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PubMedDate not supplied

Evaluation of dextromethorphan and carbetapentane as anticonvulsants and N-methyl-D-aspartic acid antagonists in mice.

Two antitussives, dextromethorphan and carbetapentane, which have been reported to bind to a common binding site in brain tissue and produce anticonvulsant effects in rats, were evaluated for their anticonvulsant effects against maximal electroshock-induced seizures, for their neurological impairing effects on the horizontal screen test, and their protective effects against N-methyl-D-aspartic acid (NMDA)-induced lethality in mice. Both compounds protected animals against maximal electroshock-induced seizures in a dose-related fashion after either intraperitoneal or oral administration. The neurologically impairing doses were approximately 1.5 times the anticonvulsant doses. As a function of dose, dextromethorphan, but not carbetapentane, protected mice from NMDA-induced lethality. Since carbetapentane had an anticonvulsant action without protecting against NMDA-induced lethality, these data support the hypothesis that dextromethorphan and carbetapentane may have a common anticonvulsant action separate from the phencyclidine-like, NMDA-antagonist action which only dextromethorphan exhibits.

Animals↗
PubMed2005

Dextromethorphan-induced delirium and possible methadone interaction.

INTRODUCTION: Dextromethorphan is a commonly used antitussive agent that can be purchased over the counter. It is metabolized primarily by the cytochrome P450 (CYP) 2D6 isozyme. Methadone has been found to inhibit CYP2D6, indicating a potential for interaction with dextromethorphan. CASE SUMMARY: An 83-year-old woman was evaluated for delirium, hypersomnia, confusion, lethargy, impaired concentration, and poor food intake. Symptoms resolved soon after discontinuing dextromethorphan. DISCUSSION: Vulnerability to delirium was potentially caused by coadministration of methadone, which can inhibit the CYP2D6 isozyme. CONCLUSION: Evaluation of delirium should include close investigation of the patient's medications for potential interactions with dextromethorphan.

Aged↗
PubMed2006

Binding of bufuralol, dextromethorphan, and 3,4-methylenedioxymethylamphetamine to wild-type and F120A mutant cytochrome P450 2D6 studied by resonance Raman spectroscopy.

Cytochrome P450 2D6 (CYP2D6) is one of the most important drug-metabolizing enzymes in humans. Resonance Raman data, reported for the first time for CYP2D6, show that the CYP2D6 heme is found to be in a six-coordinated low-spin state in the absence of substrates, and it is perturbed to different extents by bufuralol, dextromethorphan, and 3,4-methylenedioxymethylamphetamine (MDMA). Dextromethorphan and MDMA induce in CYP2D6 a significant amount of five-coordinated high-spin heme species and reduce the polarity of its heme-pocket, whereas bufuralol does not. Spectra of the F120A mutant CYP2D6 suggest that Phe120 is involved in substrate-binding of dextromethorphan and MDMA, being responsible for the spectral differences observed between these two compounds and bufuralol. These differences could be explained postulating a different substrate mobility for each compound in the CYP2D6 active site, consistently with the role previously suggested for Phe120 in binding dextromethorphan and MDMA.

Amino Acid Substitution↗
PubMed2004

Isradipine and dextromethorphan in methadone-maintained humans under a naloxone discrimination procedure.

In seven methadone-maintained human participants trained to distinguish between a low dose of naloxone (0.15 mg/70 kg, i.m.; i.e., Drug A) and placebo (i.e., Drug B) under an instructed novel-response drug discrimination procedure, the calcium channel blocker isradipine (0-10 mg/70 kg, p.o.; N=7) and the N-methyl-D-aspartic acid (NMDA) receptor antagonist dextromethorphan (0-60 mg/70 kg, p.o.; N=6) were tested each alone and in combination with the training dose of naloxone. Isradipine alone produced some naloxone- and novel-appropriate responding, minimal changes in self-reports and decreases in blood pressure. Dextromethorphan alone produced some novel-appropriate responding and minimal changes in self-reports and vital signs. When combined with naloxone, isradipine significantly attenuated naloxone-occasioned responding, without increasing novel-appropriate responding, and attenuated naloxone-induced increases in opioid receptor antagonist ratings and ratings measuring sedation. Dextromethorphan significantly attenuated naloxone-appropriate responding, increased novel-appropriate responding, and enhanced naloxone's effects on ratings of dysphoric effects. These results suggest that isradipine attenuates and dextromethorphan enhances some of the behavioral effects of naloxone in opioid-dependent humans.

