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CNS Drugs May 2023The sigma-1 receptor is a 223 amino acid-long protein with a recently identified structure. The sigma-2 receptor is a genetically unrelated protein with a similarly... (Review)
Review
The sigma-1 receptor is a 223 amino acid-long protein with a recently identified structure. The sigma-2 receptor is a genetically unrelated protein with a similarly shaped binding pocket and acts to influence cellular activities similar to the sigma-1 receptor. Both proteins are highly expressed in neuronal tissues. As such, they have become targets for treating neurological diseases, including Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), multiple sclerosis (MS), Rett syndrome (RS), developmental and epileptic encephalopathies (DEE), and motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). In recent years, there have been many pre-clinical and clinical studies of sigma receptor (1 and 2) ligands for treating neurological disease. Drugs such as blarcamesine, dextromethorphan and pridopidine, which have sigma-1 receptor activity as part of their pharmacological profile, are effective in treating multiple aspects of several neurological diseases. Furthermore, several sigma-2 receptor ligands are under investigation, including CT1812, rivastigmine and SAS0132. This review aims to provide a current and up-to-date analysis of the current clinical and pre-clinical data of drugs with sigma receptor activities for treating neurological disease.
Topics: Humans; Receptors, sigma; Amyotrophic Lateral Sclerosis; Neurons; Huntington Disease; Neurodevelopmental Disorders
PubMed: 37166702
DOI: 10.1007/s40263-023-01007-6 -
The Clinical Respiratory Journal Jun 2023
Randomized Controlled Trial
Reply to the letter to the editor regarding the study "The effectiveness of gabapentin and gabapentin/montelukast combination compared with dextromethorphan in the improvement of COVID-19-related cough: A randomized, controlled clinical trial".
Topics: Humans; Cough; Gabapentin; Dextromethorphan; COVID-19
PubMed: 37100403
DOI: 10.1111/crj.13619 -
European Journal of Clinical... Jun 2023Pregnancy-mediated physiological and biochemical changes contribute to alterations in the pharmacokinetics of certain drugs. There is a paucity of data on the systematic...
A cocktail probe approach to evaluate the effect of hormones on the expression and activity of CYP enzymes in human hepatocytes with conditions simulating late stage of pregnancy.
PURPOSE
Pregnancy-mediated physiological and biochemical changes contribute to alterations in the pharmacokinetics of certain drugs. There is a paucity of data on the systematic evaluation of the underlying mechanisms. The objective of the current study was to examine the impact of changes in circulating and tissue hormonal concentration during the late stage of pregnancy on the activity and expression of hepatic cytochrome P450 (CYP) enzymes using a cocktail probe approach.
METHODS
Freshly isolated primary human hepatocytes were incubated with third trimester physiologic (plasma) and projected liver (ten-fold higher) concentrations of female hormones: progesterone (2 µM), estradiol (0.3 µM), estriol (0.8 µM), estrone (0.2 µM), 17α-hydroxyprogesterone (0.1 µM), and human growth hormone (0.005 µM). The metabolic activity of the hepatocytes was assessed using a cocktail of isozyme-specific P450 probe substrates (CYP1A2 (phenacetin), CYP2C9 (diclofenac), CYP2C19 (S-mephenytoin), CYP2D6 (dextromethorphan), and CYP3A4 (testosterone)). A validated LC-MS/MS assay was used to measure the corresponding metabolite concentrations. CYP450 protein and mRNA levels were measured using western blot and qRT-PCR, respectively.
RESULTS
Female hormones at projected third-semester hepatic concentrations significantly enhanced mRNA and protein expression and increased the metabolic activity of CYP3A4. The expression and activity of other CYP450 enzymes studied were not affected by mixtures of female hormones at concentrations used.
CONCLUSION
The increased activity of CYP3A4 is consistent with the clinically observed increase in clearance of CYP3A4 substrates during pregnancy. Overall expression and activity of CYP450 isozymes are differentially regulated during pregnancy.
Topics: Humans; Female; Pregnancy; Cytochrome P-450 CYP3A; Chromatography, Liquid; Tandem Mass Spectrometry; Cytochrome P-450 Enzyme System; Hepatocytes; Hormones; Microsomes, Liver
PubMed: 37060457
DOI: 10.1007/s00228-023-03489-1 -
Trials Mar 2023Pain management is a critical component of comprehensive postsurgical care, as it influences patient safety and outcomes, and inadequate control has been associated with...
A double-blinded, placebo-controlled, randomized study to evaluate the efficacy of perioperative dextromethorphan compared to placebo for the treatment of postoperative pain: a study protocol.
