Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical management of proliferative diabetic retinopathy has changed very little in the last 5 decades, relying primarily on laser ablation of the retinal vasculature. Several lines of clinical and experimental evidence suggest that somatostatin analogues may be efficacious in inhibiting neovascularization associated with proliferative retinopathy but the mechanism of action for these compounds is unclear. Inhibition of growth hormone secretion and the subsequent suppression of insulin-like growth factor 1 (IGF-1) production by somatostatin has been suggested as the mechanism of action, however, in vitro studies suggest that somatostatin analogues suppress endothelial cell growth through a direct, somatostatin receptor-mediated inhibition of pro-survival signaling pathways. The advent of a new generation of modified peptide and peptidomimetic somatostatin analogues has allowed investigators to more carefully define the receptor subtypes responsible for somatostatin-induced endothelial cell death and may eventually lead to the clinical development of somatostatin analogues that can reduce endothelial cell proliferation, independent of suppression of circulating hormone levels.
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PMID:The therapeutic problem of proliferative diabetic retinopathy: targeting somatostatin receptors. 1144 Feb 76

The local microenvironment at the sites of cancer metastases protects tumour cells from anticancer drug-induced apoptosis via mechanisms, such as soluble growth factors and cytokines. The concept of antisurvival factor (ASF) therapy as a component of anticancer treatments aims at neutralising the protective effect conferred upon cancer cells by the survival factor(s) derived by the local microenvironment, in order to enhance the sensitivity and/or reverse the resistance of tumour cells to other anticancer therapeutic strategies. Herein, we review the translation of this concept from ex vivo studies to clinical applications in the setting of prostate cancer refractory to androgen ablation (stage D3). At this stage, which predominantly involves bone metastases, insulin-like growth factor 1 (IGF-1) production (either growth hormone (GH)-dependent or GH-independent) can protect tumour cells from apoptosis, despite the significant suppression of androgens. The application of the ASF therapeutic concept involves the combination of dexamethasone (which suppresses GH-independent IGF-1) and somatostatin analogue (which suppresses endocrine, GH-dependent IGF-1) with the pro-apoptotic effect of the testicular androgen suppression by sustained use of LHRH analogues. In stage D3, patients who had failed anti-androgen withdrawal, chemotherapy and also had several other adverse prognostic features, the ASF-based combination achieved durable objective responses and major symptomatic improvement, paving the way for future applications of this approach. The ASF-based combination therapy illustrates a novel paradigm in cancer treatment: anti-tumour treatment strategies may not only aim at directly inducing cancer cell apoptosis, but can also target the tumour microenvironment and neutralise the protection it confers on metastatic cancer cells. The favourable toxicity profile of this therapeutic approach calls for its testing in a randomised controlled setting in metastatic prostate cancer and, conceivably, in other IGF-1-responsive malignancies.
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PMID:Combination of dexamethasone and a somatostatin analogue in the treatment of advanced prostate cancer. 1182 17

Somatostatin analogues are a therapeutic option in patients with chronic overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). These factors are also involved in the pathogenesis of diabetic retinopathy. Somatostatin receptors are expressed in the retina and are therefore possible targets of somatostatin analogues in the treatment of retinal vascular diseases like diabetic retinopathy. The somatostatin analogue octreotide has shown promise as a safe and effective treatment for advanced diabetic retinopathy and diabetic macular edema. The compound blocks the local and systemic production of GH and IGF-1, and thus inhibits the angiogenic effect. Evidence from animal models, and clinical trials in patients with diabetic retinopathy, suggest that octreotide can delay, and to some extent reverse diabetic retinopathy.
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PMID:[Therapy of diabetic retinopathy with somatostatin analogues]. 1500 9

The role of somatostatin and growth hormone in eye diseases recently became a matter of interest because of its link with proliferative diabetic retinopathy. In diabetic patients the pathologic proliferation of blood vessels as a result of retinal ischemia is a major cause of blindness. The hypoxic portions of the retina release angiogenic factors, stimulating neovascularization. Somatostatin is a natural peptide hormone that affects the release of a number of other hormones, such as growth hormone, glucagon, insulin and gastrin. The somatostatin analog promises to be safe and effective treatment for severe diabetic retinopathy. This compound has been shown to block the local and systemic production of insulin-like growth factor 1 and growth hormone, which promote the angiogenesis and endothelial cell proliferation associated with proliferative retinopathy. Several studies have confirmed that using somatostatin analogs to block insulin-like growth factor 1 production is effective in reducing neovascularization and preventing disease progression to proliferative stage of diabetic retinopathy. Long-acting somatostatin analogs are currently being tested for the treatment of diabetic retinopathy. The development of somatostatin analogs with increased selectivity for receptor subtypes will provide improved outcomes in the management of patients with diabetic retinopathy.
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PMID:Diabetes mellitus and retinopathy. 1507 18

