Octreotide-mediated neurofunctional recovery in rats following traumatic brain injury. Role of H2S, Nrf2 and TNF-α.

PURPOSE: To explore the role and mechanisms of octreotide in neurofunctional recovery in the traumatic brain injury (TBI) model. METHODS: Rats were subjected to midline incision followed by TBI in the prefrontal cortex region. After 72 hours, the behavioural and neurological deficits tests were performed, which included memory testing on Morris water maze for 5 days. Octreotide (15 and 30 mg/kg i.p.) was administered 30 minutes before subjecting to TBI, and its administration was continued for three days. RESULTS: In TBI-subjected rats, administration of octreotide restored on day 4 escape latency time (ELT) and increased the time spent in the target quadrant (TSTQ) on day 5, suggesting the improvement in learning and memory. It also increased the expression of H2S, Nrf2, and cystathionine-γ-lyase (CSE) in the prefrontal cortex, without any significant effect on cystathionine-ß-synthase. Octreotide also decreased the TNF-α levels and neurological severity score. However, co-administration of CSE inhibitor (D,L-propargylglycine) abolished octreotide-mediated neurofunctional recovery, decreased the levels of H2S and Nrf2 and increased the levels of TNF-α. CONCLUSIONS: Octreotide improved the neurological functions in TBI-subjected rats, which may be due to up-regulation of H2S biosynthetic enzyme (CSE), levels of H2S and Nrf2 and down-regulation of neuroinflammation.

Beneficial effects of octreotide in alcohol-induced neuropathic pain. Role of H 2S, BDNF, TNF-α and Nrf2.

PURPOSE: To explore the role and molecular mechanisms of neuroprotective effects of octreotide in alcohol-induced neuropathic pain. METHODS: Male Wistar rats were employed and were administered a chronic ethanol diet containing 5% v/v alcohol for 28 days. The development of neuropathic pain was assessed using von Frey hair (mechanical allodynia), pinprick (mechanical hyperalgesia) and cold acetone drop tests (cold allodynia). The antinociceptive effects of octreotide (20 and 40 µg·kg-1) were assessed by its administration for 28 days in ethanol-treated rats. ANA-12 (0.25 and 0.50 mg·kg-1), brain-derived neurotrophic factor (BDNF) receptor blocker, was coadministered with octreotide. The sciatic nerve was isolated to assess the biochemical changes including hydrogen sulfide (H2S), cystathionine ß synthase (CBS), cystathionine γ lyase (CSE), tumor necrosis factor-α (TNF-α), BDNF and nuclear factor erythroid 2-related factor 2 (Nrf2). RESULTS: Octreotide significantly attenuated chronic ethanol-induced neuropathic pain and it also restored the levels of H2S, CBS, CSE, BDNF, Nrf2 and decreased TNF-α levels. ANA-12 abolished the effects of octreotide on pain, TNF-α, BDNF, Nrf2 without any significant effects on H2S, CBS, CSE. CONCLUSIONS: Octreotide may attenuate the behavioral manifestations of alcoholic neuropathic pain, which may be due to an increase in H2S, CBS, CSE, BDNF, Nrf2 and a decrease in neuroinflammation.

TGF-ß1/Smad2/3 signaling pathway modulates octreotide antisecretory and antiproliferative effects in pituitary somatotroph tumor cells.

Octreotide (OCT) is used to inhibit hormone secretion and growth in somatotroph tumors, although a significant percentage of patients are resistant. It has also been tested in nonfunctioning (NF) tumors but with poor results, with these outcomes having been associated with SSTR2 levels and impaired signaling. We investigated whether OCT inhibitory effects can be improved by TGF-ß1 in functioning and nonfunctioning somatotroph tumor cells. OCT effects on hormone secretion and proliferation were analyzed in the presence of TGF-ß1 in WT and SSTR2-overexpressing secreting GH3 and silent somatotroph tumor cells. The mechanism underlying these effects was assessed by studying SSTR and TGFßR signaling pathways mediators. In addition, we analyzed the effects of OCT/TGF-ß1 treatment on tumor growth and cell proliferation in vivo. The inhibitory effects of OCT on GH- and PRL-secretion and proliferation were improved in the presence of TGF-ß1, as well as by SSTR2 overexpression. The OCT/TGF-ß1 treatment induced downregulation of pERK1/2 and pAkt, upregulation of pSmad3, and inhibition of cyclin D1. In vivo experiments showed that OCT in the presence of TGF-ß1 blocked tumor volume growth, decreased cell proliferation, and increased tumor necrosis. These results indicate that SSTR2 levels and the stimulation of TGF-ß1/TGFßR/Smad2/3 pathway are important for strengthening the antiproliferative and antisecretory effects of OCT.

