sign in sign up
<<
Home , Aminoglutethimide, Glutarimide, Hydantoin

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 was marketed as an in was introduced as an anti- the 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 , 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 , particularly of aldo- 1959; Defer, 1960; Verdeau-Pailles, 1961). All these sterone, and , probably by interfer- papers reported varying degrees of in either ing with the conversion of to delta-5- grand mal, petit mal or psychomotor epilepsy. . Nevertheless, in one study, of 2 years' duration, Aminoglutethimide has also been shown to modify using aminoglutethimide with other , the extra-adrenal 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 . The Six years later it was withdrawn from the market at Council concluded that in view of its limited efficacy the request of the United States Food and Drugs and high frequency of untoward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 , , drowsiness, be- clinical advantage. havioural changes, , , leukopenia, respiratory 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- imides. A series of compounds based convulsant aminoglutethimide found a place as a on a-phenyl-a-ethyl (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 and adrenal proceeded in 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 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 -bound block of 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 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 . 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 findings with (Camacho et al., 1966) and studies in rats showed Aminoglutethimide 411 that the drug induced adrenal hypertrophy (Pittman of cholesterol to delta 5-pregnenolone by inhibiting & Brown, 1966). The systematic biochemical and the adrenal mitochondrial cholesterol side-chain clinical investigation of the effects of aminogluteth- cleaving system known as the 'desmolase imide on the adrenal glands which followed is review- complex'. The exact point at which inhibition takes ed below. place remains uncertain but the studies of Kahnt & Neher (1966) utilizing beef adrenal slices, in vitro, Histological evidence of adrenocortical inhibition suggest that the drug inhibits 20o-hydroxylation of Post-mortem specimens from four- cholesterol. Kowal (1967) has confirmed these find- teen patients who had received aminoglutethimide ings and produced complete inhibition of steroido- (in addition to one or more other anti-convulsants) genesis with aminoglutethimide (0-05 m-mole) in were examined. Striking histological changes were monolayer cultures of functional adrenal tumour seen in ten patients. These included cellular hyper- cells. The effects of ACTH on cell morphology and trophy, cytoplasmic vacuolation and excessive accu- glucose consumption were not inhibited and thus mulation of lipid in the cortex of the glands the drug appeared to inhibit the steroidogenic en- (Camacho et al., 1966). zymes directly at levels producing no toxic effects on Similar findings have been described more the living cell. This investigator has also shown com- recently by Givens, Coleman & Britt (1968) who petitive inhibition of 11 3-hydroxylation by high administered aminoglutethimide (750-1000 mg/day) concentrations of aminoglutethimide. It should also to four adults awaiting . Three patients be noted that like , aminoglutethimide had metastatic carcinoma of the breast, two were has been shown to decrease 11-o-hydroxylation and euadrenal and one was receiving a suppressive dose increase 21a-hydroxylation of in vitro of . The fourth patient had metastatic (Sheppard, Beasley & Wacker, 1966). non-functioning . The Experimental studies in humans followed as a anatomical changes found in the euadrenal subjects logical extension of the in vitro studies and work in were: an increase in size and weight of the adrenal animals. Camacho et al. (1967) and Cash et al. (1967) glands, a marked golden-yellow colour, an increased showed that the inhibitory effect of aminogluteth- size of the zona fasciculata, marked diminution in imide on steroidogenesis blocks the production of the size of the zona glomerulosa and an increase in adrenal cortisol, and androgens and also the lipid-positive