Adult↗
PubMed2005

Validation of a liquid chromatography-mass spectrometry method to assess the metabolism of dextromethorphan in rat everted gut sacs.

A rapid, sensitive and selective liquid chromatography-mass spectrometry (LC-MS) method was developed for the simultaneous assay of dextromethorphan and its metabolites in tissue culture medium and its intestinal metabolism studied with the rat everted gut sac model. The method was validated in the concentration range of 0.1-2.5 microM (27.1 ng/mL-0.677 microg/mL) for dextromethorphan and 0.005-0.5 microM for dextrorphan and 3-methoxymorphinan (1.28 ng/mL-0.128 microg/mL) and 3-hydroxymorphinan (1.22 ng/mL-0.122 microg/mL). The limits of quantification (LOQ) were 0.0025 microM (12.5 fmoles, 3.4 pg, 5 microL injected) for dextromethorphan; 0.0025 microM for dextrorphan, 3-methoxymorphinan (24.9 fmoles, 6.4 pg injected), and 3-hydroxymorphinan (25.1 fmoles, 6.1 pg injected) with 10 microL injected. The detection of dextrorphan and 3-methoxymorphinan showed that both the P450 isoforms CYP3A and 2D were active in the intestinal mucosa and metabolised dextromethorphan during its passage across the mucosa.

Animals↗
PubMed2006

Spectrophotometric determination of pipazethate HCl, dextromethorphan HBr and drotaverine HCl in their pharmaceutical preparations.

A simple, accurate and highly sensitive spectrophotometric method is proposed for the rapid determination of pipazethate hydrochloride, dextromethorphan hydrobromide and drotaverine hydrochloride using chromotrope 2B (C2B) and chromotrope 2R (C2R). The method consists of extracting the formed ion-associates into chloroform in the case of pipazethate HCl and dextromethorphan HBr or into methylene chloride in the case of drotaverine HCl. The ion-associates exhibit absorption maxima at 528, 540 and 532 nm with C2B and at 526, 517 and 522 nm with C2R for pipazethate HCl, dextromethorphan HBr and drotaverine HCl, respectively. The calibration curves resulting from the measurements of absorbance-concentration relations (at the optimum reaction conditions) of the extracted ion-pairs are linear over the concentration range 4.36-52.32 microg mL(-1) for pipazethate, 3.7-48.15 microg mL(-1) for dextromethorphan and 4.34-60.76 microg mL(-1) for drotaverine, respectively. The effect of acidity, reagent concentration, time, solvent and stoichiometric ratio of the ion-associates were estimated. The molar absorptivity and Sandell sensitivity of the reaction products were calculated. Statistical treatment of the results reflects that the procedure is precise, accurate and easily applied for the determination of the drugs under investigation in pure form and in their pharmaceutical preparations.

Antitussive Agents↗
PubMed2003

Dextromethorphan prevents the diethyldithiocarbamate enhancement of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice.

In this report we show that dextromethorphan, a non-opioid cough suppressant, prevents the neurodegeneration of dopaminergic neurons in the substantia nigra of mice treated with diethyldithiocarbamate (DDC) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This effect is further substantiated by the assessment of dopamine (DA) content in the striatum of these animals. Dextromethorphan does not attenuate the striatal DA fall induced by MPTP alone but completely prevents DDC-induced enhancement after the combined treatment. Moreover, a study of DA metabolites has confirmed this neuroprotective property. The striatal levels of serotonin, which were studied as a control neuronal marker, did not change with any of the treatments administered. Furthermore, we show that dextromethorphan reduces the toxicity of glutamate against dopamine neurons in mesencephalic cell cultures. In line with previous data suggesting that dextromethorphan can prevent neuronal damage, our observations supply new evidence regarding the possibility of this compound being of therapeutic use in neurodegenerative diseases.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1997

Dextrorphan, but not dextromethorphan, exerts weak antidystonic effects in mutant dystonic hamsters.

