Influence of dexaminoglutethimide, an optical isomer of aminoglutethimide, on the disposition of estrone sulfate in postmenopausal breast cancer patients.

Aminoglutethimide (AG) has been the most widely used aromatase inhibitor in breast cancer patients to date. Commercially, AG (Orimeten) is available as a racemate (DL-AG). Previous studies suggested the stereoisomers of AG (D-AG and L-AG) to differ considerably in their affinities and potencies to inhibit different cytochrome P-450-dependent enzymes, with D-AG being the potent aromatase inhibitor. DL-AG, apart from being an aromatase inhibitor, is known to enhance the metabolism of plasma estrone sulfate (E1S). In the present study we compared the effects of D-AG (500 mg daily) and DL-AG (1000 mg daily) on plasma estrogen levels and estrone (E1) and E1S clearance rates, determined after the injection of [14C]E1 and [3H]E1S, in a cross-over study involving 12 postmenopausal breast cancer patients. Treatment with DL-AG and D-AG suppressed plasma E1S to 18.6% and 15.0% of pretreatment levels, whereas E1 and estradiol E2 levels fell to 18.6% and 23.4% of their pretreatment levels during treatment with DL-AG and to 17.7% and 23.4% during treatment with D-AG, respectively. Thus, both treatment options suppressed all estrogens measured to a similar extent. The clearance rate of E1S increased from a mean pretreatment value of 5.9 to 14.0 and 10.0 L/h during treatment with DL-AG and D-AG, respectively (P < 0.05, comparing the two on-treatment situations), whereas the production rate of E1S decreased from a pretreatment value of 1.44 to 0.64 nmol/h with DL-AG and 0.36 nmol/h with D-AG (P < 0.05, comparing on-treatment values). These findings are consistent with the hypothesis that the D- as well as the L-form of AG may enhance the clearance rate of E1S. The finding of a higher estrogen production rate during treatment with DL-AG compared to D-AG probably reflects an increased plasma level of the estrogen precursor androstenedione (mean levels of androstenedione of 2.54 and 1.27 nmol/L during treatment with D-AG and DL-AG, respectively; P < 0.05).

Catatonia associated with glutethimide withdrawal.

Catatonia is a syndrome that is often considered as a subtype of schizophrenia, although studies have shown that it is most often associated with affective disorders. There are also many medical causes of catatonia. A case is presented in which glutethimide withdrawal seems the most likely explanation for catatonic symptoms.

Catatonialike symptomatology and withdrawal dyskinesias.

The authors describes a patient who presented catatonialike symptoms and dyskinesias associated with glutethimide discontinuance and antihistamine use. He hypothesizes that altered dopamine metabolism may produce some of the unusual neuropsychiatric characteristics of glutethimide withdrawal. Drug-withdrawal catatonia may be an additional entity in the differential diagnosis of catatonialike states of organic etiology.

Clinical implications of warfarin interactions with five sedatives.

The intensity, uniformity and time course of anticoagulant interference by phenobarbital, secobarbital, glutethimide, chloral hydrate and methaqualone were systematically investigated in 16 patients receiving coumarin therapy. Each subject received an individualized fixed daily dose of warfarin and served as his own pre- and postsedative treatment control. Prothrombin times were measured four times weekly during five long-term experiments. Anticoagulant inhibition was observed during the administration of phenobarbital, secobarbital and glutethimide; there was no significant change in prothrombin test results during the trials of chloral hydrate and methaqualone. Barbiturates and glutethimide should not be administered to patients receiving coumarin drugs. The concurrent use of drugs from these groups is decreasing according to a survey of 200 hospital medical records. Chloral hydrate and methaqualone interact pharmacologically with orally administered anticoagulant agents, but the effect is not clinically significant. It is concluded that chloral hydrate and methaqualone may be administered safely without additional caution in prothrombin test monitoring during oral anticoagulant therapy.

Drug-induced manifestation of hereditary hepatopathy.

PIP: Drug treatment appears to have induced the manifestation of undetected enzymopathy in 4 case studies. 2 patients had acute intermittent porphyria and 2 had Gilbert's syndrome. In acute intermittent porphyria, the effects of enzyme inducers may overproduce DALA-synthetase which may lead to an acute porphyria attack. In Gilbert's syndrome, enzyme activity is hormone-dependent and studies have shown that synthetic estrogens are inhibitory to conjugation with glucuronide. Therefore, drug use may result in the manifestation of hereditary or genetic defects.^ieng