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PubMed2004

Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase.

Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra and depletion of the neurotransmitter dopamine in the striatum. Progress in the search for effective therapeutic strategies that can halt this degenerative process remains limited. Mechanistic studies using animal systems such as the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rodent PD model have revealed the involvement of the brain's immune cells and free radical-generating processes. We recently reported that dextromethorphan (DM), a widely used anti-tussive agent, attenuated endotoxin-induced dopaminergic neurodegeneration in vitro. In the current study, we investigated the potential neuroprotective effect of DM and the underlying mechanism of action in the MPTP rodent PD model. Mice (C57BL/6J) that received daily MPTP injections (15 mg free base/kg body weight, s.c.) for 6 consecutive days exhibited significant degeneration of the nigrostriatal dopaminergic pathway. However, the MPTP-induced loss of nigral dopaminergic neurons was significantly attenuated in those mice receiving DM (10 mg/kg body weight, s.c.). In mesencephalic neuron-glia cultures, DM significantly reduced the MPTP-induced production of both extracellular superoxide free radicals and intracellular reactive oxygen species (ROS). Because NADPH oxidase is the primary source of extracellular superoxide and intracellular ROS, we investigated the involvement of NADPH oxidase in the neuroprotective effect of DM. Indeed, the neuroprotective effect of DM was only observed in the wild-type but not in the NADPH oxidase-deficient mice, indicating that NADPH oxidase is a critical mediator of the neuroprotective activity of DM. More importantly, due to its proven safety record of long-term clinical use in humans, DM may be a promising agent for the treatment of degenerative neurological disorders such as PD.

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

PubMed2005

Femtomolar concentrations of dextromethorphan protect mesencephalic dopaminergic neurons from inflammatory damage.

Inflammation in the brain has increasingly been recognized to play an important role in the pathogenesis of several neurodegenerative disorders, including Parkinson's disease (PD). Progress in the search for effective therapeutic strategies that can halt this degenerative process remains limited. We previously showed that micromolar concentrations of dextromethorphan (DM), a major ingredient of widely used antitussive remedies, reduced the inflammation-mediated degeneration of dopaminergic neurons through the inhibition of microglial activation. In this study, we report that femto- and micromolar concentrations of DM (both pre- and post-treatment) showed equal efficacy in protecting lipopolysaccharide (LPS) -induced dopaminergic neuron death in midbrain neuron-glia cultures. Both concentrations of DM decreased LPS-induced release of nitric oxide, tumor necrosis factor-alpha, prostaglandin E2 and superoxide from microglia in comparable degrees. The important role of superoxide was demonstrated by DM's failure to show a neuroprotective effect in neuron-glia cultures from NADPH oxidase-deficient mice. These results suggest that the neuroprotective effect elicited by femtomolar concentrations of DM is mediated through the inhibition of LPS-induced proinflammatory factors, especially superoxide. These findings suggest a novel therapeutic concept of using "ultra-low" drug concentrations for the intervention of inflammation-related neurodegenerative diseases.

Animals↗

PubMed2006

3-Hydroxymorphinan, a metabolite of dextromethorphan, protects nigrostriatal pathway against MPTP-elicited damage both in vivo and in vitro.

We investigated the neuroprotective property of analogs of dextromethorphan (DM) in lipopolysaccharide (LPS) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models to identify neuroprotective drugs for Parkinson's disease (PD). In vivo studies showed that daily injections with DM analogs protected dopamine (DA) neurons in substantia nigra pars compacta and restored DA levels in striatum using two different models for PD. Of the five analogs studied, 3-hydroxymorphinan (3-HM), a metabolite of DM, was the most potent, and restored DA neuronal loss and DA depletion up to 90% of the controls. Behavioral studies showed an excellent correlation between potency for preventing toxin-induced decrease in motor activities and neuroprotective effects among the DM analogs studied, of which 3-HM was the most potent in attenuating behavioral damage. In vitro studies revealed two glia-dependent mechanisms for the neuroprotection by 3-HM. First, astroglia mediated the 3-HM-induced neurotrophic effect by increasing the gene expression of neurotrophic factors, which was associated with the increased acetylation of histone H3. Second, microglia participated in 3-HM-mediated neuroprotection by reducing MPTP-elicited reactive microgliosis as evidenced by the decreased production of reactive oxygen species. In summary, we show the potent neuroprotection by 3-HM in LPS and MPTP PD models investigated. With its high efficacy and low toxicity, 3-HM may be a novel therapy for PD.

