pasireotide and Body-Weight

To evaluate the effect of pasireotide on β-cell and adipose function in patients with Cushing's disease (CD).. 12 months of treatment with pasireotide in CD is associated with an impairment of insulin secretion and an improvement of adipose function without any interference in insulin sensitivity.

Topics: Adipokines; Adult; Blood Glucose; Body Weight; Cohort Studies; Female; Hormones; Humans; Injections, Subcutaneous; Insulin; Insulin Resistance; Male; Middle Aged; Pituitary ACTH Hypersecretion; Somatostatin; Treatment Outcome; Young Adult

Acromegaly is a serious hormonal disorder resulting from a pituitary adenoma causing excess growth hormone (GH) production. Somatostatin analogs such as octreotide have been the medical treatment of choice. SOM230, a novel somatostatin analog, was compared with octreotide with respect to pharmacokinetic (PK) profiles and inhibition of GH secretion in acromegalic patients.. In a double-blind, 3-period, crossover, proof-of-concept study, 12 patients with active acromegaly were randomized to single subcutaneous doses of SOM230 (100 and 250 microg) and octreotide (100 microg). Concentrations of SOM230, octreotide, and GH were determined at designated times after dosing and at baseline. The PK properties of SOM230 and octreotide and the relationship of PK with GH were investigated by a nonlinear mixed-effects modeling analysis.. The apparent clearance for SOM230 is approximately half of that for octreotide (8.0 L/h versus 15.8 L/h). The elimination half-life for SOM230 is about 5 times longer than that for octreotide (11.8 hours versus 2.3 hours). The relationship between GH levels and plasma concentrations of SOM230 and octreotide is well described by a direct inhibitory model. The test drug concentration level at which half of the maximum drug effect is observed (EC50) is 46 and 553 pg/mL for octreotide and SOM230, respectively, with large interpatient variability (coefficients of variation, 164% and 65%, respectively), mainly attributable to the heterogeneous responses among patients.. SOM230 demonstrates a lower clearance and longer half-life than octreotide, which compensates for the lower potency in GH inhibition. As a result of the lower interpatient variability for EC50 , SOM230 is expected to have a more uniform clinical GH inhibition than octreotide for acromegalic patients at a clinically effective dosing regimen.

Topics: Acromegaly; Adult; Age Factors; Algorithms; Body Weight; Circadian Rhythm; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Female; Human Growth Hormone; Humans; Injections, Subcutaneous; Luminescent Measurements; Male; Middle Aged; Models, Biological; Octreotide; Sex Factors; Somatostatin

To examine pasireotide's effect on intestinal anastomotic healing under physiological conditions and following preoperative whole-body irradiation.. Forty-five male Wistar rats received an ileoileal end-to-end anastomosis. Group 1 (Co, n = 9) served as control. Group 2 (SOM, n = 10) received pasireotide (60 mg/kg) 6 days preoperatively. Group 3 (R-Co, n = 13) was subjected to 8 Gy whole-body irradiation 4 days preoperatively. Finally, group 4 (R-SOM, n = 13) received pasireotide 6 days preoperatively and whole-body irradiation 4 days preoperatively. On postoperative day 4, anastomotic bursting pressure, histology, IGF-1 staining, and collagen density were examined.. Mortality was higher in irradiated animals (30.8% vs. 5.3%, p = 0.021), and anastomotic bursting pressure was significantly lower (median, R-Co = 83 mmHg; R-SOM = 101 mmHg; Co = 149.5 mmHg; SOM = 169 mmHg). Inflammation measured by leukocyte infiltration following irradiation was reduced (p = 0.023), and less collagen was observed, though this was not statistically significant. Bursting pressure did not significantly differ between Co and SOM and between R-Co and R-SOM animals respectively. Semi-quantitative scoring of IGF-1, fibroblast bridging, or collagen density did not reveal significant differences among the groups.. Whole-body irradiation decreases the quality of intestinal anastomotic wound healing and increases mortality. Pasireotide does not significantly lessen this detrimental effect.

Topics: Anastomosis, Surgical; Animals; Blood Glucose; Body Weight; Cause of Death; Disease Models, Animal; Granulocytes; Injections; Insulin-Like Growth Factor I; Intestines; Male; Postoperative Complications; Pressure; Rats, Wistar; Somatostatin; Tissue Adhesions; Whole-Body Irradiation; Wound Healing