The effects of dextromethorphan and its metabolite dextrorphan on severity of dystonia were examined in mutant dystonic hamsters, an animal model of idiopathic paroxysmal dystonia, in which recent examinations have shown antidystonic effects of selective N-methyl-D-aspartate (NMDA) receptor antagonists. Dextromethorphan and dextrorphan are non-competitive NMDA receptor antagonists which additionally exhibit affinity for sigma receptors. Dextrorphan (20 and 40 mg/kg i.p.) significantly retarded the progression of dystonia at the higher dose, whereas dextromethorphan (20, 40, 60 mg/kg i.p.) failed to exert any antidystonic effects even at high doses which caused severe effects. The lack of antidystonic efficacy of dextromethorphan may be related to its higher affinity to sigma receptors compared with dextrorphan.

Animals↗
PubMed1999

Dextromethorphan modulates the AP-1 DNA-binding activity induced by kainic acid.

We have recently reported that dextromethorphan attenuates the neurotoxicity induced by kainic acid in a dose-related fashion. Pretreatments with dextromethorphan (50 mg/kg, p.o. x2) significantly reduced the activator protein-1 DNA-binding activity and the Fos-related antigen-immunoreactive protein induced by kainic acid (10 mg/kg, i.p.) in the CA1, but not the CA3 or the dentate gyrus sector of the rat hippocampus. Paradoxically, dextromethorphan itself caused an elevated activator protein-1 DNA-binding activity and Fos-related antigen-immunoreactive protein in the CA1 region which lasted for at least 4 days. The results suggest that the CA1 area is the critical site for mediating the putative neuroprotective effect induced by dextromethorphan.

Animals↗
PubMed1996

Determination of dextromethorphan metabolic phenotype by salivary analysis with a reference to genotype in Chinese patients receiving renal hemodialysis.

BACKGROUND: The polymorphic metabolism of debrisoquin and sparteine by cytochrome P450IID6 (CYP2D6) is genetically determined. Determination of the CYP2D6 metabolic phenotype with conventional urine analytic methods is not feasible in anuric patients with renal failure. The possibility of using salivary analysis, with dextromethorphan as a probe drug, to determine the CYP2D6 metabolic phenotype in patients with renal failure was evaluated. METHODS AND RESULTS: One hundred four Chinese patients with renal failure were recruited. All 104 patients were receiving hemodialysis. Saliva was collected before and at 3 hours after each patient took a capsule of dextromethorphan hydrobromide (30 mg). Four patients were excluded because of insufficient samples of saliva. The distribution of logarithms of the metabolic ratios (log[MR]) in the 100 patients appeared to be normal. Administration of quinidine sulfate (200 mg twice daily) to nine of the patients significantly and markedly increased the dextromethorphan metabolic ratios. The metabolic ratios of nine patients pretreated with quinidine were higher than any of the 100 patients with renal failure who did not receive quinidine pretreatment. A metabolic ratio of 33 separated these two groups. Genomic deoxyribonucleic acid was extracted from whole blood in a subset of patients. Polymerase chain reaction (PCR)-based methods were used to detect the CYP2D6 and B mutant genes. Mutant B alleles (which are common in white poor metabolizers) of CYP2D6 genes were not detected in any of the 47 subjects tested. A PCR-based test of cytosine (C188) to thymine (T188) polymorphism at 188 base pairs in exon 1 of CYP2D6 genes was performed in 61 patients. Subjects who were homozygous for C188 had significantly (p = 0.0067) lower log[MR] values than those who were homozygous for T188. CONCLUSIONS: Determination of dextromethorphan metabolic ratios in saliva is feasible in patients with renal failure requiring hemodialysis. All subjects in this study appeared to be "extensive metabolizer" phenotype for CYP2D6, and no poor metabolizer was identified. From the results with quinidine pretreatment, a metabolic ratio of 33 is suggested to be a tentative antimode for identification of poor metabolizers in patients with renal failure.

