In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6. (9/196)

AIMS: To examine the potency of ticlopidine (TCL) as an inhibitor of cytochrome P450s (CYP450s) in vitro using human liver microsomes (HLMs) and recombinant human CYP450s. METHODS: Isoform-specific substrate probes of CYP1A2, 2C19, 2C9, 2D6, 2E1 and 3A4 were incubated in HLMs or recombinant CYPs with or without TCL. Preliminary data were generated to simulate an appropriate range of substrate and inhibitor concentrations to construct Dixon plots. In order to estimate accurately inhibition constants (Ki values) of TCL and determine the type of inhibition, data from experiments with three different HLMs for each isoform were fitted to relevant nonlinear regression enzyme inhibition models by WinNonlin. RESULTS: TCL was a potent, competitive inhibitor of CYP2C19 (Ki = 1.2 +/- 0.5 microM) and of CYP2D6 (Ki = 3.4 +/- 0.3 microM). These Ki values fell within the therapeutic steady-state plasma concentrations of TCL (1-3 microM). TCL was also a moderate inhibitor of CYP1A2 (Ki = 49 +/- 19 microM) and a weak inhibitor of CYP2C9 (Ki > 75 microM), but its effect on the activities of CYP2E1 (Ki = 584 +/- 48 microM) and CYP3A (> 1000 microM) was marginal. CONCLUSIONS: TCL appears to be a broad-spectrum inhibitor of the CYP isoforms, but clinically significant adverse drug interactions are most likely with drugs that are substrates of CYP2C19 or CYP2D6.  (+info)

Subtypes of codeine cough syrup abusers. (10/196)

This paper highlights the abuse potential of the codeine containing cough syrups, which may take two forms. One, experimental abuse in school or college students which later persists in a dependent pattern. Two, pre-existing opioid abusers, as a substitute which starts after the school or college years. The short term treatment outcome is better in the former group in that they are able to maintain abstinence for a relatively longer period.  (+info)

Dextromethorphan and its metabolite dextrorphan block alpha3beta4 neuronal nicotinic receptors. (11/196)

Dextromethorphan (DM), a structural analog of morphine and codeine, has been widely used as a cough suppressant for more than 40 years. DM is not itself a potent analgesic, but it has been reported to enhance analgesia produced by morphine and nonsteroidal anti-inflammatory drugs. Although DM is considered to be nonaddictive, it has been reported to reduce morphine tolerance in rats and to be useful in helping addicted subjects to withdraw from heroin. Here we studied the effects of DM on neuronal nicotinic receptors stably expressed in human embryonic kidney cells. Studies were carried out to examine the effects of DM on nicotine-stimulated whole cell currents and nicotine-stimulated (86)Rb(+) efflux. We found that both DM and its metabolite dextrorphan block nicotinic receptor function in a noncompetitive but reversible manner, suggesting that both drugs block the receptor channel. Consistent with blockade of the receptor channel, neither drug competed for the nicotinic agonist binding sites labeled by [(3)H]epibatidine. Although DM is approximately 9-fold less potent than the widely used noncompetitive nicotinic antagonist mecamylamine in blocking nicotinic receptor function, the block by DM appears to reverse more slowly than that by mecamylamine. These data indicate that DM is a useful antagonist for studying nicotinic receptor function and suggest that it might prove to be a clinically useful neuronal nicotinic receptor antagonist, possibly helpful as an aid for helping people addicted to nicotine to refrain from smoking, as well as in other conditions where blockade of neuronal nicotinic receptors would be helpful.  (+info)

Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease. (12/196)

BACKGROUND: Chronic cough is associated with an increased sensitivity to inhaled capsaicin in a number of conditions but there are no data for patients with more severe asthma or chronic obstructive pulmonary disease (COPD). Moreover, the relationships between the capsaicin response (expressed as the concentration of capsaicin provoking five coughs, C5), self-reported cough, and routine medication is not known. METHODS: The cough response to capsaicin in 53 subjects with asthma, 56 subjects with COPD, and 96 healthy individuals was recorded and compared with a number of subjective measures of self-reported cough, measures of airway obstruction, and prescribed medication. In asthmatic subjects the relationships between the cough response to capsaicin and mean daily peak flow variability and non-specific bronchial hyperresponsiveness to histamine were also examined. RESULTS: Subjects with asthma (median C5 = 62 mM) and COPD (median C5 = 31 mM) were similarly sensitive to capsaicin and both were more reactive than normal subjects (median C5 >500 mM). Capsaicin sensitivity was related to symptomatic cough as measured by the diary card score in both asthma and COPD (r = -0.38 and r = -0.44, respectively), but only in asthma and not COPD when measured using a visual analogue score (r = -0.32 and r = -0.05, respectively). Capsaicin sensitivity was independent of the degree of airway obstruction and in asthmatics was not related to PEF variability or PC(20) for histamine. The response to capsaicin was not related to treatment with inhaled corticosteroids but was increased in those using anticholinergic agents in both conditions. CONCLUSIONS: These data suggest that an increased cough reflex, as measured by capsaicin responsiveness, is an important contributor to the presence of cough in asthma and COPD, rather than cough being simply secondary to excessive airway secretions. The lack of any relationship between capsaicin responsiveness and airflow limitation as measured by the FEV(1) suggests that the mechanisms producing cough are likely to be different from those causing airways obstruction, at least in patients with COPD.  (+info)

