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PubMed1999

Preincisional dextromethorphan treatment decreases postoperative pain and opioid requirement after laparoscopic cholecystectomy.

UNLABELLED: In the present study, we examined whether preincisional treatment with dextromethorphan (DM) provides preemptive analgesia. Ninety patients scheduled for laparoscopic cholecystectomy were included. Patients receiving chlorpheniramine maleate (CPM) 20 mg via an IM injection 30 min before skin incision were designated as the control group. Patients in Group A received DM 40 mg (containing CPM 20 mg) IM after removal of the gallbladder, whereas in Group B, DM 40 mg (containing CPM 20 mg) was administered IM 30 min before skin incision. Meperidine (1 mg/kg IM) was given for postoperative pain relief as required. Times to first meperidine injection, total meperidine consumption, worst pain score, bed rest time, and side effects were recorded for 48 h after surgery. Times to first meperidine injection were 9.3+/-15.9, 17.4+/-3.4, and 28.6+/-3.9 h for the control group and Groups A and B, respectively. The total meperidine consumption was 90.7+/-11.9, 77.5+/-12.7, and 20.0+/-4.4 mg for the control group and Groups A and B, respectively. The worst visual analog pain scores were 6.0+/-0.2, 6.0+/-0.2, and 4.0+/-0.4 for the control group and Groups A and B, respectively. The bed rest times were 21.0+/-0.5, 20.0+/-0.5, and 19.0+/-0.4 h for the control group and Groups A and B, respectively. The number of patients who required meperidine injection was 26, 22, and 12 for the control group and Groups A and B, respectively. We conclude that DM is more effective in producing postoperative analgesia when it is administered preincision rather than after the gallbladder removal treatment, which suggests a preemptive analgesic effect. IMPLICATIONS: Preincisional dextromethorphan (40 mg IM) treatment offers a preemptive analgesic effect, thus improving the postoperative pain management.

Analgesics, Opioid↗
PubMed1998

Dextromethorphan potentiates the effect of morphine in rats with peripheral neuropathy.

Neuropathic pain responds poorly to opioids. We now report that combination of systemic morphine (2 mg/kg) and dextromethorphan (45 mg/kg), a clinically available antitussive with NMDA-antagonist properties, markedly alleviated mechanical and cold allodynia-like behavior in a rat model of peripheral mononeuropathy. Neither drug produced a significant effect on its own at these doses. The anti-allodynic effect of morphine plus dextromethorphan was reversed by naloxone. The present results suggest that a combination of NMDA-antagonist and opiates might be effective in treating neuropathic pain. Furthermore, the effect of this drug combination is mainly mediated via opioid receptors.

Analgesics, Opioid↗
PubMed1992

Tolerability of oral dextromethorphan in patients with a history of brain ischemia.

Twelve patients with a history of cerebral ischemia were randomized to treatment with the N-methyl-D-aspartate antagonist dextromethorphan (60 or 90 mg p.o. q.i.d.) or placebo for 2 weeks in a randomized, safety study. Neuropsychological testing did not detect evidence of cognitive dysfunction; however, side effects including lightheadedness, drowsiness, nausea, decreased coordination, and unsteady gait were reported by several patients while taking dextromethorphan.

Aged↗
PubMed1990

Simultaneous determination of dextromethorphan and three metabolites in plasma and urine using high-performance liquid chromatography with application to their disposition in man.

A simple, sensitive, and reproducible high-performance liquid chromatrography assay is described for the simultaneous determination of dextromethophan, dextrorphan, 3-hydroxymorphinan, and 3-methoxymorphinan in plasma and urine. A conventional solvent-solvent extraction procedure was used for the isolation of the analytes from plasma and urine samples. The compounds were separated on a cyano column (150 x 4.6 mm, 5-micron particle size) using a mobile phase of acetonitrile/triethylamine/distilled water (17:0.06:82.94, vol/vol), pH 3.0, and then were measured by fluorescence detection. Calibration curves in the range 2-200 ng/ml for plasma and 0.05-10 micrograms/ml for urine were linear and passed through the origin. The precision and accuracy were greater than 90% and the lowest detectable concentrations were 0.5 ng/ml for 3-hydroxymorphinan and 3-methoxymorphinan and 1 ng/ml for dextromethorphan and dextrophan in plasma. The utility of this method is demonstrated in a preliminary study of dextromethorphan metabolism and pharmacokinetics in man.

Chromatography, High Pressure Liquid↗
PubMed2001

Pharmacokinetic drug interaction potential of risperidone with cytochrome p450 isozymes as assessed by the dextromethorphan, the caffeine, and the mephenytoin test.

Two published case reports showed that addition of risperidone (1 and 2 mg/d) to a clozapine treatment resulted in a strong increase of clozapine plasma levels. As clozapine is metabolized by cytochrome P450 isozymes, a study was initiated to assess the in vivo interaction potential of risperidone on various cytochrome P450 isozymes. Eight patients were phenotyped with dextromethorphan (CYP2D6), mephenytoin (CYP2C19), and caffeine (CYP1A2) before and after the introduction of risperidone. Before risperidone, all eight patients were phenotyped as being extensive metabolizers of CYP2D6 and CYP2C19. Risperidone at dosages between 2 and 6 mg/d does not appear to significantly inhibit CYP1A2 and CYP2C19 in vivo (median plasma paraxanthine/caffeine ratios before and after risperidone: 0.65, 0.69; p = 0.89; median urinary (S)/(R) mephenytoin ratios before and after risperidone:0.11, 0.12; p = 0.75). Although dextromethorphan metabolic ratio is significantly increased by risperidone (median urinary dextromethorphan/dextrorphan ratios before and after risperidone: 0.010, 0.018; p = 0.042), risperidone can be considered a weak in vivo CYP2D6 inhibitor, as this increase is modest and none of the eight patients was changed from an extensive to a poor metabolizer. The reported increase of clozapine concentrations by risperidone can therefore not be explained by an inhibition of CYP1A2, CYP2D6, CYP2C19 or by any combination of the three.

Adult↗
PubMed1989

Dextromethorphan: polymorphic serum pattern of the O-demethylated and didemethylated metabolites in man.

1. The interindividual differences in serum concentrations of dextromethorphan (DM) and its metabolites were studied in 29 healthy subjects given 120 mg orally. They were also phenotyped according to the urinary ratio of debrisoquine and 4-hydroxy-debrisoquine. 2. Four (14%) subjects were found to be poor metabolizers (PM) with a dextromethorphan/dextrorphan metabolite ratio in plasma of 3.6 or more compared with extensive metabolizers (EM) with a ratio of 0.11 or less. Significant levels of 3-hydroxymorphinan were measurable in all individuals except two, both of whom were PMs. This subdivision corresponded to the phenotype determined by the metabolic ratio of debrisoquine (r = 0.92). 3. Twelve of the 29 subjects reported adverse drug reactions after dextromethorphan administration compared with none after placebo.

Adult↗
PubMed1989

Extensive oxidative metabolism of dextromethorphan in patients with almitrine neuropathy.

Almitrine bismesylate can induce a stereotypical sensory peripheral neuropathy probably through a toxic mechanism. High plasma concentrations of almitrine have been reported in a patient with neuropathy. Since large inter-individual variations in plasma drug concentrations are found it is possible that the development of toxicity may be linked to genetically determined polymorphic oxidation of the drug. Oxidation phenotyping was performed in fifteen patients with almitrine neuropathy using dextromethorphan, a test compound subject to oxidative metabolism similar to that of debrisoquine. All patients were of the extensive metaboliser phenotype. This result shows that, in contrast to perhexiline neuropathy, almitrine neuropathy is not related to slow oxidation of the compound with regard to the particular P-450 iso-enzyme involved in dextromethorphan and debrisoquine metabolism.

Aged↗
PubMed1995

Patient-controlled analgesia (PCA) with codeine for postoperative pain relief in ten extensive metabolisers and one poor metaboliser of dextromethorphan.

Postoperative pain relief with codeine was evaluated in 11 women undergoing hysterectomy. Patient-controlled analgesia (PCA) was used to administer codeine. After the study the patients were phenotyped with respect to the O-demethylation of dextromethorphan (cytochrome P4502D6 polymorphism). Ten were extensive metabolisers and one a poor metaboliser. There was a nine-fold variation in the minimum plasma concentration of codeine consistent with pain relief (40-350 ng ml-1). Two patients did not experience any effect of codeine, one of whom was a poor metaboliser of dextromethorphan, confirmed by genotyping. In the other nine patients the effective dose of codeine varied from 4.8-25.3 mg h-1.

Adult↗
PubMed2001

Pharmacokinetics of sabeluzole and dextromethorphan oxidation capacity in patients with severe hepatic dysfunction and healthy volunteers.

AIMS: The primary objective of this study was to determine how the pharmacokinetics of sabeluzole, an investigational drug with specific effects on memory and learning abilities, are affected by chronic liver disease. Since sabeluzole is metabolised by CYP2D6, a secondary objective was to study the correlation between CYP2D6 activity (as assessed by the dextromethorphan dextrorphan metabolic ratio) and hepatic dysfunction. METHODS: The single-dose pharmacokinetics of sabeluzole (10 mg) was compared in 10 healthy Caucasian subjects and 10 patients with severe hepatic dysfunction. The urinary dextromethorphan/dextrorphan (DMP/DRP) metabolic ratio was determined after intake of 20 mg dextromethorphan (NODEX capsules). RESULTS: The terminal half-life of sabeluzole was significantly prolonged in subjects with severe hepatic dysfunction vs healthy subjects (respectively 39.3 +/- 11.5 h; 17.5 +/- 10.2 h (mean +/- s.d.)). The areas under the curve (AUC) were significantly higher in subjects with severe hepatic dysfunction than in healthy volunteers (681 +/- 200 ng ml(-1) h vs 331 +/- 282 ng ml(-1) h). There was a significant correlation between the AUC(0,infinity) and the DMP/DRP metabolic ratio in healthy volunteers and subjects with severe hepatic dysfunction. AUC was greater and elimination of sabeluzole slower in poor metabolizers compared with extensive metabolizers. CONCLUSIONS: These results suggest that a) sabeluzole dose should be reduced in patients with severe hepatic dysfunction and b) the AUC of sabeluzole is linked to individual CYP2D6 activity.

Adult↗
PubMed2007

Apomorphine-induced growth hormone response is attenuated by ethanol but not dextromethorphan.

BACKGROUND: Misuse of alcohol drinking is a major health problem. Alcohol decreases spontaneous growth hormone (GH) secretion, but the mechanism is unclear. The aim of this study was to test whether administration of alcohol (study 1) or a N-methyl d-aspartate (NMDA) receptor antagonist (study 2) attenuates the GH response to pharmacological dopaminergic stimulation. METHODS: The 2-session repeated measures design was conducted at the endocrine laboratory at the Department of Psychiatry at the Free University Berlin. Twenty healthy Caucasian males aged 35+/-10 years without a history of alcohol use disorders were tested using the Apomorphine (APO) challenge test. In study 1, we injected APO (0.01 mg/kg s.c.) 1 hour after oral administration of 1 g/kg ethanol and placebo, respectively. In study 2, the APO challenge was conducted after 0.3 mg/kg dextromethorphan (DXM) and placebo. The main outcome measures were the peak serum GH concentration and area under the time/concentration curve up to 120 minutes after APO. The effects of ethanol and DXM were tested using the Wilcoxon signed-rank tests. RESULTS: Compared with placebo, alcohol significantly decreased the APO-induced GH release (mean and SEM peak GH concentration 19.9+/-3.2 vs 6.2+/-1.9 ng/mL, p=0.002). Dextromethorphan did not change APO-induced GH response (22.5+/-5.4 vs 21.0+/-5.8 ng/mL, p=0.105). CONCLUSION: A single intermediate alcohol dose markedly reduces GH response to dopaminergic stimulation. Although alcohol is thought to stimulate dopaminergic function in certain pathways, but not necessarily in the hypothalamus, our results are in line with the alcohol effect on baseline GH secretion. Growth hormone suppression appears not to be mediated by ethanol's NMDA-antagonistic properties.

Adult↗
PubMed2006

Additive effect of dextromethorphan on the inhibitory effect of anti-NT4 on morphine tolerance.

It has been proposed that opioid tolerance is a model of neuronal plasticity similar to learning and memory. Recent evidence suggests that neurotrophins may be involved in synaptic development and plasticity. Observations indicate that neurotrophin 4 (NT4) is required for the synaptic plasticity mediating both tolerance and memory. Also there are lines of evidence to indicate that NMDA receptors are involved in the neural plasticity underlying the development of opiate tolerance. Neurotrophins affect central transmission postsynaptically by enhancing NMDA receptor responsiveness. So we used the clinically available NMDA receptor antagonist, dextromethorphan, and the neurotrophin 4 antibody, anti-NT4, concomitantly and alone to investigate their effects on morphine tolerance. Tolerance was induced by injecting morphine (7 and 10 mg/kg i.p.) once per day for 4 days. Anti-NT4 (1 microg/rat i.c.v.) was administered 15 min before morphine. Results showed that chronic concomitant treatment of anti-NT4 with morphine in both doses inhibited the development of morphine tolerance. Also acute treatment of anti-NT4 significantly reversed the tolerance that was induced by morphine 7 mg/kg but failed to reverse the tolerance of morphine 10 mg/kg. Dextromethorphan in both doses (10 or 30 mg/kg) has an additive effect on the inhibitory effect of anti-NT4 on the reversal of morphine tolerance (7 mg/kg). These findings provide additional support for the hypothesis that NMDA receptor and NT4 may be involved in neural plasticity underlying opiate tolerance.

