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Basic & Clinical Pharmacology &... Aug 2010We investigated co-analgesic effect of dextromethorphan in adolescent post-operative patients with idiopathic scoliosis. In a double-blind study, 60 patients with ASA... (Randomized Controlled Trial)
Randomized Controlled Trial
We investigated co-analgesic effect of dextromethorphan in adolescent post-operative patients with idiopathic scoliosis. In a double-blind study, 60 patients with ASA physical status I-II were randomised into two groups. Group dextromethorphan (n = 30; age: 15.9 +/- 2.4 years) was given oral dextromethorphan 30 or 45 mg 1 hr before surgery and 8, 20 and 32 hr after operation. Group placebo (n = 30; age: 16.5 +/- 2.7 years) received placebo at identical times. Post-operative analgesic requirements were assessed using nurse-controlled analgesia system. Pain was assessed using numeric rating scale before first administration of morphine and at 2, 3, 4, 6, 24 and 48 hr after operation. Blood samples were taken 20 min. after the first use of morphine (within 1 hr after operation). The total use of analgesics during surgery was lower in the dextromethorphan group. The dose of morphine providing relief immediately after surgery, as well as total analgesic requirements in the first and second day after surgery did not differ between groups. Subjectively evaluated pain intensity score (numeric rating scale) was lower for the dextromethorphan patients in the first 4 hr, but not later after surgery. Plasma levels of morphine, morphine-6-glucuronide and morphine-3-glucuronide did not differ between groups. Dextromethorphan did not influence morphine glucuronidation, in terms of promotion of formation of any morphine glucuronides. In conclusion, in young patients subjected to spine surgery, addition of dextromethorphan to morphine reduced pain only in early post-operative period. In such patients, co-analgesic action of dextromethorphan was not associated with significant changes in plasma levels of morphine metabolites.
Topics: Administration, Oral; Adolescent; Analgesics, Opioid; Dextromethorphan; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Morphine; Nurse's Role; Pain; Pain Measurement; Pain, Postoperative; Scoliosis; Spine
PubMed: 20346057
DOI: 10.1111/j.1742-7843.2010.00559.x -
Frontiers in Neurology 2018Perinatal and perioperative brain injury is a fundamental problem in infants with severe congenital heart disease undergoing neonatal cardiac surgery with...
Perinatal and perioperative brain injury is a fundamental problem in infants with severe congenital heart disease undergoing neonatal cardiac surgery with cardiopulmonary bypass. An impaired neuromotor and neurocognitive development is encountered and associated with a reduction in quality of life. New neuroprotective drugs during surgery are described to reduce brain injury and improve neurodevelopmental outcome. Therefore, our aim was to provide a systematic review and best-evidence synthesis on the effects of neuroprotective drugs on brain injury and neurodevelopmental outcome in congenital heart disease infants requiring cardiac surgery with cardiopulmonary bypass. A systematic search was performed in PubMed, Embase and the Cochrane Library (PRISMA statement). Search terms were "infants," "congenital heart disease," "cardiac surgery," "cardiopulmonary bypass," and "neuroprotective drug." Data describing the effects on brain injury and neurodevelopmental outcome were extracted. Study quality was assessed with the Cochrane Risk of Bias Tool. Two reviewers independently screened sources, extracted data and scored bias. Disagreements were resolved by involving a third researcher. The search identified 293 studies of which 6 were included. In total 527 patients with various congenital heart diseases participated with an average of 88 infants (13-318) per study. Allopurinol, sodium nitroprusside, erythropoietin, ketamine, dextromethorphan and phentolamine were administered around cardiac surgery with cardiopulmonary bypass. Allopurinol showed less seizures, coma, death and cardiac events in hypoplastic left heart syndrome (HLHS) infants (OR: 0.44; 95%-CI:0.21-0.91). Sodium nitroprusside resulted in lower post cardiopulmonary bypass levels of S100ß in infants with transposition of the great arteries after 24 ( < 0.01) and 48 ( = 0.04) h of treatment. Erytropoietin, ketamine and dextromethorphan showed no neuroprotective effects. Phentolamine led to higher S100ß-levels and cerebrovascular resistance after rewarming and at the end of surgery (both < 0.01). Risk of bias varied between studies, including low (sodium nitroprusside, phentolamine), moderate (ketamine, dextromethorphan), and high (erytropoietin, allopurinol) quality. Allopurinol seems promising for future trials in congenital heart disease infants to reduce brain injury given the early neuroprotective effects in hypoplastic left heart syndrome infants. Larger well-designed trials are needed to assess the neuroprotective effects of sodium nitroprusside, erytropoietin, ketamine and dextromethorphan. Future neuroprotective studies in congenital heart disease infants should not only focus on the perioperative period, however also on the perinatal period, since significant brain injury already exists before surgery.
PubMed: 30018590
DOI: 10.3389/fneur.2018.00521 -
Pharmacology, Biochemistry, and Behavior Mar 2018A variety of nicotinic drug treatments have been found to decrease nicotine self-administration. However, interactions of drugs affecting different nicotinic receptor...
A variety of nicotinic drug treatments have been found to decrease nicotine self-administration. However, interactions of drugs affecting different nicotinic receptor subtypes have not been much investigated. This study investigated the interactions between dextromethorphan, which blocks nicotinic α3β2 receptors as well as a variety of other receptors with sazetidine-A which is a potent and selective α4β2 nicotinic receptor partial agonist with desensitizing properties. This interaction was compared with dextromethorphan combination treatment with mecamylamine, which is a nonspecific nicotinic channel blocker. Co-administration of dextromethorphan (either 0.5 or 5 mg/kg) and lower dose of sazetidine-A (0.3 mg/kg) caused a significant reduction in nicotine SA. With regard to food-motivated responding, 3 mg/kg of sazetidine-A given alone caused a significant decrease in food intake. However, the lower 0.3 mg/kg sazetidine-A dose did not significantly affect food-motivated responding even when given in combination with the higher 5 mg/kg dextromethorphan dose which itself caused a significant decrease in food motivated responding. Interestingly, this higher dextromethorphan dose significantly attenuated the decrease in food motivated responding caused by 3 mg/kg of sazetidine-A. Locomotor activity was increased by the lower 0.3 mg/kg sazetidine-A dose and decreased by the 5 mg/kg dextromethorphan dose. Mecamylamine at the doses (0.1 and 1 mg/kg) did not affect nicotine SA, but at 1 mg/kg significantly decreased food-motivated responding. None of the mecamylamine doses augmented the effect of dextromethorphan in reducing nicotine self-administration. These studies showed that the combination of dextromethorphan and sazetidine-A had mutually potentiating effects, which could provide a better efficacy for promoting smoking cessation, however the strength of the interactions was fairly modest.
Topics: Animals; Azetidines; Behavior, Addictive; Dextromethorphan; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Female; Locomotion; Nicotine; Pyridines; Rats; Rats, Sprague-Dawley; Self Administration; Smoking Cessation Agents
PubMed: 29407477
DOI: 10.1016/j.pbb.2018.01.005 -
Substance Abuse Treatment, Prevention,... Jun 2016Dextromethorphan is a safe, effective cough suppressant, available without a prescription in the United States since 1958. Due to a perceived prevalence of abuse of...
BACKGROUND
Dextromethorphan is a safe, effective cough suppressant, available without a prescription in the United States since 1958. Due to a perceived prevalence of abuse of dextromethorphan by teens, in 2007 the Drug Enforcement Administration requested the Food and Drug Administration evaluate whether dextromethorphan should be recommended for scheduling under the Controlled Substances Act. The Food and Drug Administration held an Advisory Committee meeting in 2010 to provide a scientific and medical evaluation of dextromethorphan and its abuse potential.
