UMLS:C0010200 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0010200 (cough)
23,843 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We administered methylnaltrexone, a peripheral opioid receptor antagonist, to guinea pigs previously injected with morphine sulfate to determine whether the compound could block opioid-induced cough suppression without blocking antinociception. The effects of methylnaltrexone (2.0, 1.6, 0.8 mg/kg) and of naltrexone (0.32, 0.16, 0.02 and 0.01 mg/kg) were compared in animals who had been injected with morphine sulfate (8.1 mg/kg). At 2.0 mg/kg methylnaltrexone, number of coughs returned to baseline value and nociception remained unaffected. At the two higher doses of naltrexone (0.32 and 0.16 mg/kg), morphine-induced antitussive effect was blocked, but antinociception was reversed. Our results suggested that methylnaltrexone possesses opioid antagonist activity in receptors peripheral to the blood-brain barrier. Its peripheral activity makes methylnaltrexone a clinically interesting agent for maintaining the cough reflex in those who must take opioids for analgosia.
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PMID:Effects of methylnaltrexone on morphine-induced cough suppression in guinea pigs. 884 13

This paper provides an overview of our current understanding of the serotonergic and opioidergic mechanisms of cough and antitussives. Systemic administration of 8-OH-DPAT, at doses of 0.1 and 0.3 mg/kg, ip, markedly reduced the number of coughs in rats in a dose-dependent manner. The antitussive effects of 8-OH-DPAT, dihydrocodeine and dextromethorphan were significantly reduced by pretreatment with methysergide, but not with ketanserin. Therefore it is possible to speculate that 5-HT1 receptors, in particular the 5-HT1A receptors, may be more important than others with respect to the effect of antitussive drugs. DAMGO, a selective mu-opioid receptor agonist, and U-50,488H, a highly selective kappa-opioid receptor agonist, have potent antitussive effects when administered either icv or ip. However, we did not observe a cough-depressant effect of DPDPE, a selective delta-opioid receptor agonist. These results indicate that the antitussive effects of opioids are mediated predominantly by mu- and kappa-opioid receptors. On the other hand, naloxonazine, a selective mu 1-opioid receptor antagonist, had no effect on the antitussive effects associated with icv DAMGO. These results indicate that mu 2- rather than mu 1-opioid receptors are involved in mu-opioid receptor-induced antitussive affects. Antitussive effects of dextromethorphan and noscapine were significantly and dose-dependently reduced by pretreatment with rimcazole, a specific antagonist of sigma sites. However, rimcazole did not have a significant effect on the antitussive effect of morphine. These results suggest that sigma sites may be involved in the antitussive mechanism of non-narcotic antitussive drugs.
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PMID:Role of opioidergic and serotonergic mechanisms in cough and antitussives. 923 74

This paper provides an overview of our current understanding of the central mechanisms of cough and antitussives. Systemic administration of 8-OH-DPAT at doses of 0.1 and 0.3 mg/kg, i.p. markedly reduced the number of coughs in rats in a dose-dependent manner. The antitussive effect of 8-OH-DPAT, dihydrocodeine and dextromethorphan significantly was reduced by pretreatment with methysergide, but not ketanserin. Therefore, it is possible to speculate that the 5-HT1 receptors, in particular the 5-HT1A receptors, may be more important than others with respect to the effect of antitussive drugs. DAMGO, a selective mu-opioid receptor agonist, and U-50,488H, a highly selective kappa-opioid receptor agonist, have potent antitussive effects when administered either i.c. or i.p. However, we did not observe a cough-depressant effect of DPDPE, a selective delta-opioid receptor agonist. These results indicate that the antitussive effects of opioids are mediated predominantly by mu- and kappa-opioid receptors. On the other hand, naloxonazine, a selective mu 1-opioid receptor antagonist, had no effect on the antitussive effects associated with i.c.v. DAMGO. These results indicate that mu 2-rather than mu 1-opioid receptors are involved in mu-opioid receptor-induced antitussive effects. Antitussive effects of dextromethorphan and noscapine were significantly and dose-dependently reduced by pretreatment with rimcazole, a specific antagonist of sigma sites. However, rimcazole did not have a significant effect on the antitussive effect of morphine. These results suggest that sigma sites may be involved in the antitussive mechanism of non-narcotic antitussive drugs.
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PMID:[Mechanisms of central antitussives]. 972 82

In this study, the activity of the delta-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The delta-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of SB 227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not that of SB 227122. These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor.
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PMID:The antitussive activity of delta-opioid receptor stimulation in guinea pigs. 1064 Mar 21

