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

Growth hormone and growth factors have been implicated in the pathogenesis of diabetic retinopathy. Hypophysectomy has been proposed as a treatment for proliferative diabetic retinopathy unresolved by panretinal photocoagulation (PPC). SMS 201-995, a long acting somatostatin analogue which slows down growth hormone secretion, may provide a non-invasive therapy for these rare cases. To assess this possibility, we studied the feasibility and efficiency of long-term SMS 201-995 treatment in diabetics. SMS 201-995 was injected subcutaneously with a continuous pump system at a dose of 400 micrograms/d into 4 insulin dependent diabetic patients suffering from proliferative diabetic retinopathy progressing despite a pan-photocoagulation. The mean age of these patients was 29 +/- 3 years and mean disease duration 18 +/- 3 years. Treatment periods lasted from 6 to 20 months (mean 15 months). Mean 24-hour growth hormone levels decreased by 57% after only one month of treatment (7.4 +/- 1.9 mU/l to 3.2 +/- 0.9 mU/l). The decline continued up to the third month. After the sixth month, signs of resistance to the drug were noted. The frequency of 24-hour GH peaks over 10 mU/l followed a parallel pattern. No rebound was observed when the treatment was progressively discontinued. In 2 patients neovascularization stopped. In the other 2 the process regressed. In all treatment had beneficial effects on the retina. Overall visual acuity improved (7.8 +/- 0.8/10e vs 5.5 +/- 0.8/10e). These effects were obtained within 3 to 6 months. Glycosylated haemoglobin levels did not change (8.8 +/- 1.3% to 9.0 +/- 0.8%). Insulin doses decreased 41% (46.5 +/- 1.7 U/d to 27.3 +/- 3.0 U/d). No severe hypoglycaemia occurred.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stabilization of severe proliferative diabetic retinopathy by long-term treatment with SMS 201-995. 129

A pilot study on the use of a continuous infusion of somatostatin, by subcutaneous pumps in the management of proliferative diabetic retinopathy is reported. Two patients out of eight with proliferative retinopathy demonstrated improvement. One patient demonstrated regression of disc new vessels and the other a reduced area of retinal capillary non-perfusion, both demonstrated by fluorescein angiography. Control patients showed worsening of fluorescein leakage over the observation period of four to six weeks whereas the other six patients given the somatostatin infusion did not demonstrate any deterioration. The mechanism of action of somatostatin in this study is unknown but it is thought to have direct anti-angiogenic properties as well as inhibiting growth hormone secretion.
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PMID:Effect of a long-acting somatostatin analogue (BIM23014) on proliferative diabetic retinopathy: a pilot study. 168 91

Preretinal neovascularization and chronic retinal oedema are the two major sight-threatening complications that can occur during diabetic retinopathy. Ocular neovascularization is strongly associated with retinal ischaemia, and growth factors have been implicated in its pathogenesis. The ischaemic retina is assumed to secrete growth factors that stimulate residual vessels to proliferate. Interest has focused on basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), platelet-derived growth factor (PDGF), transforming growth factor beta (TGF beta) and more recently vascular endothelial cell growth factor (VEGF). Histologic studies have demonstrated the presence of growth factor proteins and receptors and/or their mRNA, mainly VEGF, PDGF, and bFGF, in preretinal membranes of patients with proliferative diabetic retinopathy. Elevated intravitreal levels of IGF-1 and VEGF correlating with neovascular activity have been found in some patients. However, a direct causal relationship between ischaemia, growth factors and neovascularization has not been clearly demonstrated despite considerable research work. To date, the growth factor correlating most closely with neovascularization is VEGF. As many growth factors seem to be produced during the neovascular process, their specific inhibition probably will have limited effects. Laser photocoagulation of the retina has proved beneficial for regression of new vessels, probably through destruction of the ischaemic retina producing neovascular growth factors, and is currently the only treatment for proliferative diabetic retinopathy. Inhibition of IGF-1 by somatostatin analogs has produced unsatisfactory results. Other vascular inhibitors are currently being studied.
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PMID:Growth factors and diabetic retinopathy. 913

