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Elisabetta Bertol – One of the best experts on this subject based on the ideXlab platform.

  • Levamisole, Aminorex and Pulmonary Arterial Hypertension: A Review
    Razavi International Journal of Medicine, 2015
    Co-Authors: Steven B. Karch, Fabio Vaiano, Elisabetta Bertol
    Abstract:

    Context: An epidemic of Aminorex-associated pulmonary arterial hypertension (PAH), resulting in multiple fatalities, occurred in the 1970s ending only after the drug was removed from the market. In 2009, when it was found that horses de-wormed with the anthelmintic levamisole, metabolized that drug to Aminorex, the same drug that caused the 1970s outbreak of PAH. The discovery would not have been cause for concern except to horseracing enthusiasts, who feared horse doping. However, at about the same time the relationship between levamisole and Aminorex was discovered, cocaine cartels began adulterating cocaine with levamisole. The rationale for adulterating cocaine with levamisole remains to be established. The purpose of this short review article is to discuss possible reasons for levamisole contamination, new discoveries about the human pharmacokinetics of Aminorex, and the possible relationship between Aminorex and pulmonary arterial hypertension in man. Evidence acquisition: Medline contents, as well as estimates published by the U.S. drug enforcement agency (DEA), US state department, and the European monitoring center for drugs and drug abuse (EMCDDA) were reviewed and relevant articles retrieved. There is uniform agreement among the various monitoring agencies analyzed. Results: Approximately 70 percent of the U.S. cocaine supply and 40 percent of the European cocaine supply is contaminated with levamisole. Aminorex has the same binding affinities for serotonin and other neurotransmitters as amphetamine. As serotonin is considered to be an important factor in the development of PAH, the possibility of another epidemic of Aminorex-induced PAH, this time among cocaine abusers, seems real, and threatening. Conclusions: The results of the first human pharmacokinetic studies of Aminorex were first characterized in 2013. The results suggest that while humans could produce Aminorex from levamisole, they probably do not convert very much. Even though cases of PAH have been reported in cocaine users, the latest pharmacokinetic studies suggest that very little Aminorex is actually produced from the ingested levamisole, probably not enough to cause PAH. However, since both cocaine and Aminorex can cause PAH the situation remains unclear. the lack of a clear answer is partially the development of an insidious pulmonary hypertension, producing subtle and non-specific symptoms in its early stages.

  • Aminorex associated with possible idiopathic pulmonary hypertension in a cocaine user
    Forensic science international, 2014
    Co-Authors: Steven B. Karch, Fabio Vaiano, Francesco Mari, Beatrice Defraia, Luca Messerini, Elisabetta Bertol
    Abstract:

    Abstract The conversion of levamisole to Aminorex in horses was first described in 2009 and, for the first time, confirmed in humans two years later by our laboratory. Aminorex and levamisole interfere with serotonin metabolism and both are proven cause of potentially fatal idiopathic pulmonary hypertension (IPH). Because most of the world’s seizures of illicit cocaine is now contaminated with levamisole, this raises the possibility that users of levamisole adulterated cocaine users may be at risk for IPH. Here we describe the first case of IPH in a user of levamisole-contaminated cocaine. Levamisole and Aminorex were both identified and quantified in hair and other biological specimens by means gas chromatography/mass spectrometry system (levamisole: urine, 75.05 ng/mL; blood, 15.05 ng/mL; brain, >0.15 ng/g; liver, >0.15 ng/g; hair, 12.15 ngmg; Aminorex: urine, 38.62 ng/mL; blood, 8.92 ng/mL, brain >0.15 ng/g; liver, 0.15 ng/g; hair 7.35 ng/mg; cocaine, benzoylecgonine, morphine, 6-acetylmorphine, methadone, 2-ethylidine-1, 5-dimetil-3, 3 diphenylpyrrolidine were also detected). Moreover histological changes associated with IPH were observed in the lung. As IPH produces relatively non-specific symptoms in its early stages, this index case may serve as a harbinger of many more cases to come. It should also alert clinicians to the possibility that their patient may be suffering from this relatively rare disorder.