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

PubMed1992

Toxicological findings in a death involving dextromethorphan and terfenadine.

A case of fatal self-poisoning with dextromethorphan, an antitussive, and terfanadine, an antihistamine H1, is reported. Both drugs were quantified in several postmortem tissues and fluids using capillary gas chromatography coupled to mass spectrometry. Results are discussed in the light of the existing literature.

Adult↗

PubMed1995

National Association of Medical Examiners Pediatric Toxicology (PedTox) Registry Report 3. Case submission summary and data for acetaminophen, benzene, carboxyhemoglobin, dextromethorphan, ethanol, phenobarbital, and pseudoephedrine.

Data are presented from the National Association of Medical Examiners' (St. Louis, MO, U.S.A.) Pediatric Toxicology (PedTox) Registry. A total of 839 case reports have been submitted to the registry. Reported here are the concentrations of several drugs and potentially toxic substances observed in children who have died of various causes, often non-drug-related. Except for carbon monoxide, for each of the substances addressed in this report, there is insufficient information in the literature to distinguish "lethal" from "non- or sublethal" concentrations in children, and the data are presented only to provide a working frame of reference. For 30 infants whose deaths were attributed to causes other than phenobarbital, the median blood phenobarbital concentration was 7.8 mg/L, with a range of 0.1-22.4 mg/L. For eight infants whose deaths were not attributed to ethanol, the mean blood ethanol concentration was 0.029 gm/dl and ranged from 0.011 gm/dl to 0.050 gm/dl. Blood dextromethorphan concentrations in seven infants showed a mean of 0.38 mg/L and ranged from 0.10 mg/L to 0.95 mg/L. In 15 infants, blood pseudoephedrine concentrations ranged between 0.07 mg/L and 13.0 mg/L, with a mean concentration of 3.55 mg/L. Blood carboxyhemoglobin saturations for 38 children aged < or = 5 years, who died in fires and were dead on the scene and not resuscitated, ranged between 29% and 94%, with a mean saturation of 64%. Blood benzene concentrations in eight children aged < or = 6 years who died in fires and were dead on the scene showed a mean concentration of 2.3 mg/L and a range of 0.2-4.9 mg/L. For 33 children aged < or = 5 years whose deaths were attributed to nondrug causes, the mean blood acetaminophen concentration was 9.9 mg/L, and the range was 1.0-34.5 mg/L. These data are not well controlled in terms of testing methodology or cause of death determinations and should not be used as the sole source of information when assessing whether or not a death is caused by one of these substances. Further data and controlled studies are needed to work toward establishing lethal concentrations of certain drugs and toxic substances in children, and the reporting of cases to the PedTox Registry is encouraged.

Acetaminophen↗

PubMed2002

Dextromethorphan reduces immediate and late postoperative analgesic requirements and improves patients' subjective scorings after epidural lidocaine and general anesthesia.

Central N-methyl-D-aspartate receptors modulate postoperative pain. We compared the effects of preincision oral dextromethorphan (DM), an N-methyl-D-aspartate receptor antagonist, on postoperative IV patient-controlled analgesia morphine demand and on subjective variables in 80 patients undergoing lower-body procedures who were randomly assigned to epidural lidocaine (LA; 16 mL, 1.6%) or general anesthesia (GA). The patients were premedicated 90 min before surgery with placebo or DM 90 mg (20 patients per group) in a double-blinded manner. Postoperative IV patient-controlled analgesia morphine administration started when subjective pain intensity was > or =4 of 10 (visual analog scale) and lasted 2 h. Observation continued up to 3 days, during which patients could use diclofenac. LA-DM and GA-DM patients required 45%-50% less morphine and diclofenac compared with their placebo counterparts (P < 0.001). However, GA-DM patients made twice as many attempts to self-administer morphine as LA-DM patients (P = 0.005). Eight LA-DM versus two GA-DM patients (P < 0.01) used no morphine or diclofenac. All DM patients experienced significantly (P < 0.001) less pain, were less sedated, and felt better than their placebo counterparts; however, compared with placebo, DM improved subjective scorings in the GA patients more significantly (P < 0.05) than in the LA patients. We conclude that oral DM 90 mg in patients undergoing surgery under LA or GA reduces morphine and diclofenac use by approximately 50% in the immediate and late postoperative period compared with placebo. Subjectively scored levels of pain, sedation, and well-being were better as well.

