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Clinical and Translational Science Oct 2022CYP2D6 substrates are among the most highly prescribed medications in teenagers and also commonly associated with serious adverse events. To investigate the relative...
CYP2D6 substrates are among the most highly prescribed medications in teenagers and also commonly associated with serious adverse events. To investigate the relative contributions of genetic variation, growth, and development on CYP2D6 activity during puberty, healthy children and adolescents 7-15 years of age at enrollment participated in a longitudinal phenotyping study involving administration of 0.3 mg/kg dextromethorphan (DM) and 4-h urine collection every 6 months for 3 years (7 total visits). At each visit, height, weight, and sexual maturity were recorded, and CYP2D6 activity was determined as the urinary molar ratio of DM to its metabolite dextrorphan (DX). A total of 188 participants completed at least one visit, and 102 completed all seven study visits. Following univariate analysis, only CYP2D6 activity score (p < 0.001), urinary pH (p < 0.001), weight (p = 0.018), and attention-deficit/hyperactivity disorder (ADHD) diagnosis (p < 0.001) were significantly correlated with log(DM/DX). Results of linear mixed model analysis with random intercept, random slope covariance structure revealed that CYP2D6 activity score had the strongest effect on log(DM/DX), with model-estimated average log(DM/DX) being 3.8 SDs higher for poor metabolizers than for patients with activity score 3. A moderate effect on log(DM/DX) was observed for sex, and smaller effects were observed for ADHD diagnosis and urinary pH. The log(DM/DX) did not change meaningfully with age or pubertal development. CYP2D6 genotype remains the single, largest determinant of variability in CYP2D6 activity during puberty. Incorporation of genotype-based dosing guidelines should be considered for CYP2D6 substrates given the prevalent use of these agents in this pediatric age group.
Topics: Adolescent; Child; Humans; Cytochrome P-450 CYP2D6; Dextromethorphan; Dextrorphan; Longitudinal Studies; Phenotype
PubMed: 35997001
DOI: 10.1111/cts.13380 -
Translational Psychiatry Jun 2023Esmethadone (REL-1017) is the opioid-inactive dextro-isomer of methadone and a low-affinity, low-potency uncompetitive NMDA receptor antagonist. In a Phase 2,... (Randomized Controlled Trial)
Randomized Controlled Trial
Esmethadone (REL-1017) is the opioid-inactive dextro-isomer of methadone and a low-affinity, low-potency uncompetitive NMDA receptor antagonist. In a Phase 2, randomized, double-blind, placebo-controlled trial, esmethadone showed rapid, robust, and sustained antidepressant effects. Two studies were conducted to evaluate the abuse potential of esmethadone. Each study utilized a randomized, double-blind, active-, and placebo-controlled crossover design to assess esmethadone compared with oxycodone (Oxycodone Study) or ketamine (Ketamine Study) in healthy recreational drug users. Esmethadone 25 mg (proposed therapeutic daily dose), 75 mg (loading dose), and 150 mg (Maximum Tolerated Dose) were evaluated in each study. Positive controls were oral oxycodone 40 mg and intravenous ketamine 0.5 mg/kg infused over 40 min. The Ketamine study included oral dextromethorphan 300 mg as an exploratory comparator. The primary endpoint was maximum effect (E) for Drug Liking, assessed using a bipolar 100-point visual analog scale (VAS). A total of 47 and 51 participants completed the Oxycodone Study and the Ketamine Study, respectively (Completer Population). In both studies, esmethadone doses ranging from therapeutic (25 mg) to 6 times therapeutic (150 mg) had a meaningful and statistically significantly (p < 0.001) lower Drug Liking VAS E compared with the positive control. Results were consistent for all secondary endpoints in both studies. In both studies, all doses of esmethadone were statistically equivalent to placebo on Drug Liking VAS E (p < 0.05). In the Ketamine Study, Drug Liking VAS E scores for esmethadone at all tested doses were significantly lower vs. dextromethorphan (p < 0.05) (exploratory endpoint). These studies indicate no meaningful abuse potential for esmethadone at all tested doses.