Pharmacological Acromegaly Treatment: Cost-Utility and Value of Information Analysis.

OBJECTIVES: To conduct a cost-utility analysis comparing drug strategies involving octreotide, lanreotide, pasireotide, and pegvisomant for the treatment of patients with acromegaly who have failed surgery, from a Brazilian public payer perspective. METHODS: A probabilistic cohort Markov model was developed. One-year cycles were employed. The patients started at 45 years of age and were followed lifelong. Costs, efficacy, and quality of life parameters were retrieved from the literature. A discount rate (5%) was applied to both costs and efficacy. The results were reported as costs per quality-adjusted life year (QALY), and incremental cost-effectiveness ratios (ICERs) were calculated when applicable. Scenario analyses considered alternative dosages, discount rate, tax exemption, and continued use of treatment despite lack of response. Value of information (VOI) analysis was conducted to explore uncertainty and to estimate the costs to be spent in future research. RESULTS: Only lanreotide showed an ICER reasonable for having its use considered in clinical practice (R$ 112,138/US$ 28,389 per QALY compared to no treatment). Scenario analyses corroborated the base-case result. VOI analysis showed that much uncertainty surrounds the parameters, and future clinical research should cost less than R$ 43,230,000/US$ 10,944,304 per year. VOI also showed that almost all uncertainty that precludes an optimal strategy choice involves quality of life. CONCLUSIONS: With current information, the only strategy that can be considered cost-effective in Brazil is lanreotide treatment. No second-line treatment is recommended. Significant uncertainty of parameters impairs optimal decision-making, and this conclusion can be generalized to other countries. Future research should focus on acquiring utility data.

Beneficial effects of octreotide in alcohol-induced neuropathic pain. Role of H 2S, BDNF, TNF-α and Nrf2

ABSTRACT Purpose To explore the role and molecular mechanisms of neuroprotective effects of octreotide in alcohol-induced neuropathic pain. Methods Male Wistar rats were employed and were administered a chronic ethanol diet containing 5% v/v alcohol for 28 days. The development of neuropathic pain was assessed using von Frey hair (mechanical allodynia), pinprick (mechanical hyperalgesia) and cold acetone drop tests (cold allodynia). The antinociceptive effects of octreotide (20 and 40 µg·kg-1) were assessed by its administration for 28 days in ethanol-treated rats. ANA-12 (0.25 and 0.50 mg·kg-1), brain-derived neurotrophic factor (BDNF) receptor blocker, was coadministered with octreotide. The sciatic nerve was isolated to assess the biochemical changes including hydrogen sulfide (H2S), cystathionine β synthase (CBS), cystathionine γ lyase (CSE), tumor necrosis factor-α (TNF-α), BDNF and nuclear factor erythroid 2-related factor 2 (Nrf2). Results Octreotide significantly attenuated chronic ethanol-induced neuropathic pain and it also restored the levels of H2S, CBS, CSE, BDNF, Nrf2 and decreased TNF-α levels. ANA-12 abolished the effects of octreotide on pain, TNF-α, BDNF, Nrf2 without any significant effects on H2S, CBS, CSE. Conclusions Octreotide may attenuate the behavioral manifestations of alcoholic neuropathic pain, which may be due to an increase in H2S, CBS, CSE, BDNF, Nrf2 and a decrease in neuroinflammation.

