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Pharmaceuticals (Basel, Switzerland) Aug 2022Excessive Ca currents via N-methyl-D-aspartate receptors (NMDARs) have been implicated in many disorders. Uncompetitive NMDAR channel blockers are an emerging class of...
Excessive Ca currents via N-methyl-D-aspartate receptors (NMDARs) have been implicated in many disorders. Uncompetitive NMDAR channel blockers are an emerging class of drugs in clinical use for major depressive disorder (MDD) and other neuropsychiatric diseases. The pharmacological characterization of uncompetitive NMDAR blockers in clinical use may improve our understanding of NMDAR function in physiology and pathology. REL-1017 (esmethadone-HCl), a novel uncompetitive NMDAR channel blocker in Phase 3 trials for the treatment of MDD, was characterized together with dextromethorphan, memantine, (±)-ketamine, and MK-801 in cell lines over-expressing NMDAR subtypes using fluorometric imaging plate reader (FLIPR), automated patch-clamp, and manual patch-clamp electrophysiology. In the absence of Mg, NMDAR subtypes NR1-2D were most sensitive to low, sub-μM glutamate concentrations in FLIPR experiments. FLIPR Ca determination demonstrated low μM affinity of REL-1017 at NMDARs with minimal subtype preference. In automated and manual patch-clamp electrophysiological experiments, REL-1017 exhibited preference for the NR1-2D NMDAR subtype in the presence of 1 mM Mg and 1 μM L-glutamate. Tau off and trapping characteristics were similar for (±)-ketamine and REL-1017. Results of radioligand binding assays in rat cortical neurons correlated with the estimated affinities obtained in FLIPR assays and in automated and manual patch-clamp assays. In silico studies of NMDARs in closed and open conformation indicate that REL-1017 has a higher preference for docking and undocking the open-channel conformation compared to ketamine. In conclusion, the pharmacological characteristics of REL-1017 at NMDARs, including relatively low affinity at the NMDAR, NR1-2D subtype preference in the presence of 1 mM Mg, tau off and degree of trapping similar to (±)-ketamine, and preferential docking and undocking of the open NMDAR, could all be important variables for understanding the rapid-onset antidepressant effects of REL-1017 without psychotomimetic side effects.
PubMed: 36015145
DOI: 10.3390/ph15080997 -
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 -
The American Journal of Emergency... Nov 2022Dextromethorphan polistirex is an extended-release formulation of dextromethorphan hydrobromide, marketed as Delsym® (Reckitt; Parsippany, NJ), with a duration of...
Dextromethorphan polistirex is an extended-release formulation of dextromethorphan hydrobromide, marketed as Delsym® (Reckitt; Parsippany, NJ), with a duration of action roughly two to three times that of the standard formulation. The polistirex binder is responsible for the prolonged duration of action by slowing the release of active ingredient; the liberated dextromethorphan has unchanged pharmacokinetics and clinical effects. A 23-month-old male presented following a 900 mg (71.4 mg/kg) dextromethorphan polistirex ingestion 90 min prior. On arrival, he was unresponsive, tachycardic, and hypertensive with mydriasis, roving eye movements, rotary nystagmus, and opisthotonos. Approximately 90 min after arrival, he required intubation for airway protection. The blood dextromethorphan concentration from 75 min after arrival was 110 ng/mL (10-40 ng/ml therapeutic). He was extubated approximately 13 h after arrival and discharged that day. Most pediatric dextromethorphan overdoses produce mild symptoms that are not considered to be life-threatening. Life threatening overdoses are rare. The toxic dextromethorphan dose and blood concentration as well as the toxicokinetics of the polistirex formulation are not well defined. Our case suggests that a blood dextromethorphan concentration exceeding 100 ng/mL can be toxic in this age group, however further study is needed.
Topics: Humans; Child; Male; Infant; Child, Preschool; Dextromethorphan; Drug Overdose; Excipients; Delayed-Action Preparations; Nystagmus, Pathologic
PubMed: 35989201
DOI: 10.1016/j.ajem.2022.08.006 -
The Clinical Respiratory Journal Sep 2022Cough is one of the most common presenting symptoms of COVID-19, which can persist for weeks or months. (Randomized Controlled Trial)
Randomized Controlled Trial
The effectiveness of gabapentin and gabapentin/montelukast combination compared with dextromethorphan in the improvement of COVID-19- related cough: A randomized, controlled clinical trial.
