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PubMed1988

Dextromethorphan pretreatment induces antipyrine clearance in the rat.

Numerous agents that undergo extensive first-pass metabolism have been shown to inhibit oxidative drug metabolism. To examine whether this effect is related to the chemical structure or pharmacokinetic characteristics of the inhibiting agent, we determined the effect of dextromethorphan (a compound which exhibits pharmacokinetic similarities to, but is chemically dissimilar from, previously studied agents) on the disposition of antipyrine. A single oral dose of dextromethorphan hydrobromide, 100 mg/kg, 1 hr prior to antipyrine administration had no significant effect on the pharmacokinetics of this model substrate. The administration of dextromethorphan at the same dose twice daily for 3 days and an additional dose 1 hr prior to antipyrine administration resulted in a 33% increase in the clearance of antipyrine. These data indicate that dextromethorphan is capable of inducing hepatic microsomal enzymes. Studies are needed to determine if this effect also occurs upon chronic administration in humans. These data suggest that the pharmacokinetic characteristic of extensive first-pass metabolism is not necessarily associated with inhibition of drug metabolism.

Animals↗

PubMed1990

Polymorphic formation of morphine from codeine in poor and extensive metabolizers of dextromethorphan: relationship to the presence of immunoidentified cytochrome P-450IID1.

We studied the oxidation capacity in liver biopsies of a series of extensive metabolizers (n = 10) and poor metabolizers (n = 2) as identified by in vivo phenotyping with dextromethorphan. Codeine and dextromethorphan were used as probe drugs in vitro. The data were compared with the contents of cytochrome P-450IID1 as quantitated by Western immunoblotting by use of a specific monoclonal antibody (MAb 114/2). The O-demethylation of codeine was highly correlated with the O-demethylation of dextromethorphan (r = 0.90). The N-demethylation of codeine was catalyzed at a considerably higher rate than the O-demethylation. The N-demethylation to O-demethylation ratio of codeine was 46 in the poor metabolizer and, on average, 6.2 (range, 2.6 to 11) in the extensive metabolizers, respectively. The band intensity in Western blots correlated with the rate of O-demethylation of codeine (r = 0.95) and of dextromethorphan (r = 0.88) in the extensive metabolizers. The comeasurement of the O-demethylation and N-demethylation of codeine may provide a tool with which to phenotype individuals in vitro with respect to the polymorphism of the cytochrome P-450IID1.

Antibodies, Monoclonal↗

PubMed1991

Salivary analysis for determination of dextromethorphan metabolic phenotype.

Debrisoquin oxidative phenotype is a determinant of pharmacologic response for many drugs. Poor and extensive metabolizers can be identified by the dextromethorphan metabolic ratio (dextromethorphan/dextrorphan). We developed and tested a method to determine debrisoquin phenotype on the basis of the metabolic ratio in saliva. Each of 62 normal volunteers was given a 50 mg capsule of dextromethorphan hydrobromide and collected urine (0 to 8 hours) and saliva (at 3 hours). Dextromethorphan and dextrorphan in saliva and urine were assayed by HPLC. The distributions of paired urinary and 3-hour salivary metabolic ratios of samples from 61 subjects were compared. The urinary and salivary metabolic ratios were distributed trimodally and bimodally, respectively. The Spearman rank correlation coefficient for logarithm of urinary metabolic ratio vs that of salivary metabolic ratio was 0.704. All the poor metabolizers identified by urinary metabolic ratio were also identified by the metabolic ratio in saliva at 3 hours (100% concordance). This study demonstrates that salivary analysis for determination of dextromethorphan metabolic phenotype is feasible.

Administration, Oral↗

PubMed1996

Neuroprotection by dextromethorphan in acute experimental subdural hematoma in the rat.