Aged↗

PubMed1994

Dextromethorphan inhibits ischemia-induced c-fos expression and delayed neuronal death in hippocampal neurons.

BACKGROUND: Dextromethorphan (DM), a widely used antitussive agent, has been shown to possess both anticonvulsant and neuroprotective properties functionally related to its inhibitory effects on glutamate-induced neurotoxicity. The current study was designed to determine whether DM administration prevents delayed neuronal degeneration in central nervous system areas after global forebrain ischemia and whether this correlates with inhibition of induction of the immediate early gene c-fos. METHODS: Mongolian gerbils, anesthetized with 2% halothane in air at 37 degrees C, received either 0.9% sodium chloride (vehicle, n = 9) or 50 mg/kg DM in vehicle (n = 9) by intraperitoneal injection before bilateral carotid artery occlusion. After 1 h of reperfusion under anesthesia, the animals were killed and the brains removed. Immunohistochemistry was used to detect neurons expressing Fos protein. Computer-assisted image analysis quantified changes in the number of labeled neurons as a function of drug treatment. To determine the extent of delayed neuronal degeneration within the hippocampus, other animals were treated with either DM (n = 7) or vehicle (n = 6) before carotid artery occlusion and allowed to survive for 1 week. RESULTS: Global forebrain ischemia produced consistent patterns of Fos-like immunoreactivity in the hippocampus and neocortex of vehicle-treated animals. DM inhibited the induction of c-fos from 65% to 91%. DM also protected against delayed neuronal degeneration in the CA1 region of the hippocampus (P < 0.001). CONCLUSIONS: The induction of nuclear-associated Fos protein represents a sensitive marker of cellular responses to ischemia and a method to assay the effectiveness of pharmacologic interventions. DM markedly inhibited ischemia-induced Fos expression and prevented cell death in CA1. DM given before conditions of ischemia or decreased central nervous system perfusion may be highly beneficial.

Animals↗

PubMed1988

Simplified phenotyping with dextromethorphan by thin-layer chromatography: application to clinical laboratory screening for deficiencies in oxidative drug metabolism.

Identifying individuals with a deficient capacity for oxidative drug metabolism is of increasing clinical importance. Dextromethorphan (DM) is gaining wide acceptance as a probe drug to characterize individual expression of a specific cytochrome P-450 isozyme. The thin-layer chromatography (TLC) technique described in the present study is a rapid and inexpensive alternative to the methods currently available for assessing the urinary metabolic profile of DM. Sixty-five healthy volunteers participated in the study by ingesting 213 mmol DM and collecting all urine for the ensuing 8 h. Urine samples were analyzed by TLC and high-performance liquid chromatography (HPLC) after treatment with beta-glucuronidase. Based on the relative color intensities of DM and its O-demethylated metabolite, dextrorphan, the TLC analysis provided an accurate phenotype assessment. A greater intensity of the parent drug relative to the metabolite indicates a poor metabolizer phenotype whereas a reversed relative intensity indicates the extensive metabolizer phenotype. The phenotype assignments made by TLC were verified by comparison with the quantitative results (based on metabolic ratios) obtained from HPLC analysis. Complete agreement was found between the two methods. The routine implementation of phenotype determination into clinical protocols can be realized with this facile TLC technique.

Adolescent↗

PubMed2003

NMDA-receptor antagonism via dextromethorphan and ifenprodil modulates graded anxiety test performance of C57BL/6 mice.