INTRODUCTION
Cough is one of the most common presenting symptoms of COVID-19, which can persist for weeks or months.
OBJECTIVE
The goal of this study was to evaluate the effectiveness of gabapentin (GBT) alone and in combination with montelukast (MTL) for improving cough.
METHODS
In this open-label randomized controlled clinical trial, eligible cases were patients hospitalized with moderate to severe COVID-19 who had cough with a Breathlessness, Cough, and Sputum Scale (BCSS) score of at least 2 based on its cough subscale. The participants were randomly assigned to three groups including two experimental groups and one control group. The first and second experimental groups received GBT and GBT/MTL, respectively, whereas the control group received dextromethorphan (DXM). Treatment duration was 5 days in all groups. Before and after the interventions, the severity of cough was evaluated using BCSS scale and Visual Analog Scale (VAS).
RESULTS
A total of 180 patients were included; GPT, GPT/MTL, and DXM consisted of 76, 51, and 53 patients, respectively. There was no significant difference between the three groups in terms of age, gender, and comorbidities (P > 0.05). Regarding BCSS and VAS scores, there was significant reduction from the baseline values in all groups (P < 0.0001), with the change rate being significantly higher in DXM group. The amount of reduction of BCSS in the GPT/MTL group was significantly more than the GPT group, whereas there was no significant difference between the two groups regarding VAS score. Although the duration of hospitalization differed between the groups with the GPT/MTL group having the shortest duration, the difference was statistically significant only between the GPT and GPT/MTL groups (P < 0.0001).
CONCLUSION
GPT, both alone and in combination with MTL, improves cough frequency and severity in hospitalized patients with COVID-19, with the combination being more efficacious. This regimen may be useful in patients who cannot tolerate opioids.
Topics: Acetates; COVID-19; Cough; Cyclopropanes; Dextromethorphan; Gabapentin; Humans; Quinolines; SARS-CoV-2; Sulfides; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 35908849
DOI: 10.1111/crj.13529 -
Drug Metabolism and Disposition: the... Jul 2022Cytochrome P450 2D6 (CYP2D6), is responsible for the metabolism and elimination of approximately 25% of clinically used drugs, including antidepressants and...
Cytochrome P450 2D6 (CYP2D6), is responsible for the metabolism and elimination of approximately 25% of clinically used drugs, including antidepressants and antipsychotics, and its activity varies considerably on a population basis primary due to genetic variation. CYP2D6 phenotype can be assessed following administration of an exogenous probe compound, such as dextromethorphan or debrisoquine, but use of a biomarker that does not require administration of an exogenous compound ( drug) has considerable appeal for assessing CYP2D6 activity in vulnerable populations, such as children. The goal of this study was to isolate, purify and identify an "endogenous" urinary biomarker (M1; m/z 444.3102) of CYP2D6 activity reported previously. Several chromatographic separation techniques (reverse phase HPLC, cation exchange and analytical reverse phase UPLC) were used to isolate and purify 96 μg of M1 from 40 L of urine. Subsequently, 1D and 2D NMR, and functional group modification reactions were used to elucidate its structure. Analysis of mass spectrometry and NMR data revealed M1 to have similar spectroscopic features to the nitrogen-containing steroidal alkaloid, solanidine. 2D NMR characterization by HMBC, COSY, TOCSY, and HSQC-TOCSY proved to be invaluable in the structural elucidation of M1; derivatization of M1 revealed the presence of two carboxylic acid moieties. M1 was determined to be a steroidal alkaloid with a solanidine backbone that had undergone C-C bond scission to yield 3,4-seco-solanidine-3,4-dioic acid (SSDA). SSDA may have value as a dietary biomarker of CYP2D6 activity in populations where potato consumption is common. Endogenous biomarkers of processes involved in drug disposition and response may allow improved individualization of drug treatment, especially in vulnerable populations, such as children. Given that several CYP2D6 substrates are commonly used in pediatrics and the ubiquitous nature of potato consumption in western diets, SSDA has considerable appeal as non-invasive biomarker of CYP2D6 activity to guide treatment with CYP2D6 substrates in children and adults.
