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).

Glutethimide treatment of disabling action tremor in patients with multiple sclerosis and traumatic brain injury.

Glutethimide has been used to control essential tremor. Its efficacy in the treatment of disabling cerebellar and rubral tremor was assessed in an open study of six patients with multiple sclerosis and two patients with traumatic brain injury. Functional and quantitative tremor severity was assessed before treatment and 7 to 14 days after a stable dose was achieved. Six of eight patients exhibited visible functional benefit from treatment with glutethimide; abstract testing results correlated well with functional status in most cases. Four patients chose to continue to receive medication. Controlled trials of glutethimide to compare its efficacy with that of other medications used in the treatment of action tremor are indicated.

The use of glutethimide for treatment of essential tremor.

Two patients with long-standing intention tremor that was interfering with their ability to maintain employment were treated with glutethimide. In both patients, this agent successfully suppressed tremor at doses of 1,000 mg and 4,000 mg per day. Glutethimide has been taken for as long as 14 years in one patient without evidence of side effects.

Thalidomide in severe orogenital ulceration.

Thalidomide was given to 15 patients with severe orogenital ulceration (OGU). 4 patients underwent a double-blind controlled trial with glutethimide as placebo and 11 were treated openly. Treatment with thalidomide produced complete resolution of ulcers in 14 and significant improvement in the remaining patient. No peripheral neuropathies developed. Patients did not respond to glutethimide. Thalidomide is an effective treatment for severe OGU. Adequate contraceptive measures should be taken during treatment.

Unconjugated hyperbilirubinemia. Physiologic evaluation and experimental approaches to therapy.

The plasma concentration of unconjugated bilirubin is determined by the rate at which newly synthesized bilirubin enters the plasma (bilirubin turnover) and the rate of irreversible bilirubin removal by the liver (hepatic bilirubin clearance). Measurement of each of these variables by kinetic studies with radiolabeled bilirubin permits a precise classification of cases of unconjugated hyperbilirubinemia into those due to increased bilirubin turnover (for example, hemolysis), those due to decreased bilirubin clearance (for example, Gilbert's syndrome), and those in which both mechanisms operate. The ability to quantitate hepatic bilirubin clearance makes it possible to detect gilbert's syndrome even in the presence of concomitant hemolysis. Of the hereditary disorders of bilirubin metabolism, Gilbert's syndrome is common but innocuous, whereas Crigler-Najjar syndrome is rare but devastating. An unusual case of Crigler-Najjar syndrome is described in which bilirubin encephalopathy developed at age 10. Various modalities used in an attempt to reduce her plasma bilirubin concentration by either increasing bilirubin clearance or reducing bilirubin turnover are described.