The majority of N-methyl-D-aspartate receptors (NMDA-R) in the adult forebrain are di- or triheteromers composed of NR1, NR2A and NR2B subunits. Subunit non-selective NMDA-R antagonists produce anxiolytic-like effects together with motor and sensory side-effects. The graded anxiety test (GAT), permits the within-task distinction of drug effects on anxiety from those on activity and perception. By testing NMDA-R subunit selective agents in the GAT it might be possible to determine whether their effects on anxiety, activity and perception are interrelated, and whether separate NMDA-R subtypes are involved. Dextromethorphan (weakly NR2A-selective) (10 and 30 mg/kg, i.p.) and ifenprodil (highly NR2B-selective) (1, 3 and 5 mg/kg, i.p.) were tested in the GAT. Both drugs failed to induce anxiolysis devoid of side-effects. However, the 10 mg/kg dose of dextromethorpan showed an anxiolytic, whereas the 30 mg/kg dose showed an anxiogenic, behavioral profile. Since the selective blockade of the NR2B subunit by ifenprodil had no clear anxiolytic effect, the anxiolytic potential of NMDA subunit non-selective agents might involve NR2A-containing receptors.

Animals↗

PubMedDate not supplied

Preoperative cotreatment with dextromethorphan and ketorolac provides an enhancement of pain relief after laparoscopic-assisted vaginal hysterectomy.

OBJECTIVES: Both N-methyl-D-aspartate receptor antagonists and nonsteroidal anti-inflammatory drugs have been demonstrated to produce better postoperative pain relief. The concept of multimodal analgesia has also been used for clinical pain management. The aim of the present study was to examine the analgesic effect of preoperative cotreatment with dextromethorphan (DM) and ketorolac on postoperative pain management after laparoscopic-assisted vaginal hysterectomy (LAVH). METHODS: Eighty ASA physical status I or II patients scheduled for LAVH were included and randomly assigned to 1 of 4 groups. Patients received intramuscular (IM) chorpheniramine 20 mg+ intravenous (IV) 2 mL of normal saline, IM DM 40 mg+IV 2 mL of normal saline, IM chorpheniramine 20 mg+IV 60 mg (2 mL) of ketorolac, and IM DM 40 mg+IV ketorolac 60 mg as the groups C, DM, Keto, and DM+Keto, respectively. All patients were given a patient-controlled analgesia (PCA) with morphine for pain relief postoperatively. Analgesic effects were evaluated using Visual Analog Scale pain scores at rest and during coughing, time to first PCA request for pain relief, total morphine consumption, bed rest time, and the time to first passage of flatus for 48 hours after surgery. RESULTS: Patients in DM and Keto groups had significantly better pain relief than patients in group C. Patients in DM+Keto group exhibited the best postoperative pain relief among groups in the following several categories: time to first trigger of PCA, total morphine consumption, the worst Visual Analog Scale, bed rest time, and the time to first passage of flatus, demonstrating an enhanced effect between DM and ketorolac. Neither synergistic nor antagonistic interaction was observed between DM and ketorolac. DISCUSSION: Preoperative treatment with both DM and ketorolac diminish postoperative pain. Our results suggest that the N-methyl-D-aspartate antagonist-DM and the nonsteroidal anti-inflammatory drugs-ketorolac cotreatment provide an enhancement of analgesia for postoperative pain management in patients after LAVH surgery.

Adult↗

PubMed1991

Differential foetal development of the O- and N-demethylation of codeine and dextromethorphan in man.

1. Codeine and dextromethorphan were N-demethylated in human foetal liver microsomes at high rates which were close to the activities in adult livers. In contrast, foetal liver microsomes did not catalyze the O-demethylation of these drugs at mid-gestation. 2. The metabolic data were in accordance with the absence of P450IID6 and the presence of P450 IIIA as determined by Western blotting with anti-human P450 IID6 (MAb 114/2) and anti-rat P450 IIIA (PCN 2-13-1/C2) monoclonal antibodies, respectively. 3. The inhibitory effects of midazolam and dehydroepiandrosterone support the contention that the N-demethylase is a human foetal form of the cytochrome P450 IIIA family. Consistent with this we found that blotting with the MAb PCN 2-13-1/C2, which recognizes an epitope specific for the P450 III family, correlated well with the N-demethylase activities.

Antibodies, Monoclonal↗

PubMed1996

Single and multiple dose pharmacokinetics of nefazodone in subjects classified as extensive and poor metabolizers of dextromethorphan.