staining deposits in the cells of the their hormonally active precursors. These findings zona fasiculata. The latter observation was also were confirmed by Fishman et al. (1967) in both present in the patient receiving prednisolone. normal healthy volunteers and patients. In addition Similar changes have also been demonstrated in rats both investigators showed that the administration and puppies receiving aminoglutethimide (Camacho of the drug decreases the cortisol secretion rate and et al., 1966). lowers the level of plasma and urinary 17-OHCS. In general, inhibition of cortisol secretion was most Mechanism of adrenocortical inhibition obvious in patients with Cushing's syndrome due to Experimental studies undertaken by Wilroy, autonomous steroid secretion by adrenal tumours. Camacho & Trouy (1966) in rats and dogs, the In normal subjects, large doses of aminogluteth- additional work in rats and the in vitro studies of imide were accompanied by increases in plasma Dexter et al. (1966 and 1967), have shown that ACTH and it is likely that these compensatory in- aminoglutethimide produces a decrease in cortico- creases were responsible for the maintenance of sterone production which is accompanied by an in- near-normal cortisol secretion rates and plasma 17- crease in plasma ACTH. Marked hypertrophy of the OHCS levels in these subjects. The most consistent adrenals occurs, this being due to both the adrenal effect of the drug was on aldosterone secretion rates growth-promoting effect ofthe increased endogenous which were lowered in patients with primary aldo- ACTH and also to the increased water, cholesterol steronism as well as in patients with Cushing's syn- and cholesterol esters found in the glands. There drome and normal healthy subjects. The fall in aldo- was no evidence to suggest that the conversion of sterone secretion was accompanied by an increase in pregnenolone to was impaired and it urinary sodium, a decrease in urinary potassium, a was, therefore, concluded from these studies that the rise in plasma renin activity and some lowering of drug inhibits conversion of cholesterol to pregneno- blood pressure in hypertensive patients. Schteingart lone and that the accumulation of cholesterol in the & Conn (1967) have reported that the of adrenal glands can be attributed to the combined 17-ketosteroids (17KS) in the urine falls just after effects of the increased endogenous ACTH and a commencement of therapy with aminoglutethimide direct action of the drug. but later returns to initial values. Investigation of Cash et al. (1967) have demonstrated that amino- the separate 17KS fractions has shown that the fall glutethiriide interferes with the enzymic conversion primarily involves 11-oxy-17-ketosteroids, whereas 412 S. W. M. Hughes and D. M. Burley 11-deoxy-17-ketosteroids ( and an- also alters the extra-adrenal metabolism of cortisol, drosterone) either do not alter or have a slight ten- with the result that urinary 170HCS have been found dency to rise (Horky & Kichel, 1969). to be disproportionately low in relation to the corti- Long-term therapy with high doses of amino- sol output and plasma 170HCS determinations glutethimide may, particularly in children, result in a (Fishman et al. 1967; Schteingart & Conn, 1967). decreased adrenal reserve capacity which can persist Possible effects of the drug on assay procedures were for a considerable period following withdrawal of the discounted by Fishman et al. (1967) and recent work drug (Camacho et al. 1967). On the other hand, by Hagen & Butler (1969) now suggests that the Fishman et al. (1967) considered that in most of cortisol is influenced either by in- patients the inhibition is quickly reversible on dis- hibition of the 11 P-dehydrogenase system orpossibly continuing medication. in the stimulation of the delta 4-3-keto reductase system. These possiblities have emerged as a result Inhibition ofgonadal steroid production of work on the catabolism of cortisol-4-14C before Since pregnenolone is a major precursor of all and after aminoglutethimide in a patient with steroid hormones aminoglutethimide would also be Addison's disease. In this work the concentrations expected to interfere with the synthesis of gonadal of several urinary metabolites were recorded: tetra- androgens