Analgesics, Opioid↗
PubMed2005

The effect of CYP2D6 polymorphisms on dextromethorphan metabolism in Mexican Americans.

CYP2D6 is one of the most polymorphic of the cytochrome P450 enzymes. Genetic differences in this enzyme have been reported in whites, blacks, and Asians. However, there is very little information about polymorphisms of this enzyme in Mexican Americans. The objectives of the present study were to assess the metabolic activity of CYP2D6 in a Mexican American population using dextromethorphan and to correlate this metabolic activity with a genotypic analysis. The sample consisted of 50 Mexican American subjects and 25 non-Mexican American controls. Overnight urine samples were collected and analyzed by high-performance liquid chromatography to calculate the metabolic ratio of dextromethorphan to dextrorphan. Blood samples were collected for genotypic analysis of CYP2D6 alleles. The frequency of the poor metabolizer phenotype was the same in the Mexican American group and the non-Mexican American group (6% vs 5.5%). The frequency of alleles in the Mexican American group was similar to frequencies published in other reports for non-Hispanic whites: *4 = 0.17, *5 = 0.02, *10 = 0.01, *17 = 0.02, *xN = 0.03. These results indicate that compared with non-Hispanic whites, Mexican Americans have a similar proportion of poor metabolizer phenotype and similar genetic polymorphisms of CYP2D6.

Adult↗
PubMed1985

Effects of the antitussive fominoben (PB89) on hypoxia in chronic obstructive lung disease: comparison with dextromethorphan using a double-blind method.

We studied the effects of a non-narcotic, centrally acting antitussive, fominoben (PB89), on hypoxia in sixty patients suffering from chronic obstructive lung diseases (COLD), utilizing a double-blind method and using the antitussive dextromethorphan as a reference drug. By the oral administration of a dose of 2 fominoben tablets (160 mg) three times a day for 2 weeks, a significant increase in arterial O2 pressure (PaO2), a decrease in arterial CO2 pressure (PaCO2), and a rise in pH were observed. However, alveolar-arterial O2 difference (A-aDO2) was not improved. On the other hand, after administration of a dose of 2 dextromethorphan tablets (30 mg) three times a day for 2 weeks, no increase in PaO2, no decrease in PaCo2 and no improvement in A-aDO2 were observed, although a rise in pH was seen. The increase in PaO2 by fominoben was marked in COLD with dyspnoea. No improvement of A-aDO2 despite a decrease in PaCO2 suggests that fominoben might increase alveolar ventilation, in spite of its effect as an antitussive, exerting a favourable effect on hypoxia. It is, therefore, speculated that the cough centre and the respiratory centre are capable of functioning independently of each other.

Aged↗
PubMed1992

The treatment of a chronic organic mental disorder with dextromethorphan in a man with severe mental retardation.

Response to dextromethorphan (15 mg b.i.d.), an antitussive agent not usually considered to have psychotropic properties, was seen in a 25-year-old man with severe developmental disabilities, congenital rubella, and an organic mental disorder. Dextromethorphan affects CNS serotonergic systems, and this was the probable therapeutic mechanism. This and other published cases suggest the existence of a distinct organic mental syndrome in developmentally disabled persons which responds to drugs that increase indoleaminergic activity.

Adult↗
PubMed2004

Preoperative oral dextromethorphan attenuated tourniquet-induced arterial blood pressure and heart rate increases in knee cruciate ligament reconstruction patients under general anesthesia.

UNLABELLED: The precise mechanism of tourniquet-induced arterial blood pressure increase is unknown. We determined the effect of preoperative oral dextromethorphan (DM) on arterial blood pressure and heart rate changes during tourniquet inflation in knee cruciate ligament reconstruction patients under general anesthesia. Patients in the DM group (n = 38) received oral DM 30 mg, and patients in the control group (n = 38) received oral placebo 2 h before the induction of anesthesia. Anesthesia was maintained with sevoflurane 2.0% and N(2)O in 33% oxygen, and the trachea was intubated until the end of surgery. Arterial blood pressure and heart rate were measured at 0, 30, and 60 min after the start of tourniquet inflation. Systolic arterial blood pressure and heart rate at 60 min in the control group were significantly more than those in the DM group (131.1 +/- 15.8 mm Hg versus 123.6 +/- 15.9 mm Hg [P < 0.05] and 74.1 +/- 11.3 bpm versus 67.8 +/- 8.5 bpm [P < 0.01], respectively). The percentage increase in systolic arterial blood pressure and heart rate in the DM group was also attenuated when compared with that in the control group (P < 0.05). In conclusion, preoperative oral DM 30 mg significantly attenuated arterial blood pressure and heart rate increases during tourniquet inflation under general anesthesia. IMPLICATIONS: We demonstrated that preoperative oral dextromethorphan 30 mg significantly attenuated arterial blood pressure and heart rate increases at 60 min during tourniquet inflation in patients undergoing knee cruciate ligament reconstruction under general anesthesia.