Angiotensin Converting Enzyme Inhibitors (ACEI) like captopril and enalapril, can induce persistant cough in man. Noscapine, an antitussive alkaloid, can be used to suppress ACEI-induced cough. Some workers have suggested a role for bradykinin in precipitation of ACE-induced cough. Work carried out in our laboratory has shown noscapine to be a non-competitive inhibitor of bradykinin in guinea pig ileum. It is therefore possible that noscapine suppresses cough by blocking the effect of bradykinin receptor activation in the airways. Guinea pigs were placed in a cough-chamber connected to an air pump and a pressure transducer. Capsaicin was sprayed into the chamber and cough was recorded as a distinctive change in air pressure inside the cough-chamber. Animals treated with 1 mg/kg captopril and enalapril for 7 days, showed increased cough response. Ten microgram/kg FR190997, a non-peptide agonist of the bradykinin B2 receptor, also increased the cough response. Noscapine at 0.5, 1 and 2 mg/kg was able to reverse the effects of ACEI and FR190997. Naloxone, a specific opioid receptor inhibitor, did not block the antitussive effects of noscapine in enalapril or FR190997 treated guinea pigs. This antitussive effect of noscapine is not mediated via the mu, kappa or delta opioid receptors. It is therefore possible that noscapine exerts its antitussive action by interfering with the bradykinin cough mediation.
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PMID:Interaction of noscapine with the bradykinin mediation of the cough response. 1290 13

Cough is an important defensive reflex of the airway and a common symptom of respiratory disease. After an upper respiratory tract virus infection, cough is transient, but is more persistent with conditions such as asthma, rhinosinusitis, gastroesophageal reflux, chronic obstructive pulmonary disease (COPD) and lung cancer. Treatment directed at these conditions may improve cough, but there remains a need to control cough directly. The most effective antitussives are opioids, such as morphine, codeine or pholcodeine, but they produce side effects including drowsiness, nausea, constipation and physical dependence. Opioids such as k- and d-opioid receptor agonists, non-opioids such as nociceptin, neurokinin and bradykinin receptor antagonists, vanilloid receptor VR(1) antagonists, blockers of sodium-dependent channels, and maxi-K calcium-dependent channel activators of afferent nerves may all represent novel antitussives and this needs to be confirmed in clinical trials.
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PMID:Current and future prospects for drugs to suppress cough. 1291 74

1. Gastro-oesophageal acid reflux may cause airway responses such as cough, bronchoconstriction and inflammation in asthmatic patients. Our previous results suggest that microvascular leakage induced, in the guinea-pig airways, by intra-oesophageal hydrochloric acid (HCl) infusion was mainly dependent on the release of tachykinins. Nociceptin, an endogenous ligand of the opioid receptor NOP, has been shown to inhibit bronchoconstriction and cough in guinea-pig or cat by inhibiting tachykinin release. 2. The purpose of this study was to investigate the effects of nociceptin on the intra-oesophageal HCl-induced airway microvascular leakage evaluated by Evans blue dye extravasation measurement in anaesthetised guinea-pigs pretreated with propranolol, atropine and phosphoramidon. 3. Infusion of intra-oesophageal HCl led to a significant increase in plasma extravasation in the main bronchi and trachea. This increase was abolished when animals underwent a bilateral vagotomy. 4. Airway microvascular leakage was inhibited by nociceptin (3-30 microg x kg(-1) i.v.) in a dose-dependent manner (maximal inhibition at the dose of 30 microg x kg(-1): 19.76+/-1.13 vs 90.92+/-14.00 ng x mg(-1) tissue for nociceptin and HCl infusion, respectively, in the main bronchi, P<0.01). The NOP receptor agonist [Arg(14),Lys(15)]N/OFQ mimicked the inhibitory effect of nociceptin, but at a 10-fold lower dose (3 microg x kg(-1) i.v). The NOP receptor antagonist J-113397 had no effect on plasma protein extravasation by itself, but was able to block the inhibitory effect of nociceptin. 5. Morphine (1 mg x kg(-1)) had a similar inhibitory effect as that of nociceptin. Naloxone pretreatment abolished the effect of morphine, but was enable to block the inhibitory effect of nociceptin. 6. Under similar conditions, nociceptin, in the previous range of concentration, was unable to counteract the airway microvascular leakage induced by substance P (SP). 7. These results suggest that airway plasma extravasation induced by intra-oesophageal HCl instillation might be inhibited by specific stimulation of the NOP receptor with nociceptin. Nociceptin is likely to act at a pre-junctional level, by inhibiting tachykinin release, since it was unable to prevent SP-induced airway plasma extravasation.
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PMID:Nociceptin inhibits airway microvascular leakage induced by HCl intra-oesophageal instillation. 1499 1

