We treated four patients with acromegaly for 8 to 24 weeks with SMS 201-995, the long-acting somatostatin analogue, in dosages of 100 to 300 micrograms a day given subcutaneously. A rapid amelioration of the clinical signs and symptoms and near normalization of laboratory test results occurred in all patients. Mean plasma growth hormone concentrations (+/- S.E.M.), as measured over 24 hours, fell from an initial value of 57 +/- 18 micrograms per liter to 7.5 +/- 2 micrograms per liter at the end of the investigational period. Likewise, levels of plasma somatomedin-C, which were originally elevated in all patients, dropped to the normal or nearly normal range. The suppression of insulin secretion and the resulting hyperglycemia that were observed at the beginning of treatment became less marked as therapy progressed. There was evidence of slight tumor shrinkage in three of the subjects. No side effects were recorded throughout the treatment period. These preliminary results suggest that SMS 201-995 represents an additional option for the management of acromegaly, especially in patients who do not benefit sufficiently from surgery or radiotherapy and do not respond well to treatment with dopaminergic drugs.
The acute effect of the somatostatin analog SMS 201-995 (SMS) was investigated in eight acromegalic patients. This substance is an octapeptide [DPhe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-(ol)] that inhibits GH release in experimental animals and man. After a control day, 50 micrograms SMS were injected sc, and plasma GH and insulin and blood glucose levels were measured at multiple intervals for 24 h. GH significantly (P less than 0.001) decreased in seven of eight acromegalic patients from 30 +/- 5 (+/- SE) to an average of 10.7 +/- 4 micrograms/l from 1-10 h after drug administration. No rebound effect occurred. Postprandial blood glucose levels were significantly (P less than 0.01) higher between 2 and 4 h after SMS treatment compared with control day values, and there was a substantial reduction in insulin secretion, as estimated by the area under the curve (P less than 0.01), during the first 3 h after SMS administration. Circulating GH was not altered by SMS or the dopamine agonist mesulergine in one patient, but the combination of both substances (50 micrograms SMS, sc, and 0.5 mg mesulergine, orally) reduced GH to below 50% of basal. In vitro studies showed that 1 PM, 0.1 nM, and 10 nM SMS or natural somatostatin exerted a similar inhibitory effect (12-39% reduction; P less than 0.01 for all three strengths) on GH release by cultured human pituitary tumor cells. In conclusion, the somatostatin derivative SMS exerts a potent and prolonged inhibitory action on GH secretion and a shorter lasting suppression of insulin in acromegalic patients. Therefore, it may represent a useful tool in the chronic management of this condition.
Ten acromegalic patients, four previously untreated, were studied before and at regular intervals during treatment with the long-acting somatostatin analog SMS 201-995 (200-300 micrograms daily for 2 or 3 sc injections for 16-108 weeks). All patients had rapid clinical improvement, with disappearance of excessive perspiration, paresthesias, and headache within the first 6 weeks of therapy. The mean 24-h serum GH concentrations fell from 44.0 +/- 7.8 (+/-SE) micrograms/L before to 5.9 +/- 1.0 microgram/L at the end of therapy. The GH levels from 2-6 h after the acute administration of 50 micrograms SMS 201-995 before the start of therapy correlated significantly with the mean 24-h GH concentrations after 16-108 weeks of treatment (P less than 0.05). The initially increased serum somatomedin-C (Sm-C) levels normalized in 5 of these 10 patients; the mean values were 7.3 +/- 0.9 U/mL before and 2.9 +/- 0.7 U/mL at the end of therapy. The Sm-C and mean GH levels continuously decreased during long term therapy; the concentrations after 1.5-2 yr of therapy were significantly lower than those after 6-12 months of therapy (P less than 0.01 and P less than 0.01, respectively). A slight decrease in the size of the pituitary tumor was noted by computed tomography in three of six patients. Transient clinically detectable steatorrhea occurred in two patients. Postprandial hyperglycemia occurred during therapy in eight patients, while in two patients with type 2 diabetes mellitus carbohydrate tolerance improved in one and deteriorated in the other. SMS 201-995 is a highly effective medical treatment for acromegaly. Clinically improvement occurs rapidly, and the inhibition of serum GH and Sm-C levels persisted even after more than 1 yr of therapy. No important subjective side-effects were noted. SMS 201-995 is an excellent drug in patients in whom acromegaly persists after surgery and for interim treatment to shorten the period of clinical activity after irradiation.
An unexpected 20-week-old pregnancy was found in a young acromegalic who had been treated with 10 mg bromocriptine/day for 10 months. The drug was continued throughout the period of gestation. No growth of the pituitary adenoma was noticed. The intrauterine development of the fetus was normal. Bromocriptine therapy had no discernible effect on the expected patterns of secretion of placental hormones, but inhibited completely the increase of PRL in the serum of the mother. Maternal plasma GH concentrations were very high in spite of the treatment and progressively declined after delivery. The plasma GH level was normal in the child, but PRL was very low at birth and increased in the following days. The expected high PRL concentration was found in the amniotic fluid. This case study suggests that bromocriptine crosses the human placenta and affects the fetal pituitary, maternal GH does not influence fetal or amniotic GH, and amniotic fluid PRL correlates poorly with either maternal or fetal blood levels and is not affected by bromocriptine.
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