DISCUSSION
To address reports of abuse, particularly by teens in the United States, the Consumer Healthcare Products Association initiated an abuse mitigation plan in 2010 with specific goals related to awareness of the behavior, perception of risk, social disapproval, and access to the products. In identifying abuse interventions, experts acknowledge that substance abuse among teens is a highly complex behavior and indicate that the best course of action is to address prevention by focusing on the factors that impact teen behavior.
CONCLUSION
It is noteworthy that the annual prevalence of over-the-counter cough medicine abuse has sharply decreased since 2010. While a true cause-and-effect relationship cannot be assured, the Consumer Healthcare Products Association and its member companies believe that the increased awareness of the issue since the 2010 Food and Drug Administration Advisory Committee meeting, and the subsequent implementation of a well-delivered and targeted abuse mitigation plan that addressed the levers influencing teen decisions is contributing to the observed reduction in abuse. During the period of 2010-2015, reported abuse of dextromethorphan by 8(th), 10(th), and 12(th) graders decreased 35 %. The authors believe this reduction supports the view of the Consumer Healthcare Products Association at the outset of the abuse mitigation plan effort and today: Controlled substance scheduling or prescription requirements would result in a reduction in the legitimate use of this medicine that has benefits that far outweigh its risks. Instead, there are more targeted, more effective, and less disruptive interventions to address dextromethorphan abuse.
Topics: Adolescent; Antitussive Agents; Dextromethorphan; Female; Health Education; Humans; Male; Program Development; Substance-Related Disorders; United States
PubMed: 27333886
DOI: 10.1186/s13011-016-0067-0 -
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 -
International Journal of Molecular... Nov 2021Medial vascular calcification has emerged as a key factor contributing to cardiovascular mortality in patients with chronic kidney disease (CKD). Vascular smooth muscle...
Medial vascular calcification has emerged as a key factor contributing to cardiovascular mortality in patients with chronic kidney disease (CKD). Vascular smooth muscle cells (VSMCs) with osteogenic transdifferentiation play a role in vascular calcification. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors reduce reactive oxygen species (ROS) production and calcified-medium-induced calcification of VSMCs. This study investigates the effects of dextromethorphan (DXM), an NADPH oxidase inhibitor, on vascular calcification. We used in vitro and in vivo studies to evaluate the effect of DXM on artery changes in the presence of hyperphosphatemia. The anti-vascular calcification effect of DXM was tested in adenine-fed Wistar rats. High-phosphate medium induced ROS production and calcification of VSMCs. DXM significantly attenuated the increase in ROS production, the decrease in ATP, and mitochondria membrane potential during the calcified-medium-induced VSMC calcification process ( < 0.05). The protective effect of DXM in calcified-medium-induced VSMC calcification was not further increased by NADPH oxidase inhibitors, indicating that NADPH oxidase mediates the effect of DXM. Furthermore, DXM decreased aortic calcification in Wistar rats with CKD. Our results suggest that treatment with DXM can attenuate vascular oxidative stress and ameliorate vascular calcification.
Topics: Animals; Cell Line; Dextromethorphan; Humans; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Oxidative Stress; Rats; Rats, Inbred WKY; Uremia; Vascular Calcification
PubMed: 34830159
DOI: 10.3390/ijms222212277 -
Journal of Molecular Medicine (Berlin,... Dec 2020The outbreak of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus continually led to infect a large...
