Drugs and Toxins
Appetite Suppressants
The use of appetite suppressants including aminorex fumarate and fenfluramine derivatives for more than three months is associated with a 30 times greater risk of developing pulmonary arterial hypertension. The relationship between appetite suppressants and pulmonary arterial hypertension was identified in the 1960s when a 20-fold increase in pulmonary hypertension was reported in Switzerland, Austria, and the former West Germany following the introduction of aminorex fumarate to the marketplace. The increase in the number of cases subsided when the substance was banned. Fenfluramine derivatives have also been used as anorexic agents since the 1960s. In a study of 73 pulmonary arterial hypertension/familial pulmonary arterial hypertension patients, 25% of the patient group was found to have been exposed to fenfluramines. This observation followed the introduction of the fenfluramine derivative dexfluramine and extensive increases in fenfluramine sales in France over the period 1985-1992. The Surveillance of North American Pulmonary Hypertension Study investigated 579 patients with pulmonary hypertension and found a strong association between the use of fenfluramine derivatives and the development of primary pulmonary hypertension (PPH, now classified as pulmonary arterial hypertension and familial pulmonary arterial hypertension). The association was stronger with longer duration of use and more pronounced in recent users when compared with remote users. Both fenfluramine and dexfluramine were withdrawn from the U.S. market in 1997, only 18 months after they launched.
These agents may initiate the disease process by several mechanisms. Aminorex and dexfenfluramine have been shown to directly inhibit the voltage-gated potassium channels Kvl.5 and Kv2.1. Aminorex has been shown to induce 5-HT release from platelets and inhibit 5-HT metabolism, while fenfluramine derivatives have been shown to interact with the 5-HTT. The WHO states that other appetite suppressants such as amphetamines are “very likely” to have a causative role in pulmonary hypertension as well.
L-Tiyptophan
The food supplement L-tryptophan is commonly used to treat premenstrual syndrome, insomnia, depression, and drug detoxification. In the late 1980s, L-tryptophan was linked with a newly characterized disease — eosinophiliamyalgia syndrome (EMS), of which 1,500 cases have been reported in the United States. In severe cases of the disease, the pulmonary circulation is affected, and in some individuals pulmonary arterial hypertension has been reported. The FDA continues to express its concern about products containing the food supplement L-tryptophan but has not prohibited the marketing of such products.
Toxic Rapeseed Oil
So-called toxic oil syndrome was first recognized in Spain in 1981 and is an interesting example of how pulmonary hypertension can develop following exposure to chemicals. A total of 20,688 cases of the toxic oil syndrome were reported, and the WHO determined the cause of the condition to be related to the consumption of contaminated rapeseed oil. One study following 322 patients with toxic oil syndrome found that 8.1% of the group developed pulmonary hypertension. After an eight-year follow-up period, severe pulmonary hypertension had developed in 2% of pulmonary hypertension sufferers. It was estimated that pulmonary hypertension was the cause of death in 1.6% of toxic oil syndrome sufferers. Histopathological changes — characterized by the presence of plexiform lesions — observed on examining the lungs of the patient population were similar to those seen in pulmonary arterial hypertension.
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