Current and Potential Drugs for Treatment of Obesity

Bray, George A.; Greenway, Frank L.

doi:10.1210/edrv.20.6.0383

Cited by 232 publications

(185 citation statements)

References 622 publications

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“…Our patient developed PPH after use of amfepramone on a short-term basis, as is reported for BMPR2 mutation carriers after fenfluramine [3]. Indeed, you expect to find some BMPR2 mutation carriers in PPH patients without anorexigen use.…”

Section: From the Authorssupporting

confidence: 75%

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Amfepramone does not cause primary pulmonary hypertension

Sacco¹

2004

Eur Respir J

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The article by ABRAMOWICZ et al. [1] should show the first case of primary pulmonary hypertension (PPH) associated with the use of amfepramone (diethylpropion), an anorectic drug, and BMPR2 mutation. In my opinion, the relationship between amfepramone and the rise of PPH in this case is unproven.BMPR2 mutation is related to PPH without use of anorectics. Autosomal dominant germline mutations in BMPR2 have been identified in y55% of familial cases and in 25% of patients with negative family history [2].There are three different types of anorectic drugs: fenfluramines (fenfluramine and dexfenfluramine), serotonin releasers; noradrenergic agents (i.e. amfepramone), noradrenaline releasers; and sibutramine, a noradrenaline and serotonin reuptake inhibitor [3].It is true that BMPR2 mutations combined with exposure to fenfluramine derivatives increase the risk of developing PPH, but the mechanisms of the lesions, with any probability, are associated with the serotoninergic pathway [4][5][6]. Amfepramone is a noradrenaline releaser and not a serotonin stimulant.However, after ABENHAIM et al. [7] showed a correlation between anorectics and PPH, a second much larger study was performed in the USA [8]. This study showed that: 1) only the use of fenfluramines for o6 months remained associated with the diagnosis of PPH; and 2) when only recent users of fenfluramines (i.e. those using them in the 6 months preceding diagnosis) were counted as exposed, the associated adjusted odds ratios from the logistic regression that reflected the directions of associations were higher.Therefore: 1) Abramowicz9s patient had a mutation, which could, per se, cause PPH; 2) there are no data that amfepramone causes PPH; 3) a direct relationship between noradrenergic pathway and PPH has never been supposed; 4) the exposure to anorectic drug was too short; and 5) the period between amfepramone use and the onset of symptoms is too long.Considering this case, if we use the common algorithms for the assessment of adverse drug reactions [9][10][11], the result is unlikely. It is very difficult to be able to suppose that the use of amfepramone could have any relationship, even indirectly, in the rise of primary pulmonary hypertension.

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Section: From the Authorssupporting

confidence: 75%

“…amfepramone), noradrenaline releasers; and sibutramine, a noradrenaline and serotonin reuptake inhibitor [3].…”

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confidence: 99%

Amfepramone does not cause primary pulmonary hypertension

Sacco¹

2004

Eur Respir J

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“…The systemic absorption of orlistat is negligible and the potential for systemic adverse events has been indicated as practically non-existent. Due to the pharmacological mode of action of orlistat 5 there is an increased likelihood of gastrointestinal events. As pointed out by Sjostro Èm et al 2 the GI events were more common in the orlistat-treated patients during the ®rst year of their collaborative multicenter trial, the frequency being lower during year 2 among participants who continued on orlistat treatment.…”

Section: Discussionmentioning

confidence: 99%

“…These include intestinal¯atulence, borborygmi and abdominal cramps. 5 The most troubling were fecal incontinence, oily spotting and¯atus with discharge. In a large European Multicentre Orlistat study group 2 adverse gastrointestinal (GI) events were a common reason for premature withdrawals in the orlistat treated group.…”

Section: Introductionmentioning

confidence: 99%

Gastrointestinal side effects of orlistat may be prevented by concomitant prescription of natural fibers (psyllium mucilloid)