Adult↗
PubMed1996

Determination of cytochrome P450 3A4/5 activity in vivo with dextromethorphan N-demethylation.

Dextromethorphan is used widely in vivo to phenotype the polymorphically expressed cytochrome P450 (CYP) 2D6. Dextromethorphan is N-demethylated in vitro to 3-methoxymorphinan by human CYP3A4/5. We examined whether the dextromethorphan/3-methoxymorphinan urinary metabolic ratio (MR) could be used as an in vivo probe of CYP3A. Urinary excretion of 3-methoxymorphinan was excretion rate-limited in extensive metabolizers of CYP2D6, which necessitated a longer urine collection, 0 to 72 hours, to obtain true MR values for CYP3A. The urine excretion of dextromethorphan and 3-methoxymorphinan was delayed in poor metabolizers of CYP2D6 but appeared to be formation rate-limited. The delayed excretion in poor metabolizers necessitated longer urine collection intervals, 0 to 11 days, to estimate the true CYP3A MR and 0 to 8 days to estimate the true CYP2D6 MR. However, a 72-hour collection in poor metabolizers was used as an index of the true dextromethorphan/3-methoxymorphinan MR. Rifampin (300 mg b.i.d. for 7 days) significantly reduced the 0- to 72-hour dextromethorphan/3-methoxymorphinan MR consistent with an 830% (+/- 1808%) induction of CYP3A activity (n = 8), whereas erythromycin (250 mg q.i.d. for 7 days) significantly increased the dextromethorphan/3-methoxymorphinan MR, corresponding to a 34% +/- 44% inhibition of activity (n = 7) in extensive metabolizers and poor metabolizers. The changes in CYP3A activity were independent of CYP2D6 phenotype and were also observed after 24- and 48-hour urine collections in extensive metabolizers and poor metabolizers. In addition, MRs reflecting CYP2D6 and CYP3A were not significantly correlated. We conclude that the commonly used antitussive dextromethorphan can be used as an in vivo marker of CYP3A and CYP2D6 activity.

Administration, Oral↗
PubMed1999

Analysis of the CYP2D6 gene in relation to dextromethorphan O-demethylation capacity in a Japanese population.

OBJECTIVE: To analyze the CYP2D6 allele frequencies in a Japanese population and to evaluate the effects of CYP2D6 variants on in vivo CYP2D6 activity as measured by the dextromethorphan metabolic ratio (MR). METHODS: Ninety-eight unrelated, healthy Japanese men were phenotyped with dextromethorphan and genotyped by the polymerase chain reaction amplification method for 7 CYP2D6 alleles. RESULTS: The CYP2D6*1, CYP2D6*10, CYP2D6*2, CYP2D6*5, CYP2D6*4, and CYP2D6*21 allele frequencies in our Japanese subjects were 0.423, 0.408, 0.092, 0.061, 0.020, and 0.010, respectively. Thirty-three subjects (33.7%) were heterozygous for *10/*1, and 18 (18.4%) and 17 (17.3%) subjects were homozygous for *1 and *10, respectively. Subjects who were homozygous for *10 showed the highest dextromethorphan MR among these 3 genotypes. Eighteen subjects (18.3%) were heterozygous for *2, but their dextromethorphan MR values were not greater than the MR values of subjects who were homozygous for *1. One subject was a poor metabolizer phenotypically, and he was homozygous for *5. CONCLUSIONS: The CYP2D6 allele frequencies in our Japanese subjects differed from those determined in previous studies of white subjects or mainland Chinese subjects. Individuals homozygous for *10 who have relatively low in vivo CYP2D6 activity represent almost 20% of the Japanese population. In addition, we did not identify any subjects with amplified *2 among our 98 Japanese men.