Topics: Humans; Oxycodone; Receptors, N-Methyl-D-Aspartate; Dextromethorphan; Ketamine; Analgesics, Opioid; Cross-Over Studies; Double-Blind Method; Illicit Drugs
PubMed: 37286536
DOI: 10.1038/s41398-023-02473-8 -
Clinical Pharmacology and Therapeutics Mar 2022rs5758550 has been associated with enhanced transcription and suggested to be a useful marker of CYP2D6 activity. As there are limited and inconsistent data regarding...
rs5758550 has been associated with enhanced transcription and suggested to be a useful marker of CYP2D6 activity. As there are limited and inconsistent data regarding the utility of this distant "enhancer" single nucleotide polymorphism (SNP), our goal was to further assess the impact of rs5758550 on CYP2D6 activity toward two probe substrates, atomoxetine (ATX) and dextromethorphan (DM), using in vivo urinary metabolite (DM; n = 188) and pharmacokinetic (ATX; n = 70) and in vitro metabolite formation (ATX and DM; n = 166) data. All subjects and tissues were extensively genotyped, the "enhancer" SNP phased with established CYP2D6 haplotypes either computationally or experimentally, and the impact on CYP2D6 activity investigated using several linear models of varying complexity to determine the proportion of variability in CYP2D6 activity captured by each model. For all datasets and models, the "enhancer" SNP had no or only a modest impact on CYP2D6 activity prediction. An increased effect, when present, was more pronounced for ATX than DM suggesting potential substate-dependency. In addition, CYP2D6*2 alleles with the "enhancer" SNP were associated with modestly higher metabolite formation rates in vitro, but not in vivo; no effect was detected for CYP2D6*1 alleles with "enhancer" SNP. In summary, it remains inconclusive whether the small effects detected in this investigation are indeed caused by the "enhancer" SNP or are rather due to its incomplete linkage with other variants within the gene. Taken together, there does not appear to be sufficient evidence to warrant the "enhancer" SNP be included in clinical CYP2D6 pharmacogenetic testing.
Topics: Adolescent; Alleles; Atomoxetine Hydrochloride; Child; Cytochrome P-450 CYP2D6; Dextromethorphan; Genotype; Haplotypes; Humans; Pharmacogenomic Testing; Phenotype; Polymorphism, Single Nucleotide
PubMed: 34716917
DOI: 10.1002/cpt.2469 -
Journal of Pain and Symptom Management Jan 2000Recent clinical data suggest that chronic pain due to nerve or soft tissue injury may result in the sensitization of the central nervous system, mediated in part by the... (Review)
Review
Recent clinical data suggest that chronic pain due to nerve or soft tissue injury may result in the sensitization of the central nervous system, mediated in part by the excitatory amino acids, glutamate and aspartate. Only a handful of N-methyl-D-aspartate antagonists are clinically available. These include ketamine, dextromethorphan, memantine, and amantadine, as well as three clinically used opioids (methadone, dextropropoxyphene, and ketobemidone). This review summarizes the single-dose efficacy of the first two compounds in the treatment of experimental and neuropathic pain. In all examples presented here, NMDA-receptor antagonists with affinity at the phencyclidine site have been shown to modulate pain and hyperalgesia but are limited by dose-limiting side effects. Thus, provided their therapeutic ratio is favorable, NMDA-receptor antagonists may be effective in the treatment of some types of chronic pain.
Topics: Analgesics; Clinical Trials as Topic; Dextromethorphan; Excitatory Amino Acid Antagonists; Humans; Ketamine; Nervous System Diseases; Pain; Receptors, N-Methyl-D-Aspartate; Research Design
PubMed: 10687335
DOI: 10.1016/s0885-3924(99)00125-6 -
Advances in Therapy Sep 2017Obeticholic acid (OCA), a potent and selective farnesoid X receptor agonist, is indicated for the treatment of primary biliary cholangitis (PBC). We investigated the...
Assessment of Pharmacokinetic Interactions Between Obeticholic Acid and Caffeine, Midazolam, Warfarin, Dextromethorphan, Omeprazole, Rosuvastatin, and Digoxin in Phase 1 Studies in Healthy Subjects.
INTRODUCTION
Obeticholic acid (OCA), a potent and selective farnesoid X receptor agonist, is indicated for the treatment of primary biliary cholangitis (PBC). We investigated the potential drug-drug interaction effect of OCA on metabolic CYP450 enzymes and drug transporters.