  • Aminorex poisoning in cocaine abusers
    International journal of cardiology, 2011
    Co-Authors: Steven B. Karch, Francesco Mari, Viola Bartolini, Elisabetta Bertol
    Abstract:

    Levamisole is found in more than 80% of illicit cocaine seized within United States borders. Percentages are somewhat lower in Europe. In 2009, controlled in vivo studies demonstrated that horses metabolize levamisole to Aminorex. Earlier this year our laboratory demonstrated that the same conversion occurs in man. Levamisole itself causes aplastic anemia and numerous reports have begun to appear in the literature, but the conversion of levamisole to Aminorex is of much more concern. Aminorex ingestion was responsible for a five-year epidemic (1967-1972) of idiopathic pulmonary hypertension (IPH) confined to Switzerland, Austria, and Germany, the only countries where Aminorex had been marketed as an anorectic. The incidence of IPH reverted to normal levels as soon as Aminorex was withdrawn. In most cases onset of symptoms in IPH began after six to nine months of Aminorex use, with average dosage ranges of 10 to 40 mg per day. The outcome was almost uniformly fatal. The conversion rate of levamisole to Aminorex has not been established, but given the high daily intake of cocaine by many abusers, it seems likely that many of them will have ingested enough contaminated cocaine to ultimately cause IPH. Until the disease is well established, the symptoms of IHP are vague, and existing drug registries specifically exclude drug abusers, making it difficult to track these cases. This review is intended to draw attention to what may be a slowly emerging new epidemic.

Steven B. Karch – One of the best experts on this subject based on the ideXlab platform.

  • Levamisole, Aminorex and Pulmonary Arterial Hypertension: A Review
    Razavi International Journal of Medicine, 2015
    Co-Authors: Steven B. Karch, Fabio Vaiano, Elisabetta Bertol
    Abstract:

    Context: An epidemic of Aminorex-associated pulmonary arterial hypertension (PAH), resulting in multiple fatalities, occurred in the 1970s ending only after the drug was removed from the market. In 2009, when it was found that horses de-wormed with the anthelmintic levamisole, metabolized that drug to Aminorex, the same drug that caused the 1970s outbreak of PAH. The discovery would not have been cause for concern except to horseracing enthusiasts, who feared horse doping. However, at about the same time the relationship between levamisole and Aminorex was discovered, cocaine cartels began adulterating cocaine with levamisole. The rationale for adulterating cocaine with levamisole remains to be established. The purpose of this short review article is to discuss possible reasons for levamisole contamination, new discoveries about the human pharmacokinetics of Aminorex, and the possible relationship between Aminorex and pulmonary arterial hypertension in man. Evidence acquisition: Medline contents, as well as estimates published by the U.S. drug enforcement agency (DEA), US state department, and the European monitoring center for drugs and drug abuse (EMCDDA) were reviewed and relevant articles retrieved. There is uniform agreement among the various monitoring agencies analyzed. Results: Approximately 70 percent of the U.S. cocaine supply and 40 percent of the European cocaine supply is contaminated with levamisole. Aminorex has the same binding affinities for serotonin and other neurotransmitters as amphetamine. As serotonin is considered to be an important factor in the development of PAH, the possibility of another epidemic of Aminorex-induced PAH, this time among cocaine abusers, seems real, and threatening. Conclusions: The results of the first human pharmacokinetic studies of Aminorex were first characterized in 2013. The results suggest that while humans could produce Aminorex from levamisole, they probably do not convert very much. Even though cases of PAH have been reported in cocaine users, the latest pharmacokinetic studies suggest that very little Aminorex is actually produced from the ingested levamisole, probably not enough to cause PAH. However, since both cocaine and Aminorex can cause PAH the situation remains unclear. the lack of a clear answer is partially the development of an insidious pulmonary hypertension, producing subtle and non-specific symptoms in its early stages.

