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The Medical Letter on Drugs and... Dec 2023
Topics: Humans; Antidepressive Agents; Selective Serotonin Reuptake Inhibitors
PubMed: 38133585
DOI: 10.58347/tml.2023.1691a -
British Journal of Clinical Pharmacology Dec 2023The aim of this study is to demonstrate the use of PBPK modelling to explore the impact of ethnic differences on drug PK.
AIMS
The aim of this study is to demonstrate the use of PBPK modelling to explore the impact of ethnic differences on drug PK.
METHODS
A PBPK model developed for lansoprazole was used to predict the clinical PK of lansoprazole in Japanese subjects by incorporating the physiological parameters of a Japanese population into the model. Further verification of the developed Japanese population with clinical studies involving eight other CYP substrates-omeprazole, ticlopidine, alprazolam, midazolam, nifedipine, cinacalcet, paroxetine and dextromethorphan-was also carried out.
RESULTS
The PK of lansoprazole in both Caucasian and Japanese subjects was well predicted by the model as the observed data were within the 5th and 95th percentiles across all the clinical studies. In age- and sex-matched simulations in both the Caucasian and Japanese populations, the predicted PK (mean ± SD) of a single oral dose of 30-mg lansoprazole was higher in the Japanese population in all cases, with more than twofold higher AUC of 5.98 ± 6.43 mg/L.h (95% CI: 4.72, 7.24) vs. 2.46 ± 2.45 mg/L.h (95% CI: 1.98, 2.94) in one scenario. In addition, in two out of the nine clinical DDIs of lansoprazole and the additional CYP substrates simulated using the Japanese population, the predicted DDI in Japanese was more than 1.25-fold that in Caucasians, indicating an increased DDI liability.
CONCLUSIONS
By accounting for various physiological parameters that characterize a population in a PBPK model, the impact of the different identified interethnic differences on the drug's PK can be explored, which can inform the adoption of drugs from one region to another.
PubMed: 38072775
DOI: 10.1111/bcp.15982 -
Drug Metabolism and Disposition: the... Jan 2024Cytochrome P450 2D6 (CYP2D6) is a critical hepatic drug-metabolizing enzyme in humans, responsible for metabolizing approximately 20%-25% of commonly used medications...
Cytochrome P450 2D6 (CYP2D6) is a critical hepatic drug-metabolizing enzyme in humans, responsible for metabolizing approximately 20%-25% of commonly used medications such as codeine, desipramine, fluvoxamine, paroxetine, and tamoxifen. The CYP2D6 gene is highly polymorphic, resulting in substantial interindividual variability in its catalytic function and the pharmacokinetics and therapeutic outcomes of its substrate drugs. Although many functional CYP2D6 variants have been discovered and validated, a significant portion of the variability in the expression and activity of CYP2D6 remains unexplained. In this study, we performed a genome-wide association study (GWAS) to identify novel variants associated with CYP2D6 protein expression in individual human livers, followed by a conditional analysis to control for the effect of functional CYP2D6 star alleles. We also examined their impact on hepatic CYP2D6 activity. Genotyping on a genome-wide scale was achieved using the Illumina Multi-Ethnic Genotyping Array (MEGA). A data-independent acquisition (DIA)-based proteomics method was used to quantify CYP2D6 protein concentrations. CYP2D6 activity was determined by measuring the dextromethorphan O-demethylation in individual human liver s9 fractions. The GWAS identified 44 single nuclear polymorphisms (SNPs) that are significantly associated with CYP2D6 protein expressions with a value threshold of 5.0 × 10 After the conditional analysis, five SNPs, including the cis-variants rs1807493 and rs1062753 and the trans-variants rs4073010, rs729559, and rs80274432, emerged as independent variants significantly correlated with hepatic CYP2D6 protein expressions. Notably, four of these SNPs, except for rs80274432, also exhibited a significant association with CYP2D6 activities in human livers, suggesting their potential as novel and independent cis- and trans-variants regulating CYP2D6. SIGNIFICANT STATEMENT: Using individual human livers, we identified four novel cis- and trans-pQTLs/aQTLs (protein quantitative trait loci/activity quantitative trait loci) of Cytochrome P450 2D6 (CYP2D6) that are independent from known functional CYP2D6 star alleles. This study connects the CYP2D6 gene expression and activity, enhancing our understanding of the genetic variants associated with CYP2D6 protein expression and activity, potentially advancing our insight into the interindividual variability in CYP2D6 substrate medication response.
Topics: Humans; Cytochrome P-450 CYP2D6; Fluvoxamine; Genome-Wide Association Study; Liver; Paroxetine
PubMed: 38050015
DOI: 10.1124/dmd.123.001548 -
Drugs in R&D Mar 2024Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is the opioid inactive dextro-isomer of racemic methadone. Esmethadone is a low potency...
BACKGROUND AND OBJECTIVE
Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is the opioid inactive dextro-isomer of racemic methadone. Esmethadone is a low potency N-methyl-D-aspartate (NMDA) receptor channel blocker with higher affinity for GluN2D subtypes. Esmethadone showed robust, rapid, and sustained antidepressant effects in patients with major depressive disorder (MDD) with inadequate response to ongoing serotonergic antidepressant treatment.
METHODS
Here we described the results of in vitro and phase 1 clinical trials aimed at investigating the esmethadone metabolism and possible drug-drug interactions.
RESULTS
Esmethadone is primarily metabolized to EDDP (2-ethylene-1,5-dimethyl-3,3-diphenylpyrrolidine) by multiple enzymes, including CYP3A4/5 and CYP2B6. In vitro studies showed that esmethadone inhibits CYP2D6 with IC of 9.6 μM and is an inducer of CYP3A4/5. The clinical relevance of the inhibition of CYP2D6 and the induction of CYP3A4 were investigated by co-administering esmethadone and dextromethorphan (a substrate for CYP2D6) or midazolam (a substrate for CYP3A4) in healthy volunteers. The administration of esmethadone at the dosage of 75 mg (which is the loading dose administered to patients in MDD clinical trials) significantly increased the exposure (AUC) of both dextromethorphan and its metabolite dextrorphan by 2.71 and 3.11-fold, respectively. Esmethadone did not modify the pharmacokinetic profile of midazolam, while it increased C and AUC of its metabolite 1'-hydroxymidazolam by 2.4- and 3.8-fold, respectively. A second study evaluated the effect of the CYP3A4 inhibitor cobicistat on the pharmacokinetics of esmethadone. Cobicistat slightly increase (+32%) the total exposure (AUC) of esmethadone.
CONCLUSIONS
In summary, esmethadone demonstrated a negligible effect on CYP3A4 induction and its metabolism was not meaningfully affected by strong CYP3A4 inhibitors while it increