SEARCH · PubMed Health

Results for “Dextromethorphan”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 361 records · Page 20Linked to original sources

PubMed1992

Nasal delivery of [14C]dextromethorphan hydrochloride in rats: levels in plasma and brain.

Dextromethorphan (DM) is a neuroprotective agent. The mechanism of action is believed to be by N-methyl-D-aspartate receptor blockade. The concentration of DM in the brain is believed to be dose and route dependent. Delivery by the nasal route has received a lot of attention recently, because drug absorption from this route follows intravenous profiles with no first-pass effect. The uptake of DM in the brain from the nasal route was 65.9% compared with the intravenous route, whereas the plasma bioavailability from the nasal route was 78.8%. The nasal route is a viable alternative to the parenteral route for DM administration.

Absorption↗

PubMed1998

A trial of dextromethorphan in parkinsonian patients with motor response complications.

The effects of the NMDA antagonist dextromethorphan (DM) on levodopa-associated dyskinesias and motor fluctuations were studied in patients with advanced Parkinson's disease. During initial open-label dose escalation, 6 of 18 patients reported a beneficial effect at their individually determined optimal DM dose (range, 60-120 mg/day). The 12 remaining patients either experienced reversible side effects, particularly mild drowsiness, or decreased levodopa efficacy, and were therefore excluded from the study. The six responders entered the double-blind, placebo-controlled, crossover study with two 2-week arms separated by 1 week wash-out. On the last day of each arm, motor ratings were performed every 20 minutes for 8 consecutive hours. In addition, motor complications and Activities of Daily Living (ADL) were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) and patient diaries. With DM, dyskinesias improved by 25% according to physician's ratings and by 40% according to UPDRS interviews, without compromising the anti-Parkinson effect of levodopa. Motor fluctuations and ADL scores also improved significantly. Although the narrow therapeutic index of DM limits its clinical usefulness, these findings support the view that drugs acting to inhibit glutamatergic transmission at the NMDA receptor can ameliorate levodopa-associated motor complications.

Activities of Daily Living↗

PubMed1986

Potentiation of disruptive effects of dextromethorphan by naloxone on fixed-interval performance in rats.

A centrally acting antitussive agent dextromethorphan (DM) was tested to determine its possible interaction with naloxone in rats responding under a fixed-interval schedule of positive reinforcement. A sugar sweetened milk reward was used as a positive reinforcer. Under the same experimental conditions the effects of morphine alone and in combination with naloxone were also determined. Low dose DM (10 mg/kg) produced a slight increase, while higher doses (20-40 mg/kg) produced dose-dependent decreases in response rate. Morphine (0.3, 1.0 and 3.0 mg/kg) produced dose-dependent decreases in response rate. When doses of naloxone (0.1-1.0 mg/kg) were administered after the injection of DM the rate-decreasing effects of DM were potentiated even after the rate-increasing dose of naloxone (0.1 mg/kg) was used. When a dose of naloxone (0.1 mg/kg) was administered after the injection of morphine the rate-decreasing effects of morphine were markedly antagonized, i.e., the morphine dose-response curve was shifted to the right. The observed potentiation of DM disruption by naloxone on fixed-interval performance in rats is consistent with findings showing that naloxone potentiates the disruptive behavioral effects of a number of drugs that are psychotomimetic in man.

Animals↗

PubMed1991

Oxidative polymorphism of dextromethorphan in a Burundi population.

The wide availability, metabolism by the same cytochrome P450 as debrisoquine and, above all, the inocuity of dextromethorphan (DMP) favour the frequent choice of this drug as the test substance in determining oxidation phenotypes. 100 healthy Burundian volunteers (94 m and 6 f) in this study ingested 50 mg DMP bromhydrate, i.e. 38.5 mg of DMP base. Urine was collected for 8 h following the dose and TLC was used to analyse it. The method was particularly useful in view of its low cost, speed and the ease of applying it to a large study group. 5% of the Burundian subjects were poor metabolizers.

Adult↗

PubMed1993

Dextromethorphan O-demethylation polymorphism in Jordanians.

