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Evaluation of the neuroprotective effect of dextromethorphan in the acute phase of ischaemic stroke.Archives of Medical Science : AMS Jun 2011Stroke is the second leading cause of death in the world. However, there is still no approved neuroprotective drug for acute ischaemic stroke. To clarify the...
INTRODUCTION
Stroke is the second leading cause of death in the world. However, there is still no approved neuroprotective drug for acute ischaemic stroke. To clarify the neuroprotective efficacy and safety of dextromethorphan in stroke, the following study was carried out.
MATERIAL AND METHODS
Forty patients with acute stroke causing moderate deficit were randomized to be treated with either dextromethorphan 300 mg per day or placebo for 5 days. Plasma level of dextromethorphan and its active metabolite was not evaluated in this study. The NIHSS score was calculated on day 5 and the Barthel activities of daily living index and Rankin score were checked after 3 months by a blinded investigator. Collected data were analysed using the t-test and χ(2) test.
RESULTS
In the dextromethorphan-treated group, the mean NIHSS score was 16.8 ±3.9 at baseline, and was 14.2 ±4.8 for the placebo-treated group (p = 0.069). At day 5, there was also no significant difference regarding NIHSS score (p = 0.167). At the 3-month follow-up, there was no significant difference regarding Barthel scale and Rankin score between the dextromethorphan and placebo groups.
CONCLUSIONS
The results of our study suggest that although low-dose and short-term oral administration of dextromethorphan seems to be not neuroprotective, it does not worsen either patients' condition or NIHSS score. Moreover, patients treated with dextromethorphan showed a significant reduction in seizures (complication after stroke), but had increased chance of MI and renal failure by almost 5% when compared to the placebo-treated groups. More prolonged studies with a higher number of cases are recommended.
PubMed: 22295030
DOI: 10.5114/aoms.2011.23413 -
European Journal of Clinical... May 2010To evaluate variability in cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A, N-acetyltransferase 2 (NAT2), and xanthine oxidase (XO) activity in HIV-infected patients and...
AIMS
To evaluate variability in cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A, N-acetyltransferase 2 (NAT2), and xanthine oxidase (XO) activity in HIV-infected patients and compare this with data from uninfected, healthy volunteers.
METHODS
Ten HIV-infected men and seven women on medication affecting CYP enzyme activity were phenotyped four times over 2 months using caffeine, dextromethorphan, and midazolam. Urinary caffeine and dextromethorphan metabolite ratios were used to phenotype CYP1A2, NAT2, XO, and CYP2D6 activity and midazolam plasma clearance was used to phenotype CYP3A activity. Plasma and urine samples were analyzed by validated LC/UV or LC/MS methods for midazolam, caffeine, and dextromethorphan. Noncompartmental pharmacokinetics and nonparametric statistical analyses were performed, and the data compared with those of healthy volunteer historic controls.
RESULTS
Compared with age and sex-matched healthy volunteers, HIV-infected subjects had 18% lower hepatic CYP3A4 activity, 90% lower CYP2D6 activity, 53% lower NAT2 activity, and 22% higher XO activity. No significant difference was found in CYP1A2 activity. Additionally, 25% genotype-phenotype discordance in CYP2D6 activity was noted in HIV-infected subjects. Intraindividual variability in enzyme activity increased by 42-62% in HIV-infected patients for CYP1A2, NAT2, and XO, and decreased by 33% for CYP2D6. Interindividual variability in enzyme activity increased by 27-63% in HIV-infected subjects for CYP2D6, CYP1A2, and XO, and decreased by 38% for NAT2. Higher plasma TNFalpha concentrations correlated with lower CYP2D6 and CYP3A4 activity.
CONCLUSIONS
Infection with HIV or stage of HIV infection may alter Phase I and II drug metabolizing enzyme activity. HIV infection was related to an increase in variability of these drug-metabolizing enzymes. Altered metabolism may be a consequence of immune activation and cytokine exposure.
Topics: Adult; Arylamine N-Acetyltransferase; Caffeine; Cytochrome P-450 Enzyme System; Dextromethorphan; Female; HIV Infections; Humans; Interleukin-6; Male; Midazolam; Phenotype; Tumor Necrosis Factor-alpha; Xanthine Oxidase
PubMed: 20084375
DOI: 10.1007/s00228-009-0777-6 -
Daru : Journal of Faculty of Pharmacy,... Dec 2020Conversion in the metabolism of drugs occurs in diabetes mellitus. Considering the importance of metabolic enzymes' activities on the efficacy and safety of medicines,...
INTRODUCTION
Conversion in the metabolism of drugs occurs in diabetes mellitus. Considering the importance of metabolic enzymes' activities on the efficacy and safety of medicines, the changes in liver enzymatic activity of CYP2D1 and its related hepatic clearance, by using Dextromethorphan as probe in the animal model of type I and type II diabetes, before and after treatment, was assessed in this study.
METHODS
Male Wistar rats were randomly divided into 6 groups. Seven days after induction of diabetes type I and type II, treatment groups were received insulin and metformin daily for 14 days, respectively. In day 21, rats were subjected to liver perfusion by Krebs-Henseleit buffer containing Dextromethorphan as CYP2D1 probe. Perfusate samples were analyzed by HPLC fluorescence method in order to evaluate any changes in CYP2D1 activity.
RESULTS
The average metabolic ratio of dextromethorphan and hepatic clearance were changed from 0.012 ± 0.004 and 6.3 ± 0.1 in the control group to 0.006 ± 0.0008 and 5.2 ± 0.2 in the untreated type I diabetic group, and 0.008 ± 0.003 and 5.0 ± 0.6 in the untreated type II diabetic rats. Finally, the mean metabolic ratio and hepatic clearance were changed to 0.008 ± 0.001 and 5.4 ± 0.1, and 0.013 ± 0.003 and 6.1 ± 0.4 in the treated groups with insulin and metformin, respectively.
CONCLUSION
In type I diabetic rats, corresponding treatment could slightly improve enzyme activity, whereas the hepatic clearance and enzyme activity reached to the normal level in type II group. Graphical abstract .
Topics: Animals; Cytochrome P450 Family 2; Dextromethorphan; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Gene Expression Regulation; Hepatobiliary Elimination; Hypoglycemic Agents; Insulin; Male; Metformin; Niacinamide; Rats; Rats, Wistar; Streptozocin
PubMed: 32378154
DOI: 10.1007/s40199-020-00350-z -
Drug Metabolism and Disposition: the... Aug 2018Metabolic phenotype can be affected by multiple factors, including allelic variation and interactions with inhibitors. Human CYP2D6 is responsible for approximately 20%...
CYP2D6 Allelic Variants *34, *17-2, *17-3, and *53 and a Thr309Ala Mutant Display Altered Kinetics and NADPH Coupling in Metabolism of Bufuralol and Dextromethorphan and Altered Susceptibility to Inactivation by SCH 66712.
Metabolic phenotype can be affected by multiple factors, including allelic variation and interactions with inhibitors. Human CYP2D6 is responsible for approximately 20% of cytochrome P450-mediated drug metabolism but consists of more than 100 known variants; several variants are commonly found in the population, whereas others are quite rare. Four CYP2D6 allelic variants-three with a series of mutations distal to the active site (*34, *17-2, *17-3) and one ultra-metabolizer with mutations near the active site (*53), along with reference *1 and an active site mutant of *1 (Thr309Ala)-were expressed, purified, and studied for interactions with the typical substrates dextromethorphan and bufuralol and the inactivator SCH 66712. We found that *34, *17-2, and *17-3 displayed reduced enzyme activity and NADPH coupling while producing the same metabolites as *1, suggesting a possible role for Arg296 in NADPH coupling. A higher-activity variant, *53, displayed similar NADPH coupling to *1 but was less susceptible to inactivation by SCH 66712. The Thr309Ala mutant showed similar activity to that of *1 but with greatly reduced NADPH coupling. Overall, these results suggest that kinetic and metabolic analysis of individual CYP2D6 variants is required to understand their possible contributions to variable drug response and the complexity of personalized medicine.
Topics: Alleles; Catalytic Domain; Cytochrome P-450 CYP2D6; Dextromethorphan; Ethanolamines; Humans; Imidazoles; Inactivation, Metabolic; Kinetics; Mutation; NADP; Phenotype; Pyrimidines
PubMed: 29784728
DOI: 10.1124/dmd.117.079871 -
Journal of Taibah University Medical... Apr 2021This study investigates the impact of repeated oral exposure to two cough syrups containing codeine and dextromethorphan (DXM) on male Wistar rats.
OBJECTIVE
This study investigates the impact of repeated oral exposure to two cough syrups containing codeine and dextromethorphan (DXM) on male Wistar rats.
METHODS
We divided 35 rats into seven groups of five rats each. Group A was given 0.5 mL of distilled water, Groups B, C, and D were given 0.1, 0.2 and 0.4 mL/kg body weight () of cough syrup containing codeine (CSC), respectively, and Groups E, F, and G were administered 0.1, 0.2 and 0.4 mL/kg of cough syrup containing DXM, respectively. The treatment was continued for 28 days. The rats were euthanised under mild diethyl ether anaesthesia. The kidney, liver, and blood of the rats were examined for further analyses.
RESULTS
Significant ( < 0.05) alterations were observed in the liver function tests: ALT, AST, ALP, albumin, and total bilirubin. All doses of CSC and DXM significantly increased the ALT levels ( < 0.05). Furthermore, similar significant alterations were observed for the kidney function parameters such as creatinine, urea, and uric acid (p < 0.05). All doses of DXM caused significant elevations in the levels of urea ( < 0.05). The histopathological evaluations also showed slight changes in the architecture of the liver, kidney, and brain tissues.
CONCLUSION
The findings of this study suggest that overdose of these cough syrups may predispose the consumer to hepatic and renal injuries.
PubMed: 33897324
DOI: 10.1016/j.jtumed.2021.01.002 -
Behavioural Neurology 2021Prenatal exposure to buprenorphine renders offspring vulnerable to cerebral impairments. In this study, our data demonstrate, for the first time, that prenatal exposure...
Prenatal exposure to buprenorphine renders offspring vulnerable to cerebral impairments. In this study, our data demonstrate, for the first time, that prenatal exposure to buprenorphine escalates astrocyte activation concurrent with indications of endoplasmic reticulum (ER) stress in the hippocampi of neonates, and this can be prevented by the coadministration of dextromethorphan with buprenorphine. Furthermore, dextromethorphan can inhibit the accumulation of GPR37 in the hippocampus of newborns caused by buprenorphine and is accompanied by the proapoptotic ER stress response that involves the procaspase-3/CHOP pathway. Primary astrocyte cultures derived from the neonates of the buprenorphine group also displayed aberrant ER calcium mobilization and elevated basal levels of cyclooxygenase-2 (COX-2) at 14 days while showing sensitivity to lipopolysaccharide-activated expression of COX-2. Similarly, these long-lasting defects in the hippocampus and astrocytes were abolished by dextromethorphan. Our findings suggest that prenatal exposure to buprenorphine might instigate long-lasting effects on hippocampal and astrocytic functions. The beneficial effects of prenatal coadministration of dextromethorphan might be, at least in part, attributed to its properties in attenuating astrocyte activation and hippocampal ER stress in neonates.
Topics: Apoptosis; Astrocytes; Buprenorphine; Dextromethorphan; Endoplasmic Reticulum Stress; Female; Humans; Infant, Newborn; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 34336001
DOI: 10.1155/2021/6301458 -
Basic and Clinical Neuroscience 2019We investigated the sexually dimorphic effects of Dextromethorphan (DM) on cognitive and depression-like behaviors as well as on hippocampal histology in rats following...
INTRODUCTION
We investigated the sexually dimorphic effects of Dextromethorphan (DM) on cognitive and depression-like behaviors as well as on hippocampal histology in rats following acute administration.
METHODS
Wistar rats of both sexes were treated with 25 or 50 mg/kg of DM for 7 days via intraperitoneal injection. At the end of the administration, behavioral studies were performed on the Tail Suspension Test (TST) for depressive-like behaviors and the Y-maze for cognitive behaviors. The rats' brains were excised and processed for routine histological analysis.
RESULTS
Our results showed that DM significantly increased (P<0.05) immobility time in the TST in male rats but not female ones, and decreased percentage alternation (P<0.001) on the Y-maze in both male and female rats. Histological analysis revealed no morphological changes in the hippocampus following DM treatment.
CONCLUSION
DM impairs cognitive functions in both male and female rats without histologic defects in the hippocampus. However, the induced depressive-like behaviors following DM administration may be sexually dependent.
PubMed: 32231776
DOI: 10.32598/bcn.9.10.275 -
The American Journal on Addictions 2008Dextromethorphan (DM) is a low-affinity, non-competitive NMDA receptor antagonist that has shown promise in preclinical and preliminary clinical studies for the... (Randomized Controlled Trial)
Randomized Controlled Trial
Dextromethorphan (DM) is a low-affinity, non-competitive NMDA receptor antagonist that has shown promise in preclinical and preliminary clinical studies for the reduction of opioid withdrawal symptoms, but when used at higher doses, it is associated with deleterious side effects attributed to its metabolite, dextrorphan. A clinical trial was therefore conducted to test the withdrawal-suppressant effect of a combination of dextromethorphan with quinidine (DM/Q). Quinidine inhibits the metabolism of dextromethorphan, reducing dextrorphan levels. Opioid-dependent patients were admitted to an inpatient unit, stabilized for three days on morphine (25 mg, sc, every six hours), and randomly assigned on day 2 to DM/Q (30 mg/30 mg, twice a day) (n = 22) or matching placebo (n = 9) prior to the discontinuation of morphine on day 4. Withdrawal symptoms, measured with the Modified Himmelsbach Opioid Withdrawal Scale (MHOWS), increased significantly on days 4 and 5 (Z = 3.70, p = .0002), and by day 6, 90% of the sample (28/31) had dropped out of the study. There were no differences between treatment groups on either outcome measure. The combination of dextromethorphan and quinidine appears ineffective as a primary treatment for opioid withdrawal. Future studies should examine dextromethorphan as an adjunct to other anti-withdrawal medications and focus more on the relationship between dextrorphan levels and withdrawal suppression.