  • Aminorex associated with possible idiopathic pulmonary hypertension in a cocaine user
    Forensic science international, 2014
    Co-Authors: Steven B. Karch, Fabio Vaiano, Francesco Mari, Beatrice Defraia, Luca Messerini, Elisabetta Bertol
    Abstract:

    Abstract The conversion of levamisole to Aminorex in horses was first described in 2009 and, for the first time, confirmed in humans two years later by our laboratory. Aminorex and levamisole interfere with serotonin metabolism and both are proven cause of potentially fatal idiopathic pulmonary hypertension (IPH). Because most of the world’s seizures of illicit cocaine is now contaminated with levamisole, this raises the possibility that users of levamisole adulterated cocaine users may be at risk for IPH. Here we describe the first case of IPH in a user of levamisole-contaminated cocaine. Levamisole and Aminorex were both identified and quantified in hair and other biological specimens by means gas chromatography/mass spectrometry system (levamisole: urine, 75.05 ng/mL; blood, 15.05 ng/mL; brain, >0.15 ng/g; liver, >0.15 ng/g; hair, 12.15 ngmg; Aminorex: urine, 38.62 ng/mL; blood, 8.92 ng/mL, brain >0.15 ng/g; liver, 0.15 ng/g; hair 7.35 ng/mg; cocaine, benzoylecgonine, morphine, 6-acetylmorphine, methadone, 2-ethylidine-1, 5-dimetil-3, 3 diphenylpyrrolidine were also detected). Moreover histological changes associated with IPH were observed in the lung. As IPH produces relatively non-specific symptoms in its early stages, this index case may serve as a harbinger of many more cases to come. It should also alert clinicians to the possibility that their patient may be suffering from this relatively rare disorder.

  • Aminorex poisoning in cocaine abusers
    International journal of cardiology, 2011
    Co-Authors: Steven B. Karch, Francesco Mari, Viola Bartolini, Elisabetta Bertol
    Abstract:

    Levamisole is found in more than 80% of illicit cocaine seized within United States borders. Percentages are somewhat lower in Europe. In 2009, controlled in vivo studies demonstrated that horses metabolize levamisole to Aminorex. Earlier this year our laboratory demonstrated that the same conversion occurs in man. Levamisole itself causes aplastic anemia and numerous reports have begun to appear in the literature, but the conversion of levamisole to Aminorex is of much more concern. Aminorex ingestion was responsible for a five-year epidemic (1967-1972) of idiopathic pulmonary hypertension (IPH) confined to Switzerland, Austria, and Germany, the only countries where Aminorex had been marketed as an anorectic. The incidence of IPH reverted to normal levels as soon as Aminorex was withdrawn. In most cases onset of symptoms in IPH began after six to nine months of Aminorex use, with average dosage ranges of 10 to 40 mg per day. The outcome was almost uniformly fatal. The conversion rate of levamisole to Aminorex has not been established, but given the high daily intake of cocaine by many abusers, it seems likely that many of them will have ingested enough contaminated cocaine to ultimately cause IPH. Until the disease is well established, the symptoms of IHP are vague, and existing drug registries specifically exclude drug abusers, making it difficult to track these cases. This review is intended to draw attention to what may be a slowly emerging new epidemic.

Frank Musshoff – One of the best experts on this subject based on the ideXlab platform.

  • Determination of levamisole, Aminorex, and pemoline in plasma by means of liquid chromatography-mass spectrometry and application to a pharmacokinetic study of levamisole.
    Drug testing and analysis, 2014
    Co-Authors: Cornelius Hess, Natalie Ritke, Burkhard Madea, Konrad Sydow, Lena-maria Mehling, Hauke Ruehs, Frank Musshoff
    Abstract:

