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Enkephalinase inhibitor

Danielle Aguiar Diniz, Júlia Alvarenga Petrocchi, Larissa Caldeira Navarro, Tâmara Cristina Souza, Marina Gomes Miranda E Castor, Igor Dimitri Gama Duarte, Thiago Roberto Lima Romero
PURPOSE: Studies conducted since 1969 have shown that the release of serotonin (5-HT) in the dorsal horn of the spinal cord contributes to opioid analgesia. In the present study, the participation of the opioidergic system in antinociceptive effect serotonin at the peripheral level was examined. METHODS: The paw pressure test was used with mice (Swiss, males from 35 g) which had increased pain sensitivity by intraplantar injection of PGE2 (2 μg). Serotonin (250 ng), administered locally to the right paw of animals, produces antinociception in this model...
November 15, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Jennifer R Deuis, Zoltan Dekan, Joshua S Wingerd, Jennifer J Smith, Nehan R Munasinghe, Rebecca F Bhola, Wendy L Imlach, Volker Herzig, David A Armstrong, K Johan Rosengren, Frank Bosmans, Stephen G Waxman, Sulayman D Dib-Hajj, Pierre Escoubas, Michael S Minett, Macdonald J Christie, Glenn F King, Paul F Alewood, Richard J Lewis, John N Wood, Irina Vetter
Human genetic studies have implicated the voltage-gated sodium channel NaV1.7 as a therapeutic target for the treatment of pain. A novel peptide, μ-theraphotoxin-Pn3a, isolated from venom of the tarantula Pamphobeteus nigricolor, potently inhibits NaV1.7 (IC50 0.9 nM) with at least 40-1000-fold selectivity over all other NaV subtypes. Despite on-target activity in small-diameter dorsal root ganglia, spinal slices, and in a mouse model of pain induced by NaV1.7 activation, Pn3a alone displayed no analgesic activity in formalin-, carrageenan- or FCA-induced pain in rodents when administered systemically...
January 20, 2017: Scientific Reports
Elżbieta Kamysz, Maciej Sałaga, Małgorzata Sobocińska, Artur Giełdoń, Jakub Fichna
AIM: The pharmacotherapy of inflammatory bowel disease is difficult and currently available treatments bring mostly poor and unsatisfactory results. RESULTS: The purpose of this work was the synthesis of opiorphin, sialorphin, spinorphin and a series of their analogs and the in vitro characterization of their effect on degradation of enkephalin by neutral endopeptidase and aminopeptidase N. Consequently, we investigated in vivo the anti-inflammatory effect of the most active inhibitors selected in the in vitro studies (Pal-KKQRFSR & Pal-KKQHNPR)...
December 2016: Future Medicinal Chemistry
Korinna Ulbricht, Peter Layer, Viola Andresen
Chronic, non-infectious diarrhea can be caused by a variety of gastrointestinal diseases. In anamnesis, it is important to take accompanying warning symptoms and specific triggers into account. The fecal inflammatory marker calprotectin may help differentiating between organic and functional gastrointestinal disorders, but it is not specific. Among other options, gelling fibres, Loperamide and Cholestyramine as well as probiotics are available for the symptomatic treatment of chronic diarrhea. For long-term treatment of chronic diarrhea with the enkephalinase inhibitor racecadotril, which is approved for acute diarrhea, only limited data are available...
September 2016: Deutsche Medizinische Wochenschrift
Elisabeth Bonnard, Hervé Poras, Marie-Claude Fournié-Zaluski, Bernard P Roques
Neuropathic pain remains difficult to treat due to the involvement of various pathophysiological mechanisms in its pathogeny. Among the different opioidergic systems the enkephalinergic one is primarily recruited via activation of delta opioid receptor (DOP) in chronic pain and of mu opioid receptor (MOP) in acute pain. To investigate the role of their endogenous ligands Met and Leu-enkephalin in neuropathic pain control, a dual inhibitor of their degrading enzymes, PL265, which acts restrictively at the level of peripheral nociceptors, was administered per os to assess its efficacy in pain prevention and alleviation using a partial sciatic nerve ligation model (PSNL) in mice...
October 5, 2016: European Journal of Pharmacology
Vishnuvardhan Chiguru, Allakonda Lingesh, Srinivas R, Satheeshkumar N
Racecadotril, an enkephalinase inhibitor, was subjected to hydrolysis (acidic and alkaline), oxidation, photolysis and thermal stress, as per ICH specified conditions. The drug showed extensive degradation under acidic, basic hydrolysis and oxidative stress conditions whereas, it was stable under other stress conditions. A total of seven degradation products (DPs) were observed. The chromatographic separation was optimized on Acquity HSS Cyano (100×2.1mm, 1.8μ) column using 0.1% formic acid and acetonitrile as mobile phase in gradient mode...
