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PubMed2000

Inhibition of the 5-HT(1A) receptor-mediated inwardly rectifying K(+) current by dextromethorphan in rat dorsal raphe neurones.

The effect of dextromethorphan (DM) on the inwardly rectifying K(+) currents mediated by 5-HT(1A) receptors in acutely dissociated dorsal raphe (DR) neurones of rats was studied using nystatin-perforated patch and conventional whole-cell patch recording configurations under voltage-clamp conditions. DM rapidly and reversibly inhibited the K(+) currents induced by 10(-7) M 5-HT in a concentration-dependent manner with a half-maximum inhibitory concentration of 1.43 x 10(-5) M. The inhibitory effect of DM was neither voltage- nor use-dependent. DM caused a suppression of the maximum response of the 5-HT concentration-response curve, thus suggesting a non-competitive type of inhibition. In neurones perfused intracellularly with a pipette-solution containing the nonhydrolyzable GTP analog GTPgammaS, 5-HT activated K(+) currents in an irreversible manner. DM suppressed the current irreversibly activated by intracellular GTPgammaS even in the absence of the agonist. DM also inhibited the inwardly rectifying K(+) currents regulated by alpha(2)-adrenoceptors in freshly isolated rat locus coeruleus neurones. These results suggest that DM may inhibit the G-protein coupled inwardly rectifying K(+) channels, but not the neurotransmitter receptors, in the central nervous system.

Animals↗

PubMed2000

Dextromethorphan alters methamphetamine self-administration in the rat.

Various lines of evidence indicate that methamphetamine (METH) self-administration in rats is under dopaminergic control, and NMDA receptors have been shown to control the release of dopamine at its synapse. Consequently, the aim of this study was to observe the effects of dextromethorphan (DM), a non-competitive NMDA antagonist, in rats self-administering METH. The hypothesis was that acute pretreatment of DM (25 mg/kg) would alter response to METH. DM significantly altered self-administration by reducing the number of correct responses for three METH self-administration doses (0.05, 0.1, 0.25 mg/kg). The same pretreatment did not affect responding for food reward. These findings show that the DM was able to selectively alter METH self-administration.

Animals↗

PubMed2001

The effect of the NMDA receptor blocker, dextromethorphan, on cribbing in horses.

Stereotypic cribbing in horses is thought to involve excess dopaminergic activity within the striatum. Various models of stress-induced stereotypies including cribbing in horses postulate that stress stimulates the release of endorphins, triggering the release of striatal dopamine. Dopamine in turn activates basal ganglia motor programs, reinforcing behavior via a reward mechanism. Furthermore, the release of dopamine by endorphins has been shown to depend on activation of NMDA receptors. In the present study, horses identified as cribbers and volunteered by their owners were treated with the NMDA receptor antagonist dextromethorphan (DM). When DM was administered via jugular injection (1 mg/kg), eight of nine horses responded with reductions in cribbing rate (CR) compared to baseline, and cribbing was suppressed completely for a period of time in almost half of the horses tested.

Animals↗

PubMed2003

Attenuation of the stimulant and convulsant effects of cocaine by 17-substituted-3-hydroxy and 3-alkoxy derivatives of dextromethorphan.

Pharmacological evidence has suggested a role for both sigma and N-methyl-D-aspartate (NMDA) receptors in the behavioral stimulant effects of cocaine and its convulsant effects observed at higher doses. A series of dextromethorphan (DM) analogs with a range of affinities for sigma-1 binding sites and for the NMDA receptor ion channel were used to explore the contribution of these two mechanisms in controlling the stimulant and convulsant effects of cocaine. These compounds were potent and efficacious blockers of both stimulant and convulsant effects produced by acute cocaine administration in mice (cocaine 10 or 75 mg/kg ip for locomotor activity or convulsions, respectively). Generally, the DM analogs blocked these effects of cocaine at doses that did not display ataxic and sedative side effects as measured in the inverted screen test. In contrast to the high-affinity NMDA blockers, (+)-MK-801 (dizocilpine) and dextrorphan (DX), DM and analogs did not stimulate locomotor activity. There was no significant correlation between the affinities of the DM analogs for the sigma-1 or the phencyclidine (PCP) binding site and their potencies to produce behavioral effects on their own or to attenuate the behavioral or toxic effects of cocaine. The present study has identified a series of agents that have cocaine-blocking effects that appear to be distinct from that of classical sigma-1 receptor ligands and that of traditional uncompetitive NMDA receptor antagonists. These findings point to potentially novel pharmacological strategies for blocking cocaine stimulant and toxic effects.