and oestrogens. To date comparatively hydrocortisol excretion doubled, whilst tetrahydro- little work has been published on this aspect of the and cortolone decreased. There was no action of aminoglutethimide. Pittman & Brown significant change in the 17KS. (1966) described ovarian enlargement in intact rats and a suggestion of uterine enlargement in hypo- Comparisons with chemically-related drugs physectomized rats treated with the drug. Eversole Although the evidence now available has con- & Thompson (1967) and Zavadil, Schreiber & firmed beyond doubt that aminoglutethimide can Kmentova-Zbuzkova (1968) have shown that in affect thyroid and adrenal cortical metabolism, it is rats, large doses of aminoglutethimide stopped the nevertheless noteworthy that the original reports of oestrous cycle and produced sterility associated with endocrinological side-effects attributed to the drug enlarged follicular . Gaunt, Steinetz & Chart were all reported in patients who were receiving addi- (1968) confirmed the latter findings and concluded tional anticonvulsants. It is, therefore, of interest to that the effects oflong-term administration ofamino- review the literature on the side-effects of the main glutethimide in females were consistent with the drugs concerned-the , and hypothesis that it reduced oestrogen secretion, as -particularly since all these drugs may be judged by decreased uterine weight in intact but not considered to be chemically related to aminogluteth- in castrated animals. Anomalous increases in body imide. weight were not seen in males, or in females after Phenytoin is known to affect the catabolism of ovariectomy. In this context it should be noted that plasma cortisol by increasing 6-hydroxylation, but Philbert et al. (1966) failed to notice any changes in standard ACTH stimulation tests yield normal values the menstrual cycle of six women who had received for 170HCS and plasma cortisol in patients receiv- aminoglutethimide for several weeks, nor were there ing the drug (Werk, MacGee & Sholiton, 1964). any significant changes in the oestrogen and preg- Phenytoin has, however, been reported to produce nanediol levels in three hirsute women who were signs of virilization in young females and young known to have normal ovarian function. Cash, males (Livingstone, 1956), hirsutism (Livingstone, Petrini & Brough (1969) have described ovarian Petersen & Boks, 1955) and hypertrichosis, brown dysfunction and resulting virilization of a young pigmentation and (Bray, 1959). Sparberg (1963) female following aminoglutethimide (1000 mg daily), has reviewed the literature relating to the effect of but it should be noted that treatment was of 6 years phenytoin on the pituitary-adrenal axis and has con- duration. cluded that depressed adrenal cortical function and Gaunt et al. (1968) found no evidence in rats to diminished response of the pituitary hypothalamic suggest inhibition of testicular function and it axis can occur. This depression is not clinically sig- appears, therefore, that, in animals, gonad steroido- nificant but may lead to misdiagnoses of adrenal genesis may be affected by aminoglutethimide in the cortical insufficiency or panhypopituitarism. Spar- female but that the adrenal gland is far more suscep- berg (1963) has also reviewed the effect of phenytoin tible to the drug. on thyroid metabolism. It appears that this drug competes for the binding sites of thyroxine-binding Peripheral metabolism of globulin thus producing a low serum protein-bound In addition to its effect as an inhibitor of adrenal iodine. There is no evidence that the drug actually steroid synthesis, and possibly gonadal steroid syn- affects thyroid function in man and it should be thesis, it has been shown that aminoglutethimide noted that Rallison et al. (1967) whilst examining Aminoglutethimide 413 the effects of aminoglutethimide on thyroid meta- included in this work and also failed to have any bolism in rats, also examined the effects of phenytoin, effect. Cohen (1968) has shown that glutethimide can primidone and glutethimide under the same condi- be made to inhibit the desmolase enzyme complex tions and failed to find any significant changes in but it was far less potent (< 1 %) than aminogluteth- thyroid function. imide in