Postgraduate Medical Journal (July 1970) 46, 409-416. Aminoglutethimide: a 'side-effect' turned to therapeutic advantage S. W. M. HUGHES D. M. BURLEY B.Pharm., D.C.C., M.P.S., M.I.Biol. M.B., B.S., M.R.C.S., L.R.C.P. Medical Division, CIBA Laboratories, Horsham, Sussex Summary glutethimide was marketed as an anticonvulsant in Aminoglutethimide was introduced as an anti- the United States in May 1960. convulsant drug in the U.S.A. in 1960. Reports on the therapeutic use of aminogluteth- The occurrence of a number of side-effects, includ- imide appeared in both the North American medical ing several endocrine effects such as goitrogenesis, literature (Lambros, 1958; LaVeck, 1960; Pearce, sexual precocity and virilization, led to its with- 1960; Aguilar, Martin & McNaughton, 1961) and drawal. the European medical literature (Guareschi, Gian- Further investigation indicated that the drug in- nelli & Marinato, 1956; Sheehan, 1958; Fabisch, hibited adrenal biosynthesis, particularly of aldo- 1959; Defer, 1960; Verdeau-Pailles, 1961). All these sterone, cortisol and androgens, probably by interfer- papers reported varying degrees of efficacy in either ing with the conversion of cholesterol to delta-5- grand mal, petit mal or psychomotor epilepsy. pregnenolone. Nevertheless, in one study, of 2 years' duration, Aminoglutethimide has also been shown to modify using aminoglutethimide with other anticonvulsants, the extra-adrenal metabolism of cortisol. it was found to be impossible to discontinue any of The possible clinical applications of these 'side- the companion drugs (Aguilar et al., 1961) and in effects' are discussed. 1962 the American Medical Association's Council on Drugs (Journal ofthe American Medical Associa- Aminoglutethimide was first described in the tion, 1962), reviewing new drugs and developments pharmacological literature in 1956. It was clinically in therapeutics, described aminoglutethimide as a evaluated as an anti-convulsant and became com- 'moderately effective' anticonvulsant for oral treat- mercially available in the United States in 1960. ment of various types of convulsive seizure. The Six years later it was withdrawn from the market at Council concluded that in view of its limited efficacy the request of the United States Food and Drugs and high frequency of untoward reactions, amino- Administration on account of side-effects. It is the glutethimide was only indicated as a supplement to purpose of this paper to describe the events leading other anticonvulsants in those patients not respond- to the withdrawal of aminoglutethimide and also ing to conventional therapeutic regimes. At that time to review the subsequent biochemical and clinical side-effects were reported to occur in almost half of investigations which have resulted in the previously the patients treated. These commonly included unwanted side-effects of this drug being utilized to morbilliform rashes, dizziness, drowsiness, be- clinical advantage. havioural changes, ataxia, headache, leukopenia, respiratory depression and, more rarely, exfoliative Anticonvulsant activity dermatitis and one case of agranulocytosis with In 1956 Gross et al. reported the structure, activity ulcerative stomatitis. and metabolism of a series of a,a disubstituted Thus, although not highly regarded as an anti- glutaric acid imides. A series of compounds based convulsant aminoglutethimide found a place as a on a-phenyl-a-ethyl glutarimide (glutethimide) which second-line drug, and in 1966 it was estimated that had known sedative-hypnotic and anticonvulsant it was being used by approximately 5000 patients activity, was examined in mice and p-(a-amino- annually. phenyl)-a-ethyl glutarimide (aminoglutethimide) was shown to have markedly greater anticonvulsant F.D.A. withdrawal activity, but considerably less sedative-hypnotic In 1963 Cash, a Detroit paediatrician, noted the effect, than the parent compound. Clinical evaluation occurrence of goitrous hypothyroidism and adrenal proceeded in Europe and North America and amino- insufficiency in an 8 year-old female patient who had 410 S. W. M. Hughes and D. M. Burley been admitted to the Sinai Hospital. The patient the exception of a slight reduction in radio-iodine exhibited a bronze skin typical of Addison's disease uptake. These studies, therefore, confirmed that but had no history of adrenal disorder. It was, how- aminoglutethimide interferes with thyroid meta- ever, noted that she was an epileptic and had re- bolism and that it has a goitrogenic action. ceived aminoglutethimide for the previous 5 months. When Rallison et al. (1964) first reported the Studies in this patient, and others receiving amino- effects of aminoglutethimide on thyroid metabolism, glutethimide, and experimental work in rats and they