METHODS
Five phase 1 single-center, open-label, fixed-sequence, inpatient studies were conducted in healthy adult subjects to evaluate the effect of oral daily doses of 10 or 25 mg OCA on single-dose plasma pharmacokinetics of specific probe substrates for enzymes CYP1A2 (caffeine, R-warfarin), CYP3A (midazolam, R-warfarin), CYP2C9 (S-warfarin), CYP2D6 (dextromethorphan), CYP2C19 (omeprazole), and drug transporters, BCRP/OATP1B1/OATP1B3 (rosuvastatin), and P-gp (digoxin).
RESULTS
OCA showed no substantial suppression/inhibition of S-warfarin, digoxin, and dextromethorphan and weak interactions with caffeine, omeprazole, rosuvastatin, and midazolam. The maximal pharmacodynamic responses (E ) to warfarin-based INR, PT, and aPTT were reduced by 11%, 11%, and 1%, respectively, for the 10-mg dose group and by 7%, 7% and 0%, respectively, for the 25-mg dose group. Overall, drugs dosed in combination with OCA were well tolerated, and most adverse events were mild in severity. No clinically important trends were noted in laboratory evaluations, vital signs, or 12-lead ECGs.
CONCLUSION
In these studies, OCA showed weak to no suppression/inhibition of metabolic enzymes and drug transporters at the highest recommended therapeutic dose in patients with PBC. On the basis on these analyses, monitoring and maintenance of target INR range are required during coadministration of OCA with drugs that are metabolized by CYP1A2 (R-warfarin).
FUNDING
Intercept Pharmaceuticals, Inc.
Topics: Adult; Aged; Aged, 80 and over; Caffeine; Chenodeoxycholic Acid; Cholangitis; Cytochrome P-450 Enzyme System; Dextromethorphan; Digoxin; Drug Interactions; Female; Healthy Volunteers; Humans; Male; Midazolam; Middle Aged; Omeprazole; Rosuvastatin Calcium; Warfarin
PubMed: 28808886
DOI: 10.1007/s12325-017-0601-0 -
Family Practice Mar 2023Despite the frequent use of symptomatic therapies in cough, evidence of their benefits is lacking. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Despite the frequent use of symptomatic therapies in cough, evidence of their benefits is lacking.
OBJECTIVE
We compared the effectiveness of 3 symptomatic therapies and usual care in acute bronchitis.
METHODS
Multicenter, pragmatic, multiarm parallel group, open randomized trial in primary care (ClinicalTrials.gov, Identifier: NCT03738917) was conducted in Catalonia. Patients ≥18 with uncomplicated acute bronchitis, with cough<3 weeks as the main symptom, scoring ≥4 in either daytime or nocturnal cough (7-point Likert scale), were randomized to usual care, dextromethorphan 15 mg t.i.d., ipratropium bromide inhaler 20 µg 2 puffs t.i.d, or 30 mg of honey t.i.d., all taken for up to 14 days. The main outcome measure was the number of days with moderate-to-severe cough. A symptom diary was given. A second visit was scheduled at days 2-3 for assessing evolution, with 2 more visits at days 15 and 29 for clinical assessment, evaluation of adverse effects, re-attendance, and complications.
RESULTS
We failed to achieve the sample size scheduled due to the COVID-19 pandemic. We finally recruited 194 patients. The median number of days with moderate-to-severe cough (score ≥ 3) in the usual care arm was 5 (interquartile range [IQR], 4, 8.75), 5 in the ipratropium bromide arm (IQR, 3, 8), 5 in the dextromethorphan arm (IQR, 4, 9.75), and 6 in the honey arm (IQR, 3.5, 7). The same results were obtained in the Kaplan-Meier survival analysis for the median survival time of each arm with the usual care as the reference group.
CONCLUSION
The symptomatic treatment evaluated has shown to be ineffective against cough.
Topics: Humans; Adult; Antitussive Agents; Cough; Dextromethorphan; Honey; Cholinergic Antagonists; Pandemics; COVID-19; Bronchitis; Ipratropium; Acute Disease
PubMed: 36239199
DOI: 10.1093/fampra/cmac112 -
British Journal of Clinical Pharmacology Nov 2021To evaluate the effect of severe chronic obstructive pulmonary disease (COPD) on drug metabolism by comparing the pharmacokinetics of patients with severe COPD with...
AIMS
To evaluate the effect of severe chronic obstructive pulmonary disease (COPD) on drug metabolism by comparing the pharmacokinetics of patients with severe COPD with healthy volunteers and using the modified Inje drug cocktail.
