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PubMed2005

Simultaneous determination of phenytoin and dextromethorphan in urine by solid-phase extraction and HPLC-DAD.

A rapid and simple high-performance liquid chromatographic method with photodiode array detection was developed for the separation and the simultaneous determination of phenytoin and dextromethorphan in human urine. Analysis was performed in less than 4.5 min in isocratic mode on a reversed-phase C18 column (5 microm; 150 x 4.6 mm) using a mobile phase composed of acetonitrile-buffer phosphate 0.01 M (60:40, v/v) adjusted to pH 6.0, at 1 mL/min flow rate and UV absorbance at 210 nm. The elution order of analytes was dextromethorphan (DXM), Internal Standard (IS), and phenytoin (PHT). Calibration curves were linear in the 7.5-25 microg/mL range for PHT and in the 10-30 microg/mL range for DXM. Spike recoveries for urine samples prepared at three spiking levels ranged from 97.8 to 102.3% for PHT and from 94.8 to 100.4% for DXM. The detection limit (LOD) values ranged from 0.08 microg/mL for PHT to 0.5 microg/mL for DXM. The quantitation limit (LOQ) values ranged from 0.3 microg/mL for PHT to 1.6 microg/mL for DXM. The sample preparation method involves a rapid and simple procedure based on solid-phase extraction using a C18 reversed-phase column. Validation of the optimised method was carried out according to the ICH guidelines. The method developed in this study allows the reliable simultaneous analysis of PHT and DXM, drugs that were never quantified together in previously reported analytical methods. The described method has the advantage of being rapid and easy and it could be applied in therapeutic monitoring of these drugs in human urine of epileptic patients.

Anticonvulsants↗
PubMed1994

Measurement of liver microsomal cytochrome p450 (CYP2D6) activity using [O-methyl-14C]dextromethorphan.

The activity of human liver microsomal cytochrome P4502D6 (CYP2D6) is readily estimated by following the O-demethylation of [O-methyl-14C]dextromethorphan. The basis of the assay is the quantitative measurement of [14C]formaldehyde (0.05-4.0 microM) after addition of NaOH to the microsomal incubates and extraction with methylene chloride. The assay is relatively simple, sensitive (limit of detection is approximately 5.0 pmol HCHO/h/mg microsomal protein) and does not require the use of HPLC or an internal standard. Formation of radiolabeled formaldehyde in human liver microsomes is linear for 20 min, up to a final protein concentration of 1.0 mg/ml. Furthermore, the O-demethylase activity in a panel of microsomes prepared from a series of human livers was significantly correlated with the immunochemically determined levels of CYP2D6 protein (r = 0.925, p < 0.001), and was inhibited (> 89%) by quinidine and lobeline. In addition, [O-methyl-14C]-dextromethorphan O-demethylation was exclusively catalyzed by cDNA-expressed CYP2D6 in microsomes prepared from human B-lymphoblast cells. The method is suitable for rapid screening of compounds as potential CYP2D6 cosubstrates and/or inhibitors.

B-Lymphocytes↗
PubMed1979

Comparison of the antitussive effects of codeine phosphate 20 mg, dextromethorphan 30 mg and noscapine 30 mg using citric acid-induced cough in normal subjects.

1. Protection by codeine 20 mg, dextromethorphan 30 mg, noscapine 30 mg, and placebo against citric acid-induced cough was determined in eighteen healthy subjects. 2. Drug differences occurred at 2 1/2 h following ingestion of the drugs but not at 1 1/4 h. 3. Only coideine 20 mg had a greater antitussive action than placebo, but dextromethorphan 30 mg also did not differ from codeine 20 mg. 4. This technique may offer a useful screening test for the activity of new potential antitussive compounds in man.

Antitussive Agents↗
PubMed2000

The role of dextromethorphan in pain control.

PURPOSE: To review the clinical benefits of dextromethorphan (DM) in pain management, describe its neuropharmacological properties. SOURCE: A Medline search was made for experimental and clinical data on DM use from 1967 to date using keywords nociception, acute and chronic pain control, N-methyl-D-aspartate, antagonists, dextromethorphan. PRINCIPLE FINDINGS: The 930 DM citations mostly described its antitussive, metabolic and toxicological aspects, animal studies and its possible role in minimizing post-brain ischemia complications in humans. The use of DM in acute pain revealed eight original studies involving 443 patients, as well as two preliminary reports and our own unpublished data on 513 patients. Most of the 956 patients had general anesthesia. Eight studies (154 patients) and one case report dealt with chronic pain management. This N-methyl-D-aspartate (NMDA) receptor antagonist binds to receptor sites in the spinal cord and central nervous system, thereby blocking the generation of central acute and chronic pain sensations arising from peripheral nociceptive stimuli and enabling reduction in the amount of analgesics required for pain control. DM attenuated the sensation of acute pain at doses of 30-90 mg, without major side effects, and reduced the amount of analgesics in 73% of the postoperative DM-treated patients. Studies in secondary pain models in healthy volunteers and in various types of chronic pain showed DM to be associated with unsatisfactory pain relief. CONCLUSION: DM attenuates acute pain sensation with tolerable side effects. Its availability in oral form bestow advantages over other NMDA antagonists.

Animals↗
PubMed2001

Dextromethorphan attenuation of postoperative pain and primary and secondary thermal hyperalgesia.

PURPOSE: To determine the effect of 90 mg dextromethorphan (DM) p.o. vs placebo 90 min preoperatively, on the immediate and delayed postoperative course. METHODS: Thirty patients undergoing laparoscopic cholecystectomy or inguinal hernioplasty under general anesthesia were studied. Half (DM) received 90 mg dextromethorphan and half received placebo 90 min before anesthesia. Intravenous Patient Controlled Aanalgesia with morphine was available for two hours within a six-hour observation period; 75 mg diclofenac i.m. prn was given later in PACU and on-ward (24 hr). Pain was assessed using the visual analogue scales. Thermal thresholds for cold and hot sensation and for pain (by limit method) were evaluated at the site of skin incision (primary-) and distantly (secondary hyperalgesia). Von Frey filaments were applied testing touch sensation. Sedation level and morphine consumption were also assessed in PACU. RESULTS: Demographic, surgical and perioperative parameters were similar; no untoward effects were encountered. Pain intensity and sedation were lower, and the feeling of well-being was greater, in the DM patients: one vs five (median), two vs five, five vs two, respectively, P <0.01 (90 min time-point). Thermal application revealed absence of primary and secondary hyperalgesia only in the DM patients; von Frey filaments induced similar pain sensation in both groups. Mean morphine/group, morphine/weight and diclofenac injection rates were approximately 55% lower in the DM group: 2.1 +/- 1.2 (SD) vs 4.7 +/- 2.3, 0.03 +/- 0.02 vs 0.07 +/- 0.03, 1.0 +/- 0.3 vs 2.4 +/- 0.2, respectively, P <0.01. CONCLUSIONS: Compared with placebo, DM enabled reduction of postoperative analgesics consumption, improved well-being, and reduced sedation, pain intensity and primary and secondary thermal hyperalgesia.

Adult↗
PubMedDate not supplied

Effect of methamphetamine on the pharmacokinetics of dextromethorphan and midazolam in rats.

Methamphetamine is the fourth most frequently reported compound associated with drug abuse on admission of patients to treatment centres after cocaine, heroin and marijuana. It is metabolized in the organism with a reaction that is catalyzed by cytochrome P450, mainly by the CYP2D and CYP3A subfamily, 4-hydroxyamphetamine and amphetamine being dominant metabolites. The present pharmacokinetic study was undertaken to investigate the possible influence of methamphetamine (10 mg/kg, i.p., once daily for six days) on the pharmacokinetics of dextromethorphane as a model substrate for rat cytochrome P-4502D2 and midazolam as a model substrate for CYP3A1/2. Animals received a single injection of dextromethorphane (10 mg/kg) or midazolam (5 mg/kg) in the tail vein 24 h after the last dose of methamphetamine or administration of placebo. The results of pharmacokinetic analysis showed a significantly increased rate of dextrorphane and 3-hydroxymorphinan formation, and a marked stimulatory effect of methamphetamine on CYP2D2 metabolic activity. Similarly, the kinetics of midazolam's metabolic conversion to hydroxy derivates of midazolam indicated a significant increase in CYP3A1/2 activity. The results showed that the administration of methamphetamine significantly stimulated the metabolic activity of CYP2D2 as well as that of CYP3A1/2. With regard to the high level of homology between human and rat CYP isoforms studied, the results may have a clinical impact on future pharmacotherapy for methamphetamine abuse.

Alcohol Oxidoreductases↗
PubMed1998

Monotherapy with dextromethorphan or tirilazad--but not a combination of both--improves outcome after transient focal cerebral ischemia in rats.

Cell death after cerebral ischemia is mediated by a massive release of excitatory amino acids, generation of free radicals, and - a crucial step - calcium influx into cells. We examined the hypothesis that concurrent administration of drugs ameliorating brain damage via different mechanisms would result in a synergistic neuroprotective effect. The neuroprotective efficacy of two clinically available drugs - the N-methyl-D-aspartate and calcium-channel antagonist dextromethorphan (DM) and the antioxidant tirilazad - were studied in monotherapy and in combination in a rat model of transient focal ischemia. Male Sprague-Dawley rats were subjected to 90 min of middle-cerebral-artery occlusion by an intraluminal filament technique. The animals were randomly assigned to one of four treatments (n=10 each): (1) vehicle-treated controls, (2) DM, (3) tirilazad, (4) DM+tirilazad. Drugs or vehicles were administered 15 min before ischemia and at reperfusion. Local cerebral blood flow (LCBF) was bilaterally recorded by continuous laser Doppler flowmetry. Functional deficits were quantified by daily neurological examinations. Infarct volume was assessed planimetrically after 7 days. DM prevented post-ischemic hypoperfusion. Tirilazad did not influence LCBF. Monotherapy with DM or tirilazad improved neurological function and reduced infarct volume by 45% and 48%, respectively. Combination therapy failed to influence neurological recovery and infarct volume. Although, from pharmacological point of view, a synergistic neuroprotective effect is expected, combination of dextromethorphan and tirilazad may lead to mutual inhibition or potentiate adverse effects.

Animals↗
PubMed1988

Dextromethorphan and dextrorphan as calcium channel antagonists.

Dextromethorphan and dextrorphan, which reduce excitatory amino acid-induced neurotoxicity, decreased K+ depolarization-evoked 45Ca2+ uptake into brain synaptosomes and cultured neural (PC12) cells. Half-maximal inhibition of synaptosomal 45Ca2+ uptake occurred with 48 microM dextromethorphan or 200 microM dextrorphan, which are similar to concentrations associated with protection from excitotoxicity. The ability to decrease Ca2+ flux through N-type (synaptosomal) and L-type (PC12) voltage-gated Ca2+ channels may therefore contribute to the neuroprotective effects of these compounds.

Animals↗
PubMed1991

SKF 525-A and cytochrome P-450 ligands inhibit with high affinity the binding of [3H]dextromethorphan and sigma ligands to guinea pig brain.

The DM1/sigma 1 site binds dextromethorphan (DM) and sigma receptor ligands. The broad binding specificity of this site and its peculiar subcellular distribution prompted us to explore the possibility that this site is a member of the cytochrome P-450 superfamily of enzymes. We tested the effects of the liver microsomal monooxygenase inhibitor SKF 525-A (Proadifen), and other P-450 substrates on the binding of [3H]dextromethorphan, [3H]3-(-3-Hydroxyphenyl)-N-(1-propyl)piperidine and (+)-[3H]1,3-Di-o-tolyl-guanidine ([3H]DTG) to the guinea pig brain. SKF 525-A, l-lobeline and GBR-12909 inhibited the binding of the three labeled ligands with nM affinity. Each drug has identical nM Ki values for the high-affinity site labeled by the three ligands. This indicated that they displaced the labeled ligands from the common DM1/sigma 1 site. Debrisoquine and sparteine, prototypical substrates for liver debrisoquine 4-hydroxylase, displayed Ki values of 9-13 and 3-4 microM respectively against the three labeled ligands. These results, the broad specificity of the DM1/sigma 1 binding site, and its peculiar subcellular distribution, raises the possibility that this binding site is a member of the cytochrome P-450 superfamily of isozymes, rather than a neurotransmitter receptor. These findings may have important implications for the understanding of the therapeutic, side effects and toxicity of several neurotropic drugs.

Animals↗
PubMed1989

Efflux of rubidium in rat cortical synaptosomes is blocked by sigma and dextromethorphan binding site ligands.

Large concentrations of potassium were used to stimulate the release of rubidium-86 from preloaded cortical synaptosomes, so that the pharmacological sensitivity of this efflux could be examined. Potassium channel blockers, 4-aminopyridine and tetraethylammonium, inhibited the evoked release of rubidium. Sigma ligands, e.g. pentazocine, cyclazocine, rimcazole, 1,3-di(2-tolyl)guanidine (DTG) and haloperidol, as well as the antitussives, carbetapentane, caramiphen and dextromethorphan, significantly reduced potassium-stimulated efflux of rubidium. By contrast, 3-hydroxyphenyl-propylpiperidine (3-PPP), 5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclohepten-5,10-imine (MK-801), phencyclidine (PCP), ketamine and D-2-amino-5-phosphonovalerate (D-AP5) were all inactive. This suggests that inhibition of potassium-stimulated efflux of rubidium is correlated with activity at the sigma and/or dextromethorphan binding sites rather than at the N-methyl-D-aspartate (NMDA)/PCP receptor-channel complex.

Animals↗
PubMed1995

An attempt to attenuate experimental pain in humans by dextromethorphan, an NMDA receptor antagonist.

Dextromethorphan (100 mg, orally), an NMDA receptor antagonist, did not significantly attenuate pain intensity or unpleasantness induced by experimental ischemia or by topical capsaicin in healthy human subjects, nor did it increase the threshold for heat pain or mechanical pain. A dose of 200 mg produced marked side effects. Thus, systemically administered dextromethorphan does not attenuate pain at clinically applicable doses in humans.

Adult↗
PubMed1994

Dextromethorphan for the treatment of neuropathic pain: a double-blind randomised controlled crossover trial with integral n-of-1 design.

The aim was to compare the analgesic effectiveness and adverse effect incidence of oral dextromethorphan (DM) with placebo in patients with neuropathic pain. The first 10-day treatment period was a multiple-dose double-blind randomised controlled cross-over comparison of 13.5 mg of DM 3 times a day (t.d.s.) with placebo t.d.s.: 5 treatment pairs, each pair 1 day DM and 1 day placebo. The second 10-day treatment period used 27 mg of DM t.d.s. vs. placebo, with the same design. The study incorporated a 5 pair n-of-1 design for each of the 2 doses of DM. Patients took the study medication in addition to any pre-existing analgesic regime. Patients who reported benefit could continue with DM after the study. Nineteen patients with chronic neuropathic pain were studied over two 10-day treatment periods. Outcome measures were pain intensity, pain relief, adverse effects, mood, sleep and global rating of treatment. These were recorded by daily patient diaries and by clinic assessments before and after each treatment period. There were no significant differences between DM and placebo on any of the clinic assessment outcome measures. Two patients had significantly better analgesia on more than one outcome measure on within-patient testing. One had better analgesia with DM. The other had better analgesia with placebo. Ten patients had no adverse effects on either dose of DM. Two patients withdrew during the first treatment period because of adverse effects (which included increased pain intensity), and 5 during the second period. Five patients continued with DM after the study for 1-3 months. No long-term clinical benefit was apparent in those who continued with open DM. Dextromethorphan at either 40.5 or 81 mg daily did not relieve neuropathic pain.

