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At least 19 recordsLinked to original sources
PubMed1990

Pharmacokinetic comparison of a dextromethorphan-salbutamol combination tablet and a plain dextromethorphan tablet.

We compared in this double-blind crossover study the bioavailability of dextromethorphan from a dextromethorphan-salbutamol combination tablet (Redol comp) and from a plain dextromethorphan tablet (Extuson) by determining dextrorphan concentrations after single-dose oral administration in 10 healthy volunteers. The absorption of salbutamol from the combined preparation was also determined. The absorption of dextromethorphan was slightly faster from the plain dextromethorphan preparation. The peak concentration of dextrorphan was achieved at 1.5 h after Extuson and at 2 h after Redol comp (1,053.0 +/- 366.5 ng/ml and 901.5 +/- 210.9 ng/ml, NS). AUC0-12 values of dextrorphan were 4,315.6 +/- 295.0 (ng/ml)h after Extuson and 3,983.8 +/- 205.6 (ng/ml)h after Redol comp (p less than 0.05). Salbutamol was well absorbed from the combined preparation and the peak concentration was achieved at 3 h (6.57 +/- 2.95 ng/ml). Four subjects reported side-effects typical for salbutamol after the combination tablet. No side-effects were reported after the plain dextromethorphan tablet. On the basis of the present study, we conclude that the absorption of dextromethorphan from the preparations tested is almost equal and the dextromethorphan-salbutamol combination can be administered in tablet form for the treatment of cough.

Adult↗
PubMed1987

Antitussive effect of dextromethorphan and dextromethorphan-salbutamol combination in healthy volunteers with artificially induced cough.

The antitussive effects of dextromethorphan (30 mg) + salbutamol (2 mg), dextromethorphan (30 mg) alone and placebo on artificial cough induced by citric acid were compared in 19 healthy non-smoking volunteers in a double-blind crossover study. The method using inhaled citric acid with increasing concentrations to establish the cough threshold level showed an acceptable reproducibility and proved to be suitable for comparison of antitussive drugs. The cough threshold level was assessed before as well as 90 and 180 min after each medication. After placebo the cough threshold level showed no statistically significant rise. However, significant rises were shown following dextromethorphan (p less than 0.001) and the dextromethorphan-salbutamol combination (p less than 0.001). Between the treatments significant differences were shown in favour of the dextromethorphan-salbutamol combination. The results indicate that salbutamol has antitussive action enhancing the effect of plain dextromethorphan.

Adult↗
PubMed1986

The treatment of acute transient cough: a placebo-controlled comparison of dextromethorphan and dextromethorphan-beta 2-sympathomimetic combination.

The efficacy of an antitussive-beta 2-sympathomimetic combination (dextromethorphan-salbutamol) was compared with that of a plain antitussive (dextromethorphan) and a placebo in a double-blind trial in 108 out-patients with cough associated with acute respiratory infection. The dextromethorphan-salbutamol combination was superior to dextromethorphan or placebo in the suppression of cough at night, although a spontaneous improvement occurred in all treatment groups during the 4-day treatment period. No statistically significant differences between the treatments were shown in the symptom scores for the cough frequency and severity during the day, sputum quantity or ease of expectoration. A significant improvement in cough during the day was observed in all treatment groups. The results suggest that the use of antitussives is usually unnecessary; the only indication might be symptomatic relief, especially at night. An antitussive combined with a beta 2-sympathomimetic might be the most effective treatment in this type of cough.

Acute Disease↗
PubMed1990

The treatment of heroin addicts with dextromethorphan: a double-blind comparison of dextromethorphan with chlorpromazine.

According to the hypothesis that the development of physical dependence on and tolerance to opiates depends on the inhibition by opiates of L-asparaginase and L-glutaminase activities in the brain, and the blockade by opiates of the aspartatergic/glutamatergic receptors especially NMDA, four female and fourty-four male heroin addicts were included in a double-blind clinical trial. Four mg chlorpromazine (CPZ) was administered every hour and 10 mg diazepam (DIA) every 6 hours to a group consisting of two female and nineteen male inpatients. The remaining subjects received 15 mg non-opioid antitussive dextromethorphan (DM) instead of CPZ. The withdrawn addicts were controlled twice a day and yawning, lacrimation, rhinorrhoea, perspiration, goose flesh, muscle tremor, dilated pupils, anorexia, joint and muscle aches, restlessness, insomnia, emesis, diarrhea, craving and rejection of smoking as abstinence syndrome signs were observed and rated on a scale of 1, 2 and 3 points according to their intensity. All signs, except perspiration and emesis, were significantly less intense in the group given DM + DIA than CPZ + DIA. The other plus points included the immediate stop of craving and the early onset of smoking in DM + DIA group. The results are considered to be supporting evidence for the hypothesis emphasizing the blockade of NMDA receptors by opiates in opiate addiction. Furthermore, the decrease caused by non-opioid NMDA antagonists in the responsiveness of NMDA receptors appears very promising for the treatment of opiate addicts.