Adult↗
PubMed2001

Comparative effects of dextromethorphan and dextrorphan on morphine, methamphetamine, and nicotine self-administration in rats.

The effects of dextromethorphan and its metabolite dextrorphan on morphine, methamphetamine and nicotine self-administration and on responding for a nondrug reinforcer (water) were assessed in rats. Both dextromethorphan and dextrorphan decreased morphine self-administration at 10-30 mg/kg, s.c., decreased methamphetamine self-administration at 20 and 30 mg/kg, s.c., and decreased nicotine self-administration at 5-30 mg/kg, s.c.; doses of both drugs less than 40 mg/kg, s.c. did not affect responding for water. The equal potencies of dextromethorphan and dextrorphan suggest mediation of these effects by a non-NMDA receptor mechanism, possibly involving blockade of alpha3beta4 nicotinic receptors. The results also suggest that dextromethorphan should be tested extensively as a potential treatment for diverse populations of drug-abusing patients.

Analgesics, Opioid↗
PubMed2002

Modulation of formalin-induced behaviors and edema by local and systemic administration of dextromethorphan, memantine and ketamine.

The present study examined the effects of local peripheral and systemic administration of three clinically used excitatory amino acid receptor antagonists (dextromethorphan, memantine, ketamine) on pain behaviors and edema produced by formalin (1.5% and 5%) in rats. Peripheral administration of dextromethorphan produced a locally mediated suppression of flinching behaviors induced by 1.5% and 5% formalin, but biting/licking behaviors were not affected. Memantine and ketamine had no effect on either of these behaviors. All three agents augmented edema produced by 1.5% and 5% formalin. When administered alone, dextromethorphan, memantine and ketamine produced an intrinsic paw swelling response, and this was blocked by the biogenic amine receptor antagonists mepyramine, phentolamine, methysergide and ketanserin. Following systemic administration, all three agents suppressed biting/licking behaviors, had no effect on flinching behaviors, and suppressed paw swelling induced by 5% formalin to varying degrees. These results provide evidence for a peripherally mediated antinociceptive action of dextromethorphan in the rat formalin test, but this may not necessarily be due to block of excitatory amino acid receptors as it is not observed with memantine or ketamine. All three agents produce a peripherally mediated paw swelling, which is likely due to blockade of biogenic amine reuptake. Systemic administration of all three agents produces antinociceptive and anti-inflammatory actions that may be due to block of excitatory amino acid receptors in the spinal cord.

Animals↗
PubMed1998

Long-term use of high-dose benzoate and dextromethorphan for the treatment of nonketotic hyperglycinemia.

OBJECTIVE: The objective of this study was to test the hypotheses that reduction of glycine and blocking of the N-methyl-D-aspartate receptor channel complex would be beneficial for both seizure reduction and developmental progress in patients with nonketotic hyperglycinemia. METHODS: We administered benzoate (at doses of 500 to 750 mg/kg/day) and dextromethorphan (at doses of 3.5 to 22.5 mg/kg/day) to four infants with nonketotic hyperglycinemia with follow-up of 3 months to 6 years. RESULTS: Benzoate reduced to normal the glycine concentration in plasma and substantially reduced but did not normalize the glycine concentration in cerebrospinal fluid. Dextromethorphan was a potent anticonvulsant in some but not all patients. There was remarkable interpatient variability in dextromethorphan metabolism. Three patients are living (ages ranging from 4 to 6 years) and are moderately to severely developmentally delayed; two are free of seizures. The third patient, with the slowest development, had intractable seizures for nearly a month before diagnosis, and although seizure-free for 30 months, now has grand-mal seizures. One patient died of intractable seizures at 3 months. CONCLUSIONS: These outcomes suggest that benzoate and dextromethorphan are not uniformly effective in nonketotic hyperglycinemia, but for some patients they improve arousal, decrease or eliminate seizures, and allow for some developmental progress. Trials with additional patients and other receptor channel blockers are warranted.