this respect. The literature for the barbiturates, primidone and These experimental findings are brought into glutethimide contains no reference to endocrinolo- clinical perspective by the work of McMahon & gical side-effects. Nevertheless, several investigators Foley (1967) who have reported a double-blind have recently considered it desirable to re-examine comparison of glutethimide, quinalbarbitone and the position of glutethimide in view of the findings placebo. Each treatment was given for 7 days and associated with its para-amino derivative. the glutethimide was administered at the maximum As mentioned previously glutethimide was included recommended dose of 1 g daily. In this trial adrenal by Rallison et al. (1967) in their rat studies and was cortical response to ACTH remained normal and no found not to interfere with thyroid metabolism. differences appeared between the three treatment The effects of glutethimide on steroidogenesis in groups. That glutethimide was found not to inter- the rat adrenal in vitro have been studied by Johns- fere with adrenal cortical metabolism in normal ton, Krisle & Troop (1968). Relatively high concen- clinical dosage was not surprising since the drug has trations (20-30 mg/100 g) of the drug were shown to been in widespread use as a hypnotic for 12 years and inhibit corticosterone synthesis, this effect being it seems unlikely that serious endocrinological side- demonstrable regardless of whether the glutethimide effects would have passed unnoticed during this was administered to the rat prior to adrenalectomy time. Furthermore, the evidence available on the fate or directly into the incubation fluid. The conversion of orally administered glutethimide (Keberle, 1962) of pregnenolone and of deoxycorticosterone to and aminoglutethimide (Douglas & Nicholls, 1965), corticosterone is inhibited, indicating a block of in man, suggests that the metabolism of these two 11 -hydroxylation. Glutethimide was also found to drugs may differ significantly. suppress 21-hydroxylation as evidenced by a reduced The clinical literature of phenglutarimide, a para- conversion of 11 -hydroxyprogesterone to corti- sympatholytic substance in limited use for control- costerone. Chronic treatment of the intact rat with ling disorders of extra-pyramidal origin affecting glutethimide significantly lowered the plasma cortico- muscular tonus and motor function, contains no sterone concentration but did not affect adrenal references to endocrinological side-effects. weight or cholesterol concentration. Gaunt et al. (1968) have shown that intravenous The future for aminoglutethimide glutethimide has no effect on cortisol secretion in The experimental studies previously cited indicate dogs except at high, near lethal, dosages (approxi- that the most important single action of amino- mately 50 mg/kg) whereas aminoglutethimide is glutethimide is the inhibition of bio- active at 10 mg/kg. These same workers have also synthesis immediately prior to the production of drawn attention to the fact that high doses of glut- delta-5 pregnenolone. It would, therefore, seem ethimide, unlike aminoglutethimide may act in vivo reasonable to employ aminoglutethimide clinically as do other central depressants by suppressing in patients where it is desirable to block the produc- ACTH release. This has been inferred from the tion of the whole range of adrenal steroids. In observations that in dogs with endogenous ACTH practice, however, the main interest has so far been production blocked by , aminoglut- directed to clinical problems in patients with exces- ethimide inhibits the steroidogenic response to an sive cortisol and aldosterone production. ACTH infusion whereas glutethimide at doses of In most cases of Cushing's disease surgical treat- 50 mg/kg does not. ment is satisfactory, but there is a small number Glutethimide was also included in the series of where the operation is unsuccessful, only partially glutarimides examined in vitro by Kahnt & Neher successful, or cannot be contemplated because of (1966), for effects on synthesis. This extensive neoplasia. In such cases treatment with particular work showed that a hydrazide derivative, drugs which will block adrenal metabolism is con- known as CIBA 17368-Ba, in a concentration of sidered. 