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PubMed1992

Effects of MK 801 on morphine physical dependence: attenuation and intensification.

It has previously been reported that the noncompetitive NMDA receptor antagonists ketamine and dextromethorphan suppressed the naloxone-induced morphine abstinence syndrome. In addition, the previous blockade by ketamine and dextromethorphan of NMDA receptors has been shown to intensify the naloxone-elicited morphine abstinence syndrome. On the basis of this information, another noncompetitive NMDA receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo-a,d-cyclohepten-5,10-imine maleate (MK 801), was administered to rats in which two morphine-containing (75 x 2 morphine base) pellets had been implanted. The naloxone-precipitated abstinence syndrome in rats injected with 0.3 mg/kg MK 801 36 h after pellet implantation was found significantly more intense than controls whereas the abstinence syndrome in rats that received 0.1 mg/kg MK 801 before naloxone injection was less intense. The intensification by MK 801 given 36 h following pellet implantation was attributed to the further increase in upregulation and supersensitivity of NMDA receptors caused by morphine. The attenuation was explained by the blockade by MK 801 of NMDA receptors as occurred in the case of ketamine and dextromethorphan.

Animals↗
PubMed1991

Evidence for peripheral mechanisms mediating the antitussive actions of opioids in the guinea pig.

1. Comparisons were made between the doses required of aerosol and intraperitoneally administered morphine, dextromethorphan, codeine and the specific peripherally acting mu-receptor agonist DALDA (H-Tyr-D-Arg-Phe-Lys-NH2) to suppress citric acid-induced coughing in conscious guinea pigs. 2. Estimated ID50s for inhibition of numbers of coughs induced by an aerosol of 5% citric acid were 1.0 and 2.4 mg/kg for intraperitoneally administered morphine and dextromethorphan, respectively. 3. The estimated ID50s after inhalation of morphine and dextromethorphan as aerosols were approximately 2.2 and approximately 12 micrograms/kg, respectively. 4. Aerosilized codeine (approximately 72 micrograms/kg, n = 5) significantly inhibited coughing by 62 +/- 23% whereas 3 mg/kg, i.p. was required to significantly reduce coughing by a similar degree (60 +/- 6%, n = 7). 5. Inhalation of DALDA (approximately 7.2 micrograms/kg, n = 7) also significantly inhibited coughing. 6. The antitussive effect of inhaled morphine (approximately 7.2 micrograms/kg, n = 11) was inhibited after administration of 3 mg/kg of either naloxone hydrochloride or naloxone methylbromide intraperitoneally. 7. The results support the hypothesis that effects at a peripheral site can make a major contribution to the antitussive actions of these drugs.

Administration, Inhalation↗
PubMed2004

Influence of phenylalanine 120 on cytochrome P450 2D6 catalytic selectivity and regiospecificity: crucial role in 7-methoxy-4-(aminomethyl)-coumarin metabolism.

The polymorphic human debrisoquine hydroxylase, cytochrome P450 2D6 (CYP2D6), is one of the most important phase I drug metabolising enzymes. It is responsible for metabolising a large number of compounds that mostly share similarity in having a basic N-atom and an aromatic moiety. In homology modelling studies, it has been suggested that in fixation of this aromatic moiety, there may be an important role for phenylalanine 120 (Phe(120)). In this study, the role of Phe(120) in ligand binding and catalysis was experimentally examined by mutating it into an alanine. Strikingly, this substitution led to a completely abolished 7-methoxy-4-(aminomethyl)-coumarin (MAMC) O-demethylating activity of CYP2D6. On the other hand, bufuralol metabolism was hardly affected (K(m) of 1-hydroxylation mutant: 1.2 microM, wild-type: 2.9 microM, 4-hydroxylation mutant: 1.5 microM, and wild-type: 3.2 microM) and neither was affected dextromethorphan O-demethylation (K(m) mutant: 1.2 microM, wild-type: 2 microM, k(cat) mutant: 4.5 min(-1), and wild-type: 3.3 min(-1)). However, the Phe(120)Ala mutant also formed 3-hydroxymorphinan, the double demethylated form of dextromethorphan, which was not detected using wild-type CYP2D6. 3,4-Methylenedioxymethamphetamine (MDMA) was demethylenated by both mutant and wild-type CYP2D6 to 3,4-dihydroxymethamphetamine (3,4-OH-MA K(m) of mutant: 55 microM and wild-type: 2 microM). In addition, the mutant formed two additional metabolites; 3,4-methylenedioxyamphetamine (MDA) and N-hydroxy-3,4-methylenedioxymethamphetamine (N-OH-MDMA). Inhibition experiments of dextromethorphan O-demethylation showed a decreased affinity of the Phe(120)Ala mutant for quinidine (IC(50) mutant: 240 nM and wild-type, 40 nM), while IC(50)s for quinine were equal (1 microM). These data indicate the importance of Phe(120) in the selectivity and regiospecificity in substrate binding and catalysis by CYP2D6.

Alanine↗
PubMed2003

Multiple doses of saw palmetto (Serenoa repens) did not alter cytochrome P450 2D6 and 3A4 activity in normal volunteers.

Saw palmetto (Serenoa repens) is the most commonly used herbal preparation in the treatment of benign prostatic hyperplasia. The objective of this study was to determine whether a characterized saw palmetto product affects the activity of cytochrome P450 (CYP) 2D6 or 3A4 in healthy volunteers (6 men and 6 women). The probe substrates dextromethorphan (CYP2D6 activity) and alprazolam (CYP3A4 activity) were administered orally at baseline and again after exposure to saw palmetto (320-mg capsule once daily) for 14 days. Dextromethorphan metabolic ratios and alprazolam pharmacokinetics were determined at baseline and after saw palmetto treatment. The mean ratio of dextromethorphan to its metabolite was 0.038 +/- 0.044 at baseline and 0.048 +/- 0.080 after 14 days of saw palmetto administration (P =.704, not significant [NS]), indicating a lack of effect on CYP2D6 activity. The area under the plasma alprazolam concentration versus time curve was 476 +/- 178 h. ng. mL(-1) at baseline and 479 +/- 125 h. ng. mL(-1) after saw palmetto treatment (P =.923, NS), indicating a lack of effect on CYP3A4 activity. The elimination half-life of alprazolam was 11.4 +/- 3.1 hours at baseline and 11.6 +/- 2.7 hours after saw palmetto treatment (P =.770, NS), also indicating a lack of effect on CYP3A4 activity. Our results indicate that extracts of saw palmetto at generally recommended doses are unlikely to alter the disposition of coadministered medications primarily dependent on the CYP2D6 or CYP3A4 pathways for elimination. These conclusions must be weighed in the context of the study's limited assessments and regarded as only the initial investigation into the drug interaction potential of saw palmetto.

Adult↗
PubMed2004

The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo.

BACKGROUND: Echinacea is a widely available over-the-counter herbal remedy. Tinctures of echinacea have been shown to inhibit cytochrome P450 (CYP) in vitro. The effect of echinacea (Echinacea purpurea root) on CYP activity in vivo was assessed by use of the CYP probe drugs caffeine (CYP1A2), tolbutamide (CYP2C9), dextromethorphan (CYP2D6), and midazolam (hepatic and intestinal CYP3A). METHODS: Twelve healthy subjects (6 men) completed this 2-period, open-label, fixed-schedule study. Caffeine, tolbutamide, dextromethorphan, and oral and intravenous midazolam were administered before and after a short course of echinacea (400 mg 4 times a day for 8 days) to determine in vivo CYP activities. RESULTS: Echinacea administration significantly increased the systemic clearance of midazolam by 34%, from 32 +/- 7 L/h to 43 +/- 16 L/h (P =.003; 90% confidence interval [CI], 116%-150%), and significantly reduced the midazolam area under the concentration-time curve by 23%, from 127 +/- 36 microg. h/L to 102 +/- 43 microg. h/L (P =.024; 90% CI, 63%-88%). In contrast, the oral clearance of midazolam was not significantly altered (P =.655; 90% CI, 75%-124%), 137 +/- 19 L/h compared with 146 +/- 71 L/h. The oral availability of midazolam after echinacea dosing was significantly increased (P =.028; 90% CI, 108%-153%), from 0.23 +/- 0.06 to 0.33 +/- 0.13. Hepatic availability (0.72 +/- 0.08 versus 0.61 +/- 0.16; P =.006; 90% CI, 73%-90%) and intestinal availability (0.33 +/- 0.11 versus 0.61 +/- 0.38; P =.015; 90% CI, 125%-203%) were significantly altered in opposite directions. Echinacea dosing significantly reduced the oral clearance of caffeine, from 6.6 +/- 3.8 L/h to 4.9 +/- 2.3 L/h (P =.049; 90% CI, 58%-96%). The oral clearance of tolbutamide was reduced by 11%, from 0.81 +/- 0.18 L/h to 0.72 +/- 0.19 L/h, but this change was not considered to be clinically relevant because the 90% CIs were within the 80% to 125% range. The oral clearance of dextromethorphan in 11 CYP2D6 extensive metabolizers was not affected by echinacea dosing (1289 +/- 414 L/h compared with 1281 +/- 483 L/h; P =.732; 90% CI, 89%-108%). CONCLUSIONS: Echinacea (E purpurea root) reduced the oral clearance of substrates of CYP1A2 but not the oral clearance of substrates of CYP2C9 and CYP2D6. Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites. The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites. Caution should be used when echinacea is coadministered with drugs dependent on CYP3A or CYP1A2 for their elimination.

Administration, Oral↗
PubMed2005

Is antagonism of alpha3beta4 nicotinic receptors a strategy to reduce morphine dependence?

18-Methoxycoronaridine, a synthetic iboga alkaloid congener, has been previously shown to attenuate several signs of morphine withdrawal in rats. The recently discovered action of 18-methoxycoronaridine to block alpha3beta4 nicotinic receptors may be responsible for this effect. To test this hypothesis the effects of non-selective alpha3beta4 receptor antagonists, dextromethorphan, mecamylamine, bupropion, and their combinations, were assessed on of acute naltrexone-precipitated (1 mg/kg i.p.) morphine withdrawal in rats. Dextromethorphan (5-40 mg/kg, s.c.), mecamylamine (0.25-4 mg/kg, i.p.) and bupropion (10-30 mg/kg, i.p.) alone produced variable effects on signs of withdrawal. However, two low-dose combinations, i.e., dextromethorphan (5 mg/kg, s.c.) and mecamylamine (0.25 mg/kg, i.p.), mecamylamine (0.25 mg/kg, i.p.) and bupropion (10 mg/kg, i.p.) as well as the three-drug combination significantly attenuated diarrhea and weight loss; none of the agents administered alone had these effects. The results of the present study provide evidence that alpha3beta4 nicotinic receptors are involved in the expression of at least two signs of opioid withdrawal.

Acute Disease↗
PubMed2006

Placebo-controlled comparison of a morphine/dextromethorphan combination with morphine on experimental pain and hyperalgesia in healthy volunteers.

UNLABELLED: In this double-blind, placebo-controlled, crossover study we compared the analgesic effect of a single oral dose of 30-mg dextromethorphan and 30-mg morphine combination (MS/DM) to 30 mg morphine (MS) alone and either placebo or 30 mg dextromethorphan (DM) on cutaneous sensitization induced by heat/capsaicin (topical) sensitization on the forearm and the brief thermal sensitization model on the thigh in 22 healthy volunteers. Outcome measures were areas of secondary hyperalgesia to brush and von Frey hair stimulation in both sensitization models and the painfulness of acute thermal noxious stimulation on the upper arm. Compared with placebo, both MS/DM and morphine had some effect on the secondary hyperalgesia and reduced the painfulness of a noxious thermal stimulus. The analgesic effect of MS/DM was not superior to that of morphine on any outcome measure. These results differ from preclinical studies with animal experimental pain models in which DM markedly potentiated the analgesic effects of opioids, but they are in accordance with recent clinical trials for chronic pain. PERSPECTIVE: Adding dextromethorphan to morphine (1:1 ratio) did not enhance analgesia on measures of experimental cutaneous sensitization and acute noxious thermal stimulation in healthy volunteers. The results differ from preclinical studies but agree with clinical trials. Human experimental models of pain and neuronal sensitization, which are responsive to oral opioids, allow efficient study of opioid combination analgesics and simplify the process for determining the optimal dose and/or dose ratio.

Adult↗
PubMed2004

A novel incubation direct injection LC/MS/MS technique for in vitro drug metabolism screening studies involving the CYP 2D6 and the CYP 3A4 isozymes.

A direct injection LC/MS/MS method involving a novel incubation technique was developed for the inhibition screening of CYP 2D6 and CYP 3A4 isoenzymes using dextromethorphan and midazolam as probe substrates. Both assays were performed using an electrospray ionization source in the positive ion mode. Direct injection was possible by using a short C 18, LC column (2 mm x 20 mm) with large particle diameter packing (10 microm). Analytical characteristics of the direct injection technique were studied by examining matrix effects, which showed suppression of the ESI signal between 0.20 and 0.65 min. The retention times for analytes were adjusted to approximately 0.8 min (k'>3), resulting in no matrix effect. Column lifetime was evaluated and determined to be approximately 160 direct injections of the matrix. The precision and accuracy of the control samples for the quantitation of dextromethorphan was between -0.53 and -12.80, and 3.73 and 6.69% respectively. Unlike conventional incubation techniques, incubations were carried out in an autosampler equipped with a heating accessory. This novel incubation method, which involved no stirring of the incubation mixture, estimated the Cl(int in vitro) for dextromethorphan and midazolam in human liver microsomes to be 1.65+/-0.22 ml/(hmg) and 0.861 ml/(min mg) respectively. The autosampler tray maintained uniform temperature and was sensitive to changes in temperature between 33 and 41 degrees C. High-throughput screening was performed using known inhibitors of the CYP 2D6 isozyme, and the system was evaluated for its ability to differentiate between these inhibitors. The strong inhibitor quinidine resulted in a 25.6% increase in t(1/2), the medium potency inhibitor chlorpromazine resulted in an increase of 6.14% and the weak inhibitor primaquine had no significant effect on half-life. This technique involves no sample preparation, demonstrated run times of 2 min per injection and can be fully automated. The method should therefore prove to be a valuable tool in the drug discovery process.

Algorithms↗
PubMed1998

Effect of fluvoxamine therapy on the activities of CYP1A2, CYP2D6, and CYP3A as determined by phenotyping.

OBJECTIVE: To determine the effect of 150 mg/day fluvoxamine on the activities of CYP1A2, CYP2D6, CYP3A, N-acetyltransferase-2 (NAT2), and xanthine oxidase (XO) by phenotyping with caffeine, dextromethorphan, and midazolam. METHODS: Oral caffeine (2 mg/kg), oral dextromethorphan (30 mg), and intravenous midazolam (0.025 mg/kg) were administered to 10 white male volunteers every 14 days for 4 months and to 10 white premenopausal female volunteers during the midfollicular and midluteal phases of the menstrual cycle for 4 complete cycles (8 total phenotyping measures). The first 6 phenotyping measures were used to establish baseline activity. Subjects were given 150 mg/day fluvoxamine for the fourth month or cycle of the study. Enzyme activity for CYP1A2, CYP2D6, NAT2, and XO was expressed as urinary metabolite ratios. Midazolam plasma clearance was used to express CYP3A activity. RESULTS: No difference between baseline and weeks 2 and 4 of fluvoxamine therapy was observed for NAT2 or XO metabolite ratios. For CYP1A2, CYP2D6, and CYP3A phenotypes, significant differences existed between baseline and fluvoxamine therapy. For CYP1A2, the mean urinary metabolite ratio (+/-SD) was 7.53 +/- 7.44 at baseline and 4.30 +/- 2.82 with fluvoxamine ( P = .012). Mean CYP2D6 molar urinary dextromethorphan ratios before and after fluvoxamine therapy were 0.00780 +/- 0.00694 and 0.0153 +/- 0.0127, respectively (P = .011). Midazolam clearance decreased from 0.0081 +/ 0.0024 L/min/kg at baseline to 0.0054 +/- 0.0021 L/min/kg with therapy (P = .0091). For CYP1A2, CYP2D6, and CYP3A, fluvoxamine therapy changed the phenotyping measures by a median of -44.4%, 123.5%, and -34.4%, respectively. CONCLUSIONS: We concluded that fluvoxamine may cause significant inhibition of CYP1A2, CYP2D6, and CYP3A activity. This metabolic inhibition may have serious implications for a variety medications.

Acetyltransferases↗
PubMed1999

Investigation of terbinafine as a CYP2D6 inhibitor in vivo.

BACKGROUND: Terbinafine is an orally active antifungal used in the treatment of dermatophytoses. To date, studies evaluating the effect of terbinafine on the cytochromes P450 have failed to show any significant interactions. This prospective open-label study was designed to confirm our previous finding that terbinafine may inhibit CYP2D6. METHODS: Nine healthy volunteers were enrolled in this study-6 genotypically consistent with an extensive metabolizer phenotype and 3 genotypic poor metabolizers for CYP2D6. The change in CYP2D6 enzyme activity before (x 3) and after (monthly x 6 months) administration of terbinafine (250 mg once daily x 14 days) was evaluated with the dextromethorphan to dextrorphan urinary metabolite ratios. On each study day a predose urine sample was collected, 0.3 mg/kg dextromethorphan was administered, and urine was collected for 24 hours. Dextromethorphan and its metabolites were quantified from urine by HPLC. RESULTS: Baseline phenotype values were concordant with individual genotype. In all extensive metabolizers, the administration of terbinafine resulted in a dramatic increase in the dextromethorphan/dextrorphan ratio, converting 4 of the 6 extensive metabolizers into phenotypic poor metabolizers. On average, a 97-fold increase in ratio (range, 35 to 265) was observed for extensive metabolizers after the administration of terbinafine. No significant change was observed in the metabolite ratios of poor metabolizers during the course of the study. CONCLUSIONS: Terbinafine inhibits CYP2D6 sufficiently to produce a discordance between genotype and phenotype for the enzyme. The dextromethorphan/dextrorphan metabolite ratios increased in all individuals, with otherwise functional CYP2D6 activity. The disposition of CYP2D6 substrates coadministered with terbinafine may be significantly altered in extensive metabolizers for this cytochrome P450 isoform, who comprise approximately 93% of the population.

Adult↗
PubMed2002

Effect of low-affinity NMDA receptor antagonists on electrical activity in mouse cortical slices.

The objective of this study was to investigate the effects of three low-affinity NMDA receptor antagonists, MRZ 2/279 (1-amino-1,3,3,5,5-pentamethyl-cyclohexane HCl), AR-R 15896AR ([+]-alpha-phenyl-2-pyridine-ethanamine diHCl) and dextromethorphan on epileptiform activity in vitro. Epileptiform discharges were elicited in DBA/2 mouse cortical slices by perfusion with Mg(2+)-free artificial cerebrospinal fluid. MRZ 2/279, AR-R 15896AR and dextromethorphan all reversibly decreased the frequency of the discharges in a concentration-dependent manner. The IC(50)'s for MRZ 2/279, AR-R 15896AR and dextromethorphan were 5.2, 10.8 and 55.9 microM, respectively. These low-affinity NMDA receptor antagonists may be proved to be clinically effective with fewer adverse effects than drugs with high-affinity for the NMDA receptor-operated channel.

Animals↗
PubMed2000

Effect of St. John's wort (Hypericum perforatum) on cytochrome P-450 2D6 and 3A4 activity in healthy volunteers.

The effects of the herb St. John's wort (Hypericum perforatum), a purported antidepressant, on the activity of cytochrome P-450 (CYP) 2D6 and 3A4 was assessed in seven normal volunteers. Probe substrates dextromethorphan (2D6 activity) and alprazolam (3A4 activity) were administered orally with and without the co-administration of St. John's wort. Urinary concentrations of dextromethorphan and dextrorphan were quantified and dextromethorphan metabolic ratios (DMRs) determined. Plasma samples were collected (0-60 hrs) for alprazolam pharmacokinetic analysis sufficient to estimate tmax, Cmax, t 1/2, and AUC. Validated HPLC methods were used to quantify all compounds of interest. No statistically significant differences were found in any estimated pharmacokinetic parameter for alprazolam or DMRs. These results suggest that St. John's wort, when taken at recommended doses for depression, is unlikely to inhibit CYP 2D6 or CYP 3A4 activity.

Adult↗
PubMed2000

HPLC determination of guaifenesin with selected medications on underivatized silica with an aqueous-organic mobile phase.

A high performance liquid chromatography procedure has been developed for the simultaneous determination of guaifenesin pseudoephedrine-dextromethorphan and guaifenesin-pseudoephedrine in commercially available capsule dosage forms and guaifenesin-codeine in a commercial cough syrup dosage form. The separation and quantitation are achieved on a 25-cm underivatized silica column using a mobile phase of 60:40%) v/v 6.25 mM phosphate buffer, pH 3.0 - acetonitrile at a flow rate of 1 ml min(-1) with detection of all analytes at 216 nm. The separation is achieved within 10 min for each drug mixture. The method showed linearity for the guaifenesin-pseudoephedrine-dextromethorphan mixture in the 50-200, 7.5-30 and 2.5-10, microg ml(-1) ranges, respectively. The intra- and inter-day RSDs ranged from 0.23 to 4.20%, 0.18 to 2.85%, and 0.13 to 5.04% for guaifenesin, pseudoephedrine, and dextromethorphan, respectively. The guaifenesin pseudoephedrine mixture yielded linear ranges of 25-100 and 3.75-15 microg ml(-1) and intra- and inter-day RSDs ranged from 0.65 to 4.18% and 0.23 to 3.00% for guaifenesin and pseudoephedrine, respectively. The method showed linearity for the guaifenesin-codeine mixture in the 25-100 and 2.5-10 microg ml(-1) ranges and RSDs ranged from 0.37 to 4.25% and 0.14 to 2.08% for guaifenesin and codeine, respectively.

Antitussive Agents↗
PubMed2003

Antinociceptive effect in mice of intraperitoneal N-methyl-D-aspartate receptor antagonists in the formalin test.

Although the antinociceptive effect of NMDA antagonists in the formalin test is well recognised, these compounds can induce adverse motor effects. The aim of this study was to identify the systemic doses of NMDA antagonists that induce analgesia without causing side effects. Male Swiss mice (30-40g) received a subcutaneous (sc) injection of 1.25% formalin (50 micro l) in the dorsal surface of the right hind-paw and, 15min before or after formalin, an ip injection of one of the following NMDA receptor antagonists: MK 801 (0.01, 0.025, and 0.05mg/kg), memantine (0.1, 0.5, and 1mg/kg), ketamine (0.125, 0.25, and 0.5mg/kg), dextromethorphan (5, 10, and 20mg/kg), and CGP 37849 (4, 6, and 8mg/kg). Pain-related behaviour (licking, lifting, favouring, shaking, and flinching of the treated paw) was recorded at 5-min intervals for 60min. The NMDA receptor antagonists significantly (p<0.01) and dose-dependently reduced, versus controls, nociceptive activity during the second phase of the formalin test (from the 20th to the 60thmin): at the highest doses, 97.6+/-0.1% with MK 801; 90.4+/-0.2% with memantine; 74.7+/-0.3% with ketamine; 92.8+/-0.4% with dextromethorphan; and 80.7+/-0.3% with CGP 37849, without affecting coordination. The rank order potency of antinociceptive activity of NMDA antagonists was: MK801>memantine>ketamine>dextromethorphan>CGP37849. The NMDA antagonists administered after formalin (during the analgesic interval) did not affect the late phase of the formalin test. In conclusion, systemic administration of NMDA receptor antagonists decreases the nociception observed during the late phase of the formalin test.

Animals↗
PubMed2002

Is glutamate involved in transient lower esophageal sphincter relaxations?

Glutamate is an important excitatory amino acid and plays a major role in brain stem neurotransmission. Although the effect of glutamate on esophageal motility is well studied, its role in the triggering of transient lower esophageal sphincter relaxations (TLESRs) remains to be determined. Esophageal manometry was performed in 10 healthy volunteers using a perfused sleeve assembly. The effect of intragastric instillation of the nonspecific N-methyl-D-aspartate receptor antagonist dextromethorphan (30 mg) and the glutamate-release inhibitor riluzole (100 mg) was evaluated on esophageal motility and on the rate of TLESRs during isovolumetric gastric distension (500 ml). Dextromethorphan and riluzole had no effect on the amplitude or peristaltic velocity of esophageal pressure waves, basal LES pressure, or LES relaxation after water swallowing. Gastric distension increased the rate of TLESRs from 2.0 (1.0-3.5)/45 min to 5.0 (4.0-7.0)/45 min during placebo (P < 0.05). In contrast, the rate of TLESRs during gastric distension was significantly reduced with riluzole [4.0 (2.5-6.0)/45 min], but not with dextromethorphan. In conclusion, riluzole had no effect on swallow-induced LES relaxation, esophageal peristalsis, or gastric tone, but it reduced the number of TLESRs evoked by gastric distension. These findings suggest that glutamate may be involved in the neurocircuitry underlying TLESRs. However, as the effect was only marginal, additional studies are required to confirm our observations.

Adult↗
PubMed1991

Influence of amiodarone on genetically determined drug metabolism in humans.

