Beta-blockers were developed for the treatment of heart conditions and the first agents to be administered to human patients were pronethalol and propranolol. Ironically, pronethalol proved generally safe and effective in laboratory animals but failed the clinical test, while propranolol appeared toxic in many animal experiments yet is widely used in clinical practice.
Pronethalol was “well tolerated” by rats and dogs in prolonged toxicity tests at high doses, except for occasional effects on the central nervous system.(1) However, clinical trials revealed an unacceptable number of side-effects (2) including heart failure, a hazard not predicted by animal experiments.(1) Shortly after, long term tests in a certain (Alderley Park) strain of laboratory mouse produced cancer of the thymous gland but no carcinogenic effects were ever found in rats, guinea pigs, dogs, monkeys or other types of mouse.(1)
Pronethalol was quickly replaced by propranolol but tests in rats, dogs and mice put further development in jeopardy.(3) Moderate to high doses caused rats to collapse and dogs to vomit severely.(1) Deaths were also seen in mice shortly after dosing. When the amount of drug was reduced to that used clinically, propranolol was said to be “well tolerated”. Even so, some of the rats still had heart lesions.(1)
Later clinical observations showed that propranolol could also lower the blood pressure,(4) and today beta-blockers are widely used for the treatment of high blood pressure.
1) J.M.Cruickshank et al in Safety Testing of New Drugs, Eds. D.R.Laurence et al (Academic Press,1984)
2) W.Sneader, Drug Discovery: the evolution of modern medicine (Wiley, 1985)
3) D.R.Laurence et al (Eds.), Safety Testing of New Drugs (Academic Press,1984) 4) E.S.Snell, Pharmacy International, 1986, February, 33-37.
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