based their original suggestion of a block in the dogs demonstrated that the drug could produce organification of iodine on the evidence obtained histological changes in the adrenals suggesting a from three children who showed low protein-bound block of steroid biosynthesis (Camacho et al., 1966). iodine, and low butyl extractable iodine values, a In 1964 Rallison, Tyler & Kumagi described thyroid high thyroidal uptake of radio-iodine and a dis- enlargement and hypothyroidism in three epileptic charge of more than 50% of thyroidal radioactivity children receiving the drug. Withdrawal of the following the administration of thiocyanate. Extrac- aminoglutethimide in these children resulted in the tion and chromatography of plasma and urine failed disappearance of the goitre and restoration of nor- to reveal any abnormal iodinated compounds. Four mal thyroid function, thus confirming that the additional children, also receiving the drug, were goitres were drug-induced. These setbacks for amino- found to be clinically euthyroid and exhibited no glutethimide were followed in 1965 by the publica- abnormalities of protein-bound iodine or radio- tion ofa case ofcongenital female pseudohermaphro- iodine uptake. These workers have since investi- ditism which was considered to be due to anti- gated the nature of the antithyroidal effects ofamino- convulsant drugs, which included aminogluteth- glutethimide in rats and have consistently demon- imide, taken by the mother (Iffy et al., 1965). strated thyromegaly, diminished production of Finally during this same period the manufacturers thyroxine and di-iodotyrosine and an accumulation informed the Food and Drugs Administration (FDA) of thyroidal inorganic iodide (Rallison, Kumagi & that they had received reports of sexual precocity in Tyler, 1967). The block in the organificiation of children receiving the drug. iodine was found to be similar to the action of Thus in February 1966 aminoglutethimide was propylthiouracil and aminobenzene derivatives to recalled from the market (F.D.A. press release 16 which aminoglutethimide bears a structural resem- February 1966). The F.D.A. stated that it had re- blance. They concluded that the unpredictability of quested this action since the effectiveness of the drug antithyroidal activity among their seven patients in the treatment of convulsions was in doubt and receiving aminoglutethimide still required explana- that clinical experience had shown that it may cause tion and the experimental evidence accumulated to sexual precocity in some children, masculinization date suggests that dosage, or duration of treatment, of young females and other untoward effects. are unlikely to be responsible; individual hyper- Following the commercial withdrawal, amino- sensitivity and genetic factors are possibly involved. glutethimide was immediately reinstated as an Investigational New Drug. It was, therefore, pos- Inhibition of steroid biosynthesis sible to continue to supply epileptic patients still The early reports suggesting inhibition of adrenal requiring the drug and also to make it available to steroid biosynthesis by aminoglutethimide were research workers wishing to investigate its activities based on the findings in two children who had as a metabolic inhibitor. To date, research has centred exhibited clinical manifestations and serum electro- around the effects of the drug on thyroid metabolism lyte changes typical of adrenal insufficiency. In both and adrenal and gonadal steroid biosynthesis. of these patients the administration of ACTH failed to produce any increase in plasma or urinary 17- Anti-thyroid effect hydroxycorticoids (170HCS) and these patients still Following the initial report of goitres and hypo- remained unresponsive to ACTH 6 and 10 months thyroidism in children treated with aminogluteth- respectively after withdrawal of the drug. That imide, further animal studies were initiated to aminoglutethimide was responsible for the adrenal investigate the problem. Pittman & Brown (1966) insufficiency, and not other anticonvulsants being administered the drug for 8 days to intact and taken concomitantly, was demonstrated in one hypophysectomized rats on a low iodine diet. The patient whose condition improved after withdrawal intact animals showed a marked increase in thyroid of the aminoglutethimide but deteriorated quickly weight and depression of radio-iodine uptake. when the drug was re-administered (Camacho et al., Similar results were also obtained with another 1966 and 1967). Furthermore aminoglutethimide group of rats given amphenone B which is known had been fed to puppies and these animals had sub- to have a goitrogenic action. The hypophysecto- sequently been shown to be unresponsive to ACTH mized animals showed none of these