Chronic overproduction of growth hormone and insulin-like growth factor 1 play an important role in the pathogenesis of diabetic retinopathy. Somatostatin receptors are the targets of somatostatin analogues such as octreotide in the treatment of diabetic retinopathy. Octreotide has shown promise as a safe and effective treatment for advanced diabetic retinopathy and diabetic macular edema. One important pathomechanism in the development of diabetic complications is the activation of protein kinase C induced by high glucose due to an increased diacylglycerol level. The development of a selective PKCss inhibitor enables a new therapeutic approach for the treatment of diabetic retinopathy. Ongoing prospective clinical studies are investigating if treatment with specific PKCss inhibitors can prevent the progression of diabetic retinopathy and diabetic macular edema. The intravitreal injection of triamcinolone acetonide leads to at least temporary improvement of the diffuse diabetic macular edema. Side effects are increase of intraocular pressure, cataract, and endophthalmitis.
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PMID:[Pharmacological treatment of diabetic retinopathy]. 1559 46

Spontaneous dwarf rats (SDRs) display growth hormone (GH) deficiency due to a mutation in the GH gene. This study investigated sleep in SDRs and their somatotropic axis and compared to Sprague-Dawley rats. SDRs had almost undetectable levels of plasma GH. Hypothalamic GH-releasing hormone (GHRH) mRNA was increased, whereas GHRH-receptor (GHRH-R) and somatostatin mRNAs were decreased in SDRs. Hypothalamic GHRH and somatostatin peptide content decreased in SDRs. Quantitative immunohistochemistry for GHRH and GHRH-R corroborated and extended these findings. In the arcuate nucleus, the number of GHRH-positive cells was significantly higher, whereas GHRH-R-positive perikarya were diminished in SDRs. Cortical GHRH and GHRH-R measurements showed similar expression characteristics as those found in the hypothalamus. SDRs had less rapid eye movement sleep (REMS) and more non-REMS (NREMS) than the control rats during the light period. The electroencephalogram (EEG) delta and theta power decreased during NREMS in the SDRs. After 4-h of sleep deprivation, SDRs had a significantly reduced REMS rebound compared to the controls, whereas NREMS rebound was normal in SDRs. The enhancement in delta power was significantly less than in the control group during recovery sleep. Intracerebroventricular (icv) administration of GHRH promoted NREMS in both strains of rats; however, increased REMS and EEG delta activity was observed only in control rats. Icv injection of insulin-like growth factor 1 increased NREMS in control rats, but not in the SDRs. These results support the ideas that GHRH is involved in NREMS regulation and that GH is involved in the regulation of REMS and in EEG slow wave activity regulation during NREMS.
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PMID:Sleep in spontaneous dwarf rats. 1685 58

Anabolic steroids are frequently taken by athletes and bodybuilders together with recombinant human GH (rhGH), though there is some scientific evidence that the use of anabolic steroids reverses the rhGH-induced effects. Recently, we have shown that treatment with rhGH (0.2 IU/kg s.c., daily x 12 days) in the dog markedly reduced the canine GH (cGH) responses stimulated by EP51216, a GH secretagogue (GHS), evaluated after 3 and 5 daily rhGH injections, and that the inhibition was still present a few days after rhGH discontinuation. The aim of the present study was to evaluate in the dog the GH response to EP51216 (125 mug/kg i.v.) in a condition of enhanced androgenic function (i.e. acute injection or 15-day treatment with testosterone at the dose of 2 mg/kg i.m. on alternate days), and in the hypophysectomized rat the hypothalamic and hippocampal expression of ghrelin, the receptor of GHSs (GHS-R), GH-releasing hormone (GHRH) and somatostatin (SS) after specific hormonal replacement therapies (testosterone, 1 mg/kg/day s.c.; hydrocortisone, 500 mug/kg/day s.c.; rhGH, 400 mug/kg/day s.c.; 0.9% saline 0.1 ml/kg/day s.c.; x11 days). In the dog experiments, under baseline conditions, a single injection of EP51216 elicited an abrupt rise of plasma cGH. Twenty-four hours from the acute bolus injection of testosterone, C(max) and AUC(0-90) of the GHS-stimulated cGH response were significantly lower than baseline cGH response; 5 days later, there was still a significant decrease of either parameter versus the original values. Short-term treatment with testosterone markedly reduced the GHS-stimulated cGH responses evaluated during (5th bolus) and at the end (8th bolus) of testosterone treatment. Four and 8 days after testosterone withdrawal, the EP51216-stimulated cGH response was still significantly reduced when compared with that under baseline conditions. Plasma concentrations of insulin-like growth factor 1 (IGF-1) were stable until the 5th bolus of testosterone and decreased progressively in the remaining time of the testosterone treatment; 4 and 8 days from treatment withdrawal, IGF-1 levels were still suppressed. In rat studies, hypothalamic mRNA levels of GHS-R were significantly reduced by treatments with testosterone and hydrocortisone, whereas hippocampal expressions of ghrelin, GHRH and SS were reduced by rhGH replacement therapy. In conclusion, these studies show that a single administration of testosterone can abrogate the cGH response ensuing acute stimulation by a GHS; the inhibitory effect of testosterone on the cGH response to GHS is present during and even 8 days after termination of a short-lived treatment with testosterone; these events occur via a
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PMID:Testosterone inhibition of growth hormone release stimulated by a growth hormone secretagogue: studies in the rat and dog. 1710 85