Adult↗
PubMed1994

Screening for hydroxylation and acetylation polymorphisms in man via simultaneous analysis of urinary metabolites of mephenytoin, dextromethorphan and caffeine by capillary electrophoretic procedures.

Phenotypes for hydroxylation can be predicted by using mephenytoin and dextromethorphan as substrates, whereas phenotypes for acetylation can be determined with caffeine as probe drug. After single-dose administration of one of these drugs, of two of them simultaneously, or of the three drugs together, the major urinary metabolites (4-hydroxymephenytoin; dextrorphan, 3-methoxymorphinan, 3-hydroxymorphinan; 5-acetylamino-6-amino-3-methyluracil as decomposition product of 5-acetylamino-6-formylamino-3-methyluracil, 1-methylxanthine, respectively) of these substrates were analyzed by capillary electrophoretic techniques. No sample pretreatment other than enzymatic hydrolysis of the conjugated compounds was applied. Assays based on micellar electrokinetic capillary chromatography are shown to allow simultaneous and unambiguous phenotyping with mephenytoin and dextromethorphan or mephenytoin and caffeine. Simultaneous screening for all three polymorphisms with a single injection of a hydrolyzed urine is shown to be possible via use of multiwavelength absorption detection only. Phenotypes determined by electrokinetic capillary techniques are shown to agree with those obtained by analysis with customary assays based on high-performance liquid chromatography.

Acetylation↗
PubMed1996

Quantification of dextromethorphan and metabolites: a dual phenotypic marker for cytochrome P450 3A4/5 and 2D6 activity.

A sensitive and selective liquid chromatographic procedure using fluorimetric detection was developed to quantify dextromethorphan (DTM), 3-methoxymorphinan (3MM), dextrorphan (DT), 3-hydroxymorphinan (3OH) and two internal standards, codeine (COD) and ethylmorphine (ETM), in urine. Precision and accuracy of the assay were determined over a concentration range of 5-3200 ng/ml urine for DTM, 5-400 ng/ml urine for 3MM, 400-40 000 ng/ml urine for DT and 200-16 000 ng/ml urine for 3OH, by assaying freshly prepared calibration standards and replicates of six quality control (QC) samples on separate days. All of the inter-day and intra-day coefficients of variation (C.V.s) were less than 20% except for a low QC for 3MM. The inter-day and intra-day accuracies were less than 20% for the low QCs, less than 15% for the medium QCs and less than 12% for the high QCs, for all compounds. The limit of quantification (LOQ) was 2 ng/ml urine for DTM and 3MM, 250 ng/ml urine for DT, and 100 ng/ml urine for 3OH. Absolute recovery was 76% for DTM, 74% for 3MM, 77% for DT, 46% for 3OH, 73% for ETM, and 57% for COD. The frequency distribution of the CYP2D6 metabolic ratio (DTM/DT) illustrated a bimodal distribution whereas, the CYP3A metabolic ratio (DTM/3MM) exhibited a unimodal distribution in overnight urine samples of volunteers who ingested 30 mg dextromethorphan hydrobromide. The CYP2D6 metabolic ratio significantly correlated with 3MM/3OH (r=0.82) and DTM/3OH (r=0.95) but did not correlate with the CYP3A metabolic ratio (r=0.27).

Chromatography, High Pressure Liquid↗
PubMed1994

Determination of guaiphenesin in anti-tussive pharmaceutical preparations containing dextromethorphan by first- and second-derivative ultraviolet spectrophotometry.