6 pug/ml completely blocked corticosteroid synthesis Hitherto adrenal blockers have comprised such by inhibition of 20-hydroxylation of cholesterol. drugs as metyrapone, which inhibits specific path- Para-aminoglutethimide and ortho-aminogluteth- ways of steroid synthesis (Gaunt, Chart & Renzi, imide produced similar inhibition at a concentration 1965), or toxic agents such as ortho-para-DDD of 30 jxg/ml but concentrations of 60 jig/ml of both which may produce profound constitutional dis- glutethimide and phenglutethimide failed to have turbance (Weisenfeld & Goldner, 1962). Amino- any effect. Phenytoin and the barbiturates were also glutethimide in doses of up to 1000 mg daily only 414 S. W. M. Hughes and D. M. Burley rarely produces serious toxic effects, as has been study. Nevertheless, the combined use of these drugs described previously, and by its interference with offers a prospect of progress in the treatment of the both cortisol and aldosterone production can disease. ameliorate the most severe symptoms of Cushing's In all cases of adrenal the inhibition of syndrome, with or without the addition of sub- cortisol and aldosterone production has been rapid, stitution therapy. usually necessitating supplementary In patients with Cushing's syndrome secondary therapy. Philbert et al. (1966) have suggested that to pituitary and hypothalamic disease, falls in the rapid fall in cortisol secretion is more important cortisol production are largely compensated for by than the actual plasma level attained (cf. insulin increased production of pituitary ACTH and so to hypoglycaemia) and Horky et al. (1968), who have some extent 'cortisol blocking' is self-defeating in reported on the use of aminoglutethimide in thirty- that increased ACTH production may overcome the six patients, some treated for more than 1 year, block. Not all cases, however, are pituitary-depen- consider that conservative use of the drug enhances dent and primary adrenal tumours would be ex- the ultimate prognosis of surgical treatment by im- pected to respond satisfactorily, as would cases where proving protein metabolism and electrolyte disturb- the production of ACTH was relatively fixed, such ances prior to surgery. as with an ectopic ACTH-secreting tumour. In contrast to the cases with adrenal neoplasm, The first case of metastatic adrenal cancer treated those with bilateral adrenal hyperplasia have re- with aminoglutethimide was reported by Schtein- sponded less well to aminoglutethimide, presumably gart, Cash & Conn in 1966. This patient, with mul- as a result of compensatory increases in ACTH tiple metastases from adrenal carcinoma, was first secretion (Smilo et al. 1967). Fishman et al. (1967), treated with op'-DDD for 55 days and developed measuring plasma ACTH in normal subjects on severe toxic effects including , abdominal aminoglutethimide found a consistent rise in plasma , diarrhoea, weight loss, lethargy and ataxia. ACTH values. In patients with ectopic ACTH pro- Subsequently aminoglutethimide in a dose of duction, such as is occasionally seen with carcinoma 250 mg every 6 hr was given and supplemented of the bronchus, the compensatory increase in endo- after 8 days with because of adrenal genous ACTH was not seen until cortisol secretion insufficiency. Thereafter a continuous remission had fallen to very low levels. Such cases frequently of the Cushing's syndrome was maintained for showed relief of Cushingoid features, although there 182 days without evidence of , and the is no evidence of any effect on the tumour tissue. tumour tissue apparently remained stationary. Such cases have been reported by Schteingart & Also the aminoglutethimide, as well as exerting a Conn (1967), Bower & Harvey (1967), Gorden et al. prompt adrenal blocking effect, decreased the rate 1968) and Horky et al. (1968). of cortisol turnover which was not observed with One of the most consistent effects of amino- op'-DDD. glutethimide has been the fall in aldosterone secre- Similar therapeutic results have subsequently tion which occurs irrespective of any increase in been described by Philbert et al. (1966); Smilo, plasma renin activity. It is not surprising, therefore, Earll & Forsham, (1967); Fishman et al. (1967); that patients with primary and secondary