The O-demethylation of dextromethorphan (DMT) to dextrorphan (DRP) was studied in 241 unrelated, healthy Jordanian volunteers (171 males, 70 females). Urine was collected for 8 h following a single oral dose of DMT bromhydrate 30 mg. A thin-layer chromatographic (TLC) technique was used to identify the metaboliser phenotype. The frequency of the poor metaboliser phenotype was found to be 2.9% (approximate 95% confidence interval 0.8-5.0%). Applying the Hardy-Weinberg Law, the frequency of the recessive autosomal gene controlling poor metabolism was 0.17 (95% confidence interval 0.108-0.232).

Adolescent↗

PubMed1988

Dextromethorphan binding sites in the guinea pig brain.

1. Dextromethorphan (DM), a dextrorotatory nonopioid antitussive, binds to specific high-affinity sites in the central nervous system. These sites are distinct from the opioid and other known neurotransmitter receptor sites. Antitussives such as carbetapentane and caramiphen also bind to DM sites with a nanomolar affinity. 2. The anticonvulsant drugs phenytoin and ropizine produce an allosteric enhancement of the binding of [3H]DM to guinea pig brain. DM, carbetapentane, and caramiphen also are efficacious anticonvulsant agents in the rat maximal electroshock seizures test, and DM enhances the anticonvulsant effects of phenytoin (PHT). 3. These results suggest that drugs that bind to the DM sites could be used alone as anticonvulsants or in combination with PHT to lower its effective dose and reduce its side effects. 4. The investigation of the DM binding sites may help to open new approaches for the treatment of convulsive disorders and to explain further some of the molecular mechanisms of neutronal excitability.

Animals↗

PubMedDate not supplied

Dextromethorphan potentiates morphine-induced antinociception at both spinal and supraspinal sites but is not related to the descending serotoninergic or adrenergic pathways.

Morphine is a strong and widely used opioid analgesic in pain management, but some adverse effects limit its clinical use at high doses. The clinically available non-opioid antitussive, dextromethorphan (DM) can potentiate the analgesic effect of morphine and decrease the dose of morphine in acute postoperative pain. However, the mechanism underlying this synergistic phenomenon is still not clear. To examine if the potentiation by DM occurs through the descending pain-inhibitory pathways, ketanserin (a 5-HT2 receptor antagonist) and yohimbine (an alpha2-adrenergic receptor antagonist) were employed and found to have no significant effect on the potentiation by DM. Using local delivery of drugs in rats in the present study, potentiation of morphine-induced antinociception by DM was observed via both intrathecal and intracerebroventricular routes, suggesting that both spinal and supraspinal sites are involved. This suggests that the potentiation of morphine-induced antinociception by DM is not mediated by the serotoninergic or adrenergic descending pain-inhibitory pathways. The present results are consistent with findings in clinical studies, which showed that DM can effectively decrease the consumption of morphine in patients suffering from pain. Since DM has excellent clinical potential as a synergistic agent with morphine, further investigating and clarifying the possible pharmacological mechanism of DM are of great importance for future studies.

Adrenergic Agents↗

PubMedDate not supplied

Dextromethorphan prevents circulatory failure in rats with endotoxemia.

Dextromethorphan (DM), an antitussive agent, has been claimed to have anti-inflammatory and immunomodulatory effects in vitro. Thus, the aim of this study was to evaluate the effects of DM on sepsis induced by intravenous (i.v.) administration of lipopolysaccharide (LPS) in anesthetized Wistar rats and by intraperitoneal administration in conscious ICR mice. Results demonstrated that pretreatment with DM (1, 5 and 10 mg/kg, i.v.) significantly attenuated the deleterious hemodynamic changes (e.g., hypotension and tachycardia) in rats treated with LPS. Meanwhile, DM (5 mg/kg) significantly inhibited the elevation of plasma tumor necrosis factor-alpha and interleukin-10 levels, as well as values of GOT and GPT (as an index of liver function), and BUN and creatinine (as an index of renal function) caused by LPS. The induction of inducible NO synthase and the overproduction of NO and superoxide anions by LPS were also reduced by DM. Moreover, infiltration of neutrophils into the lungs and liver of rats 6 h after treatment with LPS was also reduced by DM. In conclusion, the beneficial effects of DM on LPS-induced sepsis result from its anti-inflammatory and antioxidant effects. Thus, DM can possibly be used as a prophylactic agent for sepsis in the future.

