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Anesthesiology Aug 2019Central pain sensitization is often refractory to drug treatment. Dextromethorphan, an N-methyl-D-aspartate receptor antagonist, is antihyperalgesic in preclinical pain... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Central pain sensitization is often refractory to drug treatment. Dextromethorphan, an N-methyl-D-aspartate receptor antagonist, is antihyperalgesic in preclinical pain models. The hypothesis is that dextromethorphan is also antihyperalgesic in humans.
METHODS
This randomized, double-blind, placebo-controlled, crossover study explores the antihyperalgesic effect of single and repeated 30-mg dose of oral dextromethorphan in 20 volunteers, using the freeze-injury pain model. This model leads to development of primary and secondary hyperalgesia, which develops away from the site of injury and is associated with central sensitization and activation of N-methyl-D-aspartate receptor in the spinal cord. The primary outcome was antihyperalgesia calculated with the area under the curve of the percentage change in mechanical pain threshold (electronic von Frey) on the area of secondary hyperalgesia. The secondary outcomes were mechanical pain threshold on the area of primary hyperalgesia and cognitive (reaction time) effect.
RESULTS
Single 30-mg results are reported. Antihyperalgesia (% · min) is significantly higher on the area of secondary hyperalgesia with dextromethorphan than placebo (median [interquartile range]: 3,029 [746; 6,195] vs. 710 [-3,248; 4,439], P = 0.009, Hedge's g = 0.8, 95% CI [0.1; 1.4]). On primary hyperalgesia area, mechanical pain threshold 2 h after drug intake is significantly higher with dextromethorphan (P = 0.011, Hedge's g = 0.63, 95% CI [0.01; 1.25]). No difference in antinociception is observed after thermal painful stimuli on healthy skin between groups. Reaction time (ms) is shorter with placebo than with dextromethorphan (median [interquartile range]: 21.6 [-37.4; 0.1] vs. -1.2 [-24.3; 15.4], P = 0.015, Hedge's g = 0.75, 95% CI [0.12; 1.39]). Nonserious adverse events occurrence (15%, 3 of 20 volunteers) was similar in both groups.
CONCLUSIONS
This study shows that low-dose (30-mg) dextromethorphan is antihyperalgesic in humans on the areas of primary and secondary hyperalgesia and reverses peripheral and central neuronal sensitization. Because dextromethorphan had no intrinsic antinociceptive effect in acute pain on healthy skin, N-methyl-D-aspartate receptor may need to be sensitized by pain for dextromethorphan to be effective.
Topics: Analgesia; Cross-Over Studies; Dextromethorphan; Double-Blind Method; Excitatory Amino Acid Antagonists; Humans; Hyperalgesia; Male; Neuralgia; Treatment Outcome
PubMed: 31094746
DOI: 10.1097/ALN.0000000000002736 -
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 -
Brain Stimulation 2023Transcranial ultrasound stimulation (TUS) is a novel non-invasive brain stimulation technique with high depth penetrance and spatial resolution. Theta-burst TUS (tbTUS)... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Transcranial ultrasound stimulation (TUS) is a novel non-invasive brain stimulation technique with high depth penetrance and spatial resolution. Theta-burst TUS (tbTUS) is a plasticity-inducing protocol which increases motor cortical excitability for up to 30 min following 80s of sonication. While this protocol may have therapeutic potential for the treatment of psychiatric and neurological disorders, the mechanisms of action of TUS remain unclear.
OBJECTIVE
We conducted the first pharmacological study to examine the mechanisms of TUS in human primary motor cortex. By administering brain-active drugs with known mechanisms of action, we aimed to elucidate the mechanisms of tbTUS.
METHODS
Fourteen healthy subjects participated in a within-subjects randomized, double-blind, cross-over study with five visits. At each visit, one of four study drugs (carbamazepine - Na channel blocker, nimodipine - L-type Ca channel blocker, lorazepam - positive allosteric modulator of gamma-aminobutyric acid (GABA) type A receptor, dextromethorphan - N-methyl-d-aspartate receptor antagonist) or placebo was administered in random order, followed by tbTUS.
RESULTS
The plasticity effects of tbTUS on motor cortex excitability measured by motor-evoked potential amplitudes elicited by transcranial magnetic stimulation were reduced by all study drugs compared to placebo.
CONCLUSION
tbTUS may induce NMDA-dependent synaptic plasticity since the effects are blocked by increased GABA receptor activities and voltage-gated Na and Ca channels blockers. These results are consistent with the hypotheses that tbTUS induced long-term potentiation-like mechanisms and that TUS involves activation of mechanosensitive Na and Ca channels. Alternatively, non-specific pharmacologically induced changes in excitatory/inhibitory balance might have interfered with the effects of tbTUS.
Topics: Humans; Motor Cortex; Cross-Over Studies; Neuronal Plasticity; Long-Term Potentiation; Evoked Potentials, Motor; Transcranial Magnetic Stimulation
PubMed: 37524296
DOI: 10.1016/j.brs.2023.07.056 -
Der Pneumologe 2020The most frequent cause of acute cough (lasting up to 3 weeks) or subacute cough (3-8 weeks) is a viral infection, which is mostly a self-limiting disease in otherwise...