METHODS
This was a single-centre pharmacokinetic study with 12 healthy participants and 7 participants with GOLD D COPD. Midazolam 1 mg, dextromethorphan 30 mg, losartan 25 mg, omeprazole 20 mg, caffeine 130 mg and paracetamol 1000 mg were simultaneously administered and intensive pharmacokinetic sampling was conducted over 8 hours. Drug metabolism by CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2, UGT1A6 and UGT1A9 in participants with COPD were compared with phenotypes in healthy controls.
RESULTS
The oral clearance (95% confidence interval) in participants with COPD relative to controls was: midazolam 63% (60-67%); dextromethorphan 72% (40-103%); losartan 53% (52-55%); omeprazole 35% (31-39%); caffeine 52% (50-53%); and paracetamol 73% (72-74%). There was a 5-fold increase in AUC for omeprazole and approximately 2-fold increases for caffeine, losartan, dextromethorphan, and midazolam. The AUC of paracetamol, which is mostly glucuronidated, was increased by about 60%.
CONCLUSION
Severe COPD is associated with a clinically significant reduction in oral drug clearance. This may be greater for cytochrome P450 substrates than for glucuronidated drugs. This supports reduced starting doses when prescribing for patients with severe COPD.
Topics: Dextromethorphan; Drug Interactions; Humans; Midazolam; Pharmaceutical Preparations; Pulmonary Disease, Chronic Obstructive
PubMed: 33855722
DOI: 10.1111/bcp.14862 -
British Journal of Clinical Pharmacology Jun 2002The aim of this study was to assess the efficacy of dextromethorphan and ketamine relative to placebo on the acute nociceptive threshold and wind-up of second pain... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
AIMS
The aim of this study was to assess the efficacy of dextromethorphan and ketamine relative to placebo on the acute nociceptive threshold and wind-up of second pain response in healthy male volunteers.
METHODS
The trial was a randomized, double-blind, placebo-controlled, three period crossover, double dummy design in 12 healthy male volunteers. During each of the three periods (which were separated by a 1 week washout period) each volunteer received either a single oral dose of 0.7 mg kg(-1) dextromethorphan and placebo to ketamine, or placebo to dextromethorphan followed by a single intravenous injection of 0.375 mg kg(-1) ketamine, or placebo to both dextromethorphan and ketamine. The trial did not schedule administration of both ketamine and dextromethorphan together. Acute nociceptive thresholds and wind-up of second pain were measured in the skin of the thenar eminence of the ventral surfaces of the right and left hands, using a SOMEDIC thermotest apparatus, before and at the estimated tmax for dextromethorphan (i.e. 2.15 h). Blood pressure and heart rate were also monitored before dosing and after the dosing regimen.
RESULTS
Neither dextromethorphan nor ketamine had any significant effect on acute nociceptive thresholds on either hand (P>0.05). Moreover, dextromethorphan was without any significant effect (P>0.05) on the wind-up of the second pain response on either hand. The lsmean number of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 15.84 vs 16.48 (-5.52, 4.24) and 11.75 vs 15.25 (-11.89, 4.90) for left- and right-hand, respectively, following dextromethorphan administration. In contrast ketamine produced significant reductions in wind-up to second pain in both the left and right hands (P=0.0002 and 0.0386, respectively). The lsmean numbers of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 28.41 vs 16.48 (6.60, 17.25) and 25.00 vs 15.25 (0.58, 18.93) for left- and right-hand, respectively.
CONCLUSIONS
Wind-up of second pain induced by noxious heat is sensitive to intervention by ketamine, which is known to block the NMDA receptor. These data infer that the wind-up phenomenon evoked by noxious heat involves the activation of NMDA receptors. This volunteer model of pain may have utility in the evaluation of agents that modulate their antinociceptive actions via NMDA mechanisms.
