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

Discussion in 'Research Chemicals' started by Kemikaru_Tenshu, Apr 11, 2006.

  1. Kemikaru_Tenshu

    Kemikaru_Tenshu Platinum Member

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    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": https://drugs-forum.com/forum/showthread.php?p=146085#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>
     
    1. 4/5,
      Great Post! Thanks for bringing this out to the open, into its own thread!
      Apr 11, 2006
  2. Kemikaru_Tenshu

    Kemikaru_Tenshu Platinum Member

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    First Post by Richard_smoker from "4-methylaminorex vs Methcathinone":

     
    Last edited: Apr 11, 2006
  3. Kemikaru_Tenshu

    Kemikaru_Tenshu Platinum Member

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    First Post by me from "4-methylaminorex vs Methcathinone":


    ~KT
     
    Last edited: Apr 11, 2006
  4. Kemikaru_Tenshu

    Kemikaru_Tenshu Platinum Member

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    Second Post by Richard_smoker from "4-methylaminorex vs Methcathinone":

     
  5. Kemikaru_Tenshu

    Kemikaru_Tenshu Platinum Member

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    Recreational Use of Aminorex and Pulmonary Hypertension

    Recreational Use of Aminorex and Pulmonary Hypertension - CHEST, Nov, 2000
    by Sean P. Gaine, Lewis J. Rubin, James J. Kmetzo, Harold I. Palevsky, Thomas A. Traill
    Hypertension has been associated with ingestion of the appetite suppressant aminorex. A similar compound, 4-methyl-aminorex (street names, "U-4-E-uh" [pronounced euphoria] or "ice"), is a "designer" drug with central stimulant activity. This drug was discovered on the property of three individuals with diagnoses of pulmonary hypertension. The association between "recreational" aminorex manufacture and ingestion and the development of pulmonary hypertension is described.
    (CHEST 2000; 118:1496-1497)
    Pulmonary hypertension has been associated with the ingestion of a variety of substances, including anorexic agents, cocaine, contaminated rapeseed cooking off, and L-tryptophan.[1] The epidemic of primary pulmonary hypertension in Austria, Switzerland, and West Germany in the 1970s was attributed to the widespread use of the anorexic agent aminorex and subsided on removal of this drug from the market.[2] Aminorex was never available legally in the United States. We describe a cluster of patients with pulmonary hypertension that we believe was the result of "recreational" aminorex ingestion.
    CASE PRESENTATION
    1 is a 39-year-old man who owns a farm in rural Pennsylvania. He presented in February 1993 with an 8-month history of exertional dyspnea and syncope, and he was found to have a pulmonary artery pressure of 56/20 mm Hg (mean, 34 mm Hg) at cardiac catheterization, The pulmonary capillary wedge. pressure was normal, but left ventricular ejection fraction was reduced to 40%. Patient 2, the 32-year-old wife of patient 1, developed exertional dyspnea and syncope in November 1993. Cardiac catheterization in August 1994 disclosed a pulmonary artery pressure of 60/38 mm Hg (mean, 48 mm Hg). Patient 3, the nephew of patient 1, age 28 years, presented in January 1993 with dyspnea and light-headedness; at cardiac catheterization in July 1993, he had a pulmonary artery pressure of 75/30 mm Hg (mean, 50 mm Hg). No underlying cause for pulmonary hypertension was found in any case, and all patients initially denied ingestion of potentially toxic substances. Left ventricular function was mildly and globally depressed in patients 1 and 2, although left-heart filling pressures were normal. Pulmonary hypertension has been persistent in all three patients, although echocardiography in patient 1 suggested that pressures may have improved. An investigation by federal Drug Enforcement Administration agents resulted in indictment of patient 1 following the discovery of a chemistry laboratory and [is greater than] 20 lb of 4-methyl-aminorex, an amphetamine analog, in a barn that was sublet on the farm. Patient 3, who was not indicted, subsequently confirmed prior 4-methyl-aminorex ingestion.
    DISCUSSION
    We present three members of a family with diagnoses of pulmonary hypertension, who were subsequently discovered to have been involved with the illicit manufacture and use of a designer drug, 4-methyl-aminorex. Officials for the Drug Enforcement Administration confirmed that the cis-isomer of 4-methyl-aminorex (street names, "U-4-E-uh" [pronounced euphoria] or "ice") has appeared on the clandestine market as a "designer" drug alternative to methamphetamine (street name, "crank"). 4-Methyl-aminorex (Fig 1), which has gained attention due to its potential as a central stimulant of abuse and because of the ease with which it is synthesized, was recently classified as a schedule I substance.[3] The drug is generally synthesized from the over-the-counter diet pill phenylpropanolamine HCl and is smoked as the free base or the HCl salt. Anecdotally, the drug is said to have a minor "speed-like" component, with a time of action of 4 to 6 h.

    [Figure 1 - Removed]

    While an autosomal dominant family history is obtained in 10 to 15% of individuals with primary pulmonary hypertension, the majority of cases of are postulated to occur sporadically following a stimulus (ie, anorexogens) that, in susceptible individuals, results in pulmonary vascular injury.[4] The occurrence of a "cluster" of pulmonary hypertension cases around the apparent illicit use of an aminorex analog has not previously been described. This case presents a most unusual occurrence of "familial" pulmonary hypertension.
    REFERENCES
    [1] Rubin LJ, Barst RJ, Kaiser LR, et al. ACCP consensus statement: primary pulmonary hypertension. Chest 1993; 104:236-250
    [2] Gurtner HP. Aminorex pulmonary hypertension, In: Fishman AP, ed. The pulmonary circulation: normal and abnormal. Philadelphia, PA: University of Pennsylvania Press, 1990; 397-412
    [3] Glennon RA, Misenheimer B. Stimulus properties of a new designer drug: 4-methylaminorex ("U4Euh"). Pharmacol Biochem Behav 1990; 35:517-521
    [4] Gaine SP, Rubin LJ. Primary pulmonary hypertension, Lancet 1998; 352:719-725
    Sean P. Gaine, MD, FCCP; Lewis J. Rubin, MD, FCCP; James J. Kmetzo, MD; Harold I. Palevsky, MD, FCCP; and Thomas A. Traill, MD
    (*) From the Division of Pulmonary and Critical Care Medicine (Dr. Gaine), Division of Cardiology (Dr. Traill), Johns Hopkins University, Baltimore, MD; the Division of Pulmonary and Critical Care Medicine (Dr. Rubin), University of California at San Diego, San Diego, CA; the Division of Cardiology (Dr. Kmetzo), Doylestown Hospital, Doylestown, PA; and the Division of Pulmonary and Critical Care Medicine (Dr. Palevsky), University of Pennsylvania, Philadelphia, PA.
    Manuscript received February 4, 2000; accepted March 23, 2000.
    Correspondence to: Lewis J. Rubin MD, FCCP, Division of Pulmonary and Critical Care Medicine, University of California at San Diego, San Diego, CA