Rapid, simple and direct assay procedures based on selective first (D1)- and second (D2)-derivative spectrophotometry, using a zero-crossing technique of measurement at 279.2 and 280.0 nm, respectively, have been developed for the specific determination of guaiphenesin in the presence of dextromethorphan, drugs with closely overlapping absorption spectra, in synthetic admixtures and in pharmaceutical dosage forms (tablets and syrups). The methods do not require extraction with organic solvents and are easier to perform than their conventional counterparts. Calibration graphs were linear (r = 0.99999 for D1 and 0.99969 for D2, respectively). Good selectivity, accuracy and precision were found. However, the performance of the analysis of guaiphenesin by the second-derivative mode deteriorated when the ratio of dextromethorphan to guaiphenesin was greater than one. Thus, the first-derivative spectrophotometry is the method of choice for the assay of tablets and syrups containing the two drugs.

Antitussive Agents↗
PubMed1991

Dextromethorphan poisoning reversed by naloxone.

Dextromethorphan, a common ingredient in cough syrups, has rarely been described to cause toxicity. The authors describe an unusual case of a known asthmatic presenting with somnolence, who appeared to be in end-stage respiratory failure. Her partial response to routine naloxone, 1 mg, was surprising. However, additional naloxone was required to completely normalize the patient's mental status. The authors suggest naloxone be administered in doses of 0.4 mg or more intravenously in suspected dextromethorphan overdose.

Adolescent↗
PubMed1995

Massive dextromethorphan ingestion and abuse.

The case of a 23-year-old man who was acutely intoxicated on dextromethorphan and who was chronically addicted to the drug is described. He consumed the highest daily dose for the longest duration yet reported in the world's English-language medical literature. Toxicity, abuse potential, and therapy of dextromethorphan intoxication are discussed.

Adult↗
PubMed2004

LC-MS/MS analysis of dextromethorphan metabolism in human saliva and urine to determine CYP2D6 phenotype and individual variability in N-demethylation and glucuronidation.

In order to establish a fast screening method for the determination of the CYP2D6 metabolic phenotype a sensitive LC-MS/MS assay to quantify dextromethorphan (DEX) and its O-demethylated metabolite dextrorphan (DOR) in human saliva was developed with limits of quantitation of 1 pmol/ml. Saliva was provided by 170 medical students 2h after oral ingestion of 30 mg (81 micromol) dextromethorphan hydrobromide. Individual ratios of the concentrations DEX/DOR (metabolic ratio, MR(DEX/DOR)) varied more than 25,000-fold (0.03-780). Two groups comprising 156 'Extensive' and 14 'Poor Metabolizers' were clearly distinguished. For the investigation of individual differences in N-demethylation and glucuronidation, four additional metabolites of DEX, 3-methoxymorphinan (MOM), 3-hydroxymorphinan (HOM), and the two O-glucuronides (DORGlu and HOMGlu) were measured by LC-MS/MS analysis of 6-h urine of 24 volunteers. The N-demethylation reactions DEX-to-MOM and DOR-to-HOM defined by the respective MR were significantly correlated. The same holds for the glucuronidation pathways (MR(DOR/DORGlu) versus MR(HOM/HOMGlu)). The three poor CYP2D6 metabolizers excreted relatively high amounts of the parent compound DEX (up to 7 micromol), but only low amounts of glucuronides (DORGlu: 0.4-1.0 micromol; HOMGlu: 0.2-0.7 micromol). For the 21 'Extensive Metabolizers', the two glucuronides were the most abundant, with relatively little interindividual variation (DORGlu: 10-44 micromol; HOMGlu: 5-17 micromol). For the excretion of the glucuronides, two normal distributions provided the best fit, indicating that the determination of the glucuronides alone could allow assignment of the CYP2D6 metabolic phenotype.

Chromatography, Liquid↗