The abilities of specific kappa-opioid agonists, U-50,488H and U-62,066E, to cause antitussive tolerance were lower than that of morphine.
(65/196)
We examined whether the chronic administration of selective kappa-opioid agonists could produce antitussive tolerance, in a comparison with the mu-opioid morphine. A certain degree of tolerance to the antitussive effects of morphine appeared in rats treated chronically with this drug. However, chronic administration of U-50,488H and U-62,066E, highly selective agonists for the kappa-opioid receptor, does not result in the development of tolerance to their respective antitussive effects. These results suggest that the ability of kappa-opioid agonists to cause tolerance to their respective antitussive effects was lower than that of a mu-opioid agonist. (+info)
Cough mixture abuse as a novel cause of folate deficiency: a prospective, community-based, controlled study.
(66/196)
Cough mixture abuse has been reported to cause severe folate deficiency and neurological defects. We carried out a prospective case-controlled survey to confirm this association and define the incidence and severity of the problem. A total of 57 cough mixture abusers and 47 other substance abusers (controls) were studied. When compared with controls, cough mixture abusers had a high incidence of low folate levels that could only be detected by screening. (+info)
Dextromethorphan in Wisconsin drivers.
(67/196)
Dextromethorphan is a synthetic analogue of codeine used in hundreds of over-the-counter medications for its antitussive effects. There have been numerous reports of dextromethorphan abuse by young adults. Dextromethorphan can produce psychoactive effects similar to that of marijuana, and higher doses will produce dissociative effects, including sensory enhancement and hallucinations. The Wisconsin State Laboratory of Hygiene examined data from blood samples submitted from January 1999 through December 2004 to determine the incidence of dextromethorphan in suspected impaired drivers. A total of 108 samples were found to be positive for dextromethorphan during this time. Dextromethorphan concentrations in these cases ranged from less than 5 to 1800 ng/mL (mean 207 ng/mL), compared to an expected therapeutic concentration range of 0.5-5.9 ng/mL. Overall, the highest dextromethorphan concentrations observed were in males aged 16-20 years. Ninety-six percent of the specimens included in this study were also found to be positive for drugs other than dextromethorphan. A review of police and drug recognition expert reports from several of these cases showed that dextromethorphan-impaired drivers exhibited poor psychomotor performance on standardized field sobriety tests, horizontal gaze nystagmus, vertical gaze nystagmus, and overall signs of central nervous system depression. (+info)
In vitro metabolism of isoline, a pyrrolizidine alkaloid from Ligularia duciformis, by rodent liver microsomal esterase and enhanced hepatotoxicity by esterase inhibitors.
(68/196)
Isoline, a major retronecine-type pyrrolizidine alkaloid (PA) from the Chinese medicinal herb Ligularia duciformis, was suggested to be the most toxic known PA. Its in vitro metabolism was thus examined in rat and mouse liver microsomes, and its toxicity was compared with that of clivorine and monocrotaline after i.p. injection in mice. Isoline was more rapidly metabolized by both microsomes than clivorine and monocrotaline and converted to two polar metabolites M1 and M2, which were spectroscopically determined to be bisline (a deacetylated metabolite of isoline) and bisline lactone, respectively. Both metabolites were formed in the presence or absence of an NADPH-generating system with liver microsomes but not cytosol. Their formation was completely inhibited by the esterase inhibitors, triorthocresyl phosphate (TOCP) and phenylmethylsulfonyl fluoride, but not at all or partially by cytochrome P450 (P450) inhibitors, alpha-naphthoflavone and proadifen (SKF 525A), respectively. These results demonstrated that both metabolites were produced by microsomal esterase(s) but not P450 isozymes. The esterase(s) involved showed not only quite different activities but also responses to different inhibitors in rat and mouse liver microsomes, suggesting that different key isozyme(s) or combinations might be responsible for the deacetylation of isoline. Isoline injected i.p. into mice induced liver-specific toxicity that was much greater than that with either clivorine or monocrotaline, as judged by histopathology as well as serum alanine aminotransferase and aspartate aminotransferase levels. Isoline-induced hepatotoxicity was remarkably enhanced by the esterase inhibitor TOCP but was reduced by the P450 inhibitor SKF 525A, indicating that rodent hepatic esterase(s) played a principal role in the detoxification of isoline via rapid deacetylation in vivo. (+info)
Pharmacology and antitussive efficacy of 4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid (5-trifluoromethyl-pyridin-2-yl)-amide (JNJ17203212), a transient receptor potential vanilloid 1 antagonist in guinea pigs.