Animals↗

PubMed1999

Dextromethorphan attenuates ethanol withdrawal syndrome in rats.

The effects of dextromethorphan (DM), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptors, have been investigated on ethanol withdrawal signs in rats. Ethanol (7.2% v/v) was given to rats in a liquid diet for 16 days. DM (10, 20, and 40 mg/kg) and saline were injected intraperitoneally at the third hour of ethanol withdrawal. DM (40 mg/kg) and ethanol dependent saline were also administered to ethanol naive rats. DM (40 mg/kg) did not produce any significant change in locomotor activity in ethanol naive rats. The effects of DM on locomotor activity and total ethanol withdrawal score were evaluated at the fourth and sixth hours of ethanol withdrawal. DM inhibited locomotor hyperactivity at these periods. DM also reduced total ethanol withdrawal score from the fourth hour to the sixth hour, and it significantly decreased audiogenic seizures. Seizure susceptibility after chronic ethanol exposure may be dependent upon sensitization or upregulation of NMDA processes and NMDA receptors. Our results suggest that inhibition of NMDA receptors by DM alleviates signs of ethanol withdrawal.

Acoustic Stimulation↗

PubMed1997

Dextromethorphan blocks opioid peptide gene expression in the rat hippocampus induced by kainic acid.

We have previously shown that dextromethorphan (DM) antagonizes kainic acid (KA)-induced neurotoxicity. Accumulating evidence indicates that the induction of seizure activity causes profound alterations in the levels of hippocampal opioid peptide mRNA. The present study was performed to further explore the effect of DM on KA-induced seizures as measured by hippocampal opioid peptide mRNA levels. Both Northern blot and in situ hybridization methods were used to examine the proenkephalin (PENK) and prodynorphin (PDYN) mRNA levels in the rat hippocampus. The robust seizure activity induced by KA correlated with a significant increase in hippocampal opioid peptide mRNA levels. Pretreatment of rats with DM decreased hippocampal PENK and PDYN mRNA levels and seizure activity induced by KA. Hippocampal PDYN mRNA levels fell quickly but PENK mRNA levels fell rather slowly, indicating that the PENK and PDYN mRNAs are differentially regulated. Our results demonstrate that DM modulates opioid peptide gene expression induced by KA, and that DM protects against KA-induced seizures.

Animals↗

PubMed2004

Dose-response relationship with increasing doses of dextromethorphan for children with cough.

BACKGROUND: The efficacy of dextromethorphan (DM) for treating acute cough is uncertain, and its use is not supported by the American Academy of Pediatrics. Nevertheless, DM is often administered to children as an antitussive. DM dosages are based on age rather than body weight, resulting in substantial variability in the relative amount of drug administered. OBJECTIVE: The aim of this work was to determine whether a dose-response relationship existed among a group of children administered a single nocturnal dose of DM for cough due to an upper respiratory tract infection. METHODS: As part of a larger double-blind, placebo-controlled trial of over-the-counter cough medications, children received DM. The administered doses (per manufacturer recommendations) were as follows: ages 2 to 5 years, 7.5 mg; ages 6 to 11 years, 15 mg; and ages 12 to 18 years, 30 mg. This resulted in a range of 0.35 to 0.94 mg/kg per dose. Subjective parental assessments of cough and sleep were obtained using a 7-point Likert-type scale that compared symptoms after medication with symptoms during the prior night (without medication). Three dose ranges were compared as a subset analysis of the group that received DM. RESULTS: Thirty-three patients (19 girls, 14 boys; median [interquartile range] age, 4.90 [2.90-6.80] years; age range, 2.10-16.50 years) received DM and completed the study. No significant differences were found for any of the outcome measures when comparing the effects of different doses of DM, but our observations suggested somewhat more symptomatic relief for patients receiving medium-dose DM (0.45 to <0.60 mg/kg per dose) or high-dose (HD) DM (0.60-0.94 mg/kg per dose) compared with low-dose DM (0.35 to <0.45 mg/kg per dose). Adverse events occurred most often in the HD group. CONCLUSIONS: Although no statistically significant differences were detectable for the outcomes studied, our observations suggest the potential for improved clinical symptom control with increasing doses of DM. Our findings may further suggest that a dose of 0.5 mg/kg should be considered in future assessments of the antitussive effect of DM in pediatric studies, to balance symptomatic relief with the avoidance of adverse events.