As part of a synthesis of evidence regarding the abuse and addiction liability of dextromethorphan (DM), an over-the-counter cough medicine available in over 140 preparations, an uncommonly published case of dextromethorphan dependence (addiction) is described, with specific, rarely published complications. The individual was interviewed and several medical databases were also reviewed (Medline, 1966-present; PubMed) for all content relating to the Keywords: dextromethorphan, abuse, dependence, cough medicine, addiction, withdrawal, psychosis. The patient evidenced history suggesting substance dependence, substance-induced psychosis and substance withdrawal in relation to DM. A literature review revealed that DM has specific serotonergic and sigma-1 opioidergic properties. Dextrorphan (DOR), the active metabolite of DM, has similar properties; however, DOR is a weaker sigma opioid receptor agonist, and a stronger NMDA receptor antagonist. DM and DOR display specific biological features of addiction, and are capable of inducing specific psychiatric sequelae. A specific, reproducible toxidrome with significant psychiatric effects occurred, when DM was abused at greater than indicated doses, with more profound and potentially life-threatening effects at even higher doses. DM withdrawal appears evident. DM's active metabolite, DOR, has pharmacodynamic properties and intoxication effects similar to dissociatives, and may be more responsible for the dissociative effect that this DM abuser sought. However, it is this same metabolite that may be fraught with the potentially life-threatening psychoses and dissociative-induced accidents, as well as addiction. While DM has been hypothesized as the most commonly abused dissociative, health-care providers seem largely unaware of its toxidrome and addiction liability.
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PMID:Dextromethorphan psychosis, dependence and physical withdrawal. 1631 53

Methylnaltrexone is a peripheral opioid receptor antagonist undergoing phase III clinical trials for the treatment of opioid-induced constipation in patients with advanced medical illness who are being treated with narcotics for pain. The compound does not cross the blood-brain barrier in humans and reverses the opioid effects without interfering with pain relief. Some opioid-induced adverse events that the drug may potentially target include constipation, nausea/vomiting, cough suppression and urinary retention. Methylnaltrexone was discovered by researchers at the University of Chicago, Chicago, Illinois, USA and is in joint development with Progenics Pharmaceuticals and Wyeth Pharmaceuticals. Progenics is conducting clinical trials with three methylnaltrexone dosage forms: subcutaneous, IV and oral. Progenics plans to complete the clinical development of methylnaltrexone alone, after which potential pharmaceutical or biotechnology partners will be looked at to provide financial support and marketing expertise, particularly outside the US market. In December 2005, Progenics and Wyeth Pharmaceutical (Wyeth) entered into an exclusive, worldwide agreement for the joint development and commercialisation of methylnaltrexone for the treatment of opioid-induced side effects, including constipation and postoperative bowel dysfunction. Under the terms of the licensing agreement, Wyeth has worldwide rights to the compound and Progenics retains the option to co-promote methylnaltrexone in the US. The companies will collaborate on the worldwide development of methylnaltrexone. Under the terms of the agreement, Wyeth has made an up-front payment to Progenics and will also make additional milestone payments. Wyeth will also pay Progenics royalties on worldwide sales, and co-promotion fees within the US. Wyeth is also responsible for all future development and commercialisation costs. Wyeth will develop oral methylnaltrexone worldwide. Progenics will lead the US development of subcutaneous and intravenous methylnaltrexone, while Wyeth will lead development of these parenteral products outside the US.UR Labs licensed methylnaltrexone from the University of Chicago. In October 2001, Progenics in-licensed the methynaltrexone patent portfolio in exchange for rights to future methynaltrexone royalties. In December 2005, Progenics acquired a substantial portion of the royalty and milestone payments in exchange for 686,000 shares of Progenic's common stock and 2.6 million US dollars in cash. In April 2005, Progenics Pharmaceuticals made a public offering of 2 million shares of its common stock, pursuant to an effective shelf registration statement. Progenics intends to use the net proceeds from this offering to fund clinical trials of methylnaltrexone, to fund clinical trials of other product candidates and for other research and development programs. All primary and secondary endpoints were statistically significant in Progenic's second phase III trial of subcutaneous methylnaltrexone (0.15 mg/kg or 0.30 mg/kg). The trial was initiated in January 2004 in 133 patients with opioid-induced constipation at 27 nursing homes and hospices in the US. Enrollment was completed in September 2005 and results announced in February 2006. In March 2005, Progenics announced results from the pivotal phase III trial of subcutaneous methylnaltrexone for the reversal of opioid-induced constipation. This trial involved a total of 150 patients from 16 hospices in the US who had advanced medical illnesses and who were receiving occasional opioids. Progenics has completed a phase IIb dose-ranging study with subcutaneous methylnaltrexone for treatment of narcotic-induced constipation in patients with cancer or AIDS. Positive top-line results from a phase II clinical trial of methylnaltrexone in the management of postoperative bowel dysfunction were reported in January 2005. The endpoints of the study included restoration of bowel function and discharge eligibility. Reversal of urinary retention was a secondary endpoint in this study. Progenics plans to complete a more in-depth analysis of this phase II data and present the finding to the US FDA. Methylnaltrexone (IV) is scheduled to enter phase III clinical studies in this indication in 2006. An NDA is expected to be submitted for the intravenous formulation of methylnaltrexone in late 2007/early 2008. Progenics also plans to initiate a phase II study of methylnaltrexone in women who have undergone hysterectomies. This patient population is also at high risk for ileus. In May 2004, Progenics Pharmaceuticals completed phase I clinical trials using two different oral formulations of methylnaltrexone. Analysis of preliminary data from 61 healthy volunteers who received methylnaltrexone at three dose levels indicated that the drug was well tolerated and exhibited predictable pharmacokinetics. Based on these phase I studies, Progenics selected an oral formulation and dose levels of methylnaltrexone that will be tested in phase II clinical trials for relief of opioid-induced constipation in patients with chronic-pain. The technology licensed from UR Labs, Inc., is the subject of issued US and European patents and several related US and foreign patent applications relating to certain compositions, formulations and uses of methylnaltrexone filed by the University of Chicago. Progenics have continued to expand the patent coverage relating to methylnaltrexone with the filing of new patent applications.
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PMID:Methylnaltrexone: MNTX. 1707 20