Octreotide-mediated neurofunctional recovery in rats following traumatic brain injury. Role of H2S, Nrf2 and TNF-α

ABSTRACT Purpose: To explore the role and mechanisms of octreotide in neurofunctional recovery in the traumatic brain injury (TBI) model. Methods: Rats were subjected to midline incision followed by TBI in the prefrontal cortex region. After 72 hours, the behavioural and neurological deficits tests were performed, which included memory testing on Morris water maze for 5 days. Octreotide (15 and 30 mg/kg i.p.) was administered 30 minutes before subjecting to TBI, and its administration was continued for three days. Results: In TBI-subjected rats, administration of octreotide restored on day 4 escape latency time (ELT) and increased the time spent in the target quadrant (TSTQ) on day 5, suggesting the improvement in learning and memory. It also increased the expression of H2S, Nrf2, and cystathionine-γ-lyase (CSE) in the prefrontal cortex, without any significant effect on cystathionine-β-synthase. Octreotide also decreased the TNF-α levels and neurological severity score. However, co-administration of CSE inhibitor (D,L-propargylglycine) abolished octreotide-mediated neurofunctional recovery, decreased the levels of H2S and Nrf2 and increased the levels of TNF-α. Conclusions: Octreotide improved the neurological functions in TBI-subjected rats, which may be due to up-regulation of H2S biosynthetic enzyme (CSE), levels of H2S and Nrf2 and down-regulation of neuroinflammation.

In vitro anti-echinococcal activity of octreotide: Additive effect of metformin linked to autophagy.

Cystic echinococcosis (CE) is a worldwide zoonosis caused by the Echinococcus granulosus larval stage. The currently available therapy for this disease is based on benzimidazoles, which are rarely curative and cause several adverse effects. Therefore, new treatment options are needed. Octreotide (Oct) is a somatostatin analogue which exhibits anti-proliferative and anti-secretory effects over several cancer cell lines expressing somatostatin receptors. Here, we assessed the in vitro pharmacological effect of Oct against the E. granulosus larval stage. The drug caused a significant dose-dependent decrease in the viability of both protoscoleces and metacestodes. SEM and TEM analysis showed ultrastructural damage in both larval forms under drug treatment. Based on this, we investigated the possible presence of an Oct binding receptor in the parasite. The putative somatostatin/allatostatin-like receptor (Eg-s/ast) conserves the characteristic topology and signature sequences of the prototype somatostatin receptor common to vertebrates and is expressed in both metacestodes and protoscoleces. Moreover, Oct treated-parasites showed the presence of autophagic structures and a significant increase in transcriptional expression of autophagy key genes such as Eg-atg6, Eg-atg8, Eg-atg12 and Eg-atg16. In addition, by in toto immunolocalization assays, an increase in the punctate pattern and Eg-Atg8 protein expression was detected in Oct-treated metacestodes. Subsequently, the combination of Oct and Met had an additive effect on the viability of both larval forms. Our results provide additional evidence for the participation of PI3K/AKT/TOR/autophagy pathway in the Echinococcus survival and suggest the concomitant use of these drugs as potential therapeutic agents in treating of CE.

A potencial theranostic agent for EGF-R expression tumors: (177)Lu-DOTA-nimotuzumab.

In this work Nimotuzumab (monoclonal antibody, recognizes the EGF-R) was radiolabeled with (177)Lu as a potential cancer therapy radiopharmaceutical. In-vitro cell binding studies and in-vivo biodistribution and imaging studies were performed to determine the radiochemical stability, targeting specificity and pharmacokinetics of the (177)Lu-labeled antibody. Nimotuzumab was derivatized with DOTA-NHS at room temperature for 2 hours. DOTA-Nimotuzumab was radiolabeled with (177)LuCl3 (15 MBq/mg) at 37°C for 1 h. The radiochemical purity was assessed by ITLC, silica gel and by RP-HPLC. Binding specificity studies were performed with EGF-R positive A431 human epithelial carcinoma and EGF-R negative MDA-MB-435 breast carcinoma cells. Biodistribution studies were performed in healthy female CD-1 mice at 1 h, 4 h, 24 h, and A431 xenografted nude mice at 10 min, 1 h, 4 h, 24 h, 48 h, and 96 h. SPECT-CT imaging studies were performed in A431 xenografted mice at 24 h post injection. DOTA-Nimotuzumab was efficiently labeled with (177) LuCl(3) at 37°C. The in vitro stability of labeled product was optimal over 24 h in buffered saline and mouse serum. Specific recognition of EGF-R by (177)Lu-DOTA-Nimotuzumab was observed in A431 cell binding studies. Biodistribution studies demonstrated increasing tumor uptake of (177)Lu-DOTA-Nimotuzumab over time, with tumor to muscle ratios of 6.26, 10.68, and 18.82 at 4 h, 24 h, and 96 h post injection. Imaging of A431 xenografted mice showed high uptake in the tumor. (177)Lu-DOTA-Nimotuzumab has the potential to be a promising therapy agent, which may be useful in the treatment of patients with EGF-R positive cancer.

