepubertal children 50 indicate that short-term Orl treatment is well-tolerated by children and has a side effect profile similar to that observed in adults. Side effects are generally mild, are limited to gastrointestinal effects such as flatulence and oily leakage, and decrease with time.…”

Section: Discussionmentioning

confidence: 99%

Effective oral treatment of unconjugated hyperbilirubinemia in Gunn rats

et al. 2005

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We sought to develop an oral treatment for unconjugated hyperbilirubinemia. In the Gunn rat model of unconjugated hyperbilirubinemia, dietary supplementation with the lipase inhibitor orlistat (Orl) or with calcium phosphate (CaP) decreases plasma unconjugated bilirubin (UCB) levels. We determined whether Orl, CaP, or their combination is superior to phototherapy, the conventional treatment, and whether the effects of Orl and CaP are influenced by dietary fat content. Gunn rats were treated with Orl (200 mg/kg chow), CaP (20 g/kg chow), Orl ؉ CaP, or continuous phototherapy (19 W/cm 2 /nm) during a low-fat (LF) diet (13 energy%) or high-fat (HF) diet (35 energy%). Plasma UCB and fecal fat excretion were measured before, during, and/or at the end of treatment. Orl treatment for 2 weeks (HF diet) reduced plasma UCB concentrations similar to phototherapy (؊34% and ؊28%, respectively); the combination of both was more effective than either treatment alone (؊48%; P < .001). After 3 weeks of a HF diet, plasma UCB was 46% lower compared with the LF diet (P < .001). Plasma UCB concentrations were negatively correlated with fecal fat excretion (r ‫؍‬ ؊0.96; P < .001). Irrespective of dietary fat content, 3 weeks of combined treatment (Orl ؉ CaP) decreased plasma UCB by approximately 50% (P < .01) and was more effective than phototherapy (P < .05) at the intensity provided. C rigler-Najjar disease is characterized by a permanent unconjugated hyperbilirubinemia due to absent (type I) or decreased (type II) activity of the hepatic enzyme bilirubin-UDP-glucuronosyltransferase. 1 Severe unconjugated hyperbilirubinemia can lead to bilirubin encephalopathy, kernicterus, and death. 2,3 Phenobarbital treatment can usually control unconjugated hyperbilirubinemia in Crigler-Najjar type II patients via residual enzyme induction. 4,5 Phenobarbital is not effective in Crigler-Najjar disease type I, however, so these patients have to undergo daily phototherapy, which has considerable disadvantages. Phototherapy becomes less effective with age, probably due to skin alterations, 6,7 a decrease in the surface area to body mass ratio, 8 and a diminishing compliance to the intensive phototherapy regimen, which may take up to 12 hours per day. 6 To prevent irreversible brain damage due to kernicterus, many patients with CriglerNajjar disease type I undergo liver transplantation in their second decade. 9,10 We sought to develop an alternative treatment for unconjugated hyperbilirubinemia based on oral administration and with equal or higher efficacy than phototherapy. The oral treatment strategy used in the present study is based on reducing the reabsorption of UCB 11,12 through intestinal capture. Reabsorption of UCB can contribute substantially to the pathogenesis

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Section: Discussionmentioning

confidence: 99%

Effective oral treatment of unconjugated hyperbilirubinemia in Gunn rats

et al. 2005

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“…The published version will differ from this one as a result of linguistic and technical corrections and layout editing. 6 …”

Section: Lipase Activity Assay Using Natural Substratementioning

confidence: 99%

Proteinaceous Pancreatic Lipase Inhibitor from the Seed of Litchi chinensis

Mhatre¹,

Bhagit²,

Yadav³

2018

Food Technol. Biotechnol.

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SummaryA study on the pancreatic lipase inhibitory activity of protein from the seed of Litchi chinensis was carried out. Protein was isolated by 70 % ammonium sulphate precipitation followed by dialysis. Lipase inhibitory activity of the protein was evaluated using both synthetic (pnitrophenyl palmitate) and natural (olive oil) substrate. Protein at the final concentration of 100 µg/mL was able to inhibit pancreatic lipase with 68.15 % inhibition on synthetic substrate and 60 % inhibition on natural substrate.Proteinaceous nature of the inhibitor was determined using trypsinization assay. Pancreatic lipase inhibitory protein was sensitive to 0.05 % trypsin treatment with loss of 61.9 % activity. IC50 of this proteinaceous pancreatic lipase inhibitor was 73.099 µg/mL using synthetic substrate. This inhibitory protein was sensitive to pH with highest inhibitory activity at pH = 8.0 and lowest at pH = 3.0. Protein was further analyzed on 10 % non-reducing sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and interestingly it showed the presence of a single band of (61 ± 2) kDa stained by Commassie  Corresponding author: Phone: +9102227432890, 02227437693; Fax: 02227431094; E-mail: raman.yadav@mgmmumbai.ac.in ORCID IDs: 0000-0001-5593-7018 (Mhatre), 0000-0003-2623-1811 (Bhagit), Food Technology and Biotechnology 56 (2) 2018 www. ftb.com.hr Please note that this is an unedited version of the manuscript that has been accepted for publication. This version will undergo copyediting and typesetting before its final form for publication. We are providing this version as a service to our readers. The published version will differ from this one as a result of linguistic and technical corrections and layout editing.2 brilliant blue. Protein band was further isolated from gel which showed 98.29 % purity on highperformance liquid chromatography. Isolated protein was finally crystallized to see the homogeneity of protein by batch crystallization method. Crystals were well formed with distinct edges. Isolated protein showed good pancreatic lipase inhibitory activity.

