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Reproduced from Glick, S. D.; Haskew, R. E.; Maisonneuve, I. M.; Carlson, J. N.; Jerussi, T. P. Eur. J. Pharmacol. 2000, 397, 93-102.

Given that sibutramine is a monoamine uptake inhibitor, there has been much debate about which type of uptake inhibition is responsible for the effects on weight loss. The extensive clinical use of selective 5-HTuptake inhibitors, e.g., fluoxetine, paroxetine, and sertraline, has shown that this property alone is not sufficient to cause significant long-term weight loss.13 The clinical use of selective NE uptake inhibitors, e.g., reboxetine and atomoxetine, has also not revealed significant long-term weight loss. Even dual 5-HT/NE uptake inhibition, e.g., duloxetine, has not been reported to produce significant weight reduction in humans. This leads to the conclusion that the DA uptake inhibition by the sibutramine metabolites, alone or in combination with 5-HT and/or NE uptake inhibition, may be a key contributor to the weight-reducing effects of sibutramine.

6.18.6.2.7.2 Indications

Sibutramine is approved for the management of obesity, including weight loss and maintenance of weight loss, and should be used in conjunction with a reduced-calorie diet. It is recommended for obese patients with an initial BMI >30 or >27kgm-2 in the presence of other risk factors (e.g., diabetes, dyslipidemia, controlled hypertension).

6.18.6.2.7.3 Issues, side effects, and contraindications

Sibutramine appears to be relatively well tolerated, with the most common side effects being dry mouth, insomnia, and constipation. The most significant concern with sibutramine is its ability to increase blood pressure and heart rate. While these changes are on average small, they can be quite significant in some patients, and thus, it is recommended that blood pressure and pulse should be measured before starting therapy and should be monitored at regular intervals thereafter. It is also recommended that sibutramine should not be used in patients with a history of coronary artery disease, congestive heart failure, arrhythmias, or stroke. Given that many obese patients have coexisting cardiovascular morbidities, these warnings preclude the use of sibutramine in such obese subjects.

6.18.6.2.8 Other anorexiant drugs

6.18.6.2.8.1 Fenfluramine

Although it is no longer on the market, fenfluramine had such an impact on the pharmacotherapy of obesity that it deserves mentioning when discussing the other anorexiants. Fenfluramine has been around since the 1960s, and D,L-fenfluramine was approved by the FDA for the short-term treatment of obesity in 1973. The use of fenfluramine got a significant boost with the publication of a series of papers in 19927 that demonstrated the magnitude and sustainability of weight loss that could be seen when fenfluramine was combined with phentermine (the combination that was known popularly as phen-fen), and in 1996, the FDA approved the D-enantiomer of fenfluramine for the long-term treatment of obesity. However, fenfluramine was withdrawn from the market in 1997 due to accumulating evidence that chronic use of fenfluramine could result in a significant incidence of valvulopathy.13

Fenfluramine is a substituted amphetamine (Figure 4), and like amphetamine, fenfluramine causes release of monoamines. Specifically, fenfluramine and its metabolite norfenfluramine cause release of 5-HTand NE (Table 7).8 In addition, high-dose fenfluramine produces a long-lasting depletion of brain 5-HT in animal models.14

Fenfluramine is metabolized in vivo (in several different species, including humans) to norfenfluramine. Like the parent compound, norfenfluramine is also a monoamine neurotransmitter-releasing agent (Table 7). In addition to monoamine neurotransmitter release, norfenfluramine is a potent agonist at the 5-HT2 family of receptors. The current literature is consistent with the anorectic effect of fenfluramine primarily due to norfenfluramine stimulation of central 5-HT2C receptors.15

The combination of fenfluramine plus phentermine appeared to produce greater efficacy in treating human obesity, suggesting that using a combination of pharmacologies may be a better overall approach to treating obesity than the use of single agents. Given that the principal pharmacology of fenfluramine is 5-HT release and that of phentermine is NE release (Table 7), it is tempting to suggest that it is the combination of these two pharmacologies that gave phen-fen such good clinical results. However, as noted above, the metabolite of fenfluramine, norfenfluramine, is a potent agonist of the 5-HT2C receptor and appears to be responsible for much of the anorectic effect of fenfluramine through this mechanism. Also, norfenfluramine can also cause release of NE, although it is less potent than phentermine in doing this. So, the exact mechanisms by which fenfluramine and phentermine produce their combined efficacy remain to be determined.

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