BACKGROUND
Pain management is a critical component of comprehensive postsurgical care, as it influences patient safety and outcomes, and inadequate control has been associated with the development of chronic pain syndromes. Despite recent improvements, the management of postoperative pain following total knee arthroplasty (TKA) remains a challenge. The use of opioid-sparing, multimodal analgesic regimens has broad support, but there is a paucity of high-quality evidence regarding optimal postoperative protocols and novel approaches are needed. Dextromethorphan stands out among both well-studied and emerging pharmacological adjuncts for postoperative pain due its robust safety profile and unique pharmacology. The purpose of this study is to evaluate the efficacy of multi-dose dextromethorphan for postoperative pain control following TKA.
METHODS
This is a single-center, multi-dose, randomized, double-blinded, placebo-controlled trial. A total of 160 participants will be randomized 1:1 to receive either 60 mg oral dextromethorphan hydrobromide preoperatively, as well as 30 mg 8 h and 16 h postoperatively, or matching placebo. Outcome data will be obtained at baseline, during the first 48 h, and the first two follow-up visits. The primary outcome measure will be total opioid consumption at 24 h postoperatively. Secondary outcomes related to pain, function, and quality of life will be evaluated using standard pain scales, the Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS, JR) questionnaire, the Patient-Reported Outcomes Measurement Information System (PROMIS-29) questionnaire, and clinical anchors.
DISCUSSION
This study has a number of strengths including adequate power, a randomized controlled design, and an evidence-based dosing schedule. As such, it will provide the most robust evidence to date on dextromethorphan utilization for postoperative pain control following TKA. Limitations include not obtaining serum samples for pharmacokinetic analysis and the single-center study design.
TRIAL REGISTRATION
This trial has been registered on the National Institute of Health's ClinicalTrials.gov (NCT number: NCT05278494). Registered on March 14, 2022.
Topics: Humans; Dextromethorphan; Analgesics, Opioid; Quality of Life; Pain, Postoperative; Analgesics; Treatment Outcome; Randomized Controlled Trials as Topic
PubMed: 36991450
DOI: 10.1186/s13063-023-07240-0 -
Clinical Pharmacology and Therapeutics Jun 2023Oral formulations prepared from the leaves of the kratom (Mitragyna speciosa) plant are increasingly used for their opioid-like effects to self-manage opioid withdrawal...
Oral formulations prepared from the leaves of the kratom (Mitragyna speciosa) plant are increasingly used for their opioid-like effects to self-manage opioid withdrawal and pain. Calls to US poison centers involving kratom exposures increased >50-fold from 2011-2017, one-third of which reported concomitant use of kratom with drugs of abuse. Many of these drugs are eliminated primarily via cytochrome P450 (CYP) 3A and CYP2D6, raising concerns for potential adverse pharmacokinetic kratom-drug interactions. The impact of a single low dose of kratom tea (2 g) on the pharmacokinetics of the CYP3A probe midazolam (2.5 mg) and CYP2D6 probe dextromethorphan (30 mg) were assessed in 12 healthy adult participants after oral administration. Kratom showed no effect on dextromethorphan area under the plasma concentration time-curve (AUC) and maximum concentration (C ; geometric mean ratio (90% confidence interval) 0.99 (0.83-1.19) and 0.96 (0.78-1.19), respectively) but a modest increase in midazolam AUC and C (1.39 (1.23-1.57) and 1.50 (1.32-1.70), respectively). Lack of change in midazolam half-life (1.07 (0.98-1.17)) suggested that kratom primarily inhibited intestinal CYP3A. This inference was further supported by a physiologically based pharmacokinetic drug interaction model using the abundant alkaloid mitragynine, a relatively potent CYP3A time-dependent inhibitor in vitro (K , ~4 μM; k , ~0.07 min ). This work is the first to clinically evaluate the pharmacokinetic drug interaction potential of kratom. Co-consuming kratom with certain drugs extensively metabolized by CYP3A may precipitate serious interactions. These data fill critical knowledge gaps about the safe use of this increasingly popular natural product, thereby addressing ongoing public health concerns.
Topics: Adult; Humans; Mitragyna; Analgesics, Opioid; Midazolam; Biological Products; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Dextromethorphan; Psychotropic Drugs; Drug Interactions; Cytochrome P-450 CYP3A Inhibitors
PubMed: 36924284
DOI: 10.1002/cpt.2891 -
Clinical Case Reports Mar 2023We admitted a 42-year-old patient with severe treatment-resistant depression and with psychiatric comorbidities. The patient attempted suicide 5 weeks after admission....
