patients receiving treatment for meningioma, 200 mg/day (Laue et al., 1990; Grunberg et al., 1993). The cause of this spontaneously resolving rash is unknown. At higher doses, up to 22 mg/kg per day given for months to patients with Cushing's syndrome, no exanthema was seen. Nausea was common in these patients. Four of eleven patients begun on RU 486 had a deterioration in clinical condition that prompted discontinuation of the agent. Again, the diagnosis of adrenal crisis was difficult to ascertain in this setting. The antiandrogenic properties of RU 486 probably underlie reports of gynecomastia and impotence in men receiving chronic therapy with RU 486: gynecomastia occurred in two of three men with Cushing's syndrome and in four of nine men with meningioma, whereas impotence was reported at a slightly lower rate (one of three and three of nine men respectively, in the two studies).

RESEARCH DIRECTIONS FOR ANTIGLUCOCORTICOIDS

The "state of the science" regarding RU 486 invokes many questions germane to glucocorticoid action, and provokes others relating to its potential therapeutic efficacy, as follows:

  1. RU 486 may be useful in better understanding renal physiology and in the treatment of some forms of hypertension. Questions in this area follow. What is the role of renal 6ß-hydroxylation in the development of hypertension and the maintenance of electrolyte balance? Does RU 486 undergo 6ß-hydroxylation in the kidney? Does RU 486 alter 11ß-hydroxysteroid dehydrogenase activity? Can RU 486 affect absolute or diurnal rhythm in blood pressure in normal individuals or in patients with essential hypertension? What is the role of 6ß-OH-cortisol in hypertensive states? Although RU 486 did not reverse hypertension caused by exogenous cortisol, could it possibly modulate 6ß-hydroxylation in a subset of patients with increased activity?

  2. Can RU 486 alter glucocorticoid-receptor number? (For example, if up-regulation occurs, could tumors be sensitized to glucocorticoids by previous RU 486 administration?)

  3. Can RU 486 modulate immune function or inflammation when given systemically to people? Specific indicators of immune function need to be developed that can be examined over a broad dose range, including doses below the threshold of activation of the HPA axis. The responses to a variety of schedules of administration, including alternate day, once weekly, and night versus morning, should be examined for time-of-day and time-course characteristics.

  4. What about local forms of administration—topical or intracavitary—for eye disease, wound healing, keloid reduction, joint abnormalities?



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