DOSE-EFFECT RELATIONSHIP AND INCIDENCE OF DIFFERENT MODALITIES OF ADMINISTRATION OF BIM-23014 ON GH SECRETION OF ACROMEGALICS

Somatostatin analogs, with prolonged half-lives have been proposed for the treatment of acromegalics. The aim of the study was to evaluate t he short term efficacy of different doses and modalities of administra tion of the new somatostatin analog, BIM 23014 (BIM), on GH secretion in acromegalics. Ten acromegalics, with evolutive disease, who previou sly had had transsphenoidal surgery (and pituitary radiotherapy in 8) were evaluated in a three step study. The first part included four pat ients who received in a random order either vehicle or 500, 1000 and 1 500 mug BIM for a day as a continuous s.c. infusion using programmable pumps at one-week interval for 24 hours to measure plasma GH levels. The second part included six patients who received in a random order e ither vehicle or 1500 mug/24h BIM as 500 mug X 3 s.c. injections, 750 mug X 2 s.c. injections and a continous s.c. infusion using programmab le pumps at one-week interval. During each period of the study blood w as sampled at 4 hour intervals for 24 hours in order to measure plasma GH and BIM levels by radioimmunoassays. The third part of the study i ncluded the same 6 patients as the second part, who received 30 mg IM of a long acting formulation of BIM. Blood was sampled before and ther eafter on days 1,3,6,9,12,15,18 and 21 following the injection for mea surement of plasma GH and BIM levels. In first group 500 mug BIM sligh tly decreased plasma GH levels. By contrast plasma GH levels fell dram atically (p < 0.01 vs control) when using 1000 and 1500 mug BIM a day (vehicle: 43.7 +/- 11.3 mug/1, 1000 mug BIM: 5.7 +/- 1.9 mug/1, 1500 m ug BIM: 1.6 +/- 0.3 mug/1). In the second group plasma BIM levels rose to 1.2 +/- 0.2, 1.7 +/- 0.2 and 3.0 +/- 0.2 ng/ ml after the injectio n of 500 mug, 750 mug and during the continuous infusion of 1500 mug B IM respectively. Plasma levels were maintained throughout the infusion . Plasma BIM levels fell 8 hours after each s.c. injection. Plasma GH levels followed opposite changes to plasma BIM levels. Concomitantly t o plasma BIM level rises, plasma GH levels fell to 4.2 +/- 1.6, 4.2 +/ - 1.1 and 2.0 +/- 0.5 mug/l 4 hours after the injection of 500 mug, 75 0 mug and during the continuous infusion of 1500 mug BIM respectively. Plasma GH levels rose to 24.2 +/- 11.9 and 20.7 +/- 9.2 mug/l 8 hours after s.c. injection of 500 mug and 750 mug BIM respectively. By cont rast plasma GH levels remained below 3.5 mug/l during continuous infus ion of 1500 mug BIM a day. Plasma GH and BIM levels were negatively co rrelated (r = - 0.82, p < 0.001). The injection of 30 mg BIM in a slow release formulation induced a fall in plasma GH levels which were sig nificantly (p < 0.02) reduced until day 15 following the injection. At the same time plasma BIM levels were higher than or close to 1 ng/ ml . This study demonstrates the short time efficacy of BIM in reducing p lasma GH levels in acromegalics. 1500 mug/24 h BIM appears the optimal dosage to decrease GH oversecretion. The treatment of acromegalic wit h BIM implies at least 3 s.c. injections a day or a continuous infusio n using pumps. In short term study, the slow-release formulations of B IM are able to reduce GH oversecretion during 2 week. The availability of such formulations for therapeutic use could avoid the drawbacks of several s.c. injections a day or of the use of portable pumps.