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Current Gastroenterology Reports Feb 2006Cirrhosis results in portal hypertension in many patients. The major complications of portal hypertension include development of ascites and esophageal or gastric... (Review)
Review
Cirrhosis results in portal hypertension in many patients. The major complications of portal hypertension include development of ascites and esophageal or gastric varices. Varices lead to hemorrhage and death in a significant proportion of patients. This review focuses on the pharmacologic approach to management of portal hypertension in patients at risk of variceal hemorrhage, or those who have already had variceal bleeding. Pharmacologic therapy is used for 1) primary prevention of bleeding, 2) management of acute bleeding, and 3) prevention of recurrent bleeding (secondary prophylaxis). For acute esophageal variceal hemorrhage, a variety of pharmacologic agents are used, including somatostatin, octreotide, vapreotide, lanreotide, terlipressin, and vasopressin (with nitrates). For primary and secondary prevention of esophageal variceal hemorrhage, beta-blockers remain the mainstay therapy.
Topics: Adrenergic beta-Antagonists; Algorithms; Antihypertensive Agents; Cardiovascular Agents; Esophageal and Gastric Varices; Esophagoscopy; Gastrointestinal Hemorrhage; Hemostatics; Humans; Hypertension, Portal; Ligation; Liver Cirrhosis; Nitrates; Portasystemic Shunt, Transjugular Intrahepatic; Recurrence; Sclerotherapy; Somatostatin; Vasoconstrictor Agents; Vasopressins
PubMed: 16510029
DOI: 10.1007/s11894-006-0058-9 -
Zeitschrift Fur Gastroenterologie Jan 2003
PubMed: 16308925
DOI: 10.1055/s-2003-36672 -
Pharmaceutical Research Aug 2005The purpose of this study was to evaluate the feasibility of delivering vapreotide, a somatostatin analogue, by transdermal iontophoresis.
PURPOSE
The purpose of this study was to evaluate the feasibility of delivering vapreotide, a somatostatin analogue, by transdermal iontophoresis.
METHODS
In vitro experiments were conducted using dermatomed porcine ear skin and heat-separated epidermis. In addition to quantifying vapreotide transport into and across the skin, the effect of peptide delivery on skin permselectivity was also measured. The influence of (1) current density, (2) pre- and post-treatment of the skin, (3) competitive ions, and (4) inclusion of albumin in the receptor on vapreotide delivery were investigated.
RESULTS
Epidermis proved to be a better model than dermatomed skin for vapreotide transport studies. Despite the susceptibility of vapreotide to enzymatic degradation, a flux of 1.7 microg/cm2 per hour was achieved after 7 h of constant current iontophoresis (0.15 mA/cm2). Post-iontophoretic extraction revealed that, depending on the experimental conditions, 80-300 microg of peptide were bound to the skin. Vapreotide was found to interact with the skin and displayed a current-dependent inhibition of electroosmosis. However, neither the pre-treatment strategies to saturate the putative binding sites nor the post-treatment protocols to displace the bound peptide were effective.
CONCLUSION
Based on the observed transport rate of vapreotide across porcine epidermis and its clinical pharmacokinetics, therapeutic concentrations should be achievable using a 15-cm2 patch.
Topics: Acetaminophen; Administration, Cutaneous; Analgesics, Non-Narcotic; Animals; Antineoplastic Agents; Cetrimonium; Cetrimonium Compounds; Epidermis; In Vitro Techniques; Iontophoresis; Skin; Skin Absorption; Somatostatin; Swine
PubMed: 16078140
DOI: 10.1007/s11095-005-5276-6 -
IDrugs : the Investigational Drugs... Nov 2000Debiopharm, under license from Tulane University, is developing vapreotide, a somatostatin analog, for the potential treatment of cancer, GI disorders and bleeding....
Debiopharm, under license from Tulane University, is developing vapreotide, a somatostatin analog, for the potential treatment of cancer, GI disorders and bleeding. Phase III trials have been initiated in France, investigating the utility of vapreotide in the treatment of prostate cancer. Phase III trials are also underway in France and Asia in patients with acute bleeding from esophageal varices. Debiopharm is also investigating the use of vapreotide in the treatment of acromegaly, gastrointestinal fistulae, AIDS-related and chemotherapy-induced diarrhea, and various neuroendocrine tumors. Vapreotide may also be useful for inducing hemostasis in cases of acute hemorrhage of the upper gastrointestinal tract.