Animals↗

PubMedDate not supplied

Analysis of pharmacokinetic parameters for assessment of dextromethorphan metabolic phenotypes.

In this study, the metabolic ratios of dextromethorphan to dextrorphan (DM/DX) in plasma were calculated at steady state after administering 2 dosage forms (Medicon) and Detusiv) of DM with different release rates. The urinary metabolic ratio for each subject was also determined based on the total drug concentration in the urine. An analysis of pharmacokinetic parameters for determining the DM metabolic phenotype was conducted. Results demonstrate that double logarithmic correlations between the metabolic ratios based on pharmacokinetic parameters of either AUC(0-tau,ss), C(max,ss), C(min,ss), or C(ave,ss) for Medicon and Detusiv and the urinary metabolic ratios were all significant. Probit plots of the metabolic ratios based on these pharmacokinetic parameters revealed 2 clusters of distribution, representing extensive and intermediate metabolizers. An antimode of 2.0 for total drug based on these pharmacokinetic parameters was determined and correspondingly referred to an antimode of 0.02 for the urinary metabolic ratio to delineate extensive and intermediate metabolizers. This model was also verified to be appropriate when using total plasma concentrations of DM and DX at any time during the period of the dosing interval at steady state to calculate the metabolic ratio for identifying extensive and intermediate metabolizers. Therefore, the metabolic ratio based on the pharmacokinetic parameters of either AUC(0-tau,ss), C(max,ss), C(min,ss), or C(ave,ss) and plasma concentrations of DM and DX in a single blood sample at steady state are proposed as an alternative way to identify phenotypes of CYP2D6.

Administration, Oral↗

PubMed1999

Preincisional dextromethorphan decreases postoperative pain and opioid requirement after modified radical mastectomy.

PURPOSE: To examine whether preincisional dextromethorphan (DM) improved analgesia after modified radical mastectomy (MRM). METHODS: Sixty patients (ASA I-II) scheduled for MRM were included and randomly allocated into two groups. Patients in the treatment group (DM) received 40 mg DM and 20 mg chlorpheniramine maleate (CPM) i.m., and those in the control group received 20 mg CPM i.m. alone 30 min before skin incision. Meperidine, 1 mg x kg(-1) i.m., was given for postoperative pain relief as required. The time to first meperidine injection, total meperidine consumption, worst pain score, bed-rest time, and side effects were recorded every 24 hr for 48 hr after surgery by a resident anesthesiologist on a double-blind basis. RESULTS: A longer time to first meperidine injection (19.2 +/- 1.6 vs 1.5 +/- 0.23 hr, P < 0.001) and lower meperidine consumption (0[10] vs 75[50] mg, median [interquartile range], P < 0.001) were observed in the DM group than in the control group. The bed-rest time was shorter in the DM than in the control group (18.0[4] vs 23.0[19] hr, P < 0.001). No difference was noted in worst VAS pain score. Meperidine-related side effects (nausea, vomiting, pruritus, dizziness, headache) were more frequent in the control (10/30) than in the DM group (3/30, P < 0.05). The number of patients who required meperidine injection for pain relief was lower in the DM (7/30) than in the control group (25/30, P < 0.005). No DM- or CPM-associated side effects were observed. CONCLUSION: Preincisional IM. DM treatment decreased postoperative pain and opioid requirement after MRM surgery.

Analgesics, Opioid↗

PubMed2004

Dextromethorphan potentiates morphine antinociception at the spinal level in rats.

