Jm. Kuhn et al., DOSE-EFFECT RELATIONSHIP AND INCIDENCE OF DIFFERENT MODALITIES OF ADMINISTRATION OF BIM-23014 ON GH SECRETION OF ACROMEGALICS, Annales d'Endocrinologie, 53(5-6), 1992, pp. 208-214
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.