Adult↗
PubMed1986

Pharmacogenetics of dextromethorphan O-demethylation in man.

The metabolism of dextromethorphan has been investigated from the aspect of genetically determined intersubject differences of oxidative drug metabolism in man. For this purpose, the urinary elimination of dextromethorphan and dextrorphan, which is the major O-demethylated metabolite in urine, has been studied in selected drug hydroxylation phenotypes. Dextromethorphan O-demethylation co-segregates with polymorphic debrisoquine hydroxylation, whereas no such co-segregation exists with the independently controlled mephenytoin polymorphism in man. The urinary dextromethorphan over dextrorphan metabolic ratio was validated for linearity of O-demethylation vs dose administered, and for varying urine collection intervals at different urinary pH values. A 94% repeatability of the dextromethorphan metabolic ratio could be established in extensive and poor metabolizer phenotypes. In a preliminary study, different rates of N-, O- and N,O- demethylation of dextromethorphan to yield D-methoxymorphinane, dextrorphan and D-hydroxymorphinane, respectively, were found in extensive- (Sprague-Dawley) and poor-metabolizer (female dark Agouti) rat strains. The observed interphenotype differences in man and the interstrain variations in an experimental animal model indicate that dextromethorphan O-demethylation is catalysed by the debrisoquine-type cytochrome P-450 isozyme. Therefore, the common genetic control of debrisoquine and dextromethorphan metabolism indicates that dextromethorphan might be used as a safe and innocuous substitute for debrisoquine in future routine phenotyping in the field of human pharmacogenetics of oxidative drug metabolism.

Adult↗
PubMed1992

Dextromethorphan: enhancing its systemic availability by way of low-dose quinidine-mediated inhibition of cytochrome P4502D6.

There has been a substantial amount of interest in the anticonvulsant and neuroprotective actions of dextromethorphan. Its therapeutic efficacy, however, is limited by its extensive first-pass elimination by way of the cytochrome P4502D6 enzyme in humans. The purpose of this research was to determine whether quinidine (a selective inhibitor of cytochrome P4502D6) could improve dextromethorphan systemic delivery in patients with amyotrophic lateral sclerosis (a neurodegenerative disease). In the absence of quinidine, 60 mg dextromethorphan every 12 hours resulted in plasma concentrations of only 12 +/- 13 ng/ml (range, less than 5 to 40 ng/ml; n = 7). The same dose of dextromethorphan in the presence of 75 mg quinidine every 12 hours resulted in dextromethorphan plasma concentrations of 241 +/- 94 ng/ml (range, 157 to 402 ng/ml; n = 5). The achievement of higher dextromethorphan plasma concentrations was also associated with an increased occurrence of adverse effects in some patients. Based on the brain/plasma ratio for dextromethorphan in rats, it is estimated that brain dextromethorphan concentrations of 1.0 to 10 micrograms/gm may be attainable in humans by inhibition of cytochrome P4502D6 activity with quinidine.

Adult↗
PubMed1992

Dextromethorphan and mephenytoin phenotyping of patients treated with thioridazine or amitriptyline.

The metabolism of most tricyclic antidepressants and some phenothiazine neuroleptics is under the genetic control of hepatic cytochrome P-450IID6, which also regulates the metabolism of dextromethorphan. This study investigated the effect of treatment with amitriptyline or thioridazine on testing for genetically regulated efficiency of the metabolism of dextromethorphan and mephenytoin. One group of 33 patients was treated with 150 mg amitriptyline a day (the AMI group); 25 other patients received a daily dose of thioridazine, either 200 mg (200-THD group; n = 7) or 400 mg (400-THD group; n = 18). Before and after 10 days of this treatment, all patients were tested with 25 mg dextromethorphan and 100 mg mephenytoin to determine their pharmacogenetic status with respect to their hepatic drug oxidizing systems (cytochrome P-450IID6 and P-450 MP). Two patients were poor metabolizers (PMs) of dextromethorphan and three of mephenytoin. Treatment with either psychotropic drug was without significant effect on the metabolism of mephenytoin, but both amitriptyline and thioridazine increased significantly the metabolic ratio of dextromethorphan/dextrorphan. Thioridazine had the effect of changing the pharmacogenetic status of 15 efficient metabolizers of dextromethorphan to poor metabolizers; amitriptyline did not have such an effect. There was no significant correlation between day-11 plasma levels of thioridazine, mesoridazine, or sulforidazine and the metabolism of dextromethorphan, but there was a correlation between the metabolism of dextromethorphan and plasma levels of amitriptyline and nortriptyline. Amitriptyline (p less than 0.05), but not thioridazine, decreases the ratio of conjugated/total dextrorphan in urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Effect of liver disease on dextromethorphan oxidation capacity and phenotype: a study in 107 patients.