Impact of gsp oncogene on the mRNA content for somatostatin and dopamine receptors in human somatotropinomas.

INTRODUCTION: It has been reported in some series that gsp+ somatotropinomas are more sensitive to somatostatin analogues (SA) and dopamine's actions which may be related to their somatostatin receptor (SSTR) and dopamine receptor (DR) profile. No previous studies have been undertaken to evaluate the SSTR and DR profile related with the gsp status in somatotropinomas. OBJECTIVES: To determine if (1) gsp status is correlated with response to octreotide LAR (LAR) and tumor expression patterns of SSTR1-5 and DR1-5 and (2) cAMP level can directly modulate SSTR and DR mRNA levels. METHODS: Response to SA was evaluated by GH and IGF-I percent reduction after 3 and 6 months of treatment with LAR. Conventional PCR and sequencing were used to identify gsp+ tumors. Quantitative real-time PCR was used to determine SSTR and DR tumor expression. Primary pituitary cell cultures of primates were used to study whether SSTR and DR expression is regulated by forskolin. RESULTS: The response to LAR did not significantly differ between patients with gsp+ and gsp- tumors; however, gsp+ tumors expressed higher levels of SSTR1, SSTR2, DR2 and a lower level of SSTR3. Forskolin increased SSTR1, SSTR2, DR1 and DR2 expression in cell cultures. CONCLUSION: Elevated SSTR1, SSTR2, and DR2 tumor expression may help improve responsiveness to SA and DA therapy; however, this study may not have been appropriately powered to observe significant effects in the clinical response. Elevated cAMP levels could be directly responsible for the upregulation in SSTR1, SSTR2 and DR2 mRNA levels observed in gsp+ patients.

Protective effect of octreotide and infliximab in an experimental model of indomethacin-induced inflammatory bowel disease.

Indomethacin administration in animals increases permeability of the small intestine, leading to inflammation that mimics Crohn's disease. Nonsteroidal anti-inflammatory drugs increase the permeability of the intestinal epithelial barrier and should therefore be used with caution in patients with Crohn's disease. We analyzed the protective effects of octreotide and the tumor necrosis factor-alpha inhibitor infliximab in a rat model of indomethacin-induced enterocolitis. Male Wistar rats received 20 mg of infliximab or 10 mug of octreotide 24 h prior to injection with indomethacin. Intestinal permeability was analyzed using Cr-51-ethylenediaminetetraacetic acid clearance. No microscopic or macroscopic alterations were observed in the rats receiving infliximab or octreotide, both of which increased permeability (P < 0.001 versus controls). Our macroscopic and microscopic findings might be related to the low specificity of infliximab and suggest that cytokines affect the intestinal epithelial barrier, as evidenced by the protective effect that infliximab had on the permeability parameters evaluated.

Evidence of subpopulations with different levels of insulin resistance in women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is non-uniformly associated with insulin resistance (IR). We examined IR in women with PCOS. METHODS: Sixty-nine PCOS women were subjected to the insulin suppression test (IST) to determine their steady-state plasma glucose (SSPG) as a direct measure of insulin sensitivity. RESULTS: SSPG exhibited a multimodal distribution suggesting the existence of subpopulations. The heterogeneous distribution of plasma glucose at 180 min (P = 0.011), with three modes, suggested differences in the plasma glucose level trajectories during the IST. Hence, the population was separated into three groups: (i) (n = 33), subjects with SSPG < or = 152.5 mg/dl, corresponding to the first to fifth deciles; (ii) (n = 29), subjects in the interval 152.5 mg/dl < SSPG < or = 300 mg/dl; (iii) (n = 7), subjects with SSPG > 300 mg/dl, corresponding to the tenth decile. Plasma glucose distributions at 180 min showed differences in their mean values and ranges among groups (P < 0.0001). The trajectories of the groups differed significantly during the IST (P < 0.0001). CONCLUSIONS: insulin sensitivity in our patients exhibited a discontinuous distribution, implying that PCOS is a heterogeneous disorder possessing subpopulations regarding IR.

