To the Editor: In their article on obesity, Rosenbaum et al.(Aug. 7 issue)1 characterize sibutramine, currently undergoingregulatory review as a drug for the treatment of obesity, ashaving both catecholaminergic and serotonergic agonist effects.Sibutramine, in fact, is not an agonist at catecholamine orserotonin receptors but instead acts by inhibiting the reuptakeof serotonin and norepinephrine at central synapses. Thus, sibutramine'smode of action is similar to that of other monoamine-reuptakeinhibitors such as venlafaxine (an inhibitor of serotonin andnorepinephrine reuptake) and fluoxetine (a selective serotonin-reuptakeinhibitor). The mode of action of drugs that alter appetiteby enhancing central monoamine activity has several implications.For instance, primary pulmonary hypertension has been associatedwith certain appetite-suppressant drugs2 (e.g., fenfluramine),as well as other drugs (e.g., cocaine), that act by causingmonoamine release.3 Rosenbaum et al. characterize the implicatedanorectic drugs as reuptake inhibitors. In fact, monoamine-reuptakeinhibitors that do not cause monoamine release, such as tricyclicantidepressant drugs, selective serotonin-reuptake inhibitors,and serotonin- and norepinephrine-reuptake inhibitors, havenot been associated with an increased risk of primary pulmonaryhypertension or neurotoxicity 4 or with the cardiac valvulopathyreported by Connolly et al.5 Given the diversity of the satiety-enhancingdrugs currently being developed, attention to the details ofthe mechanism of action may be even more important in the future.
Timothy B. Seaton, M.D. Carl M. Mendel, M.D. Steven P. Weinstein,M.D., Ph.D. Knoll Pharmaceutical Parsippany, NJ 07054
References
Rosenbaum M, Leibel RL, Hirsch J. Obesity. N Engl J Med 1997;337:396-407. [Free Full Text]
Abenheim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996;335:609-616. [Free Full Text]
Lane R, Baldwin D. Selective serotonin reuptake inhibitor-induced serotonin syndrome: review. J Clin Psychopharmacol 1997;17:208-221. [CrossRef][Medline]
McCann UD, Seiden LS, Rubin LJ, Ricaurte GA. Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine: a systematic review of the evidence. JAMA 1997;278:666-672. [Abstract]
Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997;337:581-588. [Free Full Text]
To the Editor: The excellent review of obesity contains a contradiction.The authors say that insulin causes weight gain because it increasesthe expression of neuropeptide Y messenger RNA, with subsequentcentral appetite stimulation. They later say that insulin reducesfood intake by inhibiting the expression of neuropeptide Y,and in another section, insulin is said to increase the expressionof leptin in adipose tissue. Can the authors clarify the roleof insulin in the stimulation or inhibition of food intake?
Elliott Eisenbud, M.D. 6403 Coyle Ave. Carmichael, CA 95608
The authors reply:
To the Editor: We appreciate the letter from Seaton et al. concerningthe mode of action of sibutramine. We wished to note only thatsibutramine has agonist actions in both serotonin and catecholaminesystems. The full delineation of the exact mode of action ofcentrally active anorexiant drugs will undoubtedly receive increasedscrutiny because some of these drugs may be neurotoxic,1 causeprimary pulmonary hypertension, and cause valvular heart disease.2Since our review was published, the Food and Drug Administration(FDA) and Wyeth–Ayerst Laboratories, acting on the concernabout these possible adverse effects, have removed fenfluraminesfrom the market.
We thank Dr. Eisenbud for his careful reading of the text. Onpage 401 (left-hand column), the statement, "The expressionof neuropeptide Y mRNA is increased by insulin and glucocorticoids,"is incorrect. It should read, "The expression of neuropeptideY mRNA is increased by androgens and glucocorticoids and decreasedby leptin, insulin, and estrogen."
There are two other errors. First, on page 397 (right-hand column),the statement suggesting that lesions of the median forebrainbundle are equivalent to those of the ventromedial hypothalamusis incorrect. Lesions of the median forebrain bundle are morelikely to induce anorexia in a manner similar to that of lesionsof the lateral hypothalamus. Second, on page 403, in the thirdsentence under the heading "Drug Therapy," fenfluramine shouldbe dexfenfluramine. Dexfenfluramine was approved by the FDAin 1996, but fenfluramine was approved in 1973.
Jules Hirsch, M.D. Rudolph L. Leibel, M.D. Michael Rosenbaum,M.D. Rockefeller University New York, NY 10021
References
McCann UD, Seiden LS, Rubin LJ, Ricaurte GA. Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine: a systematic review of the evidence. JAMA 1997;278:666-672.
Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997;335:581-588.
Michaud, J. L., Boucher, F., Melnyk, A., Gauthier, F., Goshu, E., Levy, E., Mitchell, G. A., Himms-Hagen, J., Fan, C.-M.
(2001). Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus. Hum Mol Genet
10: 1465-1473
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