PubMed: 35878926
DOI: 10.1124/dmd.122.000957 -
Frontiers in Pharmacology 2022Many investigational drugs with antidepressant activity are currently explored in different phases of clinical research, with indications such as major depressive...
Many investigational drugs with antidepressant activity are currently explored in different phases of clinical research, with indications such as major depressive disorder, treatment-resistant major depression, bipolar depression, post-partum depression, and late-life depression. Although the vast majority of the antidepressants in clinical use are based on the monoaminergic hypothesis of depression, recent data supported the launching on the market of two new, non-monoamine-modulating drugs. Esketamine for treatment-resistant major depression and brexanolone for post-partum depression are two exceptions from the monoaminergic model, although their use is still limited by high costs, unique way of administration (only intravenously for brexanolone), physicians' reluctance to prescribe new drugs, and patients' reticence to use them. Glutamatergic neurotransmission is explored based on the positive results obtained by intranasal esketamine, with subanesthetic intravenous doses of ketamine, and D-cycloserine, traxoprodil, MK-0657, AXS-05, AVP-786, combinations of cycloserine and lurasidone, or dextromethorphan and quinidine, explored as therapeutic options for mono- or bipolar depression. Sestrin modulators, cholinergic receptor modulators, or onabotulinumtoxinA have also been investigated for potential antidepressant activity. In conclusion, there is hope for new treatments in uni- and bipolar depression, as it became clear, after almost 7 decades of monoamine-modulating antidepressants, that new pathogenetic pathways should be targeted to increase the response rate in this population.
PubMed: 35847011
DOI: 10.3389/fphar.2022.884155 -
Journal of Clinical Medicine Jun 2022Using 2003−2018 National Ambulatory Medical Care Survey data for office-based visits and 2003−2018 National Hospital Ambulatory Medical Care Survey data for...
Using 2003−2018 National Ambulatory Medical Care Survey data for office-based visits and 2003−2018 National Hospital Ambulatory Medical Care Survey data for emergency department (ED) visits, we conducted cross-sectional analyses to examine cough medication (CM) use trends in the United States (US) ambulatory care settings. We included adult (≥18 years) patient visits with respiratory-infection-related or non-infection-related cough as reason-for-visit or diagnosis without malignant cancer or benign respiratory tumor diagnoses. Using multivariable logistic regressions, we examined opioid antitussive, benzonatate, dextromethorphan-containing antitussive, and gabapentinoid use trends. From 2003−2005 to 2015−2018, opioid antitussive use decreased in office-based visits (8.8% to 6.4%, Ptrend = 0.03) but remained stable in ED visits (6.3% to 5.9%, Ptrend = 0.99). In both settings, hydrocodone-containing antitussive use declined over 50%. Benzonatate use more than tripled (office-based:1.6% to 4.8%; ED:1.5% to 8.0%; both Ptrend < 0.001). Dextromethorphan-containing antitussive use increased in ED visits (1.8% to 2.6%, Ptrend = 0.003) but stayed unchanged in office-based visits (3.8% to 2.7%; Ptrend = 0.60). Gabapentinoid use doubled in office-based visits (1.1% in 2006−2008 to 2.4% in 2015−2018, Ptrend < 0.001) but was negligible in ED visits. In US office-based and ED ambulatory care settings, hydrocodone-containing antitussive use substantially declined from 2003 to 2018, while benzonatate use more than tripled, and dextromethorphan-containing antitussive and gabapentinoid use remained low (<3%).
PubMed: 35806956
DOI: 10.3390/jcm11133671 -
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 -
World Journal of Otorhinolaryngology -... Jun 2022Management of postoperative pain after head and neck cancer surgery is a complex issue, requiring a careful balance of analgesic properties and side effects. The... (Review)
Review
OBJECTIVE
Management of postoperative pain after head and neck cancer surgery is a complex issue, requiring a careful balance of analgesic properties and side effects. The objective of this review is to discuss the efficacy and safety of multimodal analgesia (MMA) for these patients.