Increased intracellular cyclic AMP (cAMP) in renal tubular epithelia accelerates the progression of polycystic kidney disease (PKD). Thus, decreasing cAMP levels by an adenylyl cyclase inhibitory G protein activator is considered to be an effective approach in ameliorating PKD. In fact, pasireotide (PAS) was effective in reducing disease progression in animal models of PKD. However, hyperglycemia caused by the administration of PAS is an adverse effect in its clinical use. Whereas, co-administration of octreotide (OCT) with PAS did not increase serum glucose in normal rats. In the current study, we examined the efficacy of combined treatment with OCT and PAS in PCK rats, an autosomal recessive PKD model. Four-week-old PCK males were treated with the long-acting release type of OCT, PAS, or a combination of both (OCT/PAS) for 12 weeks. After termination, serum and renal tissue were used for analyses. Kidney weight, kidney weight per body weight, renal cyst area, renal Ki67 expression, and serum urea nitrogen were significantly decreased either in the PAS or OCT/PAS group, compared with vehicle. Renal tissue cAMP content was significantly decreased by PAS or OCT/PAS treatment, but not OCT, compared with vehicle. As a marker of cellular mTOR signaling activity, renal phospho-S6 kinase expression was significantly decreased by OCT/PAS treatment compared with vehicle, OCT, or PAS. Serum glucose was significantly increased by PAS administration, whereas no difference was shown between vehicle and OCT/PAS, possibly because serum glucagon was decreased either by the treatment of OCT alone or co-application of OCT/PAS. In conclusion, since serum glucose levels are increased by the use of PAS, its combination with OCT may reduce the risk of hyperglycemia associated with PAS monotherapy against PKD progression.

Topics: Animals; Blood Glucose; Body Weight; Cyclic AMP; Disease Models, Animal; Drug Interactions; Extracellular Signal-Regulated MAP Kinases; Glucagon; Heart; Humans; Hydrocortisone; Hyperglycemia; Insulin; Insulin-Like Growth Factor I; Ki-67 Antigen; Kidney; Liver; Male; Octreotide; Phosphoproteins; Polycystic Kidney, Autosomal Recessive; Rats; Receptor, IGF Type 1; Ribosomal Protein S6 Kinases; Somatostatin

The Siberian hamster (Phodopus sungorus) is a seasonal mammal, exhibiting a suite of physiologically and behaviourally distinct traits dependent on the time of year and governed by changes in perceived day length (photoperiod). These attributes include significant weight loss, reduced food intake, gonadal atrophy and pelage change with short-day photoperiod as in winter. The central mechanisms driving seasonal phenotype change during winter are mediated by a reduced availability of hypothalamic triiodothyronine (T3), although the downstream mechanisms responsible for physiological and behavioural changes are yet to be fully clarified. With access to a running wheel (RW) in short photoperiod, Siberian hamsters that have undergone photoperiod-mediated weight loss over-ride photoperiod-drive for reduced body weight and regain weight similar to a hamster held in long days. These changes occur despite retaining the majority of hypothalamic gene expression profiles appropriate for short-day hamsters. Utilising the somatostatin agonist pasireotide, we recently provided evidence for an involvement of the growth hormone (GH) axis in the seasonal regulation of bodyweight. In the present study, we employed pasireotide to test for the possible involvement of the GH axis in RW-induced body weight regulation. Pasireotide successfully inhibited exercise-stimulated growth in short-day hamsters and this was accompanied by altered hypothalamic gene expression of key GH axis components. Our data provide support for an involvement of the GH axis in the RW response in Siberian hamsters.

Topics: Animals; Body Composition; Body Weight; Cricetinae; Eating; Growth Hormone-Releasing Hormone; Hypothalamus; Iodide Peroxidase; Male; Motor Activity; Neuropeptide Y; Organ Size; Phodopus; Photoperiod; Pro-Opiomelanocortin; Receptors, Somatotropin; Somatostatin

Pasireotide is the first pituitary-directed drug approved for treating patients with Cushing's disease (CD). Our 10-year experience with pasireotide in CD is reported here. Twenty patients with de novo, persistent, or recurrent CD after pituitary surgery were treated with pasireotide from December 2003 to December 2014. Twelve patients were treated with pasireotide in randomized trials and 8 patients with pasireotide sc (Signifor(®); Novartis AG, Basel, Switzerland) in clinical practice. The mean treatment duration was 20.5 months (median 9 months; range, 3-72 months). Urinary free cortisol (UFC) levels mean percentage change (± SD) at last follow-up was-40.4% (± 35.1; range, 2-92%; median reduction 33.3%) with a normalization rate of 50% (10/20). Ten patients achieved sustained normalized late night salivary cortisol (LNSC) levels during treatment. LNSC normalization was associated with UFC normalization in 7/10 patients. Serum cortisol and plasma ACTH significantly decreased from baseline to last follow-up. Body weight decrease and blood pressure improvement during pasireotide treatment were independent from UFC response. Glucose profile worsening was observed in all patients except one. The frequency of diabetes mellitus increased from 40% (8/20) at baseline to 85% (17/20) at last follow-up requiring initiation of medical treatment only in 44% of patients. Pasireotide treatment was associated with sustained biochemical and clinical benefit in about 60% of CD patients. Glucose profile alteration is a frequent complication of pasireotide treatment; however, it seems to be easy to manage with diet and lifestyle intervention in almost half of the patients.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Blood Glucose; Blood Pressure; Body Weight; Female; Humans; Hydrocortisone; Male; Middle Aged; Pituitary ACTH Hypersecretion; Saliva; Somatostatin; Treatment Outcome; Tumor Burden