Adolescent↗

PubMed1997

Dextromethorphan phenotyping and haloperidol disposition in schizophrenic patients.

This study examined the relationship between the metabolic ratios of dextromethorphan/dextrorphan, haloperidol disposition, and the incidence of extrapyramidal side effects in schizophrenic patients. Eighteen schizophrenic patients were phenotyped with a test dose of dextromethorphan prior to the initiation of haloperidol treatment. The metabolic ratio of dextromethorphan/dextrorphan was determined in each patient. Patients were treated with oral haloperidol 10 mg/day for 2 weeks. Blood samples for haloperidol and reduced haloperidol were obtained at week 2 of haloperidol treatment. Haloperidol and reduced haloperidol plasma concentrations were assayed by HPLC with electrochemical detection. Significant correlations of dextromethorphan/dextrorphan metabolic ratios vs. plasma haloperidol concentrations, reduced haloperidol concentrations, and reduced haloperidol/haloperidol ratios were found (r = 0.726, P = 0.0007; r = 0.782, P = 0.0001; and r = 0.619, P = 0.006, respectively). Ten patients who experienced extrapyramidal side effects had higher reduced haloperidol concentrations and reduced haloperidol/haloperidol ratios than the other patients (2.49 +/- 1.42 [S.D.] ng/ml vs. 1.10 +/- 0.46 ng/ml, P = 0.014 and 0.287 +/- 0.102 vs. 0.192 +/- 0.065, P = 0.030). The former also had a trend to have higher haloperidol concentrations and dextromethorphan/dextrorphan ratios than the latter (8.04 +/- 2.91 ng/ml vs. 5.83 +/- 1.79 ng/ml, P = 0.066 and 0.023 +/- 0.017 vs. 0.011 +/- 0.010, P = 0.077). Phenotyping patients has the potential to assist clinicians in predicting plasma drug concentrations during the subsequent neuroleptic drug treatment. Further research with phenotyping and psychotropic drug metabolism in psychiatric patients is needed.

Adult↗

PubMed1997

Dextromethorphan ameliorates effects of neonatal hypoxia on brain morphology and seizure threshold in rats.

Hypoxic injury to the brain is mediated in part by NMDA receptors. Therefore, NMDA receptor blockade with dextromethorphan (DM), a non-competitive channel blocker, was hypothesized to ameliorate injury even when given after the hypoxic insult. Rats were exposed to 8% oxygen for 3 h on postnatal day 7. Within 20 min of exposure, animals received 30 mg/kg i.p. DM or normal saline. Littermates maintained in room air for 3 h also received DM or saline. At 14 days of age, 7 days after exposure, cortical thickness and hippocampal area were measured. At 70-90 days of age, approximately two months after exposure, in a separate group of rats, seizure threshold using pentylenetetrazol (PTZ) and passive avoidance learning and retention were determined. There were no gross changes in cellular morphology and no evidence for cellular necrosis in any of the exposure groups. However, cortical thickness was decreased in animals exposed to hypoxia. DM administration prevented this decrease. Hippocampal area was unaffected. Seizure susceptibility in adulthood was increased in animals exposed to hypoxia in the neonatal period. DM prevented the decrease in seizure threshold. There was no difference in passive avoidance learning or retention as a function of neonatal exposure condition. Mild to moderate hypoxia, previously thought not to produce any histologic changes, causes significant short-term loss of cortical thickness and long-term decrease in seizure threshold. DM appears to ameliorate these effects even when given after the hypoxic insult. These results implicate the glutamate receptor system in the pathophysiology of hypoxia damage and suggest that treatment with a glutamate receptor blocker when neonatal asphyxia is suspected would help ameliorate the consequences of such an insult.

Aging↗

PubMed2001

Effects of dextromethorphan on the seizures induced by kainate and the calcium channel agonist BAY k-8644: comparison with the effects of dextrorphan.