Topics: Adult; Cytochrome P-450 CYP2D6 Inhibitors; Dextromethorphan; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Female; Heroin; Heroin Dependence; Humans; Male; Middle Aged; Muscarinic Antagonists; Patient Dropouts; Quinidine; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome
PubMed: 18463993
DOI: 10.1080/10550490802019543 -
British Journal of Clinical Pharmacology Nov 2022Ketamine and dextromethorphan are widely abused psychoactive substances. Inhibition of N-methyl-d-aspartate receptors (NMDARs) results in neurobehavioural effects...
Ketamine and dextromethorphan are widely abused psychoactive substances. Inhibition of N-methyl-d-aspartate receptors (NMDARs) results in neurobehavioural effects including hallucinations, "out of body" sensations and dissociative effects. However, little is known about a possible extended addictive class effect linked to pharmacologically-related amino-adamantane derivatives (e.g., amantadine and memantine). Using a quasi-Bayesian analytic method, we investigated the potential association between the use of approved NMDAR antagonists (i.e., dextromethorphan, ketamine, amantadine and memantine) and the reporting of drug abuse and dependence in the WHO pharmacovigilance database (VigiBase®), which includes >21 million individual case safety reports collected from >130 countries. This disproportionality analysis identified a significant association for all investigated drugs: dextromethorphan (IC = 3.03 [2.97-3.09]), ketamine (IC = 1.70 [1.57-1.83]), amantadine (IC = 0.21 [0.06-0.35]) and memantine (IC = 0.27 [0.13-0.40]), suggesting a class effect for drug abuse and dependence. This first signal requires further investigations, but health professionals need to be alert to the potential of abuse of NMDAR antagonists, especially in the current "opioid epidemic" context, due to their growing interest as non-opioid antinociceptive drugs.
Topics: Amantadine; Analgesics; Bayes Theorem; Dextromethorphan; Humans; Ketamine; Memantine; Pharmacovigilance; Receptors, N-Methyl-D-Aspartate; Substance-Related Disorders; World Health Organization
PubMed: 35665950
DOI: 10.1111/bcp.15430 -
Neurology Oct 2017To determine safety and perform a preliminary assessment of dose-dependent efficacy of dextromethorphan in normalizing electrographic spikes, clinical seizures, and... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To determine safety and perform a preliminary assessment of dose-dependent efficacy of dextromethorphan in normalizing electrographic spikes, clinical seizures, and behavioral and cognitive functions in girls with Rett syndrome.
METHODS
We used a prospective randomized, open-label trial in fast metabolizers of dextromethorphan to examine the effect of dextromethorphan on core clinical features of Rett syndrome. Interictal spike activity and clinical seizures were determined using EEG and parent reporting. Cognitive data were obtained using the Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales, while behavioral data were obtained from parent-completed checklists, the Aberrant Behavior Checklist-Community Version, and the Screen for Social Interaction. Anthropometric data were obtained according to the National Health and Nutrition Examination Survey. The Rett Syndrome Severity Scale provided a clinical global impression of the effect of dextromethorphan on clinical severity.
RESULTS
Dextromethorphan is safe for use in 3- to 15-year-old girls with Rett syndrome. Thirty-five girls were treated with 1 of 3 doses of dextromethorphan over a period of 6 months. Statistically significant dose-dependent improvements were seen in clinical seizures, receptive language, and behavioral hyperactivity. There was no significant improvement in global clinical severity as measured by the Rett Syndrome Severity Scale.
CONCLUSIONS
Dextromethorphan is a potent noncompetitive antagonist of the NMDA receptor channel that is safe for use in young girls with Rett syndrome. Preliminary evidence suggests that dextromethorphan may improve some core features of Rett syndrome.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence that dextromethorphan at various doses does not change EEG spike counts over 6 months, though precision was limited to exclude an important effect.
Topics: Adolescent; Anthropometry; Child; Child, Preschool; Dextromethorphan; Electroencephalography; Excitatory Amino Acid Antagonists; Female; Follow-Up Studies; Gait; Humans; Neuropsychological Tests; Parents; Rett Syndrome; Severity of Illness Index; Statistics, Nonparametric; Time Factors; Treatment Outcome
PubMed: 28931647
DOI: 10.1212/WNL.0000000000004515