Initial studies in humans with the novel gastrointestinal lipase inhibitor Ro 18–0647 (tetrahydrolipstatin)

Hauptman, Jonathan; Jeunet, F; Hartmann, D

doi:10.1093/ajcn/55.1.309s

Cited by 169 publications

(71 citation statements)

References 15 publications

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“…The effects of the drug on FAS are likely to have been overlooked because Orlistat is administered orally but is not significantly absorbed into the bloodstream. The drug acts in preventing absorption of dietary fat by inhibiting pancreatic lipase (another serine hy- drolase) in the digestive tract (33,34). The results of the present study indicate that Orlistat and other ␤-lactones should be considered to be a promising class of thioesterase antagonists that could be exploited for antitumor therapy.…”

Section: Discussionmentioning

confidence: 79%

A Fatty Acid Synthase Blockade Induces Tumor Cell-cycle Arrest by Down-regulating Skp2

Knowles

Axelrod

Browne

et al. 2004

Journal of Biological Chemistry

138

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In eukaryotes, fatty acid synthase (FAS) is the enzyme responsible for synthesis of palmitate, the precursor of long-chain nonessential fatty acids. FAS is up-regulated in a wide range of cancers and has been suggested as a relevant drug target. Here, two independent approaches are taken toward knocking down FAS and then probing its connection to tumor cell proliferation. In one approach, Orlistat, a drug approved for treating obesity, is used as a potent inhibitor of the thioesterase function of FAS. In a separate strategy, the expression of FAS is suppressed by targeted knock-down with small interfering RNA. In both circumstances, the ablation of FAS activity causes a dramatic down-regulation of Skp2, a component of the E3 ubiquitin ligase that controls the turnover of p27Kip1 . These effects ultimately tie into the retinoblastoma protein pathway and lead to a cell-cycle arrest at the G 1 /S boundary. Altogether, the findings of the study reveal unappreciated links between fatty acid synthase and ubiquitin-dependent proteolysis of cellcycle regulatory proteins.

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Section: Discussionmentioning

confidence: 79%

A Fatty Acid Synthase Blockade Induces Tumor Cell-cycle Arrest by Down-regulating Skp2

Knowles

Axelrod

Browne

et al. 2004

Journal of Biological Chemistry

138

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“…It inhibits the activity of pancreatic and gastric lipases, the key enzymes involved in triglyceride hydrolysis, an essential step for absorption of fat. 13 Early studies indicated that orlistat produced a dose-dependent reduction in dietary fat absorption, which is near maximal (approximately 35%) at a dose of 120 mg three times daily. 14 Its speci®c mode of action could be of particular importance since it targets one of the principal causes of weight gain, namely dietary fat.…”

Section: Introductionmentioning

confidence: 99%

One-year treatment of obesity: a randomized, double-blind, placebo-controlled, multicentre study of orlistat, a gastrointestinal lipase inhibitor

James²,

et al. 2000

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OBJECTIVE: To assess the ef®cacy and tolerability of orlistat (Xenical 1 ) in producing and maintaining weight loss over a 12-month period. DESIGN: Patients were randomized to double-blind treatment with either orlistat 120 mg or placebo three times daily, in conjunction with a low-energy diet, for 12 months. SETTING: Five centres in the UK. SUBJECTS: 228 obese adult patients with body mass index between 30 and 43 kgam 2 and mean weight 97 kg (range 74 ± 144 kg). INTERVENTIONS: All patients were prescribed a low-energy diet, providing 30% of energy from fat, designed to produce an individually tailored energy de®cit of approximately 600 kcaladay, for a run-in period of 4 weeks and then 12 months, plus orlistat 120 mg or placebo three times daily. MAIN OUTCOME MEASURES: Change in body weight (the primary ef®cacy parameter), waist circumference and adverse events were reviewed regularly, together with serum lipids, insulin, glucose and plasma levels of fat-soluble vitamins and b b carotene. RESULTS: Based on an intent-to-treat analysis, after 1 y of treatment patients receiving orlistat had lost an average of 8.5% of their initial body weight compared with 5.4% for placebo-treated patients; 35% of the orlistat group lost at least 5% of body weight compared with 21% of the placebo group (P`0.05), and 28% and 17%, respectively (P 0.04) lost at least 10% of body weight. Orlistat-treated patients showed signi®cant decreases (P`0.05) in serum levels of total cholesterol, low density lipoprotein cholesterol, and in the low density lipoprotein : high density lipoprotein ratio in comparison with placebo. Both groups had similar adverse-event pro®les, except for gastrointestinal events, which were 26% more frequent in the orlistat group but were mostly mild and transient. To maintain normal plasma levels of fat-soluble vitamins, supplements of vitamins A, D and E were given to 1.8%, 8.0% and 3.6%, respectively, of orlistattreated patients, compared with 0.9% of placebo-treated patients for each vitamin type. After 1 y, the decrease in vitamin E and b b carotene was signi®cantly greater in orlistat-treated patients compared with those receiving placebo (P`0.001). No signi®cant change was found in the mean vitamin E : total cholesterol ratio in either group after 52 weeks. Conclusions: Orlistat, in conjunction with a low-energy diet, produced greater and more frequent signi®cant weight loss than placebo during 1 y of treatment. One-third of orlistat-treated patients achieved clinically relevant weight loss ( ! 5% initial body weight). There was also an improvement in relevant serum lipid parameters. Fat-soluble vitamin supplements may be required during chronic therapy. Orlistat was well tolerated and offers a promising new approach to the long-term management of obesity.

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“…Orlistat is a lipase inhibitor and targets fat metabolism whereas Sibutramine is a β-phenethylamine that selectively inhibits the reuptake of noradrenaline, serotonin and acts by appetite suppression mechanism. Both of these drugs have shown severe side effects like gastrointestinal disorders, cardiovascular disorders etc eliciting an immediate need to design novel strategies for combating the problem of Obesity [13][14][15]. Since obesity like hypertension is a complex diseases which arises due to multifactorial reasons, so using combination of drugs might prove effective in its treatment [16,17].…”

Section: Introductionmentioning

confidence: 99%

Untitled

2017

RJLBPCS

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ABSTRACT:Obesity is a state characterized by excessive storage of triglycerides in the adipose tissue that leads to the adverse medical consequence. The increasing prevalence and morbidity associated with the disease makes it a serious issue of concern. The treatment regimens for the obesity include diet plans, increase in physical activity, anti-obesity medications and surgery. However The results in totality suggest that the combinational therapy targets key metabolic regulatory pathways like fatty acid synthesis and oxidation, energy homeostasis and adipocyte apoptosis implicating the relevance of therapeutically exploiting the combination treatment for the management of obesity. The combination of SAHA and THA seem to have promising benefits for the treatment and prevention of obesity.

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Initial studies in humans with the novel gastrointestinal lipase inhibitor Ro 18–0647 (tetrahydrolipstatin)

Cited by 169 publications

References 15 publications

A Fatty Acid Synthase Blockade Induces Tumor Cell-cycle Arrest by Down-regulating Skp2

A Fatty Acid Synthase Blockade Induces Tumor Cell-cycle Arrest by Down-regulating Skp2

One-year treatment of obesity: a randomized, double-blind, placebo-controlled, multicentre study of orlistat, a gastrointestinal lipase inhibitor

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