aldo- Horky et al. (1968) and Bochner et al. (1969). The steronism have been treated with aminoglutethimide. latter authors have carefully compared the effects of Fishman et al. (1967) reported increases in serum aminoglutethimide and op'-DDD. The efficacy of plasma potassium, sodium diuresis and decrease in the treatments were judged by measurement of a blood pressure in two out of three patients with pulmonary and by urinary 170HCS primary aldosteronism. In a case of hyperaldo- excretion. op '-DDD alone caused a gradual dimuni- steronism secondary to hepatic cirrhosis there was tion in size of the metastasis and some fall in 17- an increase in urinary sodium and decrease in OHCS excretion but no improvement in the hyper- potassium, but little change in blood pressure, corti- cortisolism. The metastasis ceased to regress after sol secretion rate, plasma 170HCS or urinary 17KS. withdrawal of the op'-DDD for a week. When The results presented by Horky et al. (1968) in aminoglutethimide was given alone there was an patients with secondary to increase in size of the metastasis and evidence of idiopathic oedema and ascitic cirrhosis of the adrenal insufficiency. op'-DDD was reintroduced were more favourable. These investigators also resulting in a possible regression of the metastasis. commented on the drug's marked diuretic effect and The authors concluded that op'-DDD retards pro- they found it extremely useful for lowering blood liferation of adrenocortical carcinoma and amino- pressure in those patients with severe . glutethimide reduces hormone secretion by the Similarly Woods et al. (1969) have recently concluded tissue. The effect of aminoglutethimide on pro- that 20% of hypertensive patients have suppressed liferation may not be favourable and requires further plasma renin activity and these patients differ from Aminoglutethimide 415 those with normal renin values in that they have BOCHNER, F., LLOYD, H.M., ROESER, H.P. & THOMAS, M.J. sodium values and (1969) Effects of cp'-DDD and aminoglutethimide on significantly higher exchangeable metastatic adrenocortical carcinoma. Medical Journal of they also respond to aminoglutethimide with a sig- , 1, 809. nificant decrease in blood pressure. These workers BOWER, B. & HARVEY, W. (1968) Aminoglutethimide (Elip- have suggested either that such patients have an ten) in the therapy of Cushing's syndrome secondary to unidentified mineralcorticoid in excessive ACTH-producing nonendocrine carcinoma. Hartford present Hospital Bulletin, 23, 132. quantities or that normal levels of aldosterone play BRAY, P.F. (1959) Diphenylhydantoin (dilantin) after 20 a supporting role in the hypertensive process. years; a review with re-emphasis treatment of 84 patients. The use of aminoglutethimide for the treatment of Paediatrics, 23, 151. advanced metastatic carcinoma of the breast in nine CAMACHO, A.M., BROUGH, A.J., CASH, R. & WILROY, R.S. in whom was has been (1966) Adrenal toxicity associated with the administration patients surgery impossible of an anticonvulsant drug. Journal of Paediatrics, 68, 852. reported by Hall et al. (1969). All patients also re- CAMACHO, A.M., CASH, R., BROUGH, A.J. & WILROY, R.S. ceive 0-75 mg of dexamethasone daily and 0-4 mg of (1967) Inhibition of adrenal steroidogenesis by amino- daily. Three patients had demon- glutethimide and the mechanism of action. Journal of the strated objective regressions of tumour which per- American Medical Association, 202, 20. for to 9 months. There was no uniform CASH, R., BROUGH, A.J., COHEN, M.N.P. & SATOH, P.S. sisted up (1967) Aminoglutethimide (Elipten-Ciba) as an inhibitor suppression of 170HCS or 17KS or oestrogen pro- of adrenal steroidogenesis: mechanism of action and duction during aminoglutethimide therapy and the therapeutic trial. Journal of Clinical Endocrinology) a(n anti-tumour response was not related to the charac- Metabolism, 27, 1239. teristic in the steroid CASH, R., PETRINI, M.A. & BROUGH, A.J. (1969) Ovarian changes urinary pattern. dysfunction associated with an anticonvulsant drug. These authors, therefore, concluded that the occur- Journal of the American Medical Association, 208, 1149. rence of responses in patients with non-suppressed COHEN, M.P. (1968) Aminoglutethimide inhibition of adrenal adrenals was due either to the suppression of an un- desmolase activity. Proceedings of the Society for Experi- known steroid by aminoglutethimide or to a direct mental Biologyl and Medicine, 1086. action of the drug itself on the tumours. DEFER, B. (1960) Essais cliniques d'un nouvel anti-comitial, The results of clinical studies in le C.16.038. Maroc Medicale, 39, 823. currently progress DEXTER, R.N., FISHMAN, L.M., BLACK, A.C. & NEY, R.L. in the United States and the in (1966) Inhibition of adrenal corticosteroid synthesis by adrenal-endocrine disorders and 'hormone depen- amino-glutethimide. Clinical Research. 