1. The single and multiple dose pharmacokinetics of nefazodone (NEF) and its active metabolites hydroxynefazodone (HO-NEF) and m-chlorophenyl-piperazine (mCPP) were evaluated in subjects classified as extensive metabolizers (EM) or poor metabolizers (PM) of dextromethorphan. 2. In a parallel design study, 10 subjects from each phenotype received either 50 mg or 200 mg oral doses of NEF as single doses on Day 1 and multiple (twice daily) doses on Days 12-22. 3. Serial plasma and urine samples were collected at specified time intervals after dosing on Days 1, 16, 18, 20 and 22. Plasma samples were analyzed for NEF, HO-NEF and mCPP. Urine samples were analyzed for mCPP and its metabolite p-hydroxy-mCPP (p-HO-mCPP) before and after hydrolyzing the samples with beta-glucuronidase. 4. For the 200 mg dose group, the single dose plasma results showed no significant differences in pharmacokinetic parameters for NEF and HO-NEF in EM compared with PM subjects. However, for mCPP, Cmax was 89 ng ml-1 in the PM subjects compared with 44 ng ml-1 in the EM subjects, AUC was higher in the PM than EM subjects (1642 ng ml-1 h and 412 ng ml-1 h, respectively), and mCPP elimination half-life increased from 6.1 h in the EM subjects to 16.4 h in the PM subjects. Upon multiple dosing, plasma levels for NEF and all metabolites reached steady state within 3 days of dosing in both groups of subjects. Steady state pharmacokinetic parameters for NEF and HO-NEF in EM and PM subjects were not significantly different. The steady state Cmax and AUC values for mCPP in the PM subjects were 182 ng ml-1 and 1706 ng ml-1 h, respectively, compared with 49.6 ng ml-1 and 182 ng ml-1 h in the EM subjects. 5. The cumulative urinary excretion of mCPP and p-HO-mCPP was different for EM and PM subjects. Excretion of total mCPP and total p-HO-mCPP was approximately four-fold lower and five-fold higher, respectively, in the EM subjects than PM subjects. 6. These results indicate that the conversion of mCPP to p-HO-mCPP is attributable to metabolism by cytochrome P450 2D6. The differences in mCPP pharmacokinetic parameters in PM subjects did not affect the time required for NEF and its metabolites to attain steady state or the number of adverse experiences in either group of subjects. Based on the results of this study, NEF may be dosed to EM and PM patients without regard to their cytochrome P450 2D6 phenotype.

Adult↗

PubMed2004

Influence of concomitant quinidine administration on dextromethorphan disposition in rats.

High doses of dextromethorphan (DM) have been clinically investigated for the treatment of multiple neuronal disorders including neuropathic pain. Several authors have suggested the concomitant administration of DM and a CYP2D6 reversible inhibitor in order to enhance the exposure of DM and limit the exposure to total dextrorphan (DX). The present study proposes to determine whether or not a single dose of quinidine is sufficient to enhance the plasma concentrations of DM in rats and keep those of DX at a minimal level. Oral doses of DM (50 mg/kg) were administered with increasing dose levels of quinidine (0, 2, 20, and 50 mg/kg) to male Sprague-Dawley rats and blood samples were collected over 24 h. Plasma concentrations of DM and total DX were determined using ESI-LC/MS/MS. Quinidine coadministration resulted in a more than twofold increase in the area under the curve of DM with an ED(50) of approximately 2 mg/kg whereas those of total DX were only increased by 21%. These results support the working hypothesis that a single dose of quinidine may enhance the plasma concentrations of DM relative to those of total DX and may therefore improve the treatment of neuropathic pain.

Animals↗

PubMed2004

Analgesic effects of preincisional administration of dextromethorphan and tenoxicam following laparoscopic cholecystectomy.