Improvement of depressive symptoms, after a suicide attempt, with dextromethorphan/bupropion combination treatment in a patient with treatment-resistant depression and psychiatric comorbidities.
We admitted a 42-year-old patient with severe treatment-resistant depression and with psychiatric comorbidities. The patient attempted suicide 5 weeks after admission. Subsequently, we initiated dextromethorphan/bupropion based on prior evidence. As a result, the patient demonstrated an improvement in mood symptoms and a reduction in suicide risk, leading to her discharge.
PubMed: 36911631
DOI: 10.1002/ccr3.7045 -
European Archives of Psychiatry and... Oct 2023This review article presents select recent studies that form the basis for the development of esmethadone into a potential new drug. Esmethadone is a promising member of... (Review)
Review
This review article presents select recent studies that form the basis for the development of esmethadone into a potential new drug. Esmethadone is a promising member of the pharmacological class of uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists that have shown efficacy for major depressive disorder (MDD) and other diseases and disorders, such as Alzheimer's dementia and pseudobulbar affect. The other drugs in the novel class of NMDAR antagonists with therapeutic uses that are discussed for comparative purposes in this review are esketamine, ketamine, dextromethorphan, and memantine. We present in silico, in vitro, in vivo, and clinical data for esmethadone and other uncompetitive NMDAR antagonists that may advance our understanding of the role of these receptors in neural plasticity in health and disease. The efficacy of NMDAR antagonists as rapid antidepressants may advance our understanding of the neurobiology of MDD and other neuropsychiatric diseases and disorders.
Topics: Humans; Excitatory Amino Acid Antagonists; Depressive Disorder, Major; Memantine; Antidepressive Agents; Alzheimer Disease
PubMed: 36890259
DOI: 10.1007/s00406-023-01571-4 -
Cureus Feb 2023We present two rare cases highlighting the rare toxicological manifestation of dextromethorphan (DXM). The DXM toxicity profile is predominantly hallucinations,...
We present two rare cases highlighting the rare toxicological manifestation of dextromethorphan (DXM). The DXM toxicity profile is predominantly hallucinations, agitation, irritability with seizures, and coma in severe overdose. The cases that follow are unique in the sense that both patients had features of opioid toxidrome, rarely manifested in DXM abuse. A young male and female in their mid-20s and early 30s, respectively, were brought to the emergency room for their excessive somnolence; both had reduced respiratory rate, bilaterally small pupils (sluggish reactive to light), and the rest of their examination findings were unremarkable. Primary stabilization in the form of noninvasive ventilation (NIV) trial and subsequent rapid sequence intubation (RSI) for persistent respiratory depression. Followed by the exhaustive exclusion of differentials, opioid-like toxidrome was treated with naloxone, and both patients made a good recovery and were discharged home in good health. The emergency physician should be prepared for the rare toxicological manifestations of commonly available over-the-counter medications among the youth. These case reports highlight the role of naloxone in DXM toxicity reversal.
PubMed: 36874326
DOI: 10.7759/cureus.34501 -
Research in Pharmaceutical Sciences Feb 2023Lysosomal-targeted drug delivery can open a new strategy for drug therapy. However, there is currently no universally accepted simulated or artificial lysosomal fluid...
BACKGROUND AND PURPOSE
Lysosomal-targeted drug delivery can open a new strategy for drug therapy. However, there is currently no universally accepted simulated or artificial lysosomal fluid utilized in the pharmaceutical industry or recognized by the United States Pharmacopeia (USP).
EXPERIMENTAL PROCEDURE
We prepared a simulated lysosomal fluid (SLYF) and compared its composition to a commercial artificial counterpart. The developed fluid was used to test the dissolution of a commercial product (Robitussin) of a lysosomotropic drug (dextromethorphan) and to investigate lysosomal trapping of two model drugs (dextromethorphan and (+/-) chloroquine).
FINDINGS/RESULTS
The laboratory-prepared fluid or SLYF contained the essential components for the lysosomal function in concentrations reflective of the physiological values, unlike the commercial product. Robitussin passed the acceptance criteria for the dissolution of dextromethorphan in 0.1 N HCl medium (97.7% in less than 45 min) but not in the SLYF or the phosphate buffer media (72.6% and 32.2% within 45 min, respectively). Racemic chloroquine showed higher lysosomal trapping (51.9%) in the model than dextromethorphan (28.3%) in a behavior supporting findings and based on the molecular descriptors and the lysosomal sequestration potential of both.
CONCLUSION AND IMPLICATION
A standardized lysosomal fluid was reported and developed for investigations of lysosomotropic drugs and formulations.
PubMed: 36846734
DOI: 10.4103/1735-5362.363591