The outbreak of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus continually led to infect a large population worldwide. SARS-CoV-2 utilizes its NSP6 and Orf9c proteins to interact with sigma receptors that are implicated in lipid remodeling and ER stress response, to infect cells. The drugs targeting the sigma receptors, sigma-1 and sigma-2, have emerged as effective candidates to reduce viral infectivity, and some of them are in clinical trials against COVID-19. The antipsychotic drug, haloperidol, exerts remarkable antiviral activity, but, at the same time, the sigma-1 benzomorphan agonist, dextromethorphan, showed pro-viral activity. To explore the potential mechanisms of biased binding and activity of the two drugs, haloperidol and dextromethorphan towards NSP6, we herein utilized molecular docking-based molecular dynamics simulation studies. Our extensive analysis of the protein-drug interactions, structural and conformational dynamics, residual frustrations, and molecular switches of NSP6-drug complexes indicates that dextromethorphan binding leads to structural destabilization and increase in conformational dynamics and energetic frustrations. On the other hand, the strong binding of haloperidol leads to minimal structural and dynamical perturbations to NSP6. Thus, the structural insights of stronger binding affinity and favorable molecular interactions of haloperidol towards viral NSP6 suggests that haloperidol can be potentially explored as a candidate drug against COVID-19. KEY MESSAGES: •Inhibitors of sigma receptors are considered as potent drugs against COVID-19. •Antipsychotic drug, haloperidol, binds strongly to NSP6 and induces the minimal changes in structure and dynamics of NSP6. •Dextromethorphan, agonist of sigma receptors, binding leads to overall destabilization of NSP6. •These two drugs bind with NSP6 differently and also induce differences in the structural and conformational changes that explain their different mechanisms of action. •Haloperidol can be explored as a candidate drug against COVID-19.
Topics: Binding Sites; COVID-19; Computer Simulation; Coronavirus Nucleocapsid Proteins; Dextromethorphan; Haloperidol; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Pandemics; Protein Binding; Protein Interaction Domains and Motifs; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 32965508
DOI: 10.1007/s00109-020-01980-1 -
JAMA Internal Medicine Sep 2018In 2010, the US Food and Drug Administration approved a combination of dextromethorphan hydrobromide and quinidine sulfate with an Orphan Drug Act designation for the...
IMPORTANCE
In 2010, the US Food and Drug Administration approved a combination of dextromethorphan hydrobromide and quinidine sulfate with an Orphan Drug Act designation for the treatment of pseudobulbar affect in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). This medication, however, is commonly prescribed off-label for behavioral symptoms in patients with dementia and/or Parkinson disease (PD).
OBJECTIVE
To investigate the prescribing patterns of dextromethorphan-quinidine, including off-label prescribing, and trends in associated costs.
DESIGN, SETTING, AND PARTICIPANTS
This population-based cohort study of patients prescribed dextromethorphan-quinidine used data from 2 commercial insurance databases. The Medicare Part D Prescription Drug Program data set was used to evaluate prescription number and total spending by the Centers for Medicare & Medicaid Services. Patients were included if they were prescribed dextromethorphan-quinidine from October 29, 2010, when the drug was approved, through March 1, 2017.
MAIN OUTCOMES AND MEASURES
The proportion of patients prescribed dextromethorphan-quinidine with a diagnosis of MS, ALS, or dementia and/or PD, as well as the number of patients with a history of heart failure (a contraindication for the drug).
RESULTS
In the commercial health care databases, 12 858 patients filled a prescription for dextromethorphan-quinidine during the study period. Mean (SD) age was 66.0 (18.5) years; 67.0% were women; and 13.3% had a history of heart failure. Combining results from both databases, few patients had a diagnosis of MS (8.4%) or ALS (6.8%); most (57.0%) had a diagnosis of dementia and/or PD. In the Medicare Part D database, the number of patients prescribed dextromethorphan-quinidine increased approximately 12-fold, from 3296 in 2011 to 40 448 in 2015. Centers for Medicare & Medicaid Services spending on this medication increased from $4.3 million in 2011 to $137.5 million by 2015.
CONCLUSIONS AND RELEVANCE
Despite approval by the US Food and Drug Administration as an orphan-designated drug for pseudobulbar affect related to ALS or MS, this study suggests that dextromethorphan-quinidine appears to be primarily prescribed off-label for patients with dementia and/or PD.
Topics: Cardiovascular Diseases; Cohort Studies; Female; Humans; Primary Prevention; Risk Factors; Women's Health
PubMed: 30039158
DOI: 10.1001/jamainternmed.2018.3131 -
Neuroreport Sep 2016Ketamine has been shown to produce rapid and robust antidepressant effects in depressed individuals; however, its abuse potential and adverse psychotomimetic effects...
Ketamine has been shown to produce rapid and robust antidepressant effects in depressed individuals; however, its abuse potential and adverse psychotomimetic effects limit its widespread use. Dextromethorphan (DM) may serve as a safer alternative on the basis of pharmacodynamic similarities to ketamine. In this proof-of-concept study, behavioral and biochemical analyses were carried out to evaluate the potential involvement of brain-derived neurotrophic factor (BDNF) in the antidepressant-like effects of DM in mice, with comparisons to ketamine and imipramine. Male Swiss, Webster mice were injected with DM, ketamine, or imipramine and their behaviors were evaluated in the forced-swim test and the open-field test. Western blots were used to measure BDNF and its precursor, pro-BDNF, protein expression in the hippocampus and the frontal cortex of these mice. Our results show that both DM and imipramine reduced immobility time in the forced-swim test without affecting locomotor activity, whereas ketamine reduced immobility time and increased locomotor activity. Ketamine also rapidly (within 40 min) increased pro-BDNF expression in an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-dependent manner in the hippocampus, whereas DM and imipramine did not alter pro-BDNF or BDNF levels in either the hippocampus or the frontal cortex within this timeframe. These data show that DM shares some features with both ketamine and imipramine. Additional studies examining DM may aid in the development of more rapid, safe, and efficacious antidepressant treatments.
Topics: Analysis of Variance; Animals; Antidepressive Agents; Behavior, Animal; Brain; Brain-Derived Neurotrophic Factor; Dextromethorphan; Dose-Response Relationship, Drug; Exploratory Behavior; Ketamine; Male; Mice; Protein Precursors; Quinoxalines; Receptors, AMPA; Statistics, Nonparametric; Swimming
PubMed: 27580401
DOI: 10.1097/WNR.0000000000000646 -
Chemico-biological Interactions Apr 2019Dextromethorphan, a wildly used over-the-counter antitussive drug, is reported to have anti-inflammatory effects. Previously, we and others have demonstrated that...
Dextromethorphan, a wildly used over-the-counter antitussive drug, is reported to have anti-inflammatory effects. Previously, we and others have demonstrated that dextromethorphan at micromolar doses displays potent hepatoprotective effects and enhances mice survival in a sepsis model. Moreover, we also observed potent anti-inflammatory and neuroprotective effects of subpicomolar concentrations of dextromethorphan in rodent primary neuron-glial cultures. The purpose of this study was to provide a proof of principle that ultralow dose dextromethorphan displays anti-inflammatory and cytoprotective effects in animal studies. Here, we report that subpico- and micromolar doses of dextromethorphan showed comparable efficacy in protecting mice from lipopolysaccharide/d-galactosamine (LPS/GalN)-induced hepatotoxicity and mortality. Mice were given injections of dextromethorphan from 30 min before and 2, 4 h after an injection of LPS/GalN (20 μg/600 mg/kg). Our results showed that dextromethorphan at subpicomolar doses promoted survival rate in LPS/GalN-injected mice. Ultralow dose dextromethorphan also significantly reduced serum alanine aminotransferase activity, TNF-α level and liver cell damage of endotoxemia mice. Mechanistic studies using primary liver Kupffer cell cultures revealed that subpicomolar concentrations of dextromethorphan reduced the NADPH oxidase-generated superoxide free radicals from Kupffer cells, which in turn reduced the elevation of its downstream reactive oxygen species (iROS) to relieve the oxidative stress and decreased TNF-α production in Kupffer cells. Taken together, these findings suggest a novel therapeutic concept of using ultralow doses of dextromethorphan for the intervention of sepsis or septic shock.
Topics: Animals; Cells, Cultured; Chemical and Drug Induced Liver Injury; Dextromethorphan; Endotoxins; Galactosamine; Kupffer Cells; Lipopolysaccharides; Mice; Oxidative Stress; Protective Agents; Reactive Oxygen Species; Sepsis; Shock, Septic; Survival Rate
PubMed: 30822415
DOI: 10.1016/j.cbi.2019.02.025