The advance of functional genomics revealed the superfamily of G-protein coupled receptors (GPCRs). Hundreds of GPCRs have been cloned but many of them are orphan GPCRs with unidentified ligands. The first identified orphan GPCR is the opioid receptor like orphan receptor, ORL1. It was cloned in 1994 during the identification of opioid receptor subtypes and was de-orphanized in 1995 by the discovery of its endogenous ligand, nociceptin or orphanin FQ (N/OFQ). This receptor was renamed as N/OFQ peptide (NOP) receptor. Several selective ligands acting at NOP receptors or other anti-N/OFQ agents have been reported. These include N/OFQ-derived peptides acting as agonists (cyclo[Cys(10),Cys(14)]N/OFQ, [Arg(14), Lys(15)]N/OFQ, [pX]Phe(4)N/OFQ(1-13)-NH(2), UFP-102, [(pF)Phe(4),Aib(7), Aib(11),Arg(14),Lys(15)]N/OFQ-NH(2)) or antagonists (Phe(1)psi(CH(2)-NH)Gly(2)]N/OFQ(1-13)-NH(2), [Nphe(1)]N/OFQ(1-13)-NH(2), UFP-101, [Nphe(1), (pF)Phe(4),Aib(7),Aib(11),Arg(14),Lys(15)]N/OFQ-NH(2)), hexapeptides, other peptide derivatives (peptide III-BTD, ZP-120, OS-461, OS-462, OS-500), non-peptide agonists (NNC 63-0532, Ro 64-6198, (+)-5a compound, W-212393, 3-(4-piperidinyl)indoles, 3-(4-piperidinyl) pyrrolo[2,3-b]pyridines) and antagonists (TRK-820, J-113397, JTC-801, octahydrobenzimidazol-2-ones, 2-(1,2,4-oxadiazol-5-yl)-1 H-indole, N-benzyl-D-prolines, SB-612111), biostable RNA Spiegelmers specific against N/OFQ, and a functional antagonist, nocistatin. Buprenorphine and naloxone benzoylhydrazone are two opioid receptor ligands showing high affinity for NOP receptors. NOP receptor agonists might be beneficial in the treatment of pain, anxiety, stress-induced anorexia, cough, neurogenic bladder, edema, drug dependence, and, less promising, in cerebral ischemia and epilepsy, while antagonists might be of help in the management of pain, depression, dementia and Parkinsonism. N/OFQ is also involved in cardiovascular, gastrointestinal and immune regulation. Altered plasma levels of N/OFQ have been reported in patients with various pain states, depression and liver diseases. This review summarizes the pharmacological characteristics of, and studies with, the available NOP receptor ligands and their possible clinical implications.
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PMID:Nociceptin/orphanin FQ peptide receptors: pharmacology and clinical implications. 1726 36

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