1. The O-demethylation of dextromethorphan to dextrorphan exhibits a genetically-controlled polymorphism, co-segregating with that of debrisoquine hydroxylation. Dextromethorphan has been proposed as a test compound to assess drug oxidation polymorphism. 2. We studied the effects of liver disease of varying severity on dextromethorphan oxidation capacity. Phenotyping was performed using the urinary dextromethorphan/dextrorphan metabolic ratio after oral administration of 40 mg dextromethorphan hydrobromide in 56 patients with cirrhosis and in 51 patients with moderately severe liver disease. 3. Dextromethorphan oxidation capacity was impaired in cirrhotic patients and, to lesser extent, in non cirrhotic patients, as compared with 103 control subjects. 4. The impairment in dextromethorphan oxidation induced by liver disease, was however, much less than that caused by the genetic deficiency. As a result, the prevalence of the poor metabolizer phenotype remained in the same range in patients with cirrhosis (1.8%) and with moderately severe disease (2.0%) as in controls (3.9%). 5. This observation shows that, although liver disease causes some impairment of dextromethorphan O-demethylation, this impairment is not sufficient to modify the assignment of phenotypes.

Adult↗
PubMed1978

Effect of salicylamide and acetaminophen on dextromethorphan hydrobromide metabolism: possible pharmacological implications.

The effect of salicylamide and acetaminophen on the metabolic fate of dextrorphan, the primary metabolite of dextromethorphan, was studied in vivo in the rat. Plasma dextrorphan levels were measured at 5-min intervals up to 20 min and at longer intervals up to 2 hr after dextromethorphan hydrobromide was administered orally either alone or in combination with salicylamide and acetaminophen. The combination gave rise to higher plasma dextrorphan levels than did dextromethorphan hydrobromide alone at most sampling times. Conjugation of dextrorphan was inhibited almost quantitatively by salicylamide and acetaminophen at the 5-min sampling time. Salicylamide alone increased the plasma dextrorphan levels when it was coadministered with dextromethorphan, but the differences were not statistically significant. The antitussive activity of dextromethorphan hydrobromide in the unanesthetized dog was faster in onset, greater in intensity, and longer in duration when it was coadministered with salicylamide and acetaminophen. It is suggested that salicylamide and acetaminophen may inhibit the metabolic inactivation of dextrorphan, thereby improving the coughinhibiting potential of dextromethorphan hydrobromide.

Acetaminophen↗
PubMed1990

Effect of orally administered dextromethorphan on theophylline- and pentylenetetrazol-induced seizures in rats.

Dextromethorphan, widely used as an antitussive, has recently been shown to protect animals against maximal electroshock and excitatory amino acid (N-methyl-D-aspartate)-induced convulsions. Its protective efficacy against theophylline-induced seizures was determined in this investigation in view of the limited effectiveness of presently available anticonvulsants against this manifestation of serious theophylline intoxication. Rats were pretreated with an oral dose of dextromethorphan (50 mg/kg) or saline solution. Fifteen minutes later, the rats were infused intravenously with theophylline [approximately 11 mg/(kg.min)] until the onset of maximal seizures. Pretreatment with dextromethorphan was associated with a significant decrease in the concentrations of theophylline in the cerebrospinal fluid and serum at the pharmacologic endpoint. To further explore this unanticipated effect, a similar experiment was performed with the convulsant pentylenetetrazol (PTZ), which was infused at a rate of approximately 3.4 mg/(kg.min) until the onset of maximal seizures. Dextromethorphan-pretreated animals required a significantly larger dose of PTZ than did controls to produce the first myoclonic jerk, but a significantly smaller dose of the convulsant to produce maximal seizures. Serum and cerebrospinal fluid concentrations of PTZ at onset of maximal seizures were significantly lower in dextromethorphan-treated than in control animals. The proconvulsant activity of dextromethorphan with respect to theophylline-induced maximal seizures is similar to that of phenytoin, and is consistent with other pharmacologic evidence of such similarity.