Experimental acute subdural hematoma in the rat has been shown to produce a zone of apparent infarction under the clot, and excitatory amino acid toxicity appears to play a role in the damage observed. We report the effect of dextromethorphan, a commonly used antitussive and a noncompetitive NMDA-type glutamate receptor antagonist, on the volume of histologic damage seen at 72 h after acute subdural hematoma in the rat. Sixty-five Long-Evans rats underwent placement of acute subdural hematoma using the "cranial window" model. Fourteen animals received oral dextromethorphan, 10 mg/kg/dose, twice daily for 3 days, and an additional 20 animals also received a single 20 mg/kg intraperitoneal dose 15 min after clot placement in addition to the oral regimen. Control animals received equal volumes of sterile water. Brain lesions in all animals were characterized by well-circumscribed infarctions underlying the subdural hematoma. Lesion volume in control animals was 88.3 +/- 9.3 mm3 (mean +/- standard error of the mean), while animals receiving dextromethorphan had significantly smaller lesions, which was independent of dosing schedule (59.9 +/- 9.2 mm3)(p = 0.0403). Animal weight was also found to be a significant covariate (p = 0.038). Because of its safety in humans and efficacy as a neuroprotectant in a variety of models, dextromethorphan may be a promising agent for clinical use, particularly in children.

Animals↗

PubMedDate not supplied

Fatal zipeprol and dextromethorphan poisonings in Korea.

Zipeprol and dextromethorphan are abused together by young people in Korea to obtain a stronger hallucinogenic effect. Because large amounts of these drugs are taken for this reason, nine fatal poisonings due to zipeprol and dextromethorphan have been reported since 1993. In this paper, the concentration of drugs in the postmortem blood and gastric contents of these victims is examined. The determination and identification of the drugs in biological fluids were conducted by gas chromatography (GC)-thermionic specific detection and GC-mass spectrometry. Linear calibration curves and high recoveries were obtained. The blood concentrations of zipeprol varied from 1.3 to 28.6 micrograms/mL, and the concentrations of dextromethorphan ranged from 1.1 to 18.3 micrograms/mL. The concentration of zipeprol in the gastric contents ranged from 26.8 to 1384.8 micrograms/g, and dextromethorphan concentrations varied from 2.1 to 243.7 micrograms/g.

Adult↗

PubMed1999

Perioperative dextromethorphan reduces postoperative pain after hysterectomy.

UNLABELLED: We studied the effect of dextromethorphan, an N-methyl-D-aspartate antagonist, on analgesic consumption and pain scoring after abdominal hysterectomy. In this double-blinded study, 50 patients were randomized into two groups. Group DM was given oral dextromethorphan 40 mg with their premedication, then 40 mg three times per day for the next 2 days. Group P received placebo at identical times. Postoperative analgesic requirements were assessed using a patient-controlled analgesia system and subsequent oral analgesic intake using a set protocol. Pain was assessed at rest and on movement using a visual analog scale 4, 24, 48, and 72 h after the operation. Median pain scores at rest were significantly lower at 48 and 72 h and also for the sum of all resting pain scores. Mean morphine consumption was less in Group DM (1.1 vs 1.5 mg/h; P = 0.054). Usage of oral diclofenac, given every 8 h as needed, did not differ between groups, but consumption of codydramol (paracetamol 500 mg and dihydrocodeine 10 mg) was significantly less in Group DM. We conclude that the use of oral dextromethorphan has an analgesia-sparing effect and some beneficial effects on pain scoring at rest after abdominal hysterectomy. IMPLICATIONS: Patients given dextromethorphan before and after surgery had a significant reduction in some pain scores at rest, but not on movement. There was a trend to lower morphine requirements in the first 24 h. Over the next 48 h, oral analgesic usage was significantly reduced.

Administration, Oral↗

PubMed1993

N-methyl-D-aspartate (NMDA)-mediated muscle relaxant action of dextromethorphan in rats.

The present study examined whether the antitussive agent dextromethorphan, which is an antagonist at the N-methyl-D-aspartate (NMDA) receptor, depresses spinal reflexes in rats. Injection of both the specific NMDA antagonist (-)-2-amino-7-phosphonoheptanoate and of dextromethorphan dose-dependently reduced the magnitude of the polysynaptic flexor reflex without affecting the monosynaptic H-reflex. In contrast, the non-NMDA antagonist 6,7-dinitroquinoxaline-2,3-dione depressed the H-reflex in a dose-dependent manner without affecting the flexor reflex. The depressant effect of dextromethorphan on the flexor reflex was prevented by co-administration with NMDA but not with the non-NMDA agonist alpha-amino-3-hydroxy-5-terthyl-4-isoxazole-propionic acid. These data suggest that dextromethorphan exerts a muscle relaxant action via the NMDA receptor.

2-Amino-5-phosphonovalerate↗

PubMed1989

An open label trial of dextromethorphan in Huntington's disease.

Because of its interactions at N-methyl-D-aspartate and haloperidol specific sigma receptors, dextromethorphan may have symptomatic or protective effects in Huntington's Disease (HD). Escalating doses of dextromethorphan in 11 HD patients produced side effects of dysarthria, rash, and incoordination. At maximum doses, performance declined on a variety of measures of HD, including functional rating scales and quantitative exam scores, consistent with dose-related side effects. Windows of symptomatic benefit were not found. Serum levels of dextromethorphan and its metabolites, including the active compound dextrorphan, showed atypical relationships to dose and side effects, suggesting complex pharmacokinetics. Although not beneficial symptomatically, further trials of dextromethorphan as protective therapy in HD may be warranted.

Adult↗

PubMed1996

A controlled one-year trial of dextromethorphan in amyotrophic lateral sclerosis.

In a one-year parallel group double-blind placebo-controlled study of dextromethorphan (1.5 mg/kg) in amyotrophic lateral sclerosis, no significant differences were observed in the rate of progression (Norris scale) in comparing 24 patients randomly assigned to the dextromethorphan group and 25 patients randomly assigned to the placebo group. Of the 24 patients in the dextromethorphan group, 17 had limb onset and 7 had bulbar onset disease; average duration of disease was 12.5 +/- 6 months and sex ratio (M:F) was 1.4:1. Of the 25 patients in the placebo group, 18 had limb onset and 7 had bulbar onset disease; average duration of disease was 9.9 +/- 6 months and sex ratio (M:F) was 1.55:1. Dextromethorphan is a weak noncompetitive N-methyl-D-aspartate (NMDA) antagonist and higher doses or other potent NMDA receptor antagonists should be tested.

Adult↗

PubMed2001

Improved postoperative pain control in pediatric adenotonsillectomy with dextromethorphan.

DESIGN: A prospective, randomized, double-blinded, placebo-controlled protocol. SETTING: An academic, tertiary care referral center. PATIENTS: Forty randomly selected children, ages 3 to 13 years, scheduled for adenotonsillectomy without other simultaneous procedures. INTERVENTION: A single, oral dose of dextromethorphan pediatric cough syrup (1 mg/kg) or placebo given 30 minutes before surgery. MAIN OUTCOME MEASURE: Total dose requirement of intravenous morphine within a 6-hour postoperative observation period. RESULTS: During routine postoperative observation, significantly fewer patients in the dextromethorphan group required no intravenous morphine compared with the placebo group (P =.03). Of those children requiring morphine, the mean dose requirement was significantly lower in the dextromethorphan group (P =.02). There was no known drug-related morbidity. CONCLUSION: Dextromethorphan syrup is a safe, non-narcotic medication that significantly reduced the requirement of intravenous morphine after pediatric adenotonsillectomy. Its routine use in this manner is recommended.

Adenoidectomy↗

PubMed1991

Toxicity with dextromethorphan-containing preparations: a literature review and report of two additional cases.

Dextromethorphan-containing cold/cough preparations are frequently prescribed and bought over the counter for use in children. Although generally considered safe, dextromethorphan has been shown to cause CNS side effects, including hyperexcitability, increased muscle tone, and ataxia. Two deaths have been reported with intentional dextromethorphan overdose. A literature review, brief review of pharmacology, and report of two cases of adverse reactions to dextromethorphan-containing preparations are presented.

Child, Preschool↗

PubMed1997

Dystonic reaction associated with dextromethorphan ingestion in a toddler.

INTRODUCTION: Accidental ingestions of cough and cold preparations containing dextromethorphan (DM) are common in the toddler age group and rarely have serious consequences. Even large intentional overdoses by adults seldom lead to serious morbidity. There have been no previous reports of an extrapyramidal reaction due to a DM ingestion. CASE REPORT: We report a 30-month-old girl who ingested approximately 38 mg/kg dextromethorphan. She presented with opisthotonus, ataxia, and bidirectional nystagmus. There was no change in her status with the administration of naloxone. The child was given diphenhydramine with clearing of her opisthotonus but persistence of her ataxia and nystagmus. DISCUSSION: A moderate ingestion of dextromethorphan in a toddler resulted in extrapyramidal symptoms with opisthotonus that responded to diphenhydramine. Dextromethorphan is known to have complex CNS effects and, in sufficient doses, may have dopamine receptor blocking activity resulting in this dystonic reaction.

Antidotes↗

PubMed1993

Abuse of over-the-counter dextromethorphan by teenagers.

Dextromethorphan, the d-isomer of the opiate agonist levorphanol, has none of the analgesic or sedative effects associated with the opiates and is approved for over-the-counter use as an antitussive. It is available, in various combinations with other medications, in nonprescription cough suppressant and common cold formulations, and its availability in the United States is not controlled. In this paper we have reported two cases of recreational use of dextromethorphan-containing cough syrup by two unrelated teenage boys. Despite the safety of this medication when used at the recommended dosage, there have been cases of "recreational" use of dextromethorphan as well as death by overdose. Although usually thought to be nonaddictive, dextromethorphan produces a substance dependence syndrome, and physicians should be aware of its abuse potential, particularly by youths.

Adolescent↗

PubMed1996

Automated determination of dextromethorphan and its main metabolites in human plasma by high-performance liquid chromatography and column switching.

An automated column-switching technique coupled to isocratic high-performance liquid chromatography (HPLC) with fluorescence detection was developed for simultaneous determination of dextromethorphan and its three major metabolites, dextrorphan, hydroxymorphinan, and methoxymorphinan. After cleavage of conjugates by incubation with glucuronidasearylsulfatase at 37 degrees C for 15 h, plasma samples were injected directly into the HPLC system. Dextromethorphan and metabolites were retained on a cleanup column (10 x 4.6 mm internal diameter [ID]) filled with cyanopropyl (CN) material (Hypersil CPS, 10-microns article size) while interfering proteins and lipids were washed to waste. After column switching, the drugs were eluted from the cleanup column and separated on Spherisorb CN material (5-microns particle size, column size 250 x 4.6 mm ID). Fluorescence detection was carried out with an excitation wavelength of 220 nm and an emission wavelength of 305 nm. Sample cleanup and HPLC separation were completed within 20 min. Regression analyses found linearity (r > 0.99) between drug concentration and detector response over a wide range-5-220 ng/ml for dextromethorphan, 5-550 ng/ml for dextrorphan, 5-500 ng/ml for hydroxymorphinan, and 5-200 ng/ml for methoxymorphinan. The limit of quantification was approximately 5 ng/ml, and the recovery was > 90% for all compounds. At concentrations of 20-500 ng/ml, the intra- and interassay coefficients of variation ranged from 3.5 to 14.6% and from 7.0 to 14.0%, respectively. The method is suitable for in vivo phenotyping of CYP2D6 activity, which catalyzes the O-demethylation of dextromethorphan to dextrorphan, and is also applicable to pharmacokinetic studies in man.

Adult↗

PubMed1995

The mephenytoin (cytochrome P450 2C 19) and dextromethorphan (cytochrome P450 2D6) polymorphisms in Saudi Arabians and Filipinos.