The most frequent cause of acute cough (lasting up to 3 weeks) or subacute cough (3-8 weeks) is a viral infection, which is mostly a self-limiting disease in otherwise healthy persons. Some herbal compounds, the antitussive dextromethorphan and ambroxol are effective for symptom relief. Antibiotics are ineffective and should not be used due to resistance development. If after appropriate diagnostic procedures the cause of chronic cough, i.e. cough lasting more than 8 weeks, cannot be attributed to a well-established respiratory disease, it meets the definition of a disease in its own right, chronic idiopathic (unexplained) cough (CIH). This is caused by hypersensitivity of the cough reflex. Thus, even weak low threshold stimuli, e.g. changing temperature, extensive speaking and odors can trigger the cough reflex. In the case of nonresponse to guideline-conform treatment the definition of chronic refractory cough is met.
PubMed: 33071698
DOI: 10.1007/s10405-020-00346-1 -
Biomedicine & Pharmacotherapy =... Nov 2023The analgesic effects of sigma-1 antagonists are undisputed, but the effects of sigma-1 agonists on pain are not well studied. Here, we used a mouse model to show that...
The analgesic effects of sigma-1 antagonists are undisputed, but the effects of sigma-1 agonists on pain are not well studied. Here, we used a mouse model to show that the administration of the sigma-1 agonists dextromethorphan (a widely used antitussive drug), PRE-084 (a standard sigma-1 ligand), and pridopidine (a selective drug being investigated in clinical trials for the treatment of neurodegenerative diseases) enhances PGE2-induced mechanical hyperalgesia. Superficial plantar incision induced transient weight-bearing asymmetry at early time points, but the mice appeared to recover at 24 h, despite noticeable edema and infiltration of neutrophils (a well-known cellular source of PGE2) at the injured site. Sigma-1 agonists induced a relapse of weight bearing asymmetry in a manner dependent on the presence of neutrophils. The effects of sigma-1 agonists were all reversed by administration of the sigma-1 antagonist BD-1063 in wild-type mice, and were absent in sigma-1 knockout mice, supporting the selectivity of the effects observed. The proalgesic effects of sigma-1 agonism were also abolished by the TRP antagonist ruthenium red and by in vivo resiniferatoxin ablation of TRPV1 + peripheral sensory neurons. Therefore, sigma-1 agonism exacerbates pain-like responses in mice with a mild inflammatory state through the action of TRPV1 + nociceptors. We also show that sigma-1 receptors are present in most (if not all) mouse and human DRG neurons. If our findings translate to humans, further studies will be needed to investigate potential proalgesic effects induced by sigma-1 agonism in patients treated with sigma-1 agonists.
PubMed: 37729726
DOI: 10.1016/j.biopha.2023.115534 -
Oncogene Mar 2021Smoking is one of the most impactful lifestyle-related risk factors in many cancer types including esophageal squamous cell carcinoma (ESCC). As the major component of...
Smoking is one of the most impactful lifestyle-related risk factors in many cancer types including esophageal squamous cell carcinoma (ESCC). As the major component of tobacco and e-cigarettes, nicotine is not only responsible for addiction to smoking but also a carcinogen. Here we report that nicotine enhances ESCC cancer malignancy and tumor-initiating capacity by interacting with cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) and subsequently activating the JAK2/STAT3 signaling pathway. We found that aberrant CHRNA7 expression can serve as an independent prognostic factor for ESCC patients. In multiple ESCC mouse models, dextromethorphan and metformin synergistically repressed nicotine-enhanced cancer-initiating cells (CIC) properties and inhibited ESCC progression. Mechanistically, dextromethorphan non-competitively inhibited nicotine binding to CHRNA7 while metformin downregulated CHRNA7 expression by antagonizing nicotine-induced promoter DNA hypomethylation of CHRNA7. Since dextromethorphan and metformin are two safe FDA-approved drugs with minimal undesirable side-effects, the combination of these drugs has a high potential as either a preventive and/or a therapeutic strategy against nicotine-promoted ESCC and perhaps other nicotine-sensitive cancer types as well.
Topics: Animals; Carcinogenesis; Cell Line, Tumor; DNA Methylation; Dextromethorphan; Drug Repositioning; Electronic Nicotine Delivery Systems; Esophageal Squamous Cell Carcinoma; Female; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Janus Kinase 2; Male; Metformin; Mice; Nicotine; SOXB1 Transcription Factors; STAT3 Transcription Factor; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 33603170
DOI: 10.1038/s41388-021-01682-z -
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 -
Progress in Biomaterials Sep 2022This work uses optimization study to formulate a patient-friendly antitussive fast-dissolving oral film based on phenylephrine hydrochloride (Phen) and dextromethorphan...
This work uses optimization study to formulate a patient-friendly antitussive fast-dissolving oral film based on phenylephrine hydrochloride (Phen) and dextromethorphan hydrobromide (Dex). The designed films were based on hydroxypropylmethyl cellulose (HPMC) with two grades (E5 and E50) as a film-forming polymer by the solvent-casting method. Polyethylene glycol with two molar masses (400 and 1000) was used as a plasticizer, while aspartame was used as a sweetener and microcrystalline cellulose intended to act as a disintegrant. To find an optimum formulation, a response surface methodology and a central composite design were employed. The percentage of HPMC E50, and PEG, as a plasticizer, were considered to be the design factors. Film thickness, surface pH, disintegration time, dissolution percent, tensile strength, elongation percent and folding endurance were considered to be the responses. A film with 11.46% E50, 88.54% E5, 25% of two drugs (8.4% of Phen and 16.6% of Dex) and 18.54% plasticizer is designed and prepared as the optimum formulation for Phen/Dex fast-dissolving oral films, with 95% confidence levels.
PubMed: 35796868
DOI: 10.1007/s40204-022-00191-w -
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 -
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