(69/196)
Transient receptor potential vanilloid 1 (TRPV1) plays an integral role in modulating the cough reflex, and it is an attractive antitussive drug target. The purpose of this study was to characterize a TRPV1 antagonist, 4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid (5-trifluoromethyl-pyridin-2-yl)-amide (JNJ17203212), against the guinea pig TRPV1 receptor in vitro followed by a proof-of-principle study in an acid-induced model of cough. The affinity of JNJ17203212 for the recombinant guinea pig TRPV1 receptor was estimated by radioligand binding, and it was functionally characterized by antagonism of low-pH and capsaicin-induced activation of the ion channel (fluorometric imaging plate reader and electrophysiology). The nature of antagonism was further tested against the native channel in isolated guinea pig tracheal rings. Following pharmacokinetic characterization of JNJ17203212 in guinea pigs, pharmacodynamic and efficacy studies were undertaken to establish the antitussive efficacy of the TRPV1 antagonist. The pK(i) of JNJ17203212 for recombinant guinea pig TRPV1 was 7.14 +/- 0.06. JNJ17203212 inhibited both pH (pIC(50) of 7.23 +/- 0.05) and capsaicin (pIC(50) of 6.32 +/- 0.06)-induced channel activation. In whole-cell patch clamp, the pIC(50) for inhibition of guinea pig TRPV1 was 7.3 +/- 0.01. JNJ17203212 demonstrated surmountable antagonism in isolated trachea, with a pK(B) value of 6.2 +/- 0.1. Intraperitoneal administration of 20 mg/kg JNJ17203212 achieved a maximal plasma exposure of 8.0 +/- 0.4 microM, and it attenuated capsaicin evoked coughs with similar efficacy to codeine (25 mg/kg). Last, JNJ17203212 dose-dependently produced antitussive efficacy in citric acid-induced experimental cough in guinea pigs. Our data provide preclinical support for developing TRPV1 antagonists for the treatment of cough. (+info)
Synthesis and antitussive evaluation of verticinone-cholic acid salt, a novel and potential cough therapeutic agent.
(70/196)
AIM: To seek a novel and potent antitussive drug based on Shedan-Chuanbei powder, a complex of traditional Chinese medicine preparation for cough therapy. METHODS: Verticinone-cholic acid (Ver-CA) salt, a novel, salifying derivative of verticinone and cholic acid, both of which are the major bioactive components in Shedan-Chuanbei powder, was synthesized. We then evaluated the antitussive activity and the acute toxicity of the salt. RESULTS: The new compound, with good solubility in water, has much more potent antitussive activity in comparison with the same dose of single verticinone and single cholic acid. The administration 3 mg/kg of Ver-CA could result in over 50% reduction of a citric acid-induced cough. Pretreatment with naloxone (0.8 mg/kg, ip) can only partially antagonize its antitussive effect. On the other hand, glybenclamide (3 mg/kg, ip), an ATP-sensitive K+ channel blocker, can also significantly reduce the antitussive effect of Ver-CA. A further acute toxicity study showed that the LD(50) values of Ver-CA were 3 times that of verticinone. CONCLUSION: Based on the studies of pharmacology and acute toxicity, the salt has a synergic and attenuated toxicity compared with single verticinone and cholic acid. Moreover, the present study also suggests that Ver-CA, a potential novel antitussive agent, may exert its antitussive effect via both the peripheral (modulated by ATP-sensitive K+ channels) and central mechanisms (modulated by the opioid receptor). (+info)
Dispensing of antibiotics, antitussives and mucolytics to asthma patients: a pharmacy-based observational survey.
(71/196)
BACKGROUND: Antibiotics, antitussives and mucolytics are commonly used in asthma, despite limited evidence for their effectiveness. The correlates of use for these medication classes in asthma were identified. METHODS: Asthma patients aged 18-50 who were regular customers of pharmacies were included in an observational study. Patients completed a questionnaire, which was complemented by computerised pharmacy records of previously dispensed medications. Users of each drug class were compared to non-users in terms of demographics, asthma characteristics and management. RESULTS: Among 886 patients (mean age: 37; 55% females), 63.2%, 55.8% and 27.2%, respectively, were users of antibiotics, mucolytics and antitussives during the previous 12 months. In multivariate analysis, dispensing of >2 units of oral corticosteroids was the major correlate of receiving antibiotics (OR=5.47; 95% CI=[3.00-9.97]), mucolytics (OR=3.93; 95% CI=[2.38-6.50]) and antitussives (OR=1.86; 95% CI=[1.18-2.94]). Compared to well-controlled patients, the probability of receiving antibiotics was significantly higher for poorly controlled patients (OR=2.01; 95% CI=[1.28-3.15]). CONCLUSIONS: Our results suggest that these drugs are mainly used during asthma exacerbations. A better understanding of the use of co-medication in asthma is required. (+info)
Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use; final rule for over-the-counter antitussive drug products; technical amendment. Final rule, technical amendment.
(72/196)
The Food and Drug Administration (FDA) is amending its regulations (exemption for certain drugs limited by new-drug applications to prescription sale, and warning and caution statements required by regulations for drugs) by removing the entries for carbetapentane citrate. This action is associated with FDA's determination that carbetapentane citrate has not been shown to be effective at the over-the-counter (OTC) doses stated in the exempting regulation. FDA made this determination in 1987 as part of its ongoing review of OTC drug products. (+info)