Siberian hamsters (Phodopus sungorus) show spontaneous daily torpor only after ∼2 mo in winter-like short photoperiods (SP). Although some SP-induced hormonal changes have been demonstrated to be necessary for the occurrence of seasonal torpor, the whole set of preconditions is still unknown. Recent findings provide evidence that the hypothalamic pituitary growth axis is involved in endocrine responses to SP exposure in the photoperiodic hamsters. To examine whether suppression of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) secretion affects the incidence of daily torpor, we used two somatostatin receptor agonists, pasireotide (SOM230) and octreotide, with different affinity profiles for receptor subtypes. Pasireotide strikingly increased the torpor frequency in male hamsters compared with sham-treated controls, and torpor duration was often increased, which in some cases exceeded 12 h. In contrast, administration of octreotide reduced the body weight of SP hamsters but had only a marginal effect on torpor frequency in males and no effect in females. Together with measured concentrations of circulating IGF-1, the present results strongly suggest that reduced activity of the GH/IGF-1 axis is not critical for stimulation of torpor expression but activation of specific somatostatin receptors is critical. This putative role for certain somatostatin receptor subtypes in torpor induction provides a promising new approach to unravel the endocrine mechanisms of torpor regulation.

Topics: Animals; Body Temperature; Body Weight; Cricetinae; Female; Hypothalamus; Male; Octreotide; Phodopus; Receptors, Somatostatin; RNA, Messenger; Seasons; Somatostatin; Torpor

The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors SSTR1, 2, 3, and 5. Acting principally through the latter, it inhibits basal and CRH-stimulated ACTH secretion from the AtT20 corticotroph cell line and ACTH release from a proportion of human corticotroph adenomas both in vitro and in vivo. Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing's disease. We have compared the effects of pasireotide and octreotide on adrenalectomy-induced mitotic and apoptotic activity in the male rat anterior pituitary. Adrenalectomized rats were treated with daily sc injections of vehicle, pasireotide, or octreotide. Changes in proliferation and apoptosis were determined 2-6 d postoperatively. Pasireotide and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis. However, the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished. Nevertheless, pasireotide and octreotide did not diminish the increase in ACTH-immunopositive cell index after adrenalectomy, indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control. In conclusion, basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide. Bilateral adrenalectomy stimulates differentiation of preexisting null cells into ACTH-positive cells. Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide, implicating SSTR2 receptors in this antimitotic response.

Topics: Adrenalectomy; Adrenocorticotropic Hormone; Animals; Body Weight; Male; Mitosis; Octreotide; Pituitary Gland, Anterior; Rats; Rats, Wistar; Receptors, Somatostatin; Somatostatin; Weight Gain

The goal of this project was to find a somatostatin (SRIF) analog with superior therapeutic potential. Receptor binding studies of new SRIF analogs were used to reveal SRIF substructures that interact with individual human SRIF receptor subtypes (sst1-sst5). Incorporation of these substructures into a stable cyclohexapeptide template led to SOM230, which binds with nanomolar affinity to sst1, sst2, sst3, and sst5. In rats, the inhibitory effect of SOM230 on GH was similar to SMS 201-995 (octreotide) at 1 h, but was 4-fold more potent at 6 h post injection, indicating increased metabolic stability. Treatment of rats with SOM230, at 1 and 10 micro g/kg.h, decreased IGF-I plasma levels, on d 2, by 68% and 90% (P < 0.01); whereas, under SMS 201-995 treatment, plasma IGF-I levels decreased by 28% and 49%, respectively. After a 2-wk infusion of rats, the suppression of IGF-I levels by SOM230 was still pronounced, whereas the response to SMS 201-995 was largely lost. This enhanced effect of SOM230 on IGF-I plasma levels was confirmed in an 8-wk study where both analogs were infused at 50 micro g/kg/h in rats. In rhesus monkey, SOM230 and SMS 201-995 treatment resulted in GH inhibition, with half-maximal inhibitory dose values of 0.5 and 0.4 micro g/kg, respectively, but plasma IGF-I levels were only lowered by SOM230 (-53%). In cynomolgus monkeys, a 2-wk infusion of SOM230, but to a much lesser extent of SMS 201-995, lowered plasma GH levels significantly (from 16.3 to 1.8 ng/ml, P = 0.007). Both in cynomolgus monkeys and beagle dogs, infusion of SOM230, but not SMS 201-995, lowered IGF-I levels significantly. In conclusion, SOM230 has a unique structure, binds almost universally to human ssts, and inhibits potently the GH/IGF-I axis cross-species. SOM230 is a candidate drug for clinical use.

Topics: Animals; Body Weight; Dogs; Eating; Growth Hormone; Hormones; Insulin-Like Growth Factor I; Macaca fascicularis; Macaca mulatta; Octreotide; Rats; Somatostatin; Time Factors