Pulmonary hypertension induced by drugs and toxins
Philippe Camus, Edward C Rosenow in Drug-induced and Iatrogenic Respiratory Disease, 2010
Aminorex resembles adrenaline and ephedrine in its chemical structure (Fig. 29.2) and acts as a potent appetite depressing agent and as a central stimulant. It has an adrenergic effect. In the 1960s there was an outbreak of chronic pulmonary hypertension in Europe. In 1967, a sudden 20-fold increase in the number of cases in adults (known at that time as primary pulmonary hypertension, according to the former nomenclature), mostly women, subjected to cardiac catheterization was observed in a Swiss medical clinic. The disease showed rapid progression, and the interval between the onset of symptoms and diagnosis was 10 months on average. The onset of the symptoms followed the beginning of the anorectic treatment by an average of 8.6 months (range 6–12 months). There were no apparent changes in either size or composition of the population, or of diagnostic procedures. About half of the patients were to some degree overweight, with a female preponderance. It was noticed that a considerable number of these patients had taken aminorex to reduce weight.3 A similar increase in the number of PAH cases observed was reported in other clinics in Switzerland,4 and in Austria and Germany, where aminorex was also available. Subsequently, a cooperative retrospective study has been conducted with participation of 23 centres in these countries. A total of 582 cases of chronic pulmonary hypertension were identified, among which 68 per cent had claimed they had used aminorex, either alone or in combination with other anorectic agents.5 Aminorex was introduced on the Swiss market in November 1965, and was withdrawn in October 1968, a few months after the communications of these findings.
Public access to data at drug agencies
Peter C. Gøtzsche, Richard Smith, Drummond Rennie in Deadly Medicines and Organised Crime, 2019
The history of the slimming pills is a dire one that confirms that drug regulators aren’t willing to learn from history. Phentermine was approved in the United States in 1959 and is still on the market, although it’s similar to amphetamine, both chemically and in its effects. In the 1960s, another appetite suppressant with amphetamine effects, aminoxaphen (Aminorex), was very popular in Europe,35 but it causes pulmonary hypertension and was withdrawn after 7 years when hundreds of patients had died under terrible conditions.
Current research and future hope
G. Michael Steelman, Eric C. Westman in Obesity, 2016
Developing drugs for the treatment of obesity comes with some special challenges. First, the drugs that have been used for the treatment of obesity have been accompanied by a litany of safety problems. This started with the first drug to be used for the treatment of obesity, thyroid hormone, which caused hyperthyroidism (107,108). Dinitrophenol was associated with cataracts, neuropathy, and even death by hyperthermia (109,110). Amphetamine was addictive, and aminorex, an amphetamine derivative with a noradrenergic mechanism, was removed from the European market for its association with primary pulmonary hypertension that carried 50% mortality (111,112). More recently, fenfluramine was removed from the market due to its association with cardiac valvulopathy, phenylpropanolamine was removed due to the risk of hemorrhagic stroke, and ephedra was removed due to systemic adrenergic stimulation (47,113,114). Most recently, sibutramine was removed from the market for an increase in nonfatal stroke, nonfatal myocardial infarction, resuscitation after cardiac arrest, or cardiovascular death (P < 0.02) in a cardiovascular safety trial (115). This history has raised the bar for ensuring the safety of obesity medications. Adding to the concern about safety is the inadequacy of BMI categorization of obesity risk. The Edmonton Obesity Staging System (EOSS) proposes dividing overweight and obesity into stages: stage 0 that has no medical issues, stage 1 that has predisease risk such as prediabetes, stage 2 that has an established disease such as diabetes, stage 3 that has complications of diseases such diabetic retinopathy, and stage 4 that is end-stage disease (116). The BMI categories approach to assessing obesity risk was evaluated using mortality data from the NHANES and compared to the EOSS. Overweight (BMI 25–30) had mortality data that almost superimposed on Class III obesity (BMI >40) using the BMI risk categories, but the EOSS gave a progressively increasing mortality risk when going from stage 0 to stage 3 (117). Being able to assess obesity risk accurately should be of considerable help to drug development. The use of any drug is a process of weighing risks and benefits. Using the staging system, one could theoretically assign or develop drugs with more risks for those with the stages of obesity associated with higher mortality risks.
Pulmonary vascular diseases
Published in Canadian Journal of Respiratory, Critical Care, and Sleep Medicine, 2020
Jason Weatherald, Vicky Mai, Steeve Provencher
Certain anorexigen medications, like aminorex and fenfluramine, have long been recognized as important potential causes of PAH. The 2018 World Symposium on PH also highlighted new evidence in support of illicit methamphetamines and dasatinib as “definite” causes of medication-induced PAH.1 Zamanian et al. recently reported a large series of methamphetamine-associated PAH patients who were more often male with worse symptoms and hemodynamics than idiopathic PAH patients.6 Methamphetamine-associated PAH also carried a 2-fold higher risk of death compared to idiopathic PAH patients. Dasatinib, a tyrosine kinase inhibitor used for treatment of chronic myelogenous leukemia, is now considered a definite cause of PAH.1 Other medications more recently (but less definitively) linked with PAH include leflunomide, sofosbuvir and other tyrosine kinase inhibitors such as bosutinib and ponatinib.1
Pulmonary arterial hypertension associated with abatacept treatment for rheumatoid arthritis: A case report
Published in Canadian Journal of Respiratory, Critical Care, and Sleep Medicine, 2018
Steven Promislow, Lisa M. Mielniczuk, George Chandy, Duncan J. Stewart, Carolyn Pugliese, Ross A. Davies
PAH is a rare complication of several drugs. Historically, anorectic drugs such as fenfluramine, dexfenfluramine, aminorex, and benfluroex are the most well-known and have all been withdrawn from the market due to, among other concerns, their propensity to cause pulmonary hypertension. More recently, immune-modulating agents such as the tyrosine kinase inhibitor dasatinib as well as interferon α and interferon β have been implicated in the development of PAH. Amphetamines have also been associated with PAH, and there is an increased risk of persistent pulmonary hypertension in newborns of mothers who are taking selective serotonin reuptake inhibitors (SSRIs).
The risk of cardiovascular complications with current obesity drugs
Published in Expert Opinion on Drug Safety, 2020
Ariana M. Chao, Thomas A. Wadden, Robert I. Berkowitz, Kerry Quigley, Frank Silvestry
Several weight loss medications have been withdrawn from the market due to adverse reactions. Cardiovascular toxicity has been a common reason for withdrawal after regulatory approval[9]. As a class, medications that act on monoamine neurotransmitters (to suppress appetite) have been the most frequently withdrawn due to associated cardiovascular toxicity. These include aminorex (pulmonary hypertension), fenfluramine and dexfenfluramine (valvulopathy), phenylpropanolamine (stroke), and sibutramine (myocardial infarction and stroke) [9,10].
Related Knowledge Centers
- Anorectic
- Dextroamphetamine
- Levamisole
- Metabolite
- Methamphetamine
- Pulmonary Hypertension
- Stimulant
- Catecholamine
- Drug
- 4-Methylaminorex