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“…Our choice was tetrahydrolipstatin, or orlistat, which is a lipophilic molecule that irreversibly binds to the catalytic site of a great number of lipases (13) and which has previously been shown to inhibit cAMPinduced insulin secretion in the clonal ␤-cell line HIT-T15 (14) and glucagon-like peptide 1 (GLP-1)-stimulated secretion in rat islets (15). The drug is widely used for treatment of obesity (16); it inhibits intestinal lipases, preventing uptake of lipids and thereby restricting caloric input. Orlistat, at therapeutic doses, is not taken up into the circulation, thereby precluding undesired systemic effects.…”

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confidence: 99%

Inhibition of Lipase Activity and Lipolysis in Rat Islets Reduces Insulin Secretion

et al. 2004

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Lipids may serve as coupling factors in K ATP -independent glucose sensing in ␤-cells. We have previously demonstrated that ␤-cells harbor lipase activities, one of which is the hormone-sensitive lipase. Whether ␤-cell lipases are critical for glucose-stimulated insulin secretion (GSIS) by providing lipid-derived signals from endogenous lipids is unknown. Therefore, using a lipase inhibitor (orlistat), we examined whether lipase inhibition reduces insulin secretion. Islet lipolysis stimulated by glucose and diglyceride lipase activity was abolished by orlistat. Incubation of rat islets with orlistat dose dependently inhibited GSIS; this inhibition was reversed by 1 mmol/l palmitate, suggesting that orlistat acts via impaired formation of an acylglyceride-derived coupling signal. Orlistat inhibited the potentiating effect of forskolin on GSIS, an effect proposed to be due to activation of a lipase. In perifused islets, orlistat attenuated mainly the second phase of insulin secretion. Because the rise in islet ATP/ADP levels in response to glucose and oxidation of the sugar were unaffected by orlistat whereas the second phase of insulin secretion was reduced, it seems likely that a lipid coupling factor involved in K ATP -independent glucose sensing has been perturbed. Thus, ␤-cell lipase activity is involved in GSIS, emphasizing the important role of ␤-cell lipid metabolism for insulin secretion. Diabetes 53:122-128, 2004A large body of evidence suggests that lipids are required for appropriate glucose sensing in pancreatic ␤-cells. For instance, when triglycerides in pancreatic islets are depleted by hyperleptinemia, pancreatic ␤-cells fail to release insulin (1). Along similar lines, perfused pancreas from fasted rats is unresponsive to a rise in glucose (2). Importantly, in both cases, glucose responsiveness is reinstated by the addition of exogenous fatty acids.The current view holds that lipids serve as coupling factors in glucose-stimulated insulin secretion (GSIS) that does not rely on closure of the ATP-sensitive K ϩ channel (K ATP independent) (3). These putative mechanisms presumably drive the second phase of GSIS and accordingly have been termed as amplifying (4), and the coupling factors have been proposed to emanate from intermediary metabolism in the ␤-cell (5). Against this background, lipids have become attractive candidates for coupling factors in K ATP -independent glucose sensing. In fact, a model has been proposed to delineate the combined events in metabolism of glucose and lipids that result in a dose-dependent regulation of insulin secretion, the socalled long-chain acyl-CoA hypothesis (3). This model is based on the observations that an increase in glucose metabolism in ␤-cells results in decreased oxidation of fats while esterification of lipids increases. As a consequence, the levels of complex lipids rise, perhaps acyl-CoA moieties, which then act as a signaling molecules coupling stimulus to secretion in the ␤-cell. We have previously demonstrated that different preparations of ␤-cells...

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Orlistat: its current status as an anti-obesity drug

Cited by 232 publications

References 30 publications

Effective oral treatment of unconjugated hyperbilirubinemia in Gunn rats

Effective oral treatment of unconjugated hyperbilirubinemia in Gunn rats

Proteinaceous Pancreatic Lipase Inhibitor from the Seed of Litchi chinensis

Inhibition of Lipase Activity and Lipolysis in Rat Islets Reduces Insulin Secretion

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