    Levamisole is an anti-helminthic drug and gained forensic interest after it was found that it was used as a cocaine adulterant. A liquid chrochromatography-mass spectrometry (LC-MS) method for the determination of levamisole and its metabolite Aminorex in human plasma is described. Selectivity is given; calibration curves were linear within a calibration range of 1 ng/mL–500 ng/mL. Limits of detection and quantification (LODs, LOQs) were 0.85 ng/mL for levamisole and 0.09 ng/mL, and 0.34 ng/mL for Aminorex, respectively. Precision data was in accordance with the GTFCh guidelines. The validated method was successfully applied to study the pharmacokinetics of levamisole after administration of 100 mg of levamisole orally. Levamisole could be detected up to 36 h after ingestion in serum, while Aminorex never exceeded the LOQ. A one-compartment model best described levamisole pharmacokinetics. The following parameters were calculated: ka = 1.2 [1/h], CL/F = 52 l/h, V/F = 347 l, f (renal) = 0.0005, t ½ = 2.0 h, AUC = 1923 ng/mL*h, cmax = 214 ng/mL, tmax = 1.98 h. Levamisole could be quantified in 42.5% of cocaine – positive plasma samples (2.2 to 224 ng/mL). Aminorex was positive in only 11.3% of the cases; however, it was never found higher than the LOQ. Pemoline, another stimulant detected in horse urine samples after administration of levamisole, was not found either in serum or in urine of this pharmacokinetic study. In post-mortem cases, levamisole and Aminorex could be detected in femoral blood and the urine of cocaine users. Pemoline was not detected. Copyright © 2014 John Wiley & Sons, Ltd.

  • Metabolism of levamisole and kinetics of levamisole and Aminorex in urine by means of LC-QTOF-HRMS and LC-QqQ-MS
    Analytical and bioanalytical chemistry, 2013
    Co-Authors: Cornelius Hess, Natalie Ritke, Sebastian Broecker, Burkhard Madea, Frank Musshoff
    Abstract:

    The antihelminthic drug Levamisole can enhance cocaine effects by conversion into the amphetamine-like drug Aminorex. We describe an LC-MS method for the determination of levamisole and its metabolite Aminorex in human urine. Selectivity is given, calibration curves were linear within the calibration range 2.5–250 ng/mL; limits of the method were LoD 0.51 ng/mL, LoQ 1.02 ng/mL for levamisole and LoD 0.65 ng/mL, LoQ 0.76 ng/mL for Aminorex. Precision data was in accordance with the guidelines (intraday precision for Aminorex ranged between 5.75 and 11.0 % for levamisole between 8.36 and 10.9 %; interday precision for levamisole 10.9–16.9 % and for Aminorex 7.64–12.7 %; accuracy data for levamisole −1.96 to –14.3 % and for Aminorex−11.9 to–18.5 %). The validated method was successfully applied to study the urinary excrexcretion of levamisole after the administration of 100 mg of levamisole orally. Levamisole and Aminorex could be detected in post-administration urine samples. Levamisole could be detected up to 39 h after ingestion, while Aminorex was detectable up to 54 h. Maximum Aminorex concentrations were 45 ng/mL urine. Further metabolites of levamisole after oral ingestion by means of liquid chrochromatography hybrid quadrupole time-of-flight high-resolution mass spectrometry (LC-QTOF-HRMS) were identified. Only 0.5 % of the ingested drug was quantified as unchanged levamisole in urine. Besides Aminorex, five isomers of Aminorex and 4 hydroxy-metabolites of Aminorex or its isomers were found. Furthermore, levamisole is also hydroxylated and eliminated free or conjugated with sulfate or glucuronide into urine.

Serge Adnot – One of the best experts on this subject based on the ideXlab platform.

