Slow-release lanreotide in the treatment of acromegaly: a study in 66 patients.

OBJECTIVE: Slow-release (SR) lanreotide is a long-acting somatostatin analog that has been developed in order to overcome the inconvenience of multiple daily subcutaneous injections of octreotide, required for metabolic control in acromegaly. Lanreotide SR has been found to be well tolerated and effective in reducing GH and IGF-I levels but clinical data are still limited compared with those with subcutaneous octreotide treatment. DESIGN: Sixty-six unselected patients with active acromegaly were therefore evaluated in a multi-center, prospective, open label study. Lanreotide SR was given at a dose of 30mg intramuscular every 7-14 days. METHODS: At baseline and after 2, 4, 8, 12, 24, 36 and 48 weeks patients underwent a clinical examination with assessment of acromegaly related symptoms, and blood was sampled for serum GH, IGF-I, prolactin, glycosylated hemoglobin, fasting glucose, hematology, kidney function and liver function tests. Biliary ultrasonography and pituitary magnetic resonance imaging were performed at baseline and after one year. RESULTS: Treatment resulted in a significant improvement in the symptom score from 2.69+/-0.27 to 1.06+/-0.17 (P<0.0001). Serum IGF-I levels fell from 699+/-38microg/l at baseline to 399+/-26microg/l (P<0.0001, n=60) after one month, after which levels remained stable: 480+/-37microg/l after 6 months (n=54) and 363+/-32microg/l after one year (n=46). GH levels dropped from 13.8+/-3.2microg/l to 4.3+/-0.7microg/l after one month (P<0.0001, n=60) and remained stable thereafter: 3.9+/-0.4microg/l (n=54) after 6 months and 3.5+/-1.1microg/l after one year (n=46). Twenty-nine out of 66 patients (44%) attained a normal age-corrected IGF-I level and 30 patients (45%) attained a GH level below 2.5microg/l. Pituitary adenoma shrinkage of at least 25% was found in 5 of 14 patients (36%) after one year. Side effects were mainly transient gastrointestinal symptoms and pain at the injection site, resulting in drug discontinuation in only 6 patients (9%). Two patients developed new gall stones. No difference was found between subcutaneous octreotide and lanreotide SR in efficacy and almost all patients preferred the easier dose administration of lanreotide SR. CONCLUSIONS: Long-term treatment of acromegaly with SR-lanreotide is effective in controlling GH and IGF-I levels and symptoms and is well tolerated in the majority of patients. Compared with subcutaneous octreotide, lanreotide SR considerably improves patient's acceptance of therapy while having the same overall efficacy.

Cholelithiasis and acromegaly: therapeutic strategies.

OBJECTIVE: The aims of this study were (i) to evaluate gall-bladder form and contents, (ii) to assess the prevalence of gallstones in acromegalic patients before octreotide treatment and the incidence of gallstone formation in patients with acromegaly during long-term (6-90 months, mean 44 months) octreotide treatment, and (iii) to test the efficacy of ursodeoxycholic acid in preventing and treating octreotide-induced cholelithiasis. DESIGN: Forty-nine patients (23 men and 26 women, aged 19-81 years) were studied by repeated gall-bladder ultrasonography performed at baseline and then every 6 months during octreotide therapy. All ultrasound scans were evaluated by the same radiologist. Statistical analysis was performed using the Chi-squared and regression analysis tests. RESULTS: Asymptomatic stones were recorded in 13/49 patients (26.5%) prior to octreotide treatment (the prevalence of cholelithiasis in the Italian population is 9.5% in men and 18.9% in women). During octreotide therapy gallstones developed in 10/36 patients (27.7%). No significant correlations with sex, age, body mass index, duration of the disease, daily dose and duration of octreotide therapy, altered gall-bladder form, family history of gallbladder stones, basal plasma values of cholesterol and triglycerides were found between the patients (10/36) who developed stones during octreotide treatment and the ones who did not (26/36). Fourteen patients (10 with newly developed stones and four with cholelithiasis diagnosed prior to octreotide) were put on ursodeoxycholic acid at the daily dose of 10 mg/kg. Gallstones completely disappeared in 6/14 patients (42.8%; five patients with newly developed stones and one with stones prior to octreotide therapy) after a mean of 30.8 months of ursodeoxycholic acid treatment. In addition, seven patients were treated with ursodeoxycholic acid at the preventive dose of 450 mg, administered as a once-a-day oral preparation in the evening. However, stones developed in one of these seven patients who was thereafter cured (gallstones completely disappeared) by the therapeutic dose of ursodeoxycholic acid of 10 mg/kg/day after 23 months of treatment. CONCLUSIONS: This study indicates that (i) acromegaly by itself is correlated with a high prevalence of gallbladder stones, (ii) the long-term treatment with octreotide increases the incidence of cholelithiasis, and (iii) ursodeoxycholic acid is useful in the treatment of gallstones in acromegalic patients but its prophylactic effect in patients on octreotide treatment requires further assessment.