Administration, Oral↗
PubMed1989

An electrophysiological study on the common antitussive drug dextromethorphan in hippocampal slices in the rat.

Dextromethorphan, a common antitussive drug derived from the opioid class of morphinans, has been reported to have antiepileptic properties in some experimental tests. The effects of dextromethorphan were tested on the synaptic responses of the interconnections between Schaffer collaterals and CA1 pyramidal cells in hippocampal slices of the rat. Dextromethorphan, up to 100-200 microM, did not affect the basal field potentials resulting from electrical stimulation of the radiatum (0.1 Hz, 100-200 microA, 75 mu sec) of CA1 pyramidal cells. Larger concentrations of the drug (300-400 microM) depressed the amplitude and increased the duration of the CA1 basal population spikes. Dextromethorphan, up to 200-300 microM, affected neither the duration nor the incidence of the additional population spikes of the epileptiform bursting, resulting from perfusion of the slice with 1 mM penicillin or in the absence of magnesium ions. The data indicate that: (1) dextromethorphan has an influence on CA1 pyramidal cells, different from that of other opioids; (2) the reported antiepileptic effects of dextromethorphan do not involve the hippocampal area.

Animals↗
PubMed1985

Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation.

Dextromethorphan hydrobromide, 25 mg po, was given to 268 unrelated Swiss subjects to study urinary drug and metabolite profiles. Rates of O-demethylation yielding the main metabolite dextrorphan were expressed by the urinary dextromethorphan/dextrorphan metabolic ratio. We found a bimodal distribution of this parameter in our population study, which indicates that there are two phenotypes for dextromethorphan O-demethylation. The antimode at a metabolic ratio of 0.3 separated the poor metabolizer (PM; n = 23; prevalence of 9%) from extensive metabolizer (EM) phenotypes. Urinary output of dextrorphan was less than 6% of the dose in all PMs and was 50% in the 245 EMs. Pedigree analysis of 14 family studies revealed an autosomal-recessive transmission of deficient dextromethorphan O-demethylation. In these families, 37 heterozygous genotypes could be identified; however, through use of the urinary drug and metabolite analysis it was not possible to identify the heterozygous genotypes within the EM phenotype group. Co-segregation of dextromethorphan O-demethylation with debrisoquin 4-hydroxylation was also studied. Complete concordance of the two phenotypic assignments was obtained, with a Spearman rank correlation coefficient of rs = 0.78 (n = 62; P less than 0.0001) for dextromethorphan and debrisoquin metabolic ratios. Presumably the two drug oxidation polymorphisms are under the same genetic control. Thus the innocuousness and ubiquitous availability of dextromethorphan render it attractive for worldwide pharmacogenetic investigations in man.

Administration, Oral↗
PubMed1988

High-pressure liquid chromatographic assay of dextromethorphan hydrobromide, guaifenesin, and sodium benzoate in an expectorant syrup.

An ion-pair reversed-phase high-pressure liquid chromatographic assay is developed that allows simultaneous quantitation of guaifenesin, dextromethorphan hydrobromide, and sodium benzoate in an expectorant syrup. The method is rapid and accurate. Average recoveries of 99.6, 99.8, and 99.7% with relative standard deviations of 0.5, 0.9, and 0.2% are obtained for guaifenesin, dextromethorphan hydrobromide, and sodium benzoate, respectively, from laboratory prepared samples. Chromatographic conditions are selected to afford a pH that provides adequate separation of guaifenesin, dextromethorphan hydrobromide, sodium benzoate, and sodium saccharin and a detection wavelength that effectively compensates for the great disparity in quantity between guaifenesin and dextromethorphan hydrobromide present in syrups. The relationships between the retention volume of dextromethorphan hydrobromide and the alkyl chain length as well as the concentration of the counterion are studied. The retention profiles for sodium saccharin, guaifenesin, sodium benzoate, and dextromethorphan hydrobromide in the apparent pH range of 2.5 to 6.6 are established.

Benzoates↗
PubMed1990

Rapid screening for polymorphisms in dextromethorphan and mephenytoin metabolism.

1. The phenotyping parameters for dextromethorphan and mephenytoin were assessed in 48 normal male volunteers following administration of each metabolic probe drug on separate occasions and together according to a randomized 3-way crossover design. 2. Neither the urinary S-/R-mephenytoin ratio nor the dextromethorphan metabolic ratio were altered significantly by coadministration of the probe drugs. 3. Five-hundred and nineteen subjects were screened for expression of mephenytoin 4-hydroxylase and dextromethorphan O-demethylase activity following the coadministration of mephenytoin and dextromethorphan. The activity was determined in each case by methods not requiring any quantitative measurements. 4. Nineteen (3.7%) of the subjects were identified as poor metabolizers (PMs) of mephenytoin and 35 subjects (6.7%) as PMs of dextromethorphan. 5. All PMs of dextromethorphan were confirmed by more rigorous evaluation of the metabolic ratio.

