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Amfepramone does not cause primary pulmonary hypertension

Dept of Endocrinology, Niguarda Hospital, Milan, Italy

CORRESPONDENCE:

To the Editor:

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 55% 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 4–6. 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 6 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) Abramowicz's 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 9–11, 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.

References

1. Abramowicz MJ, Van Haecke P, Demedts M, et al. Primary pulmonary hypertension after amfepramone (diethylpropion) with BMPR2 mutation. Eur Respir J 2003;22:560–562.[Abstract/Free Full Text]
2. Rindermann M, Grunig E, von Hippel A, et al. Primary pulmonary hypertension may be a heterogeneous disease with a second locus on chromosome 2q31. J Am Coll Cardiol 2003;41:2237–2244.[Abstract/Free Full Text]
3. Bray GA, Greenway FL. Current and potential drugs for treatment of obesity. Endocr Rev 1999;20:805–875.[Abstract/Free Full Text]
4. Kereveur A, Callebert J, Humbert M, et al. High plasma serotonin levels in primary pulmonary hypertension. Effect of long-term epoprostenol (prostacyclin) therapy. Arterioscler Thromb Vasc Biol 2000;20:2233–2239.[Abstract/Free Full Text]
5. Eddahibi S, Raffestin B, Hamon M, et al. Is the serotonin transporter involved in the pathogenesis of pulmonary hypertension?. J Lab Clin Med 2002;139:194–201.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
6. Rondelet B, Van Beneden R, Kerbaul F, et al. Expression of the serotonin 1b receptor in experimental pulmonary hypertension. Eur Respir J 2003;22:408–412.[Abstract/Free Full Text]
7. Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med 1996;335:609–616.[Abstract/Free Full Text]
8. Rich S, Rubin L, Walker AM, Schneeweiss S, et al. Anorexigens and pulmonary hypertension in the United States: results from the surveillance of North American pulmonary hypertension. Chest 2000;117:870–874.[Abstract/Free Full Text]
9. Naranjo C, Busto U, Sellers EM, et al. Clin Pharmacolz Ther 1981;30:239–245.
10. Hutchinson TA, Leventhal JM, Kramer MS, et al. An algorithm for the operational assessment of adverse drug reactions. II: demonstration of reproducibility and validity. JAMA 1979;242:633–638.[Abstract/Free Full Text]
11. Jones JK. Adverse drug reactions in the community health setting: approaches to recognizing, counselling and reporting. Fam Community Health 1982;5:58–67.[Medline] [Order article via Infotrieve]

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