Efficacy of a new long-acting injectable form of bromocriptine in hyperprolactinaemic patients.

OBJECTIVE: The objective of this study was to assess the relationship of different doses of a long-acting bromocriptine preparation (Parlodel LAR) to the degree and duration of PRL suppression. We also measured circulating bromocriptine levels and altered tolerability of the drug. DESIGN: A double-blind randomized study of three different doses 25, 50 and 100 mg of Parlodel LAR. PATIENTS: Twenty-one female patients (seven patients/dose) with both tumoral and non-tumoral hyperprolactinaemia. MEASUREMENTS: After a single injection of Parlodel LAR 25, 50 or 100 mg, serum PRL and plasma bromocriptine levels were assessed during a follow-up of 60 days together with changes in clinical symptoms and signs of hyperprolactinaemia. RESULTS: Serum PRL levels normalized in 19 of 21 patients. The suppression of PRL secretion lasted 28 days in four of seven patients treated with either 25 or 50 mg Parlodel LAR and in five of seven patients who received Parlodel LAR 100 mg. In five of seven patients treated with the 100 mg dose, serum PRL levels were still within the normal range on day 60. Plasma bromocriptine levels remained therapeutically active for 28 days in all three groups. On day 60 they were within the therapeutic range only in the 100 mg group. Clinical data show a rapid disappearance of symptoms and signs of hyperprolactinaemia. Adverse events were mostly mild and transient. CONCLUSIONS: These data support the excellent efficacy and good tolerability of Parlodel LAR in patients with hyperprolactinaemia.

A new oral slow release form of bromocriptine, Parlodel SRO, in the chronic treatment of 26 hyperprolactinemic patients.

Parlodel SRO, a new slow release form of bromocriptine, was studied in 26 patients with tumoral and non-tumoral hyperprolactinemia. Prior to the treatment, serum prolactin (PRL) levels ranged from 45 ng/ml to 7000 ng/ml and they decreased to within the normal range in all but one patient after 7 days-1 year of treatment with this new formulation of bromocriptine. The clinical improvement paralleled the normalization of PRL secretion. Tolerability was rated good or very good in 24 patients, even in the three patients who had been intolerant of oral Parlodel. In conclusion, Parlodel SRO administered as a single daily dose resulted in very effective lowering of serum PRL in patients with hyperprolactinemic disorders.

Hypocalcemic effects of rectal and intramuscular administration of synthetic salmon calcitonin.

To assess the acute biological activity of a new rectal form of synthetic salmon calcitonin (SMC), 10 healthy subjects were randomly assigned, according to a crossover design, to single doses of either 50 IU SMC intramuscularly or 100 IU SMC rectally. Ionized and total calcium were measured as SMC bioactivity indicators in blood samples collected during a 6-hour period after the administration of the drug. In all the subjects, rectal administration of 100 IU of SMC induced falls in both plasma total calcium and whole blood ionized calcium: similar levels were observed after intramuscular injection of 50 IU of SMC. The pharmacodynamic bioavailabilities for total and ionized calcium of the 100 IU suppository and the 50 IU intramuscularly were 106% and 60%. The total and ionized calcium AUCs were the same after i.m. injection and suppository. We conclude that, in normal subjects, synthetic salmon calcitonin administered by the rectal route at the dose of 100 IU is effective and has the same biological effects as 50 IU of SMC given intramuscularly. Therefore, this new rectal form may be a useful alternative to parenteral injection.

