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Archives of Medical Science : AMS 2020The extreme health and economic problems in the world due to the SARS-CoV-2 infection have led to an urgent need to identify potential drug targets for treating...
INTRODUCTION
The extreme health and economic problems in the world due to the SARS-CoV-2 infection have led to an urgent need to identify potential drug targets for treating coronavirus disease 2019 (COVID-19). The present state-of-the-art tool-based screening was targeted to identify drug targets among clinically approved drugs by uncovering SARS-CoV-2 helicase inhibitors through molecular docking analysis.
MATERIAL AND METHODS
Helicase is a vital viral replication enzyme, which unwinds nucleic acids and separates the double-stranded nucleic acids into single-stranded nucleic acids. Hence, the SARS-CoV-2 helicase protein 3D structure was predicted, validated, and used to screen the druggable targets among clinically approved drugs such as protease inhibitor, nucleoside reverse transcriptase inhibitor, and non-nucleoside reverse transcriptase inhibitors, used to treat HIV infection using molecular docking analysis.
RESULTS
Interaction with SARS-CoV-2 helicase, approved drugs, vapreotide (affinity: -12.88; score: -9.84 kcal/mol), and atazanavir (affinity: -11.28; score: -9.32 kcal/mol), approved drugs for treating AIDS-related diarrhoea and HIV infection, respectively, are observed with significantly low binding affinity and MOE score or binding free energy. The functional binding pockets of the clinically approved drugs on SARS-CoV-2 helicase protein molecule suggest that vapreotide and atazanavir may interrupt the activities of the SARS-CoV-2 helicase.
CONCLUSIONS
The study suggests that vapreotide may be a choice of drug for wet lab studies to inhibit the infection of SARS-CoV-2.
PubMed: 32399096
DOI: 10.5114/aoms.2020.94567 -
Saudi Pharmaceutical Journal : SPJ :... Dec 2018Cancer may be difficult to target, however, if cancer targeted this provides the chance for a better and more effective treatment. uantum dots (Qdots) coated vapreotide...
Cancer may be difficult to target, however, if cancer targeted this provides the chance for a better and more effective treatment. uantum dots (Qdots) coated vapreotide (VAP) as a somatostatin receptors (SSTRs) agonist can be efficient targeting issue since may reduce side effects and increase drug delivery to the target tissue. This study highlights the active targeting of cancer cells by cells imaging with improving the therapeutic outcomes. VAP was conjugated to Qdots using amine-to-sulfhydryl crosslinker. The synthesized Qdots-VAP was characterized by determination of size, measuring the zeta-potential and UV fluorometer. The cellular uptake was studied using different cell lines. Finally, the Qdots-VAP was injected into a rat model. The results showed a size of 479.8 ± 15 and 604.88 ± 17 nm for unmodified Qdots and Qdots-VAP respectively, while the zeta potential of particles went from negative to positive charge which proved the conjugation of VAP to Qdots. The fluorometer recorded a redshift for Qdots-VAP compared with unmodified Qdots. Moreover, cellular uptake exhibited high specific binding with cells which express SSTRs using confocal microscopy and flow cytometry (17.3 MFU comparing to 3.1 MFU of control, P < 0.001). Finally, an study showed a strong accumulation of Qdots-VAP in the blood cells (70%). In conclusion, Qdots-VAP can play a crucial role in cancer diagnosis and treatment of blood cells diseases when conjugated with VAP as SSTRs agonist.
PubMed: 30532637
DOI: 10.1016/j.jsps.2018.07.004 -
Alimentary Pharmacology & Therapeutics Jun 2012Vasoactive medications such as vasopressin, somatostatin and their analogues (terlipressin, vapreotide and octreotide) are commonly used for the treatment of acute... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Vasoactive medications such as vasopressin, somatostatin and their analogues (terlipressin, vapreotide and octreotide) are commonly used for the treatment of acute variceal bleeding. However, the risks and benefits of these interventions are not well understood.
AIM
To undertake a meta-analysis of the efficacy of vasoactive medications in patients having acute variceal bleeds.
METHODS
Randomised controlled trials (RCTs) of vasopressin, somatostatin and their analogues, administered to patients with acute variceal bleeds were identified based on systematic searches of nine electronic databases and multiple sources of grey literature.
RESULTS
The search identified 3011 citations, and 30 trials with a total of 3111 patients met eligibility criteria. The use of vasoactive agents was associated with a significantly lower risk of 7-day mortality (RR 0.74; 95% CI 0.57-0.95; P = 0.02; I(2) = 0%; moderate quality of evidence), and a significant improvement in haemostasis (RR 1.21, 95% CI 1.13-1.30; P < 0.001; I(2) = 28%; very low quality of evidence), lower transfusion requirements (pooled mean difference -0.70 units of blood transfused, 95% CI -1.01 to -0.38; P < 0.001; I(2) = 82%; moderate quality of evidence), and a shorter duration of hospitalisation (pooled mean difference -0.71 days; 95% CI -1.23 to -0.19; P = 0.007; I(2) = 0%; low quality of evidence). Studies comparing different vasoactive agents did not show a difference in efficacy, although the quality of evidence was very low.
CONCLUSIONS
The use of vasoactive agents was associated with a significantly lower risk of acute all-cause mortality and transfusion requirements, and improved control of bleeding and shorter hospital stay. Studies comparing different vasoactive medications failed to demonstrate a difference in efficacy.
Topics: Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hemostatics; Humans; Lypressin; Octreotide; Randomized Controlled Trials as Topic; Somatostatin; Terlipressin; Vasopressins
PubMed: 22486630
DOI: 10.1111/j.1365-2036.2012.05088.x -
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 -
British Journal of Cancer Mar 1999RC-160 (octastatin/vapreotide) is a potent octapeptide analogue of somatostatin with growth inhibitory activity in experimental tumours in vitro and in vivo, including... (Clinical Trial)
Clinical Trial
RC-160 (octastatin/vapreotide) is a potent octapeptide analogue of somatostatin with growth inhibitory activity in experimental tumours in vitro and in vivo, including breast cancer. We evaluated the efficacy and tolerability of high-dose RC-160, 3 mg day(-1) on week 1 increased to 4.5 mg day(-1) for weeks 2-4 and subsequently 6 mg day(-1) until the end of treatment, administered by continuous subcutaneous infusion in the management of 14 women with previously treated metastatic breast cancer. The age range was 37-80 years (median 58.5 years) and performance status 0-2. The treatment was well tolerated with no dose reductions being required. No grade 3 or 4 toxicities were seen. Abscess formation developed at the infusion site in eight patients and erythema and discomfort was seen in a further three patients. A significant reduction in IGF-I levels occurred by day 7 and was maintained throughout the treatment. The lowest dose of RC-160 produced the maximal IGF-I response. Although there was no reduction in prolactin levels in patients whose baseline levels were normal, elevated prolactin levels found in three patients fell to within the normal range 7 days after commencing RC-160 treatment. A small but significant rise in fasting blood glucose levels was also recorded, the highest level on treatment being 7.6 mmol l(-1). No objective tumour responses were observed, all patients showing disease progression within 3 months of commencing treatment. These findings demonstrate that high-dose RC-160, administered as a continuous subcutaneous infusion, can reduce serum levels of the breast growth factors IGF-I and prolactin but is ineffective in the management of metastatic breast cancer. Encouraging preclinical anti-tumour activity and the favourable toxicity profile in patients suggest the merit of future studies combining RC-160 with anti-oestrogen, cytotoxic and anti-angiogenic agents.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Breast Neoplasms; Disease Progression; Female; Humans; Insulin-Like Growth Factor I; Middle Aged; Neoplasm Staging; Prolactin; Somatostatin
PubMed: 10188884
DOI: 10.1038/sj.bjc.6690226 -
Neuropsychopharmacology : Official... Jul 2017Altered brain somatostatin functions recently appeared as key elements for the pathogenesis of stress-related neuropsychiatric disorders. The hippocampus exerts an...
Altered brain somatostatin functions recently appeared as key elements for the pathogenesis of stress-related neuropsychiatric disorders. The hippocampus exerts an inhibitory feedback on stress but the mechanisms involved remain unclear. We investigated herein the role of hippocampal somatostatin receptor subtypes in both stress response and behavioral emotionality using C57BL/6, wild type and sst or sst knockout mice. Inhibitory effects of hippocampal infusions of somatostatin agonists on stress-induced hypothalamo-pituitary-adrenal axis (HPA) activity were tested by monitoring peripheral blood and local hippocampus corticosterone levels, the latter by using microdialysis. Anxiolytic and antidepressant-like effects were determined in the elevated-plus maze, open field, forced swimming, and stress-sensitive beam walking tests. Hippocampal injections of somatostatin analogs and sst or sst but not sst or sst receptor agonists produced rapid and sustained inhibition of HPA axis. sst agonists selectively produced anxiolytic-like behaviors whereas both sst and sst agonists had antidepressant-like effects. Consistent with these findings, high corticosterone levels and anxiety were found in sstKO mice and depressive-like behaviors observed in both sstKO and sstKO strains. Both hippocampal sst and sst receptors selectively inhibit stress-induced HPA axis activation but mediate anxiolytic and antidepressive effects through distinct mechanisms. Such results are to be accounted for in development of pathway-specific somatostatin receptor agents in the treatment of hypercortisolism (Cushing's disease) and stress-related neuropsychiatric disorders.
Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Behavior, Animal; Corticosterone; Emotions; Hippocampus; Hypothalamo-Hypophyseal System; Male; Mice; Mice, Knockout; Octreotide; Pituitary-Adrenal System; Receptors, Somatostatin; Somatostatin; Stress, Psychological
PubMed: 27986975
DOI: 10.1038/npp.2016.281 -
Journal of Clinical Gastroenterology 2017Data on acute variceal hemorrhage (AVH) in the United States is limited and the best method to stratify risk is not clear. Taking advantage of a prospective US cohort... (Observational Study)
Observational Study
GOALS/BACKGROUND
Data on acute variceal hemorrhage (AVH) in the United States is limited and the best method to stratify risk is not clear. Taking advantage of a prospective US cohort study, we aimed to (1) describe clinical outcomes of AVH and their predictors; (2) compare predictors of 6-week mortality.
STUDY
Prospective 15-center US cohort of patients with cirrhosis presenting with endoscopically proven AVH, all of whom received antibiotics, vapreotide (a somatostain analog) infusion and endoscopic band ligation. Patients were enrolled between August 2006 and April 2008. Primary outcome was 6-week mortality. Secondary outcome was 5-day treatment failure. The prognostic value of Child-Turcotte-Pugh (CTP) class, Model for End-stage Liver Disease (MELD) score and a recent recalibrated MELD were compared.
RESULTS
Seventy eligible patient were enrolled; 18 (26%) patients died within 6-weeks of index bleed. Demographic, clinical, and laboratory data were compared between survivors and nonsurvivors. Multivariate models showed that admission CTP or the MELD score (separately) were independent predictors of survival. The discriminative values of CTP (area under receiver operating characteristic: 0.75) and MELD (area under receiver operating characteristic: 0.79) were good and not significantly different (P=0.27). However, calibration (correlation between observed and predicted mortality) test was significantly better for CTP than for MELD, with the recently described recalibrated MELD model having the worst agreement. Predicted mortality for CTP-A was <10%, CTP-B 10% to 30%; and CTP-C >33%.
CONCLUSIONS
AVH mortality of 26% in the United States is in the upper range limit compared with recent series but may be due to inclusion of patients with more advanced cirrhosis. CTP score has the best overall performance in the prediction of 6-week mortality and is best at stratifying risk.
Topics: Decision Support Techniques; Disease Progression; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Male; Middle Aged; Predictive Value of Tests; Risk Assessment; Risk Factors; Time Factors; Treatment Failure; United States
PubMed: 27779613
DOI: 10.1097/MCG.0000000000000733 -
The Journal of Neuroscience : the... Jun 2001The peptide somatostatin [somatotropin release-inhibiting factor (SRIF)] is widely distributed in the body and exerts a variety of hormonal and neural actions. Several...
The peptide somatostatin [somatotropin release-inhibiting factor (SRIF)] is widely distributed in the body and exerts a variety of hormonal and neural actions. Several lines of evidence indicate that SRIF is important in nociceptive processing: (1) it is localized in a subset of small-diameter dorsal root ganglion cells; (2) activation of SRIF receptors results in inhibition of both nociceptive behaviors in animals and acute and chronic pain in humans; (3) SRIF inhibits dorsal horn neuronal activity; and (4) SRIF reduces responses of joint mechanoreceptors to noxious rotation of the knee joint. The goal of the present study is to show that cutaneous nociceptors are under the tonic inhibitory control of SRIF. This is accomplished using behavioral and electrophysiological paradigms. In a dose-dependent manner, intraplantar injection of the SRIF receptor antagonist cyclo-somatostatin (c-SOM) results in nociceptive behaviors in normal animals and enhancement of nociceptive behaviors in formalin-injected animals, and these actions can be blocked when c-SOM is coapplied with three different SRIF agonists. Furthermore, intraplantar injection of SRIF antiserum also results in nociceptive behaviors. Electrophysiological recordings using an in vitro glabrous skin-nerve preparation show increased nociceptor activity in response to c-SOM, and this increase is blocked by the same three SRIF agonists. Parallel behavioral and electrophysiological studies using the opioid antagonist naloxone demonstrate that endogenous opioids do not maintain a tonic inhibitory control over peripheral nociceptors, nor does opioid receptor antagonism influence peripheral SRIF effects on nociceptors. These findings demonstrate that SRIF receptors maintain a tonic inhibitory control over peripheral nociceptors, and this may contribute to mechanisms that control the excitability of these terminals.
Topics: Animals; Behavior, Animal; Dose-Response Relationship, Drug; Hot Temperature; Immune Sera; In Vitro Techniques; Injections, Subcutaneous; Male; Naloxone; Narcotic Antagonists; Neural Conduction; Nociceptors; Octreotide; Pain Measurement; Peptides, Cyclic; Peripheral Nervous System; Physical Stimulation; Rats; Rats, Sprague-Dawley; Receptors, Somatostatin; Skin; Somatostatin; Stimulation, Chemical
PubMed: 11356891
DOI: 10.1523/JNEUROSCI.21-11-04042.2001 -
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 -
Endocrinology Jan 1994In the present study we investigated the effects of the somatostatin (SS) analogs octreotide, RC-160, and BIM-23014 on GH release by cultured cells of human GH-secreting...
Relative potencies of the somatostatin analogs octreotide, BIM-23014, and RC-160 on the inhibition of hormone release by cultured human endocrine tumor cells and normal rat anterior pituitary cells.
In the present study we investigated the effects of the somatostatin (SS) analogs octreotide, RC-160, and BIM-23014 on GH release by cultured cells of human GH-secreting pituitary tumors, in normal rat anterior pituitary cells, and on gastrin release by cultured cells from a human gastrinoma. In all GH-secreting adenomas and in rat anterior pituitary cells, RC-160 was the most potent compound. RC-160 significantly inhibited GH-, PRL, and/or alpha-subunit release by human GH-secreting pituitary adenoma cells in concentrations as low as 10(-12)-10(-14) M, whereas at the same concentrations, octreotide and BIM-23014 did not inhibit or were significantly less effective in inhibiting GH release (P < 0.01, RC-160 vs. octreotide and BIM-23014). In rat anterior pituitary cell cultures, the IC50 values for inhibition of GH release were, in rank order of potency, 0.1, 5.3, 47, 48, and 99 pM for RC-160, SS-14, BIM-23014, octreotide, and SS-28, respectively. Maximal inhibitory effects by the three analogs were the same in the human GH adenoma cell cultures and the rat anterior pituitary cell cultures (-60%). On the basis of these data, RC-160 appears to be about 500 times more potent than octreotide and BIM-23014 in inhibiting GH release by rat anterior pituitary cells in vitro. Forskolin (100 microM) as well as pretreatment of the cells with pertussis toxin significantly diminished the inhibitory effects of the three SS analogs and those of SS-14 and SS-28 to the same extent. The latter data suggest that octreotide, RC-160, and BIM-23014 act mainly via a pertussis toxin-sensitive G-protein and an adenylyl cyclase-dependent mechanism. In the human gastrinoma culture, RC-160 inhibited gastrin release significantly more than octreotide at 10(-12)- and 10(-14)-M concentrations (P < 0.01). In conclusion, the SS analogs octreotide, RC-160, and BIM-23014 may have significant different potencies of inhibition of hormone release in vitro, with RC-160 being the most potent SS analog and octreotide and BIM-23014 having similar potencies. Depending on the pharmacokinetic properties of these three octapeptide SS analogs, these observations may have consequences for the medical therapy of patients with SS receptor-positive endocrine tumors.
Topics: Adenoma; Animals; Cells, Cultured; Endocrine Gland Neoplasms; Female; Gastrinoma; Gastrins; Growth Hormone; Humans; Octreotide; Peptides, Cyclic; Pituitary Gland, Anterior; Rats; Rats, Wistar; Reference Values; Somatostatin; Somatostatin-28; Tumor Cells, Cultured
PubMed: 7903931
DOI: 10.1210/endo.134.1.7903931