Topics: Acute Disease; Adult; Analgesics; Cross-Over Studies; Dextromethorphan; Dextrorphan; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Humans; Injections, Intravenous; Ketamine; Male; Middle Aged; Nociceptors; Pain; Pain Threshold; Receptors, N-Methyl-D-Aspartate
PubMed: 12047485
DOI: 10.1046/j.1365-2125.2002.01602.x -
Scientific Reports Apr 2021Neuronal activity in the brain reflects an excitation-inhibition balance that is regulated predominantly by glutamatergic and GABAergic neurotransmission, and often... (Randomized Controlled Trial)
Randomized Controlled Trial
Neuronal activity in the brain reflects an excitation-inhibition balance that is regulated predominantly by glutamatergic and GABAergic neurotransmission, and often disturbed in neuropsychiatric disorders. Here, we tested the effects of a single oral dose of two anti-glutamatergic drugs (dextromethorphan, an NMDA receptor antagonist; perampanel, an AMPA receptor antagonist) and an L-type voltage-gated calcium channel blocker (nimodipine) on transcranial magnetic stimulation (TMS)-evoked electroencephalographic (EEG) potentials (TEPs) and TMS-induced oscillations (TIOs) in 16 healthy adults in a pseudorandomized, double-blinded, placebo-controlled crossover design. Single-pulse TMS was delivered to the hand area of left primary motor cortex. Dextromethorphan increased the amplitude of the N45 TEP, while it had no effect on TIOs. Perampanel reduced the amplitude of the P60 TEP in the non-stimulated hemisphere, and increased TIOs in the beta-frequency band in the stimulated sensorimotor cortex, and in the alpha-frequency band in midline parietal channels. Nimodipine and placebo had no effect on TEPs and TIOs. The TEP results extend previous pharmaco-TMS-EEG studies by demonstrating that the N45 is regulated by a balance of GABAAergic inhibition and NMDA receptor-mediated glutamatergic excitation. In contrast, AMPA receptor-mediated glutamatergic neurotransmission contributes to propagated activity reflected in the P60 potential and midline parietal induced oscillations. This pharmacological characterization of TMS-EEG responses will be informative for interpreting TMS-EEG abnormalities in neuropsychiatric disorders with pathological excitation-inhibition balance.
Topics: Adult; Cross-Over Studies; Dextromethorphan; Double-Blind Method; Electroencephalography; Electromyography; Evoked Potentials, Motor; Healthy Volunteers; Humans; Male; Motor Cortex; Nimodipine; Nitriles; Pyridones; Synaptic Transmission; Transcranial Magnetic Stimulation; Young Adult
PubMed: 33854132
DOI: 10.1038/s41598-021-87533-z -
Journal of Applied Toxicology : JAT Mar 2011Dextromethorphan is widely used in over-the-counter cough and cold medications. Its efficacy and safety for infants and young children remains to be clarified. The...
Dextromethorphan is widely used in over-the-counter cough and cold medications. Its efficacy and safety for infants and young children remains to be clarified. The present study was designed to use zebrafish as a model to investigate the potential toxicity of dextromethorphan during embryonic and larval development. Three sets of zebrafish embryos/larvae were exposed to dextromethorphan at 24, 48 and 72 h post fertilization (hpf), respectively, during the embryonic/larval development. Compared with the 48 and 72 hpf exposure sets, the embryos/larvae in the 24 hpf exposure set showed much higher mortality rates which increased in a dose-dependent manner. Bradycardia and reduced blood flow were observed for the embryos/larvae treated with increasing concentrations of dextromethorphan. Morphological effects of dextromethorphan exposure, including yolk sac and cardiac edema, craniofacial malformation, lordosis, non-inflated swim bladder and missing gill, were also more frequent and severe among zebrafish embryos/larvae exposed to dextromethorphan at 24 hpf. Whether the more frequent and severe developmental toxicity of dextromethorphan observed among the embryos/larvae in the 24 hpf exposure set, as compared with the 48 and 72 hpf exposure sets, is due to the developmental expression of the phase I and phase II enzymes involved in the metabolism of dextromethorphan remains to be clarified. A reverse transcription-polymerase chain reaction analysis, nevertheless, revealed developmental stage-dependent expression of mRNAs encoding SULT3 ST1 and SULT3 ST3, two enzymes previously shown to be capable of sulfating dextrorphan, an active metabolite of dextromethorphan.
Topics: Animals; Antitussive Agents; Behavior, Animal; Bradycardia; Craniofacial Abnormalities; Dextromethorphan; Dose-Response Relationship, Drug; Edema; Edema, Cardiac; Embryo, Nonmammalian; Embryonic Development; Feeding Behavior; Gene Expression Regulation, Developmental; Larva; RNA, Messenger; Regional Blood Flow; Sulfotransferases; Teratogens; Yolk Sac; Zebrafish; Zebrafish Proteins
PubMed: 20737414
DOI: 10.1002/jat.1576