14, 61. dent' tumours are now being awaited with interest. DEXTER, R.N.. FISHMAN, L.M., NEY, R.L., LIDDLE, G.W. It seems likely that these studies may establish new (1967) Inhibition of adrenal corticosteroid synthesis by uses for aminoglutethimide: studies of the mechanism of action. therapeutic aminoglutethimide. However, Journal of Clinical Endocrinology and Metabolis7m, 27, 473. until such time as results become available the DOUGLAS, J.S. & Nicholls, P.J. (1965) The urinary excretion original assessment by Philbert et al. (1966) still of aminoglutethimide in man. Journal of Pharmacyl a(nd provides a very useful guide to the therapeutic use of Pharmacology, 17, 115S. aminoglutethimide. These investigators outline the EVERSOLE, W.J. & THOMPSON, D.J. (1967) Effects of amino- indications for as:- glutethimide on ovarian structure and function. Federation major aminoglutethimide Proceedings, 26, 535. Secreting tumours of the adrenal gland, metastatic FABISCH, W. (1959) A with a new anticonvulsant or non-metastatic. drug a-(P-aminophenyl)-a-ethyl glutarimide preparation Non-adrenal neoplastic conditions associated with 16038 (CIBA). Journal of Mental Science, 105, 448. Cushingoid features. FISHMAN, L.M., LIDDLE, G.W., ISLAND, D.P., FLEISCHER, Failure of bilateral for the treat- N & KUCHEL, 0. (1967) Effects of amino-glutethimide on adrenalectomy adrenal function in man. Journal of Clinical Endocrinology ment of functional hypercorticism. and Metabolism, 27, 481. Of relative importance they place:- GAUNT, R., CHART, J.J. & RENZI, A.A. (1965) Inhibitors of Bilateral adrenal hyperplasia, including the adrenal corticol function. Ergebnisse ler Physiologie, of for biologischen Chemie ulnd experimentellen Pharmlakologie, preparation patients surgery. 56, 114. Primary hyperaldosteronism. GAUNT, R. STEINETZ, B.G. & CHART, J.J. (1968) Pharmaco- Whatever the outcome of future inevstigations it logic alteration of functions. Clinical now seems certain that will even- Pharmacology and Therapeutics, 9, 657. aminoglutethimide GIVENS, J.R., COLEMAN, S. & BRITT, L. (1968) Anatomical tually be better known for its inhibition of adrenal changes producted in the human adrenal cortex by amino- metabolism than for its anticonvulsant activity. glutethimide. Clinical Research, 16, 441. GORDEN, P., BECKER, C.E., LEVEY, G.S. & ROTH, J. (1968) Note: Aminoglutethimide is still under clinical trial in Efficacy of amino-glutethimide in the ectopic ACTH syn- the United Kingdom and is not available commercially. drome. Journal of Clinical Endocrinology and Metabolism, 28, 921. References GROSS, F., HOFFMAN, K., KEBRLE, J. & TRIPOD, J. (1956) AGUILAR, J.A., MARTIN, H.L. & MCNAUGHTON, F.L. (1961) Constitution, action and biological degradation of glutar- Aminoglutethimide in the treatment of epilepsy. Canadian imides. Verhandlungen der Naturforschenden Gesellschaft Medical Association Journal, 84, 374. in Basel, 67, 479. 416 S. W. M. Hughes and D. M. Burley GUARESCHI, A., GIANNELLI, A. & MARINATO, G. (1956) PHILBERT, M., LAUDAT, M.H., LAUDAT, PH. & BRICAIRE, A. L'azione di un nuovo derivato dell'imide glutarica (16038) (1966) Etude clinique et biologique d'un inhibiteur de sulla epilessia stricnica corticale. Rivista di Neurologica, l'hormonosynthese corticosurrenale: 1'aminoglutethimide. 