Amino Acid Metabolism, Inborn Errors↗
PubMed2002

Dextromethorphan and ketamine potentiate the antinociceptive effects of mu- but not delta- or kappa-opioid agonists in a mouse model of acute pain.

Animal and clinical studies have reported potentiation of opioid antinociception by NMDA receptor antagonists such as ketamine and dextromethorphan. The aim of this study was to compare these clinically available NMDA antagonists in combination with classical morphine, mu-selective fentanyl-like opioids, the delta-opioid agonist SNC80 and the kappa-opioid agonist U50,488H. Using a mouse hot-plate test, dose-response relationships were first determined for all compounds individually and then for opioids co-administered with fixed doses of ketamine or dextromethorphan. All compounds were administered intraperitoneally ED(50) values were calculated from the proportion of animals failing to exhibit any response within a fixed cut-off criterion of 30 s. To varying degrees, all compounds produced increases in response latencies over time. Dextromethorphan produced lower ED(50) values for morphine, fentanyl and sufentanil but exerted no effect on the potency of SNC80 or U50,488H. Similarly, ketamine potentiated the antinociceptive potency of morphine, fentanyl and sufentanil but not SNC80 or U50,488H. In summary, these results support the use of mu-opioid agonists in combination with NMDA antagonists, but suggest that there may be no advantage in combining dextromethorphan or ketamine with delta- or kappa-opioids in the management of acute pain.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1999

Genetic differences in the antinociceptive effect of morphine and its potentiation by dextromethorphan in rats.

The effect of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dextromethorphan on morphine-induced antinociception was studied with the hot plate test in Sprague-Dawley (SD), Wistar-Kyoto (WK), Spontaneously Hypertensive (SHR) and Dark-Agouti (DA) rats. Subcutaneous morphine at 5 mg/kg induced significant antinociception in all four rats strains. Subcutaneous dextromethorphan at 15 and 45 mg/kg, but not 5 mg/kg, significantly and dose-dependently potentiated morphine-induced antinociception in SDs, WKs and SHRs, but not in DAs. In SHRs and DAs the antinociceptive effect of morphine was followed by prolonged hyperalgesia, which was reduced (SHRs) or abolished (DAs) by dextromethorphan. These results suggest that there are significant differences among rat strains in their response to morphine and in the ability of dextromethorphan to potentiate morphine-induced antinociception. These differences are possibly of genetic origin. Moreover, these data show that morphine, at least in some strains of rats, induced a delayed and NMDA receptor-dependent hyperalgesic response, supporting the notion that administration of opiates may activate NMDA receptors, leading to reduced antinociceptive effect and the development of hyperalgesia.

Animals↗
PubMed1998

Simultaneous determination of dextromethorphan and its metabolites in human plasma by capillary electrophoresis.

A sensitive capillary electrophoretic method was developed and validated for the simultaneous determination of dextromethorphan and its metabolites, dextrorphan, 3-hydroxymorphinan, and 3-methoxymorphinan, in human plasma. After cleavage of conjugates by enzymatic hydrolysis with beta-glucuronidase, dextromethorphan and its metabolites were extracted from 1.5 ml of plasma by a liquid liquid extraction procedure using heptane-ethylacetate (50:50, v/v) and re-extracted to aqueous phase. The compounds were separated within 8 min on a fused silica capillary, 75 microm internal diameter using sodium borate (pH 9.4; 50 mM) as running buffer, and measured by UV-detection at 195 nm using a detection cell with a path length of 1.2 mm. The method was accurate and precise. Linear relationships were observed between the peak response and the concentration in the range of 1-400 ng ml(-1) plasma with correlation coefficients above 0.998. The limit of detection was 0.5-1 ng ml(-1) plasma for all compounds. The method was used for determination of plasma levels of dextromethorphan and its metabolites after transdermal and oral administration of dextromethorphan.

Administration, Cutaneous↗