PubMed: 16047258
DOI: No ID Found -
Molecular Pharmacology Jul 2005Upon hormone stimulation, the sst2 somatostatin receptor couples to adenylyl cyclase through G(i/o) proteins and undergoes rapid endocytosis via clathrin-coated pits. In... (Comparative Study)
Comparative Study
Upon hormone stimulation, the sst2 somatostatin receptor couples to adenylyl cyclase through G(i/o) proteins and undergoes rapid endocytosis via clathrin-coated pits. In this study, we determined the relationship between the ability of ligands to induce sst2 receptor internalization and inhibit adenylyl cyclase. Immunocytochemical studies demonstrated that peptide agonists [such as somatostatin-14, cortistatin-17, octreotide, vapreotide, KE108 (Tyr0-cyclo[d-diaminobutyric acid-Arg-Phe-Phe-d-Trp-Lys-Thr-Phe]), and SOM230 (cyclo[diaminoethylcarbamoyl-hydroxyproline-phenylglycine-d-Trp-Lys-(4-O-benzyl)-l-Tyr-Phe])] and nonpeptide agonists (such as L-779,976), stimulated the rapid endocytosis of sst2 receptors in human embryonic kidney 293 and CHO-K1 cells. In contrast, two antagonists did not induce receptor endocytosis by themselves and completely blocked agonist stimulation. Using a quantitative enzyme-linked immunosorbent assay to measure sst2 receptor sequestration, we found that peptide agonists varied by more than 100-fold in their potencies but exhibited the same efficacy as somatostatin14. In contrast, L-779,976 did not induce maximal receptor internalization. It is interesting that although betaarrestin-2 was recruited to cell surface sst2 receptors after stimulation with either somatostatin14 or L-779,976, the betaarrestin-receptor complex dissociated earlier in the endocytic pathway with the nonpeptide ligand. Although all agonists, including L-779,976, produced the same maximal inhibition of cyclic AMP, the potency ratio for inhibition of cyclic AMP and stimulation of receptor endocytosis varied by 15-fold. In general, native peptides showed similar potencies for cyclic AMP inhibition and receptor endocytosis, whereas short therapeutic analogs were substantially more potent at inhibiting cyclic AMP synthesis. These results demonstrate that the activity of somatostatin analogs to regulate receptor endocytosis and signaling are not tightly linked and provide compelling evidence for the induction of agonist specific states of the sst2 receptor.
Topics: Animals; CHO Cells; Cricetinae; Dose-Response Relationship, Drug; Endocytosis; Humans; Receptors, Somatostatin; Signal Transduction; Somatostatin
PubMed: 15855408
DOI: 10.1124/mol.105.011767 -
Cancer Biology & Therapy Aug 2004Somatostatin is a peptide hormone that normally suppresses growth hormone (GH), thyrotropin (TSH), insulin and gut hormone release, as well as affecting multiple aspects...
Somatostatin is a peptide hormone that normally suppresses growth hormone (GH), thyrotropin (TSH), insulin and gut hormone release, as well as affecting multiple aspects of gastrointestinal function. It achieves these pleiotropic effects by binding somatostatin receptors (SSTR), a family of five G-protein coupled membrane receptors. Somatostatin analogs, such as octreotide, lanreotide and vapreotide, are well-established treatments for tumors that over secrete these hormones. Recently, use of somatostatin analogs for treating nonendocrine malignancies are being explored. Hu et al. found progressive reduction in SSTR3 expression when comparing normal gastric mucosa versus well differentiated versus poorly differentiated gastric adenocarcinomas; octreotide inhibited growth and induced apoptosis in vitro of those cells expressing SSTR3. Potential mechanisms by which somatostatin analogs may be useful in oncology include its endocrine actions, autocrine/paracrine effects, SSTR-mediated cell signaling and SSTR-mediated cell labeling.
Topics: Antineoplastic Agents, Hormonal; Apoptosis; Cell Proliferation; Humans; Octreotide; Receptors, Somatostatin; Stomach Neoplasms
PubMed: 15326367
DOI: 10.4161/cbt.3.8.1030 -
Journal of Controlled Release :... May 2004The aim of the work was to develop biodegradable microspheres for controlled delivery of the somatostatin analogue vapreotide and maintenance of sustained plasma levels...