26, 342. Annales d'endocrinologie, 29(2), 189. HAGEN, A.A., BUTLER, F.M. (1969) The influence of amino- PITTMAN, J.A. & BROWN, R.W. (1966) Antithyroid and anti- glutethimide on the catabolism of cortisol-4-C14 in the adrenocortical activity of aminoglutethimide. Journal of human. Federation Proceedings, 28, 579. Clinical Endocrinology and Metabolism, 26, 1014. HALL, T., BARLOW, J., GRIFFITHS, C. & Saba, Z. (1969) RALLISON, M.L., TYLER, F.H. & KUMAGI, L.F. (1964) Treatment of metastatic with aminoglut- Goitrous hypothyroidism induced by an anticonvulsant ethimide. Clinical Research, 17, 402. drug. Journal of Paediatrics, 65, 1085. HORKY, K. & KOCHEL, O. (1969). Aminoglutethimide (elip- RALLISON, M.L., KUMAGI, L.F. & TYLER, F.H. (1967) ten-Ciba)-a new inhibitor of steroid biosynthesis. Goitrous hypothyroidism induced by amino-glutethimide, Annals of Internal Medicine, 70, 866. anticonvulsant drug. Journal of Clinical Endocrinology and HORKY, K., KUCHEL, O., GREGOROVA, I., JIRANKOVA, J. & Metabolism, 27, 265. MATYS, Z. (1968) Klinische erfahrungen mit aminoglutath- SCHTEINGART, D.E., CASH, R. & Conn, J.W. (1966) Amino- imid (Elipten), einem neuen inhibitor der steriodbio- glutethimide and metastatic adrenal cancer. Journal of the synthese in der nebenniere. Schweizersche medizinische American Medical Association, 198, 1007. Wochenschrift, 98, 1843. SCHTEINGART, D.E. & CONN, J.W. (1967) Effects of amino- IFFY, L., ANSELL, J.S., BRYANT, J.S. & HERRMANN, W.L. glutethimide upon adrenal function and cortisol meta- (1965) Nonadrenal female pseudohermaphroditism: an bolism in Cushing's syndrome. Journal of Clinical Endo- unusual case of fetal masculinization. Obstetrics and Gynec- crinology and Metabolism, 27, 1657. ology, 26, 59. SHEEHAN, S. (1958) One thousand cases of late onset epilepsy. JOHNSTON, G.G., KRISLE, J.R. & TROOP, R.C. (1968) Inhibi- Irish Journal of Medical Science, 6, 261. tion ofadrenal steroidogenesis by glutethimide. Proceedings SHEPPARD, H., BEASLEY, J.H. & WACKER, J.L. (1966) The of the Society for Experimental Biology and Medicine, 129, influence of NADPH or its generating system on cortico- 20. steroid biosynthesis by rat adrenal homogenates. Federa- JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION (1962), tion Proceedings, 25, 551. 179, 798. SMILO, R.P., EARLL, J.M. & FORSHAM, P.H. (1967) Suppres- KAHNT, F.W. & NEHER, R. (1966) On the adrenal biosyn- sion of tumerous adrenal hyperfunction by aminoglut- thesis of steroids in vitro. Part III. Selective inhibition of ethimide. Metabolism, 16, 374. adrenocortical function. Helvetica Chimica Acta, 49, 725. SPARBERG, M. (1963) Diagnostically confusing complications KEBERLE, H. (1962) The Metabolism of glutethimide (Dori- of diphenylhydantoin therapy: A review. Annals of nternal denR). Experientia, 18, 105. Medicine, 59/6, 914. KOWAL, J. (1967) A possible system for studying ACTH VERDEAU-PAILLES, J. (1961) Un nouvel anticonvulsant: La action during complete steroidogenic blockade. Clinical preparation CIBA 16-0-38 ou eliptene. Annales medico- Research, 15, 455. psychologiques, 119, 501. LAMBROS, V.S. (1958) A new anticonvulsant, EliptenTM. WEISENFELD, S. & GOLDNER, M.G. (1962) Treatment of Diseases of the Nervous System, 19, 349. advanced malignancy and Cushing's syndrome with DDD. LAVECK, G.D. (1960) Elipten in the Treatment of Organic Cancer Chemotherapy Abstracts, 16, 335. Epilepsy. Diseases of the Nervous System, 21, 230. WERK, E.E., MACGEE, J. & SHOLITON, L.J. (1964) Effect of LIVINGSTONE, S., PETERSEN, D. & BOKS, L.L. (1955) Hyper- diphenylhydantoin on corticol metabolism in man. trichosis in association with Journal of Clinical Investigation, 43, 1824. occurring dilantin therapy. WILROY, R.S., CAMACHO, A.M., TROUY, R.L. (1966) Inhibi- Journal of Paediatrics, 47, 351. tion of adrenal steroidogenesis by aminoglutethimide. LIVINGSTONE, S. (1956) Treatment of epilepsy with diphenyl- Southern Medical Journal, 59, 1477. sodium (dilantin sodium). Postgraduate Medi- WOODS, J.W., HILL, C., LIDDLE, G.W., STANT, E.G., cine, 20, 584. MICHELAKIS, A.M. & BRILL, A.B. (1969) Effect of an MCMAHON, F.G. & FOLEY, J. (1967) Lack of glutethimide adrenal inhibitor in hypertensive patients with suppressed effect on adrenal. Journal of Clinical Endocrinology and renin. Archives of Internal Medicine, 123, 366. Metabolism, 27, 1495. ZAVADIL, M., SCHREIBER, V., KMENTOVA-ZBUZKOVA, V. PEARCE, K.I. (1960) Elipten: A clinical evaluation of a new (1968) Die veranderungen am ovarium von ratten nach anticonvulsant. Canadian Medical Association Journal, 82, applikation von aminoglutethimid (elipten-Ciba). Endo- 953. crinologicie, 53, 405.