  • The Serotonin System as a Therapeutic Target in Pulmonary Hypertension
    Textbook of Pulmonary Vascular Disease, 2010
    Co-Authors: Serge Adnot
    Abstract:

    The effects of serotonin (5-hydroxytryptamine, 5-HT) on the pulmonary circulation attracted the interest of researchers when an increased risk of idiopathic pulmonary arterial hypertension (IPAH) was reported in patients who had used appetite suppressants that interact with 5-HT. An association between the anorexigen Aminorex and IPAH was described in the 1960s. In the 1980s, fenfluramine use was shown to be associated with an epidemic of IPAH in France and Belgium. The 5-HT hypothesis received support from the observation that pulmonary hypertension (PH) develops spontaneously in fawn-hooded rats, which have an inherited platelet-storage defect. Early studies focused on circulating 5-HT and its potential effects on the pulmonary vascular bed. They showed that patients with IPAH had increased circulating 5-HT levels even after heart–lung transplantation. In addition to its vasoactive effects, 5-HT exerts mitogenic and comitogenic effects on pulmonary artery smooth muscle cells (PASMCs). In contrast to the constricting action of 5-HT on smooth muscle cells, which is mainly mediated by 5-HT receptors (5-HT1B/D, 5-HT2A, and 5-HT2B), the mitogenic and comitogenic effects of 5-HT require the internalization of indoleamine by the 5-HT transporter (5-HTT). Accordingly, drugs that competitively inhibit 5-HTT also block the mitogenic effects of 5-HT on smooth muscle cells. The appetite suppressants fenfluramine, d-fenfluramine, and Aminorex differ from selective 5-HTT inhibitors in that they not only inhibit 5-HT reuptake, but also trigger indoleamine release and interact with 5-HTT and 5-HT receptors in a specific manner. Over the last few years, the role of the 5-HT pathway in the pathogenesis of PH has been extensively investigated, and severe alterations in several critical steps of this pathway have been found during the progression of PH. These alterations include changes in 5-HT synthesis and bioavailability, changes in 5-HT-mediating effects on target cells (PASMCs and fibroblasts), and alterations in intracellular signaling. These critical steps represent targets for future therapies and will be discussed individually.

  • Anorexigen-induced pulmonary hypertension and the serotonin (5-HT) hypothesis: lessons for the future in pathogenesis
    Respiratory research, 2001
    Co-Authors: Saadia Eddahibi, Serge Adnot
    Abstract:

    Epidemiological studies have established that fenfluramine, D-fenfluramine, and Aminorex, but not other appetite suppressants, increase the risk of primary pulmonary hypertension (PH). One current hypothesis suggests that fenfluramine-like medications may act through interactions with the serotonin (5-hydroxytryptamine [5-HT]) transporter (5-HTT) located on pulmonary artery smooth muscle cells and responsible for the mitogenic action of 5-HT. Anorexigens may contribute to PH by boosting 5-HT levels in the bloodstream, directly stimulating smooth muscle cellcell growth, or altering 5-HTT expression. We suggest that individuals with a high basal level of 5-HTT expression related to the presence of the long 5-HTT gene promoter variant may be particularly susceptible to one or more of these potential mechanisms of appetite-suppressant-related PH.

  • Commentary Anorexigen-induced pulmonary hypertension and the serotonin (5-HT) hypothesis: lessons for the future in pathogenesis
    , 2001
    Co-Authors: Saadia Eddahibi, Serge Adnot
    Abstract:

    Epidemiological studies have established that fenfluramine, D-fenfluramine, and Aminorex, but not other appetite suppressants, increase the risk of primary pulmonary hypertension (PH). One current hypothesis suggests that fenfluramine-like medications may act through interactions with the serotonin (5-hydroxytryptamine [5-HT]) transporter (5-HTT) located on pulmonary artery smooth muscle cells and responsible for the mitogenic action of 5-HT. Anorexigens may contribute to PH by boosting 5-HT levels in the bloodstream, directly stimulating smooth muscle cellcell growth, or altering 5-HTT expression. We suggest that individuals with a high basal level of 5-HTT expression related to the presence of the long 5-HTT gene promoter variant may be particularly susceptible to one or more of these potential mechanisms of appetite-suppressant-related PH

Alfred P Fishman – One of the best experts on this subject based on the ideXlab platform.