Octreotide enhances portal pressure reduction induced by propranolol in cirrhosis: a randomized, controlled trial.

BACKGROUND: In vitro, octreotide potentiates vasoconstriction in isolated, preconstricted, mesenteric arterial vessels. In cirrhotic patients, portal pressure (HVPG) reduction induced by propranolol is partly due to splanchnic vasoconstriction. AIM: To evaluate HVPG effects of octreotide administration in cirrhotic patients receiving long-term propranolol. PATIENTS AND METHODS: A randomized, controlled trial. First study: a total of 28 patients were studied at baseline and 30 and 60 minutes after octreotide (200 mug) (N = 14) or placebo (N = 14) and then treated with propranolol for approximately 30 days (106 +/- 5 mg/day). Second study: after baseline evaluation patients received octreotide or placebo as they were assigned to in the first study and measurements repeated 30 and 60 minutes later. RESULTS: In the first study baseline HVPG was 18.7 +/- 0.9 mmHg and decreased to 17.1 +/- 1.1 mmHg and 17.1 +/- 1.0 mmHg (both P < 0.05 vs baseline) at 30 and 60 minutes after octreotide, respectively. Eight patients decreased their HVPG after octreotide. In the second study baseline HVPG was 15.6 +/- 1.3 mmHg (P < 0.01 vs baseline HVPG in first study) and decreased to 14.1 +/- 1.2 mmHg and 14.1 +/- 1.3 mmHg (25.7 +/- 5% lower than baseline HVPG in the first study, P < 0.01) (both P < 0.05 vs baseline) at 30 and 60 minutes after octreotide, respectively. Nine patients (2 responders/7 nonresponders to propranolol) decreased their HVPG after octreotide. Octreotide effects may be mediated by potentiation and additive mechanisms. CONCLUSIONS: Octreotide enhances HVPG reduction induced by propranolol in cirrhotic patients.

Alterations in the brain-gut axis underlying visceral chemosensitivity in Nippostrongylus brasiliensis-infected mice.

BACKGROUND & AIMS: Visceral hypersensitivity, a hallmark of irritable bowel syndrome, is generally considered to be mechanosensitive in nature and mediated via spinal afferents. Both stress and inflammation are implicated in visceral hypersensitivity, but the underlying molecular mechanisms of visceral hypersensitivity are unknown. METHODS: Mice were infected with Nippostrongylus brasiliensis (Nb) larvae, exposed to environmental stress and the following separate studies performed 3-4 weeks later. Mesenteric afferent nerve activity was recorded in response to either ramp balloon distention (60 mm Hg), or to an intraluminal perfusion of hydrochloric acid (50 mmol/L), or to octreotide administration (2 micromol/L). Intraperitoneal injection of cholera toxin B-488 identified neurons projecting to the abdominal viscera. Fluorescent neurons in dorsal root and nodose ganglia were isolated using laser-capture microdissection. RNA was hybridized to Affymetrix Mouse whole genome arrays for analysis to evaluate the effects of stress and infection. RESULTS: In mice previously infected with Nb, there was no change in intestinal afferent mechanosensitivity, but there was an increase in chemosensitive responses to intraluminal hydrochloric acid when compared with control animals. Gene expression profiles in vagal but not spinal visceral sensory neurons were significantly altered in stressed Nb-infected mice. Decreased afferent responses to somatostatin receptor 2 stimulation correlated with lower expression of vagal somatostatin receptor 2 in stressed Nb-infected mice, confirming a link between molecular data and functional sequelae. CONCLUSIONS: Alterations in the intestinal brain-gut axis, in chemosensitivity but not mechanosensitivity, and through vagal rather than spinal pathways, are implicated in stress-induced postinflammatory visceral hypersensitivity.

Effect of acid secretion blockade on acute gastric mucosal lesions induced by Tityus serrulatus scorpion toxin in anaesthetized rats.