METHODS
Pubmed, Cochrane, Embase, Scopus, and clinicaltrials.gov were systematically searched for all comparative studies of patients receiving MMA (nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, anticonvulsants, local anesthetics, and corticosteroids) for head and neck cancer surgeries. The primary outcome was additional postoperative opioid usage, and secondary outcomes included subjective pain scores, complications, adverse effects, and 30-day outcomes.
RESULTS
A total of five studies representing 592 patients (MMA, = 275; non-MMA, = 317) met inclusion criteria. The most commonly used agents were gabapentin, NSAIDs, and acetaminophen ( = 221), NSAIDs ( = 221), followed by corticosteroids ( = 35), dextromethorphan ( = 40), and local nerve block ( = 19). Four studies described a significant decrease in overall postoperative narcotic usage with two studies reporting a significant decrease in hospital time. Subjective pain scores widely varied with two studies reporting reduced pain at postoperative day 3. There were no differences in surgical outcomes, medical complications, adverse effects, or 30-day mortality and readmission rates.
CONCLUSION
MMA is an increasingly popular strategy that may reduce dependence on opioids for the treatment of postoperative pain. A variety of regimens and protocols are available for providers to utilize in the appropriate head and neck cancer patient.
PubMed: 35782401
DOI: 10.1002/wjo2.62 -
Frontiers in Neuroscience 2022Alterations to the serotonergic system due to 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy) consumption have been extensively documented. However, knowledge of the...
Alterations to the serotonergic system due to 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy) consumption have been extensively documented. However, knowledge of the reversibility of these neurotoxic effects based on evaluations of serotonin transport (SERT) availability remains limited. This study aimed to evaluate the long-term neurotoxicity of MDMA after 66 months abstinence and explored whether Dextromethorphan, a non-competitive -methyl--aspartate (NMDA) receptor, could attenuate MDMA-induced neurotoxicity using 4-[F]-ADAM, an imaging ligand that selectively targets SERT, with positron emission tomography technology (PET). Nine monkeys () were used in this study: control, MDMA, and DM + MDMA. Static 4-[F]-ADAM PET was performed at 60 and 66 months after drug treatment. Serotonin transport (SERT) availability was presented as the specific uptake ratios (SURs) of 4-[F]-ADAM in brain regions. Voxel-based region-specific SERT availability was calculated to generate 3D PET/MR images. Structural Magnetic Resonance Imaging (MRI) volumetric analysis was also conducted at 60 months. Significantly decreased 4-[F]-ADAM SURs were observed in the striatum and thalamus of the MDMA group at 60 and 66 months compared to controls; the midbrain and frontal cortex SURs were similar at 60 and 66 months in the MDMA and control groups. All eleven brain regions showed significantly lower (∼13%) self-recovery rates over time; the occipital cortex and cingulate recovered to baseline by 66 months. DM attenuated MDMA-induced SERT deficiency on average, by ∼8 and ∼1% at 60 and 66 months, respectively; whereas significant differences were observed between the thalamus and amygdala of the MDMA and DM + MDMA groups at 66 months. Compared to controls, the MDMA group exhibited significantly increased (∼6.6%) gray matter volumes in the frontal cortex, occipital cortex, caudate nucleus, hippocampus, midbrain, and amygdala. Moreover, the gray matter volumes of the occipital cortex, hippocampus and amygdala correlated negatively with the 4-[F]-ADAM SURs of the same regions. DM ( = 2) did not appear to affect MDMA-induced volumetric changes. The 4-[F]-ADAM SURs, lower self-recovery rate and increased volumetric values indicate the occipital cortex, hippocampus and amygdala still exhibit MDMA-induced neurotoxicity after 66 months' abstinence. Moreover, DM may prevent MDMA-induced serotonergic deficiency, as indicated by increased 4-[F]-ADAM SURs and SERT availability, but not volumetric changes.
PubMed: 35692422
DOI: 10.3389/fnins.2022.837194