2001

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OBJECTIVES: This placebo-controlled open study was designed to test the hypothesis that most of the gastrointestinal (GI) side events induced by treatment of obese patients with orlistat (a gastrointestinal lipase inhibitor) could be prevented or ameliorated by concomitant use of natural ®bers (psyllium mucilloid). DESIGN: Two groups of obese women (BMI b 27 kgam 2 ) were treated with orlistat 120 mg three times a day. One group (A, n 30) was randomized to receive orlistat and, approximately 6.0 g of orange-¯avored psyllium mucilloid dissolved in water and the other group (B, n 30) received orlistat and orange-¯avored placebo. At the end of 30 days and 2 weeks of washout, group A switched to placebo and group B received psyllium while continuing orlistat three times a day. SUBJECTS: Sixty professional women, more than 21-y-old with a body mass index (BMI) between 27.3 and 48.0 kgam 2 , who were not receiving any other medication. MEASUREMENTS: Assessments included weekly visits to attending physician, ®lling a form in which GI events were recorded, monthly measurements of body weight, blood pressure and serum lipids. The frequency and severity of GI events were evaluated by a score system, based on information provided by the patients. RESULTS: Both groups A and B signi®cantly lost (P`0.01) weight after 60 days of orlistat (A 96.8 to 94.9 kg and B 98.7 to 96.5 kg). Similarly, BMI values declined signi®cantly in both groups. While in the psyllium plus orlistat group (group A) the mean AE s.e.m. of the scores re¯ecting GI events was 13.0 AE 1.8, the placebo plus orlistat group (B) had a value of 35.9 AE 2.7 (P`0.01). When the reverse situation was instituted the placebo and orlistat group presented a mean score of 36.1 AE 3.6 and the psyllium plus orlistat a mean score of 8.9 AE 1.5 (P`0.01). CONCLUSIONS: Psyllium hydrophilic mucilloid concomitantly prescribed to obese patients receiving 120 mg of orlistat three times a day is an effective and safe adjunct therapy that is helpful in controlling the GI side effects of this pancreatic lipase inhibitor.

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“…18 The rates of gastrointestinal events occurring during the treatment period were lower than those observed in clinical trials. 19,20 In clinical trials orlistat treatment was associated with gastrointestinal adverse events including oily spotting from the rectum (27%), flatus with discharge (24%), faecal Safety profile of orlistat NV Acharya et al urgency (22%) and faecal incontinence (8%). 5,6 In this study, diarrhoea was the most frequently reported gastrointestinal event with 4.9% (789) of patients reported to have experienced this event during treatment.…”

Section: Discussionmentioning

confidence: 99%

Safety profile of orlistat: results of a prescription-event monitoring study

2006

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Introduction: Orlistat, the first of a new class of drugs for the treatment of obesity, was launched in the UK in December 1998. The prescribing information recommends that treatment with orlistat should be discontinued after 12 weeks if the patient has not achieved a specified loss of weight. Objective: To monitor the safety of orlistat prescribed in the primary care setting in England using prescription-event monitoring (PEM). Methods: A postmarketing surveillance study using the observational cohort technique of PEM. Patients were identified from dispensed prescriptions issued by primary care physicians for orlistat between December 1998 and November 1999. The outcome data were event reports obtained by sending questionnaires (green forms) to the prescribing doctor at least 6 months after the first prescription for an individual patient. Incidence densities, expressed as number of first reports of an event/1000 patient-months of exposure, were calculated. Significant differences between incidence densities (IDs) for events reported in the 1st month (ID 1 ) and months 2 and 3 (ID 2-3 ) of exposure were regarded as potential signals. Reasons for stopping orlistat were analysed. Follow-up information was requested for selected events and used to assess the causal association with orlistat. Results: Green forms containing clinically useful information on 16 021 patients (median age 45 years (interquartile range 35-54); 80.1% females) were received. The events reported most frequently during the 1st month of treatment were 'not effective' (639; 4.0% of cohort), diarrhoea (371; 2.3%) and weight loss (230; 1.4%). Twelve clinical adverse events were identified for which ID 1 was significantly greater than ID 2-3 . These included non-specific events (e.g. intolerance, malaise/ lassitude, unspecified side effects), weight loss and vaginitis/vulvitis. The remaining events were gastrointestinal in nature and included diarrhoea, pain abdomen, flatulence, nausea/vomiting, rectal discharge, faecal incontinence and 'gastrointestinal unspecified' events. A similar pattern of predominately gastrointestinal events was seen for reasons for stopping and suspected adverse drug reactions. Review of selected events for causality revealed 45 events which were assessed as possibly or probably related to orlistat. Conclusions: This study shows that orlistat is fairly well tolerated. The safety profile of orlistat was similar to the prescribing information and experience reported in the literature.

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Current and Potential Drugs for Treatment of Obesity

Cited by 232 publications

References 622 publications

Amfepramone does not cause primary pulmonary hypertension

Amfepramone does not cause primary pulmonary hypertension

Gastrointestinal side effects of orlistat may be prevented by concomitant prescription of natural fibers (psyllium mucilloid)

Safety profile of orlistat: results of a prescription-event monitoring study

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