Scorpion venom (TX) promotes gastric acid and pepsin secretion leading to acute gastric mucosal lesions (AGML), when injected in animals. The goal of the present study was to observe the effects of acid gastric secretion blockers over the incidence of TX-induced AGML in vivo. To verify this model, we used male albino rats, fasted 18-20 h (n=122) and anaesthetized with urethane (1.4 g/kg, i.p.). Their trachea and left femoral vein were both cannulated; the first to avoid airway obstructions during scorpion intoxication and the second for administration of saline, TX and acid blockers. Following the surgical procedure, the animals were divided in 10 groups of at least 10 animals each. Control groups were injected with NaCl 0.9% 1 ml/kg (n=10) or TX 375 microg/kg (n=32). Test groups (n=10, each) received atropine 5 mg/kg, cimetidine 10mg/kg, ranitidine 2.5mg/kg, ranitidine 5mg/kg, omeprazol 1 mg/kg, omeprazol 4 mg/kg, octreotide 80 and octreotide 100 microg/kg 10 min before the TX was injected. After 1h of intoxication, the stomach was resected for macroscopic study and the gastric secretion was collected for volume, pH and acid output assessment. We observed that all blockers were able to completely or partially prevent the TX-induced acid secretion as well as the AGML (p<0.05). Our data suggest the TX-induced AGML can be prevented by different class of acid blockers injected before the intoxication.

[Effects of acute octreotide infusion on renal function in patients with cirrhosis and portal hypertension]. / Efectos de la infusión aguda de octreotido sobre la función renal en pacientes con cirrosis hepática e hipertensión portal.

BACKGROUND: Octreotide is used in the treatment of acute variceal bleeding, based on its inhibitory effects of post-prandial splanchnic hyperemia and splanchnic venoconstriction. The consequences of these haemodynamic changes on renal circulation are not well known in cirrhotic patients. AIM: To evaluate the effects of acute octreotide administration on several parameters of renal function, including free water clearance, in patients with cirrhosis with or without ascites. PATIENTS AND METHODS: Twenty cirrhotic patients, Child-Pugh A orB, with or without ascites, with esophageal varices, normal renal function and free of medications (vasoactive drugs or diuretics) were assigned to 2 different protocols. Protocol 1: 10 patients were randomized to receive octreotide or placebo, as a bolus followed by a continuous infusion. Glomerular filtration rate (GFR) and renal plasma flow (PRF) were measured, in basal conditions and during the drug or placebo administration. Protocol 2: 10 additional patients were randomized in the same way and free water clearance and urinary sodium excretion were again measured in the basal period and during the drug or placebo infusion. RESULTS: After octreotide or placebo administration no significant changes were observed neither in GFR nor in PRF. The free water clearance decreased significantly during octreotide administration (3.12 ml/min+/-1.04 SE vs 0.88+/-0.39, p<.03). In both protocols no changes in mean arterial pressure were observed. CONCLUSIONS: Acute administration of octreotide to cirrhotic patients with portal hypertension, with or without ascites, did not produce any change in glomerular filtration rate or in estimated renal plasm blood flow. However the free water clearance decreased significantly. This effect, under chronic administration, could be clinically important and deserves further studies.

Acute cold exposure, leptin, and somatostatin analog (octreotide) modulate thyroid 5'-deiodinase activity.

We investigated the effect of acute cold exposure, leptin, and the somatostatin analog octreotide (OCT) on thyroid type I (D1) and II (D2) deiodinase activities. Microsomal D1 and D2 activities were measured by the release of (125)I from (125)I-reverse triiodothyronine (rT(3)) under different assay conditions. Rats exposed to 4 degrees C (15, 30, 60, and 120 min) showed progressive reduction in thyroidal D1 and D2, reaching approximately 40% at 2 h (P < 0.05) despite increased circulating TSH (P < 0,05) associated with the higher thyroid D1 and D2 in hypothyroid rats. A single injection of leptin (8 microg/100 g body wt sc) induced increased thyroid and liver D1 (P < 0.05), but not thyroid D2, activities at 30 and 120 min, independently of the serum TSH rise shown only at 2 h. OCT (1 microg/kg body wt sc) increased D1 and D2 activity significantly 24 h after a single injection, with no changes in serum TSH. Therefore, leptin and somatostatin are potential physiological upregulators of thyroid deiodinases, and their low secretion during acute cold exposure may be a potential mechanism contributing to cold-induced reduction in thyroid deiodinase activity.

