Influence of Drug Properties and Routes of Drug Administration on the Design of Sustained and Controlled Release Systems

In rhesus monkeys with hypothalamic lesions that abolish gonadotropic hormone release by the pituitary gland, the constant infusion of exogenous gonadotropin-releasing hormone (GnRH) fails to restore sustained gonadotropin secretion. In marked contrast, intermittent administration of the synthetic decapeptide once per hour, the physiological frequency of gonadotropin release in the monkeys, reestablishes pituitary gonadotropin secretion. This phenomenon is attributable to the pattern of GnRH delivery rather than to the amounts of this hormone to which the cells of the pituitary are exposed. Moreover, the initiation of continuous GnRH administration in animals with lesions and in which gonadotropin secretion is reestablished by intermittent GnRH replacement can result in a "desensitization" or "down regulation" of the processes responsible for gonadotropin release.

Animal studies have indicated that the time of administration of adriamycin and cisplatin, two widely used anticancer drugs, has a profound effect on their toxicity. This effect in cancer chemotherapy was studied in 31 patients with advanced ovarian cancer. Patients received at least eight monthly courses of adriamycin that were followed 12 hours later by cisplatin, with adriamycin randomly administered at either 6 a.m. or 6 p.m. The results show that in the group receiving adriamycin in the evening and cisplatin in the morning (i) twice as many patients required reductions in dosage and delays in treatment, (ii) four times as many treatments had to be delayed, (iii) drug dosages had to be modified downward three times as often, and (iv) even with more dose attenuation and treatment delays, treatment complications were still about two times more common as in the group receiving adriamycin in the morning and cisplatin in the evening. These findings show that the circadian stage at which anticancer drugs are given to patients should be carefully considered.