Fatal Intoxications Due to Administration of Isosorbide Tablets Contaminated with Pyrimethamine

Abstract

In January 2012, 664 cases of pyrimethamine toxicity and 151 deaths were reported among cardiac patients that had recently received free medicines from pharmacy of Punjab Institute of Cardiology, Lahore, Pakistan. These patients, ages ranged from 58 to 75 years, were prescribed simvastatin, clopidogrel, aspirin soluble, isosorbide mononitrate, and amlodipine. On examination of medications being given to them, it was found that a particular batch of isosorbide mononitrate tablets was contaminated with 50 mg pyrimethamine. Cardiac patients were taking isosorbide contaminated with pyrimethamine twice daily (100 mg pyrimethamine/day), whereas therapeutic dose of pyrimethamine for malaria is 25 mg/week. Postmortem urine, cardiac blood, and femoral blood specimens of three deceased males were submitted to author's laboratory for analysis. Postmortem toxicological analysis revealed that pyrimethamine concentration fell within the range of 1-10 μg/mL by liquid chromatography. Clinical, autopsy, histopathological, and toxicological findings strongly suggested toxicity due to pyrimethamine accumulation that resulted in deaths of these cardiac patients.

Medicine recalls in Saudi Arabia: a retrospective review of drug alerts (January 2010–January 2019)

“…However, serious adverse reactions can results as reported in January 2012 in Pakistan. Isosorbide mononitrate tablets were contaminated with large doses of pyrimethamine (an antimalarial drug) which lead to the death of 151 patients and 664 cases of pyrimethamine toxicity [11].…”

Pyrimethamine toxicosis in horses given a compounded medication

“…A comparable sequence is described for human patients. Convulsions occur as early as 30 min after accidental overdose and signs of GI disturbance and bone marrow suppression begin 4-8 days later (Weniger 1979;Kabat et al 2014;Imran et al 2016). It is unclear why, in the cases described herein, neurological signs developed within 2 h in four horses and approximately 24 h post-PYR in the other four horses.…”

“…; Imran et al . ). It is unclear why, in the cases described herein, neurological signs developed within 2 h in four horses and approximately 24 h post‐PYR in the other four horses.…”

“…; Imran et al . ). A mechanism for fever in affected human patients has not been reported; however, possible causes for the horses in this report include muscle contractions during seizures, absorption of endotoxin or bacteria through injured intestinal walls, or release of endogenous pyrogens from tissues damaged by folate deficiency.…”