BACKGROUND: Pre-incisional treatment with either N-methyl-D-aspartate (NMDA) receptor antagonists or non-steroidal anti-inflammatory drugs (NSAIDs) improves postoperative pain relief. This study examines the effect on postlaparoscopic cholecystectomy (LC) pain of a combination of dextromethorphan (DM), a NMDA-receptor antagonist, and tenoxicam, a NSAID, given preoperatively. METHODS: Eighty-eight ASA I or II patients scheduled for LC were entered into a randomized, double-blind study and randomly allocated to one of four groups. Controls received 20 mg (4 ml) of chlorpheniramine maleate (CPM) IM and 4 ml of normal saline (N/S) IV. Group DM received 40 mg of DM (containing 20 mg of CPM) IM and 4 ml of N/S IV. Group T were given CPM 20 mg IM, and tenoxicam 40 mg (4 ml) IV. Group DM + T were given DM 40 mg (containing 20 mg of CPM) IM, and tenoxicam 40 mg IV. All treatments were given 30 min before skin incision. Analgesic effects were evaluated by Visual Analog Scale (VAS) pain scores at rest and during coughing, at 1, 2, 4, 12, 24 and 48 h after surgery. The time to the first request for meperidine for pain relief, and total meperidine consumption, were recorded for 48 h after surgery. RESULTS: Compared to controls, patients given DM and DM + T first requested meperidine significantly later, had lower meperidine consumption, made fewer requests for meperidine, and had lower pain scores. There were significant differences between the DM + T and T groups at 2 and 4 h in both resting and incident VAS pain scores, the incidence of meperidine requests and the time to first meperidine injection. There were significant differences between groups DM and T at 1 h for resting pain and at 2 and 4 h for incident pain. Except for a significant difference in the incident pain score 1 h after surgery, there were no other differences in pain scores between the DM and DM + T groups. Neither synergistic nor antagonistic interaction was observed between DM and tenoxicam. CONCLUSIONS: The results suggest that pretreatment with DM, but not tenoxicam, provides significant pre-emptive analgesia for postoperative pain management in patients after LC surgery. Combining DM and tenoxicam also gives good pain relief.

Adult↗

PubMed2006

A qualitative systematic review of peri-operative dextromethorphan in post-operative pain.

BACKGROUND: The N-methyl-D-aspartate (NMDA) receptor antagonist, dextromethorphan (DM), has received interest as an adjunctive agent in post-operative pain management. Clinical trials have been contradictory. This systematic review aims to evaluate the available literature examining the analgesic efficacy of DM in post-operative patients. METHODS: Twenty-eight randomized, double-blind, clinical studies, with 40 comparisons, including a variety of dosing regimens comparing DM treatment with placebo, were included. Meta-analysis was intended but deemed to be inappropriate because of the substantial difference in methodology and reporting between trials. The outcome measures (pain scores at rest, time to first analgesic request and supplemental analgesic consumption) were evaluated qualitatively by significant difference (P<0.05) as reported in the original investigations. RESULTS: DM did not reduce the post-operative pain score with a clinically significant magnitude. The time to first analgesic request was significantly prolonged in most comparisons with DM. Significant decreases in supplemental opioid consumption were observed in the majority of parenteral DM studies and in about one-half of the oral studies. The decreases were of questionable clinical importance in most comparisons, although a relationship between a decrease in opioid consumption and opioid-related side-effects was established in some studies. CONCLUSION: Based on the studies available, DM has the potential to be a safe adjunctive agent to opioid analgesia in post-operative pain management, but the consistency of the potential opioid-sparing and pain-reducing effect must be questioned. Consequently, it is not possible to recommend dose regimens or routine clinical use of DM in post-operative pain. The route of administration may be important for the beneficial effect.

Analgesics, Opioid↗

PubMed1998

Dextromethorphan and dextrorphan in rats: common antitussives--different behavioural profiles.

Dextromethorphan (DM), a widely used and well-tolerated centrally acting antitussive, has been tested in several clinical trials for its antiepileptic and neuroprotective properties. However, the use of DM in these new clinical indications requires higher doses than antitussive doses, which may therefore induce phencyclidine (PCP)-like side-effects (memory and psychotomimetic disturbances) through its metabolic conversion to the active metabolite dextrorphan (DX), a more potent PCP-like non-competitive antagonist at the N-methyl-D-aspartate (NMDA) receptor than DM. Thus, we compared the behavioural effects in rats of intraperitoneal administration of DM and DX on motor activity in an open field and on learning and memory in the Morris water maze. DM (20, 30, 40 mg/kg) produced a dose-dependent decrease in both locomotion and stereotyped behaviour with a slight ataxia for the highest dose. DX (20, 30, 40 mg/kg) induced a dose-dependent increase in locomotion and stereotypies (swaying, turning) with moderate ataxia. Assessments of learning and memory were performed with lower doses of DM (10, 20, 30 mg/kg) and DX (5, 10, 15 mg/kg) because of motivational deficits (40 mg/kg of DM, 20-40 mg/kg of DX) and motor disorders (30, 40 mg/kg of DX) in the cue learning procedure. DX (10, 15 mg/kg) impaired spatial learning with a long-lasting effect for the highest dose whereas 5 mg/kg of DX and DM (10-30 mg/kg) did not. Only 15 mg/kg of DX appeared to slightly impair working memory. DM (10-30 mg/kg) and DX (5-15 mg/kg) did not impair reference memory. Thus, the two antitussives DM and DX induced different behavioural effects suggesting sedative effects for DM and PCP-like effects for DX. However, PCP-like side-effects with DM remain possible through its metabolic conversion to DX, with very high doses and/or in extensive metabolizers and/or in aged subjects prone to cognitive dysfunction. Therefore, the identification of DM metabolism phenotype, an adapted prescription and a pharmacological modulation of the DM metabolism may avoid adverse effects.