The aim of the work was to develop biodegradable microspheres for controlled delivery of the somatostatin analogue vapreotide and maintenance of sustained plasma levels over 2-4 weeks after a single injection in rats. Vapreotide was microencapsulated into end-group capped and uncapped low molecular weight poly(lactide) (PLA) and poly(lactide-co-glycolide) (PLGA) by spray-drying and coacervation. Microspheres were prepared from single and blended (1:1) polymer types. The microparticles were characterized for peptide loading, in vitro release and pharmocokinetics in rats. Spray-drying and coacervation produced microspheres in the size range of 1-15 and 10-70 microm, respectively, and with encapsulation efficiencies varying between 46% and 87%. In vitro release of vapreotide followed a regular pattern and lasted more than 4 weeks, time at which 40-80% of the total dose were released. Microspheres made of 14-kDa end-group uncapped PLGA50:50 or 1:1 blends of this polymer with 35 kDa end-group uncapped PLGA50:50 gave the best release profiles and yielded the most sustained plasma levels above a pre-defined 1 ng/ml over approximately 14 days. In vitro/in vivo correlation analyses showed for several microsphere formulations a linear correlation between the mean residence time in vivo and the mean dissolution time (r=0.958) and also between the amount released between 6 h and 14 days and the AUC(6h-14d) (r=0.932). For several other parameters or time periods, no in vitro/in vivo correlation was found. This study demonstrates that controlled release of the vapreotide is possible in vivo for a duration of a least 2 weeks when administered i.m. to rats. These results constitute a step forward towards a twice-a-month or once-a-month microsphere-formulation for the treatment of acromegaly and neuroendocrine tumors.
Topics: Animals; Antineoplastic Agents; Area Under Curve; Biocompatible Materials; Delayed-Action Preparations; Drug Compounding; Excipients; Lactic Acid; Male; Microspheres; Particle Size; Polyesters; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Rats; Rats, Sprague-Dawley; Solubility; Solvents; Somatostatin
PubMed: 15120900
DOI: 10.1016/j.jconrel.2004.02.015 -
Digestive and Liver Disease : Official... Feb 2004Somatostatin and its analogues have been compared with a variety of other treatments for the treatment of variceal bleeding in cirrhotic patients. Meta-analyses of... (Comparative Study)
Comparative Study Meta-Analysis Review
Somatostatin and its analogues have been compared with a variety of other treatments for the treatment of variceal bleeding in cirrhotic patients. Meta-analyses of studies comparing somatostatin or octreotide with vasopressin or terlipressin have shown that somatostatin is somewhat superior to vasopressin and equivalent to terlipressin in controlling bleeding and has significantly fewer side effects; no difference in mortality was observed. Octreotide was somewhat better than vasopressin and terlipressin in controlling bleeding, with similar mortality. Meta-analysis of trials comparing somatostatin or octreotide with endoscopic sclerotherapy shows that both drugs are equivalent to sclerotherapy for bleeding control, early rebleeding and survival. Complications are much less frequent with drug treatment. Nine trials have compared endoscopic therapy with therapeutic regimens combining endoscopic treatment with somatostatin, octreotide or vapreotide. Meta-analysis show that the combined regimens increase the 5 days bleeding control rate of endoscopic treatments by over 20%, although there is no difference in mortality. Comparisons of somatostatin and octreotide with combined regimens of sclerotherapy + somatostatin and sclerotherapy + octreotide have shown that the combined regimens were better than drug treatments alone in controlling bleeding and preventing early rebleeding, while complications were significantly less frequent with drug therapy.