Amiodarone has been shown to interact with the nongenetically determined hepatic elimination of several drugs, including phenytoin and digoxin. Its influence on genetically determined metabolic pathways has not been studied in humans. We examined the effects of oral amiodarone therapy on the genetically determined metabolism of isoniazid (N-acetyltransferase), mephenytoin (cytochrome P450MEPH), and dextromethorphan (CYP2D6). Eight patients with arrhythmias were studied before and 76 +/- 16 days after amiodarone (loading dose of 1000 mg/day for 10 days followed by a maintenance dose of 200 to 400 mg/day). Genetically determined enzyme activity was assessed indirectly by calculating the metabolic ratio (parent drug/metabolite in 8-hour urine for CYP2D6 and P450MEPH and N-acetylisoniazid/isoniazid in plasma for N-acetyltransferase) after oral administration of the parent compounds. At the time of phenotyping, plasma concentrations of amiodarone and N-desethylamiodarone were 0.66 +/- 0.35 micrograms/ml and 0.65 +/- 0.26 micrograms/ml, respectively. Amiodarone increased the log(metabolic ratio) of dextromethorphan from a median of -2.5 (range, -2.9 to -2.0) to a median of -1.9 (range, -2.5 to -1.5; p less than 0.02) but did not alter the metabolic ratio of mephenytoin or isoniazid. The amount of dextromethorphan excreted in urine increased from a median of 0.084 mumol/8 hours (range, 0.041 to 0.161 mumol/8 hours) to a median of 0.205 mumol/8 hours (range, 0.064 to 0.288 mumol/8 hours; p less than 0.02) and the amount of its metabolite (dextrorphan) tended to decrease from a median of 26 mumol/8 hours (range, 15 to 37 mumol/8 hours) to a median of 20 mumol/8 hours (range, 7 to 27 mumol/8 hours; p less than 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Relation between chloroguanide bioactivation to cycloguanil and the genetically determined metabolism of mephenytoin in humans.

It has been suggested recently that the bioactivation of chloroguanide hydrochloride (proguanil) to its active antimalarial metabolite cycloguanil cosegregates with the genetically determined polymorphism of mephenytoin hydroxylation. We determined the chloroguanide to cycloguanil ratio in urine after oral administration of a single dose of 200 mg proguanil either alone or together with 100 mg racemic mephenytoin or 40 mg dextromethorphan in a randomized crossover study performed in 24 healthy subjects. The mephenytoin hydroxylation index was also determined after administration of 100 mg racemic mephenytoin either alone or together with 200 mg proguanil. Two subjects were poor metabolizers and one subject was an intermediate metabolizer of mephenytoin. These three subjects had chloroguanide to cycloguanil ratios of more than 50. The 21 subjects with the extensive metabolizer phenotype for mephenytoin hydroxylation had chloroguanide to cycloguanil ratios of less than 10. The chloroguanide to cycloguanil ratio was not significantly altered by mephenytoin or dextromethorphan coadministration. The trend toward a correlation between chloroguanide/cycloguanil ratio and log mephenytoin hydroxylation index did not reach statistical significance. Inclusion of the dextromethorphan metabolic ratio into the model did not improve the relationship. These findings confirm that the bioactivation of chloroguanide to cycloguanil cosegregates with the genetically determined activity of the CYP2C family. However, the chloroguanide to cycloguanil ratio and the mephenytoin hydroxylation index do not similarly reflect the variable activity of CYP2C.

Adult↗
PubMed1996

N-methyl-D-aspartate receptor antagonists potentiate morphine's antinociceptive effect in the rat.

The interaction between morphine and three antagonists of the N-methyl-D-aspartate (NMDA) receptor. MK-801 (non-competitive channel blocker), dextromethorphan (clinically available non-competitive antagonist) and CGS19755 (competitive receptor antagonist), was examined in rats with the hot plate test. The NMDA antagonists were administered intraperitoneally and none of them caused antinociception at doses that did not produce motor deficits (0.1 mg kg-1 MK-801, 30 mg kg-1 dextromethorphan and 5 mg kg-1 CGS19755). However, pretreatment with the NMDA antagonists at these doses 30 min prior to subcutaneous injection of 5 mg kg-1 morphine significantly potentiated the antinociceptive effect of morphine, with strongest effect observed with dextromethorphan. It is suggested that blockade of NMDA receptors enhances the antinociceptive effect of morphine and NMDA antagonists may improve the analgesic efficacy of morphine in the clinic.

Analgesics↗