September 5, 2016: Journal of Pharmaceutical and Biomedical Analysis
Solomon Tesfaye
Solomon Tesfaye speaks to Nick Ward, Commissioning Editor: Solomon Tesfaye, MB ChB, MD, FRCP, speaks about PL37; the first orally administered dual inhibitor of enkephalinases and its potential role in the treatment of painful diabetic neuropathy. Solomon Tesfaye is a Consultant Physician/Endocrinologist at Sheffield Teaching Hospitals and Honorary Professor of Diabetic Medicine at the University of Sheffield. His research projects include the epidemiology, risk factors, pathogenesis, CNS involvement and treatment of diabetic neuropathy and neuropathic pain...
April 2016: Pain Management
Edward C Emery, Ana Paula Luiz, John N Wood
INTRODUCTION: Chronic pain is a massive clinical problem. We discuss the potential of subtype selective sodium channel blockers that may provide analgesia with limited side effects. AREAS COVERED: Sodium channel subtypes have been linked to human pain syndromes through genetic studies. Gain of function mutations in Nav1.7, 1.8 and 1.9 can cause pain, whilst loss of function Nav1.7 mutations lead to loss of pain in otherwise normal people. Intriguingly, both human and mouse Nav1...
August 2016: Expert Opinion on Therapeutic Targets
Joseph Vamecq, Karine Mention-Mulliez, Francis Leclerc, Dries Dobbelaere
Recently, propranolol was suggested to prevent hyperlactatemia in a child with hypovolemic shock through β-adrenergic blockade. Though it is a known inhibitor of glycolysis, propranolol, outside this observation, has never been reported to fully protect against lactate overproduction. On the other hand, literature evidence exists for a cross-talk between β-adrenergic receptors (protein targets of propranolol) and δ-opioid receptor. In this literature context, it is hypothesized here that anti-diarrheic racecadotril (a pro-drug of thiorphan, an inhibitor of enkephalinases), which, in the cited observation, was co-administered with propranolol, might have facilitated the β-blocker-driven inhibition of glycolysis and resulting lactate production...
September 25, 2015: Pharmaceuticals
Hervé Poras, Elisabeth Bonnard, Marie-Claude Fournié-Zaluski, Bernard P Roques
The endogenous opioid system, essentially constituted by two opioid receptors which are stimulated by the natural internal effectors enkephalins (Met-enkephalin and Leu-enkephalin), is present at the different sites (peripheral, spinal, central) of the control of pain. We have demonstrated that the protection of the enkephalin inactivation by the two metallopeptidases (neprilysin and neutral aminopeptidase) increases their local concentration selectively induced by pain stimuli triggering analgesic responses...
September 18, 2015: European Journal of Medicinal Chemistry
Alexandra Bocsik, Zsuzsanna Darula, Géza Tóth, Mária A Deli, Mária Wollemann
Opioid peptides are potent analgesics with therapeutic potential in the treatment of acute and chronic pain. Their efficacy is limited by peptidases (enkephalinases). Opiorphin pentapeptide (QRFSR) is the first characterized human endogenous inhibitor of enkephalinases. The peptide is able to increase the binding and affinity of endogenous opiates to mu opioid receptors; thus, the mechanism of opiorphin may provide a new therapeutic approach in pain management. The analgesic effect of opiorphin was proven in several earlier published in vitro and in vivo studies...
August 2015: Archives of Medical Research
John J V McMurray
This review describes the role of neprilysin (also known as neutral endopeptidase or enkephalinase) in the degradation of natriuretic and other vasoactive peptides, including bradykinin and adrenomedullin. The initial development of neprilysin inhibitors, then angiotensin converting enzyme-neprilysin inhibitors and, most recently, the angiotensin receptor neprilysin inhibitor (ARNI) LCZ696 (sacubitril valsartan) as an extension of the nurohumoral basis for the treatment of heart failure is also summarised. Finally, the implications of the compelling benefits of LCZ696 compared with enalapril in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) is discussed...
March 2015: European Journal of Heart Failure
Elisabeth Bonnard, Hervé Poras, Xavier Nadal, Rafael Maldonado, Marie-Claude Fournié-Zaluski, Bernard P Roques
The peripheral endogenous opioid system is critically involved in neuropathic and inflammatory pain generation as suggested by the modulation of opioid receptors expression and enkephalins (ENKs) release observed in these painful conditions. Accordingly, an innovative approach in the treatment of these nocifensive events is to increase and maintain high local concentrations of extracellular pain-evoked ENKs, by preventing their physiological enzymatic inactivation by two Zn metallopeptidases, the neutral endopeptidase (NEP, neprilysin, EC 3...
March 2015: Pharmacology Research & Perspectives
Hervé Poras, Elisabeth Bonnard, Emilie Dangé, Marie-Claude Fournié-Zaluski, Bernard P Roques
Protecting enkephalins, endogenous opioid peptides released in response to nociceptive stimuli, is an innovative approach for acute and neuropathic pain alleviation. This is achieved by inhibition of their enzymatic degradation by two membrane-bound Zn-metallopeptidases, neprilysin (NEP, EC and aminopeptidase N (APN, EC Selective and efficient inhibitors of both enzymes, designated enkephalinases, have been designed that markedly increase extracellular concentrations and half-lives of enkephalins, inducing potent antinociceptive effects...