In all vertebrates, the regulations of growth and energy balance are complex phenomena which involve elaborate interactions between the brain and peripheral signals. Most vertebrates adopt and maintain a life style after birth, but lower vertebrates may have complex life histories involving metamorphoses, migrations and long periods of fasting. In order to achieve the complex developmental programs associated with these changes, coordinated regulation of all aspects of energy metabolism is required. Somatotropic axis (somatostatin (SRIH) growth hormone (GH) and insulin-like growth factor 1 (IGF1), is known to be involved in the regulation of growth and energy balance. Interestingly, recent studies showed that additional factors such as pituitary adenylate cyclase-activated polypeptide (PACAP), corticotropin-releasing hormone (CRH), ghrelin and leptin could also have major roles in the control of growth and metabolism in lower vertebrates (fish, amphibians and reptiles). This mini-review will survey the function of GH and metabolic regulation in lower vertebrates.
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PMID:Comparative aspects of GH and metabolic regulation in lower vertebrates. 1737 70

Despite the better options of controlling diabetes mellitus and although the prognosis of diabetic retinopathy has markedly improved by laser treatment and vitreoretinal surgery, diabetic retinopathy still is the leading cause of blindness in working age people in industrialized countries. Little has changed in the last decades regarding the prognosis of ocular complications in diabetes mellitus. We therefore need better tools and new therapeutic approaches for the prevention and treatment of diabetic ocular complications. Newer therapeutic options are directed at the causative mechanisms of diabetic retinopathy. Experimental and clinical evidence suggests that pharmacological compounds like somatostatin analogues and protein kinase C (PKC) inhibitors may be effective in the treatment of diabetic retinopathy. Chronic overproduction of growth hormone and insulin-like growth factor 1 play an important role in the pathogenesis of diabetic retinopathy. In the treatment of diabetic retinopathy somatostatin receptors are the targets of somatostatin analogues like octreotide. Octreotide has shown to be a promising treatment of diabetic retinopathy and diabetic macular edema. One important pathomechanism in the development of diabetic retinopathy is the activation of PKC induced by high glucose due to an increased diacylglycerol level. The selective PKC-beta inhibitor ruboxistaurin mesylate enables a new therapeutical approach for the treatment of diabetic retinopathy. Ongoing prospective clinical trials investigate whether the treatment with the specific PKC-beta inhibitor can prevent the progression of diabetic retinopathy and diabetic macular edema.
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PMID:Pharmacological treatment of diabetic retinopathy. 1738 65

Melatonin and resistance exercise alone have been shown to increase the levels of growth hormone (GH). The purpose of this study was to determine the effects of ingestion of a single dose of melatonin and heavy resistance exercise on serum GH, somatostatin (SST), and other hormones of the GH/insulin-like growth factor 1 (IGF-1) axis. Physically active males (n = 30) and females (n = 30) were randomly assigned to ingest either a melatonin supplement at 0.5 mg or 5.0 mg, or 1.0 mg of dextrose placebo. After a baseline blood sample, participants ingested the supplement and underwent blood sampling every 15 min for 60 min, at which point they underwent a single bout of resistance exercise with the leg press for 7 sets of 7 reps at 85% 1-RM. After exercise, participants provided additional blood samples every 15 min for a total of 120 min. Serum free GH, SST, IGF-1, IGFBP-1, and IGFBP-3 were determined with ELISA. Data were evaluated as the peak pre- and post-exercise values subtracted from baseline and the delta values analyzed with separate three-way ANOVA (p < 0.05). In males, when compared to placebo, 5.0 mg melatonin caused GH to increase (p = 0.017) and SST to decrease prior to exercise (p = 0.031), whereas both 0.5 and 5.0 mg melatonin were greater than placebo after exercise (p = 0.045) and less than placebo for SST. No significant differences occurred for IGF-1; however, males were shown to have higher levels of IGFBP-1 independent of supplementation (p = 0.004). The 5.0 mg melatonin dose resulted in higher IGFBP-3 in males (p = 0.017). In conclusion, for males 5.0 mg melatonin appears to increase serum GH while concomitantly lowering SST levels; however, when combined with resistance exercise both melatonin doses positively impacts GH levels in a manner not entirely dependent on SST.
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PMID:Effects of a single dose of N-Acetyl-5-methoxytryptamine (Melatonin) and resistance exercise on the growth hormone/IGF-1 axis in young males and females. 1795 23


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