Topics: Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Lypressin; Octreotide; Sclerotherapy; Somatostatin; Terlipressin; Vasoconstrictor Agents; Vasopressins
PubMed: 15077917
DOI: 10.1016/j.dld.2003.11.017 -
Minerva Endocrinologica Dec 2003In the last decade important progresses have been obtained in the diagnosis and therapy of endocrine gastroenteropancreatic (GEP) tumors, mainly derived from the... (Review)
Review
In the last decade important progresses have been obtained in the diagnosis and therapy of endocrine gastroenteropancreatic (GEP) tumors, mainly derived from the somatostatin receptors characterization and the introduction of long acting somatostatin analogues. Receptorial scintigraphy with radio-labeled analogues (Octreoscan) is the first choice investigation for staging and follow-up of endocrine GEP tumors, thanks to the high sensitivity in revealing the primary tumor and metastases, and for its capability to reveal lesions that are not identified by other imaging methods. Moreover, somatostatin analogues uptake by tumors allow us to use radiopharmaceutical compounds for advanced disease treatment. Between the radio-labeled drugs until now studied, interesting results have been obtained by DOTA-lanreotide (MAURITIUS), DOTA0 Tyr3-octreotide (DOTATOC) and DOTA0 Tyr3-octreotate, bound to beta-emitting radio-isotope suitable for therapeutic use. In the field of the pharmacological therapy of GEP tumors, the clinical trials show that somatostatin analogues reduce the symptoms related to functionally active tumors and stabilize or slow tumor growth improving the patient quality of life. Although somatostatin analogues alone could not be able to cure GEP tumors, their early utilization in association with surgical debulking of primary tumor and metastases, embolization or chemoembolization, and interferon, chemotherapy and radio-metabolic therapy (mainly directed to the destruction of micrometastases), increases the possibility of a radical therapeutic intervention. The continuous evolution of pharmacological research provides always new analogues (octreotide LAR, lanreotide, vapreotide, BIM-23244, BN 81644, PTR-3173, BIM-23A387, SOM-230, etc.) with different pharmacokinetic and receptorial properties and acting with more effectiveness in the different individual clinical situations. In this context there have been recently introduced also the "chimeric" analogues. On the other hand, the widespread utilization of molecular biology and immunohistochemical methods can allow, in perspective, to better define the receptorial pattern of individual endocrine tumors, after their surgical removal. The necessity to integrate endocrinological, nuclear medicine, surgical, oncologic and laboratory competencies behaves a multidisciplinary approach based on the utilization of diagnostic-therapeutic protocols supplying comparable results. It does not appear unjustified to expect, in the future, a scenery of more "individual" and more effective therapies for patients affected by GEP tumours.
Topics: Biomarkers, Tumor; Gastrointestinal Neoplasms; Humans; Multiple Endocrine Neoplasia; Nuclear Medicine; Pancreatic Neoplasms; Receptors, Somatostatin; Somatostatin
PubMed: 14752399
DOI: No ID Found -
Molecular Biology of the Cell Sep 2003The G protein-coupled sst2 somatostatin receptor acts as a negative cell growth regulator. Sst2 transmits antimitogenic signaling by recruiting and activating the...
The G protein-coupled sst2 somatostatin receptor acts as a negative cell growth regulator. Sst2 transmits antimitogenic signaling by recruiting and activating the tyrosine phosphatase SHP-1. We now identified Src and SHP-2 as sst2-associated molecules and demonstrated their role in sst2 signaling. Surface plasmon resonance and mutation analyses revealed that SHP-2 directly associated with phosphorylated tyrosine 228 and 312, which are located in sst2 ITIMs (immunoreceptor tyrosine-based inhibitory motifs). This interaction was required for somatostatin-induced SHP-1 recruitment and activation and consequent inhibition of cell proliferation. Src interacted with sst2 and somatostatin promoted a transient Gbetagamma-dependent Src activation concomitant with sst2 tyrosine hyperphosphorylation and SHP-2 activation. These steps were abrogated with catalytically inactive Src. Both catalytically inactive Src and SHP-2 mutants abolished somatostatin-induced SHP-1 activation and cell growth inhibition. Sst2-Src-SHP-2 complex formation was dynamic. Somatostatin further induced sst2 tyrosine dephosphorylation and complex dissociation accompanied by Src and SHP-2 inhibition. These steps were defective in cells expressing a catalytically inactive Src mutant. All these data suggest that Src acts upstream of SHP-2 in sst2 signaling and provide evidence for a functional role for Src and SHP-2 downstream of an inhibitory G protein-coupled receptor.
Topics: Amino Acid Motifs; Animals; Antineoplastic Combined Chemotherapy Protocols; COS Cells; Cell Division; Chlorocebus aethiops; Cricetinae; Cyclophosphamide; DNA Mutational Analysis; Doxorubicin; Intracellular Signaling Peptides and Proteins; Models, Molecular; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases; Rats; Receptors, Somatostatin; Somatostatin; Surface Plasmon Resonance; Vincristine; src-Family Kinases
PubMed: 12972574
DOI: 10.1091/mbc.e03-02-0069