Increased intraocular levels of angiogenic growth factors such as insulin-like growth factor I (IGF-I) have been demonstrated in proliferative diabetic retinopathy (PDR). It is unclear whether increased leakage of the blood retina barrier or local synthesis primarily determine intraocular levels of IGFs in man, which is of special interest regarding possible therapeutic options with somatostatin analogues in PDR. This is the first study investigating parallelly serum and vitreous levels of IGF-I/II, IGF-BP3 and the liver-derived permeability marker albumin to determine in vivo the amount of circulation-derived intraocular IGFs. A control group without retinal proliferation and patients with PDR were compared. Levels of IGF-I/II, IGF-BP3 and albumin were determined by immunological methods. Vitreous levels of albumin were 2.2-fold elevated in patients with PDR (254.1 +/- 37.2mg/dl; n = 27; p = 0.0027) compared to controls (115.7 +/- 36.2mg/dl; n =10), whereas serum levels were slightly decreased in diabetes patients (5049 +/- 196 mg/dl vs. 4330 +/- 186 mg/dl; p = 0.0283). This was comparable to an increase of IGF-I/11 and IGF-BP3 in vitreous from PDR patients (IGF-I: 2.3 +/- 1.1 ng/ml p = 0.005. IGF-II: 37.9 +/- 4.9 ng/ml; p = 0.0003. IGF-BP3: 97.9 +/- 26.9 ng/ml; p = 0.0001; n = 34) compared to controls (IGF-I: 0.7 +/- 0.1 ng/ml. IGF-II: 21.3 +/- 4.2 ng/ml. IGF-BP3: 31.3 +/- 4.9 ng/ml: n = 19). Serum levels did not differ significantly among the groups regarding IGF-I, II and IGF-BP3. Intraocular albumin and IGF-I levels calculated as percentage of the respective serum levels correlated significantly (r = 0.42; p = 0.012). This study demonstrates that influx of IGF-I, II and IGF-BP3 in PDR quantitatively parallels influx of the liver derived serum protein albumin suggesting that leakage of the blood retina barrier and serum levels of IGF primarily determine intravitreal IGF levels rather than local synthesis. Suppression of systemic IGF levels by new, highly effective somatostatin-analogues therefore provides a promising approach to prevent PDR.
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PMID:Systemic levels contribute significantly to increased intraocular IGF-I, IGF-II and IGF-BP3 [correction of IFG-BP3] in proliferative diabetic retinopathy. 1087 Nov 61

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

Retinal photocoagulation reduces the incidence of severe visual loss in proliferative diabetic retinopathy (PDR). Reduced levels of VEGF/VPF might result in an improved function of the blood-retina barrier and cause a decrease of blood derived intraocular growth factors such as IGF-I. This study investigates whether retinal photocoagulation is able to normalize the concentrations of IGF-I, IGF-II and IGF-BP3 in the vitreous humor of patients undergoing vitrectomy. Levels of IGFs and the permeability marker, albumin, were measured in serum and vitreous of 52 patients. Three groups were compared: controls without proliferating eye disease (n = 19) and patients with PDR with (PDR+; n = 25) and without (PDR-; n = 8) previous retinal photocoagulation. IGF-I, IGF-II, IGF-BP3 and albumin were determined by immunological methods and were confirmed to be increased in patients with PDR compared to controls. Retinal photocoagulation influenced neither the intraocular concentration of the permeability marker albumin (PDR+: 253.2 +/- 46 mg/dl; PDR-: 256.4 +/- 66.5 mg/dl) nor the levels of IGFs (PDR+: IGF-I: 1.2 +/- 0.1 ng/ml; p = 0.38; IGF-II: 34.8 +/- 2.2 ng/ml; p = 0.1; IGF-BP3: 75.7 +/- 9.7 ng/ml; p = 0.27; PDR-: IGF-I: 1.1 +/- 0.2ng/ml; IGF-II: 29.3 +/- 5.2 ng/ml; IGF-BP3: 61.5 +/- 18.3 ng/ml). Systemic levels of albumin and IGFs were not changed significantly by retinal photocoagulation. These results demonstrate that previous retinal photocoagulation in patients undergoing vitrectomy does not functionally reestablish the blood-retina barrier despite decreases in VEGF/VPF. The lack of influence on intraocular concentrations of the serum-derived growth factors, IGF-I, IGF-II and IGF-BP3, might in part explain the failure of previous photocoagulation in the investigated patients. These results suggest that a combined treatment with retinal photocoagulation and growth hormone-lowering drugs, such as somatostatin analogues, could be a useful treatment, which may prevent further loss of visual acuity in patients with PDR.
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PMID:Retinal photocoagulation does not influence intraocular levels of IGF-I, IGF-II and IGF-BP3 in proliferative diabetic retinopathy-evidence for combined treatment of PDR with somatostatin analogues and retinal photocoagulation? 1144 Feb 79