Animals↗

PubMed1999

Intra-individual variability and influence of urine collection period on dextromethorphan metabolic ratios in healthy subjects.

The aim of the study was to evaluate intra-individual variability in metabolic ratios (MRs) of dextromethorphan (DM) in healthy volunteers and to compare the MRs in urine collected 0-4, 0-8 and 0-24 h post-dose. Urinary molar ratios of DM to dextrorphan (MR1) and of DM to methoxymorphinan (MR2) were obtained after a single oral 27.5 mg dose of DM hydrobromide to ten healthy male and four female Caucasians (ten extensive metabolizers (EM) and four poor metabolizers (PM) of DM) to probe activities of CYP2D6 and CYP3A, respectively. Seven EM and one PM received DM on three additional occasions within 2 months. For the seven EM, the intra-individual variability (CVw) in the MRs obtained in the three urine collections ranged from 11 to 93% (MR1) and from 8 to 77% (MR2). The mean CVw estimated separately for the 4, 8 and 24 h urines by two-way analysis of variance reached 58, 57 and 44% for the MR1 and 50, 42 and 31% for the MR2, respectively. For all 14 subjects, the log-transformed ratios (MR1) obtained in the 24 h urines were highly correlated with those in either the 8 h (rs = 0.967, P < 0.0001) or 4 h urines (rs = 0.946, P < 0.0001). Correlation between the log-transformed MR2s were weaker (24 h vs. 8 h: rs = 0.829, P < 0.0001, 24 h vs. 4 h: rs = 0.831, P < 0.0001). The MR1s in 4 h and 8 h urines were only 2 and 9% less than those in 24 h urines (median differences) and varied from 48 and 47% below to 85 and 55% above (95% -CI for the differences). However, the MR2s in the 4 h and 8 h urines were shifted towards higher values by 49 and 23% and the corresponding 95% -CI limits were: 16-164% (4 h vs. 24 h) and 30-119% (8 h vs. 24 h). In conclusion, MR1 values in the 4 h urine collection agree well with those in longer collections and their use in epidemiological studies can be recommended. The intra-individual variability of approximately 50% in the MR1 has to be taken into account in clinical studies with within-subject design. Accurate determination of the MR2 requires at least a 24 h period of urine collection.

Aryl Hydrocarbon Hydroxylases↗

PubMedDate not supplied

Effects of dextromethorphan, a nonopioid antitussive, on development and expression of amygdaloid kindled seizures.

The effects of dextromethorphan (DM), a nonopioid antitussive and a functional N-methyl-D-aspartate (NMDA) antagonist, on expression and development of amygdaloid kindled seizures were examined. The maximum anticonvulsant effect of DM (30 mg/kg) on fully kindled seizures appeared within 30 min of administration and lasted for at least 2 h. DM decreased, in a dose-dependent manner [10-70 mg/kg, intraperitoneally (i.p.)], the severity of kindled seizures 30 min after injection, but the estimated ED50 was 3 times higher than the previously reported value for maximal electroshock convulsions. Furthermore, the high dose (70 mg/kg), while suppressing kindled seizures, produced myoclonus which coincided with EEG spike activity in the amygdala and the cortex. When tested on the development of kindling, 30 mg/kg DM retarded the growth of afterdischarge in the amygdala and the cortex, but had no effect on the development of behavioral seizures. DM 60 mg/kg accelerated development of kindling and produced spontaneous seizures. These results indicate that DM, unlike other NMDA antagonists, has a narrow therapeutic window as an anticonvulsant on kindled seizures and that higher doses may potentiate the kindling process.

Amygdala↗