New perspectives in medical management of hyperprolactinemia.

We performed 113 new treatments in 98 patients (pts) (69 females and 27 males), 41 with macroprolactinoma, 26 with microprolactinoma, 5 with empty sella and 26 with idiopathic hyperprolactinemia. Parlodel LA was administered in 31/113, Parlodel LAR in 51/113, Parlodel SRO in 24/113 and Cabergoline in 8/113. In each pt the clinical effect, PRL plasma level CT-scan and visual field examination were monitored. PRL plasma levels normalized in 84/98 pts. In 13/41 macroadenoma pts a complete disappearance of the adenomatous mass was observed at CT-scan after 0.5-3 years' oral bromocriptine or Parlodel LAR therapy. The clinical features normalized in most of the pts. In conclusion, the new long acting dopamine agonists may represent the future of the management of hyperprolactinemic states because of their effectiveness, tolerability and good compliance.

Medical management of acromegaly: effects of SMS 201-995 in 30 patients.

The effect of chronic administration of SMS 201-995, a long acting analogue of somatostatin, has been studied in 30 acromegalic patients (pts). CT-scan showed pituitary adenoma in 20/30 pts, empty sella in 9/30 pts and no sign of pituitary tumor in one case. SMS 201-995 was administered subcutaneously every 8 hours at the daily dose of 150-900 micrograms. Blood samples for GH, insulin and blood glucose were taken hourly from 04:00 to 20:00 h before treatment, after 15 days and then monthly or fortnightly. IGF-I plasma levels were assayed at 08:00 h in the same day as GH determinations. CT-scan controls were carried out after 12-24 months of treatment in 16/20 pts. GH plasma levels were normalized in 16/30 pts after 0.5-9 months of SMS treatment, whereas in 14/30 pts they were reduced by about 50%. In 10/16 pts the CT-scan examination showed a shrinkage of the tumor size of 20-55%, while no variation of the tumor mass was observed in the 2 pts. In conclusion our data show that SMS 201-995 is a very effective medical treatment in acromegalic patients.

Long-lasting suppression of prolactin secretion and rapid shrinkage of prolactinomas after a long-acting, injectable form of bromocriptine.

Since Corenblum reported in 1975 the first documented reduction of tumor size in two patients with macroprolactinoma, evidence has accumulated that bromocriptine causes shrinkage of PRL-secreting adenomas in most patients. Recently a long-acting form of bromocriptine (bromocriptine LA) was developed. A single dose of 50 mg i.m. decreases basal and sleep-related PRL secretion in normal subjects for 28 days. We treated 13 patients (8 women, 5 men) with PRL secreting tumors (5 macroadenomas and 8 microadenomas) with a single dose (50 mg) of bromocriptine LA. In the 5 patients with macroprolactinomas plasma PRL levels decreased markedly within 12 hours, reaching normal levels in only one patient. In all patients the suppression of PRL secretion lasted at least 28 days and the tumor size was reduced by 20% to 59% within 21 days after the injection. Visual fields improved in all 3 patients with abnormal vision prior to the injection. In one patient with bitemporal hemianopsia an almost normalization of the visual field was noted 24 hours after bromocriptine LA administration. In 7/8 patients with microprolactinomas plasma PRL levels decreased to within the normal range within 12 hours after the administration of bromocriptine LA. The normalization of PRL secretion lasted for at least 28 days. Menses resumed in all 6 women 7 to 41 days after the injection, galactorrhea disappeared in all 4 patients, and libido and potency become normal in both men with microprolactinomas. Patients treated with bromocriptine LA reported only short-lasting (1 hour - 2 days) mild or moderate adverse effects, consisting of dizziness (4 patients) and nausea (4 patients). Long-acting bromocriptine should be considered as the initial management for patients with PRL-secreting tumors. The use of bromocriptine LA could also overcome the compliance problems that occur in many patients soon after the initiation of oral bromocriptine therapy.