PURPOSE: Morphine is an effective analgesic, but adverse effects limit its clinical use in higher doses. The non-opioid antitussive, dextromethorphan (DM), can potentiate the analgesic effect of morphine and decrease the dose of morphine in acute postoperative pain, but the underlying mechanism remains unclear. We previously observed that DM increases the serum concentration of morphine in rats. Therefore, we investigated the effects of drugs administered at the spinal level to exclude possible pharmacokinetic interactions. As DM has widespread binding sites in the central nervous system [such as N-methyl-D-aspartate (NMDA) receptors, sigma receptors and alpha(3)ss(4) nicotinic receptors], we investigated whether the potentiation of morphine antinociception by DM at the spinal level is related to NMDA receptors. METHODS: We used MK-801 as a tool to block the NMDA channel first, and then studied the interaction between intrathecal (i.t.) morphine and DM. The tail-flick test was used to examine the antinociceptive effects of different combinations of morphine and other drugs in rats. RESULTS: DM (2-20 microg) or MK-801 (5-15 microg) showed no significant antinociceptive effect by themselves. The antinociceptive effect of morphine (0.5 microg, i.t.) was significantly enhanced by DM and reached the maximal potentiation (43.7%-50.4%) at doses of 2 to 10 microg. Pretreatment with MK-801 (5 or 10 microg, i.t.) significantly potentiated morphine antinociception by 49.9% or 38.7%, respectively. When rats were pretreated with MK-801, DM could not further enhance morphine antinociception (45.7% vs 50.5% and 43.3%). CONCLUSION: Our results suggest that spinal NMDA receptors play an important role in the effect of DM to potentiate morphine antinociception.

Analgesics, Opioid↗

PubMed2003

Co-administration of dextromethorphan with morphine attenuates morphine rewarding effect and related dopamine releases at the nucleus accumbens.

Morphine is one of the most effective analgesics in clinic to treat postoperative pain or cancer pain. A major drawback of its continuous use is the development of tolerance and dependence. In our previous study we found that a widely used antitussive agent in clinics, dextromethorphan [(DM); also known as a non-competitive N-methyl- d-aspartate (NMDA) antagonist], could prevent the development of morphine tolerance. In the present study, we further investigated its effect on morphine addiction. Conditioned place preference (CPP) test and behavioral sensitization of locomotor activity were used to investigate the drug-seeking related behaviors, which were in correlation with psychological dependence. Our results showed that co-administered DM was able to abolish completely the CPP effect induced by morphine, but had no effect on morphine-induced behavioral sensitization. By employing the microdialysis technique in free-moving animals, we also determined the extracellular level of dopamine and serotonin metabolites in the shell region of the nucleus accumbens (NAc) in its response to morphine with/without DM. A significant increase in dopamine metabolites following morphine administration was demonstrated in the NAc. This increase by morphine could be attenuated by co-administered DM, whereas DM itself did not show any effect. Based on our results, it is speculated that DM may effectively attenuate morphine-induced psychological dependence. Neurochemical analysis revealed that the effect of DM could be through its action on the dopaminergic mesolimbic pathway, which could be activated by morphine and attributed to the cause of rewarding.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2003

Abuse liability and stimulant properties of dextromethorphan and diphenhydramine combinations in rats.

RATIONALE: The abuse of over-the-counter (OTC) medications has been widely reported. However, there are few preclinical studies examining the behavioral effects of OTC medications at higher, abused doses. OBJECTIVES: The objectives of the current study were to determine whether the anti-histamine diphenhydramine (DIP) and the antitussive dextromethorphan (DEX), either alone or in combination, would have stimulant properties and be self-administered in animals. METHODS: For drug self-administration, naive rats with no history of exposure to other drugs were trained to self-administer i.v. DEX+DIP (0.5+0.5, 1+1 or 2+2 mg/kg per injection), DEX alone (1 mg/kg) or DIP (1 mg/kg) alone under five-response fixed-ratio (FR) schedule with a 30-s time-out after each injection in 2-h sessions 3-5 days a week. Separate groups of rats were tested on locomotor activity. After 8 consecutive days of habituation, naive rats were injected with 3, 10, or 30 mg/kg DEX or DIP alone i.p., or in combination of 3+3 mg/kg, 10+10 mg/kg, or 30+30 mg/kg DEX+DIP i.p. Saline was injected i.p. during the intervening days. Locomotor activity was measured for each session. RESULTS: DEX+DIP combinations were self-administered, but the drugs alone were not. The acquisition of DEX+DIP self-administration was rapid with a majority of rats reaching the final FR5 schedule in 22-23 sessions. The total i.v. combination dose for each final scheduled session ranged from 40 mg/kg to 160 mg/kg DEX+DIP. Significant increases in locomotor activity were observed for DIP, an effect that was significantly enhanced when DIP was given in combination with DEX. Significant mortality was also observed for the drug combination at each dose tested when given i.v., with the highest mortality following the highest dose (2+2 mg/kg). When given i.p., no mortality was observed. CONCLUSIONS: These results show that combinations of DEX and DIP have stimulant properties and are self-administered by animals. Abuse of this combination in humans would be expected.

Animals↗

PubMed2006

Impairments in water maze learning of aged rats that received dextromethorphan repeatedly during adolescent period.

RATIONALE: Dextromethorphan (DM), an over-the-counter cough suppressant, has been recently used as a drug of abuse by teenage groups in some countries, such as the United States, Canada, and Korea. We previously showed that repeated administration of DM, a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, impairs spatial learning performance in adolescent rats. OBJECTIVES: In the present study, long-term adverse effects of repetitive DM use at adolescence were examined in rats. METHODS: Male and female Sprague-Dawley rat pups received either intraperitoneal DM (40 mg/kg) or saline daily during postnatal days 28-37, and were then subjected to the Morris water maze task at the age of 18 months. Expression levels of NMDAR1, functional subunit of NMDA receptors, in the prefrontal cortex and the hippocampus were examined by Western blot analysis. Changes in plasma corticosterone levels responding to stress were determined by radioimmunoassay. RESULTS: DM-experienced male rats exhibited deficits in the probe trial, and female rats in the initial learning and the reversal training, in water maze performance. Expression levels of NMDAR1 in the brain regions were significantly increased in DM-experienced rats, compared to control rats. Stress-induced increases in plasma corticosterone levels were blunted both in male and female DM rats. CONCLUSIONS: The results suggest that repeated administration of DM at high doses during adolescent period may induce permanent deficits in cognitive function and that increased expression of NMDAR1 in the prefrontal cortex and the hippocampus may take a role in DM-induced memory deficits.

Animals↗

PubMed1999

Evaluation of the reinforcing properties and phencyclidine-like discriminative stimulus effects of dextromethorphan and dextrorphan in rats and rhesus monkeys.

RATIONALE: Dextromethorphan (DXM) and its metabolite, dextrorphan (DXO) have neuroprotective and anticonvulsant properties through their activity as N-methyl-D-aspartate (NMDA) receptor channel blockers. Based on this receptor activity, coupled with reports of DXM abuse, both were evaluated for abuse potential and phencyclidine (PCP)-like behavioral effects in two animal models. OBJECTIVES AND METHODS: The discriminative stimulus properties of DXO and DXM were tested in rats (3-56 mg/kg DXM, i.p. and 2.2-40.9 mg/kg DXO, i.p.) and rhesus monkeys (0.3-10 mg/kg DXM, i.m. and 0.25-8.0 mg/kg DXO, i. m.) trained to discriminate PCP from saline using a standard two-lever drug-discrimination paradigm under a fixed-ratio (FR) schedule of food reinforcement. In a second set of experiments, i.v. self-administration of DXO (10-100 microg/kg/infusion) and DXM (10-1000 microg/kg/infusion) were tested under a FR schedule of reinforcement in monkeys trained to lever press for infusions of PCP during daily 1-h sessions. RESULTS: In rats, both DXM and DXO produced a dose-dependent substitution for PCP. When tested in monkeys, DXM yielded partial (1 monkey) and full (2 monkeys) substitution for PCP, while DXO substituted fully for PCP in all four subjects tested. In the self-administration study, in five of the six subjects, at least one dose of DXM served as a positive reinforcer, maintaining infusion rates above those for saline. For DXO, at least one dose maintained infusion numbers well above mean saline infusion numbers in all subjects. CONCLUSIONS: Taken together, these data show that DXM has some PCP-like effects in rats and monkeys, but that they are more reliably produced by its metabolite, DXO. Thus, high doses of DXM may have some PCP-like abuse potential in humans but this potential may be associated with, or enhanced by, metabolism of DXM to DXO.

Animals↗

PubMed1999

Dextromethorphan O-demethylation polymorphism in an African-American population.