Hitherto no estimate has been available of the genetic polymorphisms of S-mephenytoin hydroxylation in the Saudi Arabian or any other Middle Eastern population. A total of 102 healthy Saudi Arabian volunteer subjects were tested simultaneously with mephenytoin and dextromethorphan. Two poor metabolizers of S-mephenytoin and two poor metabolizers of dextromethorphan were found. Also 55 healthy Filipino volunteer subjects were tested and 13 found to be poor metabolizers of S-mephenytoin, whilst none were found to be poor metabolizers of dextromethorphan. The Saudi Arabian population thus appears to resemble Europeans in the frequency of poor metabolizers of S-mephenytoin, but resembles Orientals in the frequency of poor metabolizers of dextromethorphan. The Filipino sample as expected resembles other Oriental samples in the frequencies of poor metabolizers of both drugs.

Adolescent↗

PubMed1984

Objective evaluation of dextromethorphan and glaucine as antitussive agents.

Twenty-four inpatients affected by chronic cough completed a single-dose double-blind cross-over study of placebo, glaucine 30 mg and dextromethorphan 30 mg. The study was carried out using a balanced incomplete block design, each patient receiving two of the three experimental treatments. Objective evaluation of cough was ensured by means of a writing cough recorder. Coughs after dextromethorphan and glaucine were fewer than coughs after placebo: however only glaucine was significantly different from placebo in reducing coughs. Treatments were well tolerated: clinical results included a reduction in pulse rate after both dextromethorphan and glaucine , and a large number of patients reporting side effects after dextromethorphan administration.

Adult↗

PubMed1987

Polymorphism of dextromethorphan oxidation in a French population.

Genetically-controlled drug oxidation capacity was studied using dextromethorphan, an anti-tussive drug, as the test compound in 103 healthy white French subjects (61 males and 42 females). Phenotyping was performed using the metabolic ratio (MR) calculated as MR = 0-10 h urinary output of dextromethorphan/0-10 h urinary output of dextrorphan, after oral administration of 40 mg (113.6 mumol) of dextromethorphan hydrobromide. The log MR was bimodally distributed: 99 subjects (96.1%) were phenotyped as extensive metabolizers; they had a log MR between -3.1 and -1.1, a urinary output of dextromethorphan below 5 mumol 10 h-1 and a urinary output of dextrorphan above 20 mumol 10 h-1. Four subjects (3.9%) were phenotyped as poor metabolizers; they had a log MR between -0.5 and +0.7, a urinary output of dextromethorphan above 5 mumol 10 h-1 and a urinary out of dextrorphan below 20 mumol 10 h-1.

Adult↗

PubMed2004

The use of dextromethorphan to treat repetitive self-directed scratching, biting, or chewing in dogs with allergic dermatitis.

OBJECTIVE: To evaluate the efficacy of oral dextromethorphan in dogs with a repetitive behavior problem (self-licking, self-chewing, and self-biting associated with chronic allergic dermatitis). ANIMALS: Fourteen dogs with chronic allergic dermatitis were enrolled in the study. Twelve dogs completed the study. PROCEDURE: The dogs were treated for 2 weeks each with dextromethorphan (2 mg/kg BID) and placebo in a randomized, double blind, crossover designed study. A dermatology score, including an assessment of affected areas of the integument and the level of self-directed behavior, was generated before and following each 2-week phase of the study. Owners were required to record daily the amount of time they spent with their dog and the amount of time that the dog was observed to be engaged in any of the specified self-directed behaviors. RESULTS: The percent of the observed time that the dogs were reported to be involved in self-directed behaviors was significantly less during the 2-week active drug treatment phase. The pruritus score component of the dermatology score also was significantly less during the active treatment phase. In addition, a dermatologist-rated global assessment was more favorable in 11 of 12 dogs following the active treatment phase. CONCLUSIONS: Dextromethorphan significantly reduces the percentage of time that allergic dogs spend self-licking, self-chewing, and self-biting. CLINICAL RELEVANCE: Dextromethorphan may be a useful adjunct in the management of self-directed behaviors associated with allergic dermatitis and possibly in other repetitive behaviors as well.

Analgesics, Opioid↗