BAY k-8644 (an L-type Ca(2+) channel agonist of the dihydropyridine class) is recognized as a potent convulsant agent. In this study, we used BAY k-8644 to explore the effects of dextromethorphan (DM) and its major metabolite, dextrorphan (DX), on the (pro)convulsant activity regulated by calcium channels. BAY k-8644 (2 mg/kg, s.c) potentiated seizures induced in rats by kainic acid (KA) (10 mg/kg, i.p.). DM appears more efficacious than DX in attenuation of KA-induced seizures. The anticonvulsant effect of a low dose (12.5 mg/kg, s.c.) of DM was reversed by BAY k-8644 (2 mg/kg) challenge. In contrast, BAY k-8644 (1 or 2 mg/kg) did not significantly affect an anticonvulsant effect from a higher dose (25 mg/kg) of either DM or DX. Intracerebroventricular injection of BAY k-8644 (37.5 microg) significantly induced seizures in mice. DM (12.5 or 25 mg/kg) pretreatment more significantly attenuated seizures evoked by BAY k-8644 than did DX (12.5 or 25 mg/kg). Furthermore, seizure activity induced by KA or BAY k-8644 was consistent with respective activator protein-1 DNA binding activity of the hippocampus. Therefore, our results suggest that the anticonvulsant effects of the morphinans involve, at least in part, the L-type calcium channel. They also suggest that DM is a more potent anticonvulsant than DX in the KA and BAY k-8644 seizure models.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed2000

Dual effects of dextromethorphan on cocaine-induced conditioned place preference in mice.

Dextromethorphan (DM) at supra-antitussive doses might produce psychotomimetic effects in humans. In order to understand the underlying mechanisms responsible for the behavior induced by DM, we examined the effects of DM on cocaine-induced conditioned place preference (CPP) and locomotor pattern in mice, and Fos-related antigen immunoreactivity (FRA-IR) in the striatal complex (nucleus accumbens and striatum) of the mouse brain. The effects of DM (20 and 40 mg/kg, i.p.) on the CPP for 2.5, 5, 10, and 20 mg cocaine/kg, i.p. were assessed. Pretreatment with DM dose-dependently decreased the CPP for 20 mg cocaine/kg. Similarly, pretreatment with DM appeared to reduce the CPP for 10 mg cocaine/kg, but increase the CPP for 5 mg cocaine/kg. This finding was more pronounced for 2.5 mg cocaine/kg; DM significantly increased the CPP for 2.5 mg cocaine/kg in a dose-related manner. Furthermore, these results were correlated with alterations in the locomotor pattern (marginal activity) and FRA-IR in the striatal complex. Thus, our results suggest that DM exhibits a biphasic effect on the cocaine-induced CPP and locomotor pattern.

Animals↗

PubMed2001

Dextromethorphan increases tyrosine hydroxylase mRNA in the mesencephalon of adolescent rats.

Dextromethorphan (DM), an antitussive widely available in over-the-counter, has been abused mostly in teenage groups at high doses. To examine effects of DM on the reward pathway, we injected a high dose of DM (40 mg/kg; intraperitoneally) into the adolescent rat and measured tyrosine hydroxylase (TH) mRNA by in situ hybridization in the ventral tegmental area (VTA) and the substantia nigra (SN). Remarkable increases in the level of TH mRNA were observed in the VTA and SN 2 h after DM injection. Stereotyped behavior and ataxia increased, and rearing decreased by DM administration. These results suggest that DM-induced increase in TH mRNA expression in mesencephalon contribute to the reinforcing property and the behavioral effects of DM.

Age Factors↗

PubMed1997

Evaluation of dextromethorphan and dextrorphan as a preventive treatment of soman toxicity in mice.

Phencyclidine-like drugs are effective against convulsions and brain lesions related to soman intoxication but induce severe side effects. The well tolerated antitussive dextromethorphan (DM) and its metabolite dextrorphan (DX) have antiepileptic and neuroprotective properties that we evaluated in mice against 2 LD50 of soman in a three-drug pretreatment (atropine sulfate and oxime HI-6 plus DM: 20-50 mg/kg or DX: 10-40 mg/kg i.p). Neuroprotection was evaluated by measurement of hippocampal omega 3 binding site density. DM and DX have weak anticonvulsant and neuroprotective activities which are counterbalanced at high doses by an increased mortality due to respiratory distress for DM and by ataxia for DX. Thus DM and DX do not appear to be appropriate for the pretreatment of soman intoxication.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2002

A randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients.