Adult↗
PubMed1989

Plasma-polymerized membrane electrode for the determination of dextromethorphan and dimemorfan.

Ion-selective electrodes (ISEs) responsive to the antitussives dextromethorphan and dimemorfan were constructed by the fixation of an ion-exchanger, ammonium tetraphenylborate, on a Millipore membrane by means of a plasma-polymerization technique. The electrodes showed a Nernstian response over the range of 10(-5)-10(-2) M dextromethorphan and dimemorphan, and the working pH range was 5-7. The interference from common cations such as Na+, K+ and Ca2+ was negligible but some organic cations interfered weakly. The electrodes were applied successfully for the determination of the drugs in pharmaceutical preparations.

Dextromethorphan↗
PubMed2005

Evaluation of dextromethorphan metabolism using hepatocytes from CYP2D6 poor and extensive metabolizers.

It is important to estimate the defective metabolism caused by genetic polymorphism of drug metabolizing enzymes before the clinical stage. We evaluated the utility of cryopreserved human hepatocytes of CYP2D6 poor metabolizer (PM) for the estimation of the metabolism in PM using dextromethorphan (DEX) as the probe drug for CYP2D6 substrate. The results of low formations of dextrorphan (DXO) and 3-hydroxymorphinan (3-HM) in CYP2D6 PM hepatocytes incubated with dextromethorphan reflected the clinical data. Formation of 3-methoxymorphinan (3-MEM) normalized by CYP3A4/5 activity in the PM hepatocytes reached about 2.8-fold higher than that in CYP2D6 extensive metabolizer (EM) hepatocytes, which clearly showed the compensatory metabolic pathway of O-demethylation catalyzed by CYP2D6 as seen in clinical study. On the contrary, in the condition of the EM hepatocytes with CYP2D6 inhibitors, the enhancement of 3-MEM formation was not observed. In phase II reaction, the glucuronide formation rate of DXO in the PM hepatocytes was lower than that in the EM hepatocytes, which was consistent with clinical data of DXO-glucuronide (DXO-glu) concentration. These results would suggest that CYP2D6 PM hepatocytes could be a good in vitro tool for estimating CYP2D6 PM pharmacokinetics.

Cryopreservation↗
PubMed1996

Dose escalation safety and tolerance study of the N-methyl-D-aspartate antagonist dextromethorphan in neurosurgery patients.

Experimental studies have shown that dextromethorphan, a noncompetitive N-methyl-D-aspartate antagonist is neuroprotective in experimental models of ischemic cerebral injury. The authors studied the safety and tolerability of oral dextromethorphan (DM) in humans, and correlated serum levels of this drug with cerebrospinal fluid (CSF) and brain levels. Neurosurgical patients undergoing intracranial surgery or endovascular procedures were given ascending doses of oral DM prior to and 24 hours after surgery. Serum, CSF, and brain levels of DM and its active metabolite, dextrorphan, were measured. One hundred eighty-one patients received a total of 212 courses of DM treatment in dose ranges of 0.8 to 9.64 mg/kg. Serum DM levels correlated highly with CSF and brain DM levels. Brain levels were 68-fold higher than serum levels, whereas CSF levels were fourfold lower than serum levels. The maximum DM levels attained were 1514 ng/ml (serum) 118 ng/ml (CSF), and 92,700 ng/g (brain). The maximum dextrorphan levels were 501 ng/ml (serum), 167 ng/ml (CSF), and 6840 ng/g (brain). In 11 patients, brain and plasma levels of DM were comparable to levels that have been shown to be neuroprotective in animal studies. Frequent side effects occurring at neuroprotective levels of DM included nystagmus (64%), nausea and vomiting (27%) distorted vision (27%), feeling "drunk" (27%), ataxia (27%), and dizziness (27%). All symptoms were reversible and no patient suffered severe adverse reactions. This study demonstrates that potentially neuroprotective doses of DM can be administered safely to neurosurgical patients. Brain and CSF levels of DM can be estimated from serum levels of the drug. Side effects, even at the highest levels, proved to be tolerable and reversible. Administration of DM to patients at risk for cerebral injury should be further explored.

Adult↗