dextrorphan and Cough

To define the relative antitussive effect of dextromethorphan (DEX) and its primary metabolite dextrorphan (DOR) after administration of DEX.. Data were analysed from a double-blind, randomized cross-over study in which 22 subjects received the following oral treatments: (i) placebo; (ii) 30 mg DEX hydro-bromide; (iii) 60 mg DEX hydro-bromide; and (iv) 30 mg DEX hydro-bromide preceded at 1 h by quinidine HCl (50 mg). Cough was elicited using citric acid challenge. Pharmacokinetic data from all non-placebo arms of the study were fitted simultaneously. The parameters were then used as covariates in a link PK-PD model of cough suppression using data from all treatment arms.. The best-fit PK model assumed two- and one-compartment PK models for DEX and DOR, respectively, and competitive inhibition of DEX metabolism by quinidine. The intrinsic clearance of DEX estimated from the model ranged from 59 to 1536 l x h(-1), which overlapped with that extrapolated from in vitro data (12-261 l x h(-1)) and showed similar variation (26- vs. 21-fold, respectively). The inhibitory effect of quinidine ([I]/Ki) was 19 (95% confidence interval of mean: 18-20) with an estimated average Ki of 0.017 microM. Although DEX and DOR were both active, the potency of the antitussive effect of DOR was 38% that of DEX. A sustained antitussive effect was related to slow removal of DEX/DOR from the effect site (ke0 = 0.07 h(-1)).. Physiologically based PK modelling with perturbation of metabolism using an inhibitor allowed evaluation of the antitussive potency of DOR without the need for separate administration of DOR.

Topics: Administration, Oral; Adrenergic alpha-Antagonists; Adult; Antitussive Agents; Cough; Cross-Over Studies; Dextromethorphan; Dextrorphan; Double-Blind Method; Female; Humans; Male; Quinidine

In vitro-in vivo extrapolation of clearance, embedded in a clinical trial simulation, was used to investigate differences in the pharmacokinetics and pharmacodynamics of dextromethorphan between CYP2D6 poor and extensive metabolizer phenotypes. Information on the genetic variation of CYP2D6, as well as the in vitro metabolism and pharmacodynamics of dextromethorphan and its active metabolite dextrorphan, was integrated to assess the power of studies to detect differences between phenotypes. Whereas 6 subjects of each phenotype were adequate to achieve 80% power in showing pharmacokinetic differences, the power required to detect a difference in antitussive response was less than 80% with 500 subjects in each study arm. Combining in vitro-in vivo extrapolation with a clinical trial simulation is useful in assessing different elements of study design and could be used a priori to avoid inconclusive pharmacogenetic studies.

Topics: Antitussive Agents; Clinical Trials as Topic; Computer Simulation; Cough; Cytochrome P-450 CYP2D6; Dextromethorphan; Dextrorphan; Models, Biological; Polymorphism, Genetic

Dextrorphan (CAS 125-73-5) is the active metabolite of the antitussive agent dextromethorphan (CAS 125-71-3). The activity of dextromethorphan, its specific pharmacology, acute toxicity and general pharmacology in respect to the central nervous system were investigated in comparison to dextromethorphan. The studies showed that dextrorphan exerts an antitussive activity comparable to the one of dextromethorphan, but a better tolerability and a lower toxicity. These results suggest to use dextrorphan instead of its precursor dextromethorphan in therapy.

Topics: Administration, Oral; Animals; Anticonvulsants; Antitussive Agents; Behavior, Animal; Catalepsy; Cough; Dextromethorphan; Dextrorphan; Electric Stimulation; Female; Guinea Pigs; Injections, Intravenous; Male; Mice; Motor Activity; Postural Balance; Rats; Rats, Sprague-Dawley; Sleep; Vagus Nerve

Dextromethorphan, after administration, is rapidly and extensively transformed into dextrorphan. The aim of this study was to compare the cough-suppressing activity of 6, 12, 24, 48 mg/kg, i.p., of dextrorphan (dextro rotatory isomer of racemorphan) with that of dextromethorphan, using the model of citric acid-induced coughing in the unanaesthetized, unrestrained guinea pig. A significant dose-effect relationship of dextrorphan in reducing citric acid-induced cough was observed. This effect was comparable with that of dextromethorphan. However, at 48 mg/kg, i.p., dextromethorphan had a toxic effect while dextrorphan did not. Because dextrorphan is the major metabolite of dextromethorphan and has antitussive activity comparable to that of dextromethorphan, clinical use of dextrorphan is suggested.

Topics: Animals; Antitussive Agents; Cough; Dextromethorphan; Dextrorphan; Dose-Response Relationship, Drug; Guinea Pigs

The possible antitussive effects of dextrorphan (the (+) isomer of levorphanol) and phencyclidine (PCP) were compared to well known antitussive properties of dextromethorphan in the post-halothane anesthetized decerebrate cat in which cough was elicited by direct electrical stimulation of the cough center. Dextrorphan, when injected i.a. (0.05-0.32 mg kg-1) or i.v. (1 to 3 mg kg-1), PCP i.a. (0.1-0.32 mg kg-1) or i.v. (1.0 mg kg-1) had no effect on electrically elicited cough. After i.v. administration, dextrorphan caused a variable effect on respiration but did not have any respiratory effect with i.a. administration of the drug. PCP injection i.a. at 0.32 mg kg-1 severely inhibited respiration though coughing could still be elicited. But i.v. administration of 1.0 mg/kg-1 suppressed both cough and respiration for several hours. Dextromethorphan inhibited cough upon both i.a. and i.v. injection. The mean effective i.a. dose was 0.063 mg kg-1. A ten times higher dose was necessary (0.65 mg kg-1) for cough suppression by the i.v. route. It is concluded from the i.a./i.v. ratio that dextromethorphan has specific central antitussive activity not possessed by dextrorphan and PCP.

Topics: Animals; Antitussive Agents; Cats; Cough; Decerebrate State; Dextromethorphan; Dextrorphan; Female; Levorphanol; Morphinans; Phencyclidine