The somatostatin analogue octreotide modulates Iodothyronine deiodinase activity and pituitary neuromedin B.

Somatostatin inhibits growth hormone and thyrotropin (TSH) secretion. It also enhances the inhibitory effect of thyroid hormone (TH) on TSH by poorly understood mechanisms. We investigated the acute effect of the long-acting somatostatin analogue, octreotide (OCT), on anterior pituitary type 1 (D1) and 2 (D2) deiodinase activity, on liver D1, and on pituitary content of neuromedin B (NB), an autocrine inhibitor of TSH secretion, which is positively regulated by thyroid hormones. Euthyroid or hypothyroid rats were sacrificed at different times after a single subcutaneous injection of OCT (1 microg/kg body weight [BW]). D1 and D2 activities were measured by the release of 125I from 125I reverse triiodothyronine (rT3) under different assay conditions. NB, TSH, T3, and thyroxine (T4) were quantitated by radioimmunoassay (RIA). In euthyroid rats, liver and pituitary D1 activities were decreased (50%) 6 hours after OCT injection; pituitary D2 and NB remained unchanged. In hypothyroid rats, OCT increased near to the level of normal rats both pituitary D1 activity (but not liver) and NB content, at 24 hours and at 6 and 24 hours, respectively (p < 0.05). Pituitary D2, greatly increased by hypothyroidism, showed a small (25%) but significant reduction at 3 hours, persisting at 24 hours (p < 0.01), although it remained higher than that of euthyroid control. Serum thyroid hormones were not affected by OCT injection. The results show that octreotide acutely regulates pituitary deiodinases and NB content, both representing mechanisms that potentially can contribute to somatostatin and octreotide actions on pituitary growth hormone (GH) and TSH secretion and to modulate these cells sensitivity to thyroid hormone action.

Effect of the somatostatin analogue octreotide (SMS201-995) on portal and mesenteric blood flow in rats

Várias investigaçöes revelaram que a somatostatina e análogas baixam o fluxo sanguíneo esplâncnico e portal em cirróticos e em modelos experimentais de hipertensäo portal. Tem sido experimentado habitualmente no tratamento de varizes sangrantes. O mecanismo pelo qual o hormônio age permanece obscuro. No presente estudo investigou-se o efeito da açäo prolongada do octreotide, somatostatina análoga, no fluxo sanguíneo mesentérico e portal, em ratos sadios. A administraçäo intravenosa do octreotide näo teve efeito significante na circulaçäo esplânic. Em alguns animais registrou-se, após a infusäo inicial da droga, queda pequena no fluxo venoso portal. Infusöes adicionais näo alteraram o fluxo portal. O fluxo sangüíneo mesentérico superior permaneceu inalterado. Conclui-se que o octreotide näo influiu na circulaçäo espâncnica, em ratos sadios, e que novos estudos se fazem necessários para explicar os seus efeitos em modelos de hipertensäo portal

Acute effect of the somatostatin analogue SMS-201995 on plasma glucose and triglycerides in insulin-dependent diabetic patients.

1. The effect of the long-acting somatostatin analogue SMS-201995 on diabetes control was assessed in 6 insulin-dependent diabetic patients (3 men and 3 women aged 19-38 years). 2. Plasma glucose and triglyceride profiles were obtained on 4 consecutive days, from 8:00 a.m. to 2:00 p.m. On the first 2 days the patients received their usual dose of insulin and ate at 8:00 a.m. and at noon. On the third and fourth days they received 1/3 of their usual insulin dose together with 100 micrograms SMS-201995 injected subcutaneously. 3. Postprandial glucose and triglyceride increases were blunted during the 360 min of observation on both days after SMS-201995 administration. The areas under the glucose-time plots fell from 23.72 +/- 12.29 (mean +/- SD) to 7.98 +/- 14.26 (P < 0.05) and the areas under the triglyceride-time plots from 10.51 +/- 9.01 to -3.15 +/- 4.30 g.min.dl-1 (P < 0.01). 4. No adverse reactions were observed after SMS-201995 administration for 2 days. 5. We conclude that administration of the somatostatin analogue SMS-201995 may be beneficial for insulin-dependent diabetic patients.