Adolescent↗
PubMed1988

Dextromethorphan protects against cerebral injury following transient focal ischemia in rabbits.

We investigated dextromethorphan, both a dextrorotatory opioid derivative and a clinically tested N-methyl-D-aspartate (NMDA) receptor antagonist, in a rabbit model of transient focal cerebral ischemia. Fourteen rabbits were randomly assigned to treatment with a 20 mg/kg i.v. loading dose followed by a 10 mg/kg/hr infusion of 0.4% dextromethorphan in normal saline or with an equivalent volume of normal saline alone. One hour after treatment, the rabbits underwent a 1-hour occlusion of the left internal carotid and anterior cerebral arteries followed by 4 hours of reperfusion. The seven dextromethorphan-treated rabbits showed a significant decrease in the area of neocortical severe ischemic neuronal damage (10.5%) compared with the seven normal saline-treated controls (49.6%, p less than 0.001). The dextromethorphan-treated rabbits also demonstrated significantly smaller areas of cortical edema (10.2%) on magnetic resonance imaging than the controls (38.6%, p less than 0.01). Analysis of somatosensory evoked potentials revealed recovery of the ipsilateral amplitude to contralateral values within 5 minutes of reperfusion in the dextromethorphan-treated rabbits but not in the controls (p less than 0.01). In our rabbit model of transient focal cerebral ischemia, dextromethorphan appears to protect the brain against ischemic neuronal damage and edema, as well as to promote neurophysiologic recovery. This clinically available drug should be further investigated as having potential therapeutic value in the treatment of stroke.

Animals↗
PubMedDate not supplied

Dextromethorphan. An overview of safety issues.

Dextromethorphan is a highly effective and widely used nonopioid antitussive drug. As it has been in use for more than 30 years, a large body of clinical experience has been used to formulate a safety profile. An anthology of adverse drug events has been analysed, drawn both from published case records and a data base recording dextromethorphan-related adverse events spontaneously reported by physicians or pharmacists. The resulting safety profile indicates that adverse drug reactions are infrequent and usually not severe. The predominant symptoms are usually dose related and include neurological, cardiovascular and gastrointestinal disturbances. Particular safety concerns arise when monoamine oxidase inhibiting (MAOI) drugs and dextromethorphan are coadministered. In addition to adverse drug reactions, the safety profile of dextromethorphan is affected by episodic and sporadic abuse. In fact, abuse appeared to be the most significant hazard identified by analysis of spontaneous adverse event reporting. No evidence could be found that the well documented pharmacokinetic polymorphism observed with dextromethorphan is correlated with any clinically significant safety risk if it is used for short term treatment. In summary, the safety profile of dextromethorphan is reassuring, particularly relating to overdose in adults and children.

Animals↗
PubMed1991

Differential effect of biliary and micronodular cirrhosis on oxidative drug metabolism. In vivo-in vitro correlations of dextromethorphan metabolism in rat models.

Oxidative drug metabolism is impaired in liver cirrhosis; it is unclear, however, whether this depends on the etiology of cirrhosis. Therefore, we studied the metabolism of dextromethorphan in two rat models: biliary cirrhosis induced by bile duct ligation and micronodular cirrhosis induced by chronic exposure to CCl4/phenobarbital. Results were compared with aminopyrine N-demethylation assessed by a breath test in vivo; the latter was reduced to a similar extent in biliary (-41%) and micronodular (-37%) cirrhosis compared to controls. In contrast, clearance of dextromethorphan was significantly (P less than 0.001) reduced in biliary (25.4 +/- 5.3 mL/min/kg) but not in micronodular cirrhosis (48.6 +/- 15.6) as compared to controls (62.2 +/- 16.2). Intrinsic clearance of dextromethorphan in vitro was reduced by 95% and 63% in biliary and micronodular cirrhosis, respectively (P less than 0.001 vs controls). It correlated with dextromethorphan clearance in vivo (r = 0.68, P less than 0.001) whereas correlation with aminopyrine N-demethylation was weak (r = 0.42, P less than 0.05). Our results demonstrate a differential effect of biliary and micronodular cirrhosis on isoenzymes responsible for aminopyrine and dextromethorphan demethylation.

Animals↗