OBJECTIVE: One hundred eighty-one (97 F, 84 M) unrelated healthy African-American subjects (aged 18-41 years) were phenotyped based on their dextromethorphan (DMP) O-demethylation ability. METHODS: Each subject was given 15 mg DMP orally and collected 8-h urine. The concentrations of DMP and its metabolite dextrophan (DOP) were determined by HPLC with ultraviolet detection. Metabolic ratio (MR) was expressed as the ratio of DMP to DOP molar amount in urine. RESULTS: The frequency distribution histogram of the MR was bimodal, and probit analysis of this frequency gave an antimode value of 0.34. Seven subjects [3.9%, 95% confidence interval (CI) 1.1%-6.7%] were classified as poor metabolizers (PMs). CONCLUSION: This deficient frequency is in complete agreement with the reported ones in two smaller investigations in the African-American populations.

Adolescent↗

PubMed2000

Preincisional dextromethorphan treatment for postoperative pain management after upper abdominal surgery.

Previous studies showed that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, provides a preemptive analgesic effect and preemptive analgesia improves postoperative pain management. The aim of this study was to examine whether premedication with dextromethorphan (DM) improves postoperative pain management after upper abdominal surgery. Sixty (American Society of Anesthesiologists class 1 and 2 of either gender) patients scheduled for upper abdominal surgery were included in the study. Patients were randomly assigned to one of four groups: control, DM-10, DM-20, and DM-40. In the control group, chlorpheniramine maleate (CPM, 20 mg) was injected immediately before induction of anesthesia intramuscularly (IM). In the DM-10, DM-20, and DM-40 groups, patients were premedicated with DM 10 mg, 20 mg, and 40 mg IM, respectively. After operation, patient-controlled analgesia (PCA) with morphine was given for pain relief. The time to the first PCA trigger, morphine consumption, pain scores, and analgesic-related side effects were recorded at 1, 2, 4, 24, 48, and 72 hours after surgery. The time to first PCA trigger for the control group was 17.8 +/- 1.4 minutes, for group DM-10 20.2 +/- 1.6 minutes, for group DM-20 32.4 +/- 1.9 minutes, and for DM-40 77.9 +/- 6.5 minutes. The morphine delivered and PCA triggering frequency were 5.5 +/- 0.5/11.3 +/- 0.8 times for the controls, 5.5 +/- 0.4/ 14.1 +/- 1.3 times for DM-10, 3.1 +/- 0.3/6.3 +/- 1.2 times for DM-20, and 0.2 +/- 0.1/0.3 +/- 0.2 times for DM-40 during the first hour after operation. For the first day, the figures are 19.9 +/- 1.2/23.9 +/- 1.4 for the controls, 15.6 +/- 1.2/17.3 +/- 2.4 for DM-10, 12.6 +/- 0.7/15.9 +/- 1.6 for DM-20, and 5.0 +/- 0.21/5.6 +/- 0.9 for DM-40. On the first day, the cough pain scores were 6.67 +/- 0.23, 6.53 +/- 0.16, 6.67 +/- 0.23, and 5.73 +/- 0.18 for the controls, DM-10, DM-20, and DM-40 groups, respectively. All data showed dose-dependent better pain relief in DM-premedicated patients. We conclude that DM premedication offers preemptive analgesia and reduces postoperative pain and morphine requirement.

Abdomen↗

PubMed2000

NMDA receptor challenge with dextromethorphan - subjective response, neuroendocrinological findings and possible clinical implications.

Glutamatergic NMDA receptors are believed to play a major role in the pathophysiology of numerous neuropsychiatric disorders including substance use and schizophrenia. Neuropharmacological studies measuring subjective response, psychopathology and biological parameters are helpful in studying pathophysiology of these disorders. We report preliminary data of a placebo-controlled double-blind challenge study in recently detoxified alcoholics (n = 20) and healthy controls (n = 10) using the non-competitive NMDA antagonist dextromethorphan. Findings suggest that dextrometorphan can produce ethanol-like subjective effects in both alcoholics and controls and induce a mild form of craving in alcoholics only. The results of this study give further support to the hypothesis of glutamatergic NMDA receptors mediating much of ethanol's psychotropic effects. Possible clinical implications of these findings are discussed.

Adult↗