The NMDA antagonist dextromethorphan hydrobromide (DM) may be useful in the treatment of opioid dependence, particularly as a means of reducing tolerance to methadone during replacement therapy. As a prelude to clinical efficacy studies, a randomized, double-blind, placebo-controlled study examined the safety of DM in combination with methadone in inpatient, opiate-dependent volunteers. Male participants received daily methadone (50-70 mg/day) and either DM (n=10) or placebo (n=5) during the 12-day active medication phase of the study. DM participants received doses of 120, 240, and 480 mg/day in increasing order (4 days each). DM at high doses caused mild elevations of heart rate, blood pressure, temperature, and plasma bromide. However, none of these effects was clinically significant. DM caused no significant changes in respiration, pupil diameter, or subjective drug effects measured by standard scales. Participants in the DM group reported many more adverse events than did subjects on placebo (173 vs. 21), but these effects were not clinically serious. The most commonly reported side effects were sleepiness and drowsiness. Several participants reported intoxicating effects at the highest dose. Overall, DM was well-tolerated by the methadone-maintained opiate-dependent subjects studied here. These results support the further exploration of DM as an adjunct medication during methadone replacement therapy.

Adult↗

PubMed2002

Semi-automated liquid--liquid back-extraction in a 96-well format to decrease sample preparation time for the determination of dextromethorphan and dextrorphan in human plasma.

A semi-automated, 96-well based liquid-liquid back-extraction (LLE) procedure was developed and used for sample preparation of dextromethorphan (DEX), an active ingredient in many over-the-counter cough formulations, and dextrorphan (DOR), an active metabolite of DEX, in human plasma. The plasma extracts were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS-MS). The analytes were isolated from human plasma using an initial ether extraction, followed by a back extraction from the ether into a small volume of acidified water. The acidified water isolated from the back extraction was analyzed directly by LC-MS-MS, eliminating the need for a dry down step. A liquid handling system was utilized for all aspects of liquid transfers during the LLE procedure including the transfer of samples from individual tubes into a 96-well format, preparation of standards, addition of internal standard and the addition and transfer of the extraction solvents. The semi-automated, 96-well based LLE procedure reduced sample preparation time by a factor of four versus a comparable manually performed LLE procedure.

Automation↗

PubMed2002

Simultaneous determination of dextromethorphan, diphenhydramine and phenylephrine in expectorant and decongestant syrups by capillary electrophoresis.

The separation of basic nitrogenous compounds commonly used as active ingredients in cold medicine formulations by micellar electrokinetic capillary chromatography and capillary zone electrophoresis with direct absorptiometric detection was investigated. The type and composition of the background electrolyte (BGE) were investigated with respect to separation selectivity and BGE stability. BGE of 10 mM sodium dihydrogenphosphate-sodium tetraborate buffer containing 10 mM SDS and 10% acetonitrile, pH 9.0 was found to be optimal. Dextromethorphan hydrobhromide, diphenhydramine hydrochloride and phenylephrine hydrochloride were baseline-separated in less than 11 min, giving separation efficiencies of up to 494,000 theoretical plates, reproducibility of corrected peaks areas below 3% relative standard deviation and concentration detection limits from 2.5 to 5.5 microg ml(-1). Detection was performed at 196 and 214 nm.

Chemistry, Pharmaceutical↗

PubMed1998

A sensitive assay of metoprolol and its major metabolite alpha-hydroxy metoprolol in human plasma and determination of dextromethorphan and its metabolite dextrorphan in urine with high performance liquid chromatography and fluorometric detection.

A reverse-phase High Performance Liquid Chromatographic (HPLC) method was developed for the analysis of metoprolol in the large number of human plasma samples obtained in in vitro-in vivo correlations (IVIVC) and bioavailability studies of extended release formulations of metoprolol tartrate. The metabolite, alpha-hydroxy metoprolol (OH-met), could also be quantified. The analytes were extracted from the plasma using solid phase columns, separated on a C-4 analytical column followed by fluorimetric detection. The linearity, precision, accuracy, stability, selectivity and ruggedness were validated for the concentration ranges of 1-400 ng ml-1 for metoprolol and 0.5-200 ng ml-1 for OH-met. The same chromatographic conditions were slightly modified to quantify dextromethorphan and its metabolite dextrorphan in urine in the concentration range 0.052-0.05 microgram ml-1 as a method for screening for fast metabolizers.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

Dextromethorphan- and pseudoephedrine-induced agitated psychosis and ataxia: case report.

Pseudoephedrine and dextromethorphan are therapeutic constituents of numerous commonly used, over-the-counter cough and cold preparations. Although this drug combination is generally considered quite safe if utilized in recommended doses, overmedication or overdose can result in serious neurologic and cardiovascular abnormalities that occasionally can be life-threatening. We present a case of a 2-year-old child who developed hyperirritability, psychosis, and ataxia after being overmedicated with a pseudoephedrine/dextromethorphan combination cough preparation, and discuss probable mechanisms of toxicity and risk factors for adverse events.

Antitussive Agents↗