Participation of thromboxane A(2) in the cough response in guinea-pigs: antitussive effect of ozagrel. (13/196)

1. The purpose of this study was to investigate the involvement of thromboxane A(2) (TXA(2)) in the cough response in a guinea-pig cough model. Here, we describe results obtained using a selective TXA(2) synthetase inhibitor, ozagrel, and a selective TXA(2) agonist, U-46619. 2. Guinea-pigs were anaesthetized and exposed to an aerosol of capsaicin (100 microM) to elicit coughing. The number of coughs was 20.0+/-5.8 during capsaicin provocation (5 min), but only 2. 8+/-0.4 during a 5-min inhalation of phosphate-buffered saline (PBS) (P:<0.05). 3. TXB(2) levels in BAL were 101.4+/-8.0 and 58.4+/-8.7 pg ml(-1) following capsaicin and PBS inhalation, respectively (P:<0. 01), but there was no intergroup difference in the cell populations in BAL. 4. Inhalation of U-46619 did not induce a cough response by itself at concentrations of 100 ng ml(-1) to 10 microg ml(-1). However, it caused a 2 fold increase in the number of capsaicin-induced coughs. 5. To explore the source of the TXA(2), BAL cells were stimulated with capsaicin and the supernatants collected for analysis. The TXB(2) concentration in BAL was increased dose-dependently, indicating that TXA(2) is released from BAL cells in response to capsaicin. 6. Ozagrel was administered orally 1 h before a 5 min capsaicin provocation and the number of coughs was counted during the capsaicin inhalation. Ozagrel decreased the number of coughs dose-dependently (ED(50) value, 26.3 mg kg(-1)). 7. These results show that TXA(2) modulates the capsaicin-induced cough response by increasing capsaicin-sensitivity.  (+info)

Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use; amendment of final monograph for OTC antitussive drug products. Food and Drug Administration, HHS. Final rule. (14/196)

The Food and Drug Administration (FDA) is issuing a final rule amending the final monograph for over-the-counter (OTC) antitussive drug products (products that relieve cough). Use of topical/inhalant products containing camphor or menthol near a flame, in hot water, or in a microwave oven may cause the products to splatter and cause serious burns to the user. As part of its ongoing review of OTC drug products, FDA is adding warnings and directions to inform consumers about these improper uses and is amending its final regulations for OTC drug labeling requirements to add this new flammability warning for antitussive drug products containing camphor or menthol.  (+info)

Nociceptin inhibits cough in the guinea-pig by activation of ORL(1) receptors. (15/196)

We studied the central and peripheral antitussive effect of ORL(1) receptor activation with nociceptin/orphanin FQ in conscious guinea-pigs. In guinea-pig cough studies, nociceptin/orphanin FQ (10, 30, and 90 microg) given directly into the CNS by an intracerebroventricular (i.c.v.) route inhibited cough elicited by capsaicin exposure by approximately 23, 29 and 52%, respectively. The antitussive activity of nociceptin/orphanin FQ (90 microg, i.c.v.) was blocked by the selective ORL(1) antagonist [Phe(1)gamma(CH(2)-NH)Gly(2)]nociceptin-(1-13)-NH(2) (180 microg, i.c.v.) and J113397 (10 mg kg(-1), i.p.) but not by the opioid antagonist, naltrexone (3 mg kg(-1), i.p.). Furthermore, intravenous (i.v.) nociceptin/orphanin FQ (1.0 and 3.0 mg kg(-1)) also inhibited cough approximately by 25 and 42%, respectively. These findings indicate that selective ORL(1) agonists display the potential to inhibit cough by both a central and peripheral mechanism, and potentially represent a novel therapeutic approach for the treatment of cough.  (+info)

Pharmacokinetics of sabeluzole and dextromethorphan oxidation capacity in patients with severe hepatic dysfunction and healthy volunteers. (16/196)

AIMS: The primary objective of this study was to determine how the pharmacokinetics of sabeluzole, an investigational drug with specific effects on memory and learning abilities, are affected by chronic liver disease. Since sabeluzole is metabolised by CYP2D6, a secondary objective was to study the correlation between CYP2D6 activity (as assessed by the dextromethorphan dextrorphan metabolic ratio) and hepatic dysfunction. METHODS: The single-dose pharmacokinetics of sabeluzole (10 mg) was compared in 10 healthy Caucasian subjects and 10 patients with severe hepatic dysfunction. The urinary dextromethorphan/dextrorphan (DMP/DRP) metabolic ratio was determined after intake of 20 mg dextromethorphan (NODEX capsules). RESULTS: The terminal half-life of sabeluzole was significantly prolonged in subjects with severe hepatic dysfunction vs healthy subjects (respectively 39.3 +/- 11.5 h; 17.5 +/- 10.2 h (mean +/- s.d.)). The areas under the curve (AUC) were significantly higher in subjects with severe hepatic dysfunction than in healthy volunteers (681 +/- 200 ng ml(-1) h vs 331 +/- 282 ng ml(-1) h). There was a significant correlation between the AUC(0,infinity) and the DMP/DRP metabolic ratio in healthy volunteers and subjects with severe hepatic dysfunction. AUC was greater and elimination of sabeluzole slower in poor metabolizers compared with extensive metabolizers. CONCLUSIONS: These results suggest that a) sabeluzole dose should be reduced in patients with severe hepatic dysfunction and b) the AUC of sabeluzole is linked to individual CYP2D6 activity.  (+info)