Proliferative retinopathies account for the majority of cases of vision loss throughout the world. Currently accepted therapy for retinopathy consists of retinal ablation by panretinal laser photocoagulation or cryotherapy. This technique is not without deleterious effects to patients, including diminished night vision, reduced peripheral vision and loss of precise vision, decreasing visual acuity by one to two lines in magnitude. One promising area of research into pharmacotherapeutics for retinopathies, especially proliferative diabetic retinopathy, involves the use of synthetic analogues of somatostatin. The rationale for somatostatin as a therapeutic agent for retinal neovascularization is discussed. Somatostatin analogues such as octreotide have shown promise as a safe and effective treatment for severe proliferative diabetic retinopathy by blocking the local and systemic production of growth hormone and insulin-like growth factor type 1 associated with angiogenesis and endothelial cell proliferation. There are also observations suggesting an autocrine and paracrine effect of somatostatin, perhaps directly on retinal cells, which are known to express somatostatin receptors (SSTR). SSTR2 and SSTR3 are the most important receptor subtypes mediating growth hormone secretion and endothelial cell cycle arrest, retinal endothelial cell apoptosis and release of insulin. Thus, analogues that target these receptor subtypes may prove more useful. Long-acting somatostatin analogues are currently being tested for treatment of diabetic retinopathy and are, in fact, the only therapeutic alternative for patients who fail panretinal photocoagulation. Whether such a therapy may also prove effective for other retinal vascular proliferative diseases such as retinopathy of prematurity and age-related macular degeneration remains an open question that deserves attention, given our new understanding of the cellular and molecular mechanisms by which somatostatin may exert its antiangiogenic effects.
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PMID:Somatostatin analogues as drug therapies for retinopathies. 1258 62

Ocular diseases such as proliferative diabetic retinopathy are the major cause of blindness in industrialized countries. The main pathologic features of these diseases are hypoxia and overproduction of growth factors resulting in pathologic proliferation of endothelial cells and new vessel formation. Particularly, hypoxia and growth factors, such as VEGF, IGF-1, bFGF and TGF beta(2), show a complex interaction in the onset and progression of the diseases. Therefore, to date, most therapeutic strategies for proliferative retinopathies have targeted proliferation of endothelial cells evoked by growth factors. Recently, a synthetic analog of somatostatin, octreotide, has been shown to inhibit the proliferation of various cells in vitro, including endothelial cells. In this study, we have investigated the proliferative response of bovine retinal endothelial cells (BREC) to growth factors under hypoxic conditions and the modulation by octreotide. We found a dose-dependent increase of cell proliferation with VEGF, IGF-1 and bFGF, and inhibition of hypoxia-induced cell proliferation with TGF beta(2). Moreover, growth factor-induced, but not hypoxia-induced, cell proliferation was attenuated in the presence of octreotide. In contrast, TGF beta(2) abolished hypoxia-induced BREC proliferation. Similar to octreotide BIM23027, a somatastatin receptor subtype 2 (SSTR2) receptor agonist was able to attenuate the growth factor-induced proliferation of BREC expressing mRNA and protein for SSTR2. Therefore, we postulate that octreotide exerts its effects mainly through binding to the SSTR2. Taken together, our findings point to octreotide as a promising candidate for the treatment of eye disorders involving growth factor-dependent proliferation of endothelial cells.
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PMID:Octreotide prevents growth factor-induced proliferation of bovine retinal endothelial cells under hypoxia. 1501 96

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

Neovascularization stimulated by IGF-1 mediated induction of vascular endothelial growth factor (VEGF) is one of the leading causes of blindness in humans. It plays a central role in the pathogenesis of proliferative diabetic retinopathy (DR), neovascular glaucoma, exudative age-related macular degeneration (AMD) and retinopathy of prematurity. Neovascularization is a multi-step process that involves complex interactions of a variety of mitogenic factors such as VEGF and IGF-I which are produced locally in the human eye by a variety of cells including retinal pigment epithelial (RPE) cells, retinal capillary pericytes, endothelial cells, Mueller cells and ganglion cells. We hypothesized that somatostatin would inhibit the IGF-1 signal transduction pathway in RPE cells, resulting in decreased VEGF production. We have observed expression of somatostatin receptor protein in retinal pigment epithelial (RPE) cells of the human eye using immunohistochemistry and have confirmed expression of somatostatin receptors in cultured human RPE cells using reverse transcriptase-PCR. IGF-1 induced a dose dependent increase in IGF-1R phosphorylation and in VEGF mRNA levels in cultured human RPE cells. Somatostatin and octreotide, a somatostatin analogue, inhibited IGF-1 receptor (IGF-1R) phosphorylation and decreased VEGF production. Both IGF-1R phosphorylation and accumulation of VEGF mRNA were inhibited by physiological levels of somatostatin and octreotide (1 nM). These results demonstrate somatostatin and octreotide mediated attenuation of both IGF-1R signal transduction and VEGF mRNA accumulation via somatostatin receptor type 2 (sst2). Furthermore, these data suggest a rationale for the use of octreotide as a prophylactic and therapeutic option in disease states that cause ocular neovascularization.
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PMID:Somatostatin inhibits IGF-1 mediated induction of VEGF in human retinal pigment epithelial cells. 1538 Oct 31


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