  • Primary pulmonary arterial hypertension: A look back
    Journal of the American College of Cardiology, 2004
    Co-Authors: Alfred P Fishman
    Abstract:

    For the first half of the twentieth century, the published reports on primary pulmonary hypertension (PPH) were confined to clinical pathological correlations. In the 1950s the physiological aspects began to be reported followed by epidemiologic studies triggered by an epidemic of PPH due to the ingestion of an appetite suppressant, Aminorex fumarate. The epidemic prompted a series of meetings of the World Health Organization, which led, in turn, to the creation of the U.S. Registry of Primary Pulmonary Hypertension, standardization of nomenclature, and an etiologic classification of all types of pulmonary hypertension.

  • Aminorex to fen phen an epidemic foretold
    Circulation, 1999
    Co-Authors: Alfred P Fishman
    Abstract:

    Over the years, a variety of diets and drugs for the treatment of obesity have come and gone. More recently, newspapers, radio, and television have featured the rise and fall of the latest appetite-suppressants, dexfenfluramine and the combination of fenfluramine and phentermine (fen/phen). The rise occurred after approval of dexfenfluramine by the Food and Drug Administration (FDA); the fall was prompted by an unexpected outbreak of valvular heart disease related to the use of anorectic agents.1 The outbreak of valvular heart disease was unexpected. Even though alarms had been sounded of an impending epidemic of pulmonary hypertension that would follow the turning loose of the appetite suppressants by the FDA,2 3 previous experience with these medications had not foretold an epidemic of valvular heart disease. In this article, the pathogenetic mechanisms involved in the pulmonary vascular and cardiac valvular disease are explored within the larger framework of dietary pulmonary hypertension.4 Insights into these mechanisms appear to be relevant to avoiding similar epidemics caused by anorectic agents and in developing future weight-losing medications. One major weakness in the war against overweight and obesity is the blurred outlines of the targets. Although any degree of overweight is undesirable, not all degrees of obesity call for the same type or vigor of attack. For example, the goal of a 10% reduction in weight in an individual who is mildly obese and at risk for systemic hypertension and diabetes warrants more aggressive measures than does achieving the same weight loss by an individual determined to fit into last year’s bathing suit. In turn, both of these indications are much less compelling than weight loss in a morbidly obese individual in whom quick weight loss may be lifesaving. Moreover, no matter what the goal is in treating overweight and obesity, lasting success …

  • Aminorex to fen/phen : An epidemic foretold
    Circulation, 1999
    Co-Authors: Alfred P Fishman
    Abstract:

    Over the years, a variety of diets and drugs for the treatment of obesity have come and gone. More recently, newspapers, radio, and television have featured the rise and fall of the latest appetite-suppressants, dexfenfluramine and the combination of fenfluramine and phentermine (fen/phen). The rise occurred after approval of dexfenfluramine by the Food and Drug Administration (FDA); the fall was prompted by an unexpected outbreak of valvular heart disease related to the use of anorectic agents.1 The outbreak of valvular heart disease was unexpected. Even though alarms had been sounded of an impending epidemic of pulmonary hypertension that would follow the turning loose of the appetite suppressants by the FDA,2 3 previous experience with these medications had not foretold an epidemic of valvular heart disease. In this article, the pathogenetic mechanisms involved in the pulmonary vascular and cardiac valvular disease are explored within the larger framework of dietary pulmonary hypertension.4 Insights into these mechanisms appear to be relevant to avoiding similar epidemics caused by anorectic agents and in developing future weight-losing medications. One major weakness in the war against overweight and obesity is the blurred outlines of the targets. Although any degree of overweight is undesirable, not all degrees of obesity call for the same type or vigor of attack. For example, the goal of a 10% reduction in weight in an individual who is mildly obese and at risk for systemic hypertension and diabetes warrants more aggressive measures than does achieving the same weight loss by an individual determined to fit into last year’s bathing suit. In turn, both of these indications are much less compelling than weight loss in a morbidly obese individual in whom quick weight loss may be lifesaving. Moreover, no matter what the goal is in treating overweight and obesity, lasting success …