July 10, 2014: Journal of Medicinal Chemistry
Josie Resende Torres da Silva, Marcelo Lourenço da Silva, Wiliam Alves Prado
We examined the effects of intrathecal injection of desipramine and fluoxetine (selective inhibitors of norepinephrine and 5-HT uptake, resp.), thiorphan and neostigmine (inhibitors of enkephalinase and acetylcholinesterase, resp.), gabapentin (a GABA releaser), and vigabatrin (an inhibitor of GABA-transaminase) on the antinociception induced by 2 Hz, 100 Hz, or 2/100 Hz electroacupuncture (EA) applied bilaterally to the Zusanli (ST36) and Sanyinjiao (SP6) acupoints using the rat tail-flick test. We show that 2 Hz EA antinociception lasts longer after the administration of drugs that increase the spinal availability of norepinephrine, acetylcholine, or GABA; 100 Hz EA antinociception lasts longer after drug that increases the spinal availability of norepinephrine; 2/100 Hz EA antinociception lasts longer after drugs that increase the spinal availability of endogenous opioids or GABA...
2013: Evidence-based Complementary and Alternative Medicine: ECAM
Arief Thong, Dieter Müller, Caroline Feuerstacke, Andrea Mietens, Angelika Stammler, Ralf Middendorff
Neutral endopeptidase (NEP, metallo-endopeptidase EC; enkephalinase, neprilysin, CD10, CALLA) represents a major regulator of bioactivity of natriuretic peptides. C-type natriuretic peptide (CNP) is present in high levels in epididymis and seminal plasma. However, detailed expression pattern and CNP-related function of NEP in the epididymis are unknown. Comparison of NEP protein levels in various organs revealed an extremely high expression in human and mouse epididymis. NEP was localized exclusively to apical (luminal) parts of epithelial cells...
January 25, 2014: Molecular and Cellular Endocrinology
(no author information available yet)
Worldwide, there are about two billion cases of diarrhoeal disease every year and it is the second leading cause of death in children under 5 years of age, killing 1.5 million children annually.(1) The most severe threat posed by diarrhoea is dehydration. In the UK, the incidence of diarrhoea is about one episode per person per year,(2) and approximately 10% of children younger than 5 years old present to healthcare services with gastroenteritis each year.(3) ▾Racecadotril (Hidrasec) is the first in a new class of antidiarrhoeal drug ('enkephalinase inhibitor') that has an antisecretory mechanism and is licensed in adults, children and infants (over 3 months of age) for symptomatic treatment of acute diarrhoea or as complementary treatment when causal treatment is possible...
May 2013: Drug and Therapeutics Bulletin
Martin Houde, Marc-David Jamain, Julie Labonté, Louisane Desbiens, Gunnar Pejler, Michael Gurish, Shinji Takai, Pedro D'Orléans-Juste
The serine protease chymase has been reported to generate intracardiac angiotensin-II (Ang-II) from Ang-I as well as an intermediate precursor of endothelin-1 (ET-1), ET-1 (1-31) from Big-ET-1. Although humans possess only one chymase, several murine isoforms are documented, each with its own specific catalytic activity. Among these, mouse mast cell protease 4 (mMCP-4) is the isoform most similar to the human chymase for its activity. The aim of this study was to characterize the capacity of mMCP-4 to convert Big-ET-1 into its bioactive metabolite, ET-1, in vitro and in vivo in the mouse model...
July 2013: Journal of Pharmacology and Experimental Therapeutics
Stacy Menees, Richard Saad, William D Chey
Diarrhoea and constipation are common clinical complaints that negatively affect quality of life, reduce work productivity and lead to considerable health-care expenditure. A variety of therapies have been used to treat these conditions. Unlike drugs that require systemic absorption to exert their effects, luminally acting agents improve diarrhoea and constipation by altering intestinal and/or colonic motility, as well as mucosal absorption and secretion, through a variety of mechanisms. Examples of luminally acting agents for diarrhoea include peripherally acting opiate analogues, enkephalinase inhibitors, bile-acid binding agents, nonabsorbed antibiotics, probiotics, bismuth-containing compounds, berberine and agents with possible effects on intestinal secretion or permeability...
November 2012: Nature Reviews. Gastroenterology & Hepatology
Marie Hagbom, Sumit Sharma, Ove Lundgren, Lennart Svensson
While the clinical importance of human rotavirus (RV) disease is well recognized and potent vaccines have been developed, our understanding of how human RV causes diarrhoea, vomiting and death remains unresolved. The fact that oral rehydration corrects electrolyte and water loss, indicates that enterocytes in the small intestine have a functional sodium-glucose co-transporter. Moreover, RV infection delays gastric emptying and loperamide appears to attenuate RV diarrhoea, thereby suggesting activation of the enteric nervous system...
August 2012: Current Opinion in Virology
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