Health - 4-methylaminorex (4MAR, U4EA) and Cardiac Valvular Damage/Pulmonary Hypertension

[Kemikaru_Tenshu]

Richard_smoker recently brought up what is, IMHO, an important topic.

It has long been established that Aminorex can cause pulmatory hypertension [1]. Richard_smoker alerted me to the possibility that 4-methylaminorex may cause cardiac valvular lesions like those attributed to the combination of fenfluramine and phentermine (fen/phen). He has provided a reference for this statement (which I have NOT, at this time, had a chance to review), which is included in his second post below (Originally posted in "4-Methylaminorex vs Methcathinone": http://www.drugs-forum.com/forum/sho...85#post146085).

The debate over the “safety” of the aminorex analogs has long been in dispute, and I feel that it is important to address this controversial subject, as it may be of concern to many of us. Now, primary pulmatory hypertension attributed to aminorex is believed to be linked to the release of catecholamines and norepinephrine, while “fen/phen” owes its toxicity to the unfortunate combination of the two drugs methods of inhibiting the removal of serotonin from the blood and causing the release of a large amount of serotonin into the blood. This combination results in left-side cardiac valvular lesions.

5-HT (serotonin) is removed from the blood when it undergoes oxidative deamination by monamine oxidase within the pulmonary endothelium. Phentermine, the “phen” in “fen/phen”, inhibits the clearance of 5-HT from the lungs. This allows an abnormal amount (~25%) of the 5-HT in the blood to reach the left side of the heart [2]. 5-HT is a powerful pulmonary vasoconstrictor, and vasoconstrictors are generally believed to be the primary initiating mechanism for primary pulmonary hypertension.

Fenfluramine (the “fen”) and its primary metabolite release serotonin into the synapses via the S-5-H2 receptors. This, combined with the effects of phentermine, results in ~95% of the serotonin being released into the blood reaching the left side of the heart [3].

So, this mechanism is understood and generally accepted. With aminorex, it is less clear. The general hysteria involved in the “aminorex epidemic”, which resulted in its removal from the world market, may have been an overreaction. In fact, only ~2% of those who ingested aminorex during the period of the “epidemic” developed primary pulmonary hypertension [3]. Although this number is ~20 times higher than that of the general population, this still may suggest genetic predisposition. Second, this concept of genetic predisposition is reinforced by the inability of researchers to elicit pulmonary hypertension in lab animals [4]. Also, in most of the cases of aminorex-induced hypertension the hypertension was reversible.

There are documented cases of pulmatory hypertension linked with 4-methylaminorex [5]. Though the mechanism still remains unclear, and there has been little to no studies performed in an attempt to quantify the risk. Both are likely the result of the fact that 4-MAR is not a prescribed drug.



I would like to elicit any input/comments/references/ideas that any of you have, as my own store of resources on this topic are very limited.


~KT


REFERENCES


[1] Gurtner HP. Aminorex pulmonary hypertension, In: Fishman AP, ed. The pulmonary circulation: normal and abnormal. Philadelphia, PA: University of Pennsylvania Press, 1990; 397-412

[2] Tornebrandt K, Eskilsson J, Nobin A. Heart involvement in metastatic carcinoid disease. Clin Cardiol. 1986;9:13–19

[3]http://content.nejm.org/cgi/content/full/337/9/602?ijkey=2e42ac745f246e3c1c7315cc6e19aa9f482d5a1b &keytype2=tf_ipsecsha

[4] Mielke H, Seiler KU, Stumpf U, Wasserman O. Influence of aminorex (menocil) on pulmonary pressure and on the content of biogenic amines in the lungs of rats. Naunyn Schmiedebergs Arch Pharmacol. 1972; 274

[5] Sean P. Gaine, Lewis J. Rubin, James J. Kmetzo, Harold I. Palevsky, Thomas A. Trail. Recreational Use of Aminorex and Pulmonary Hypertension - CHEST, Nov, 2000 <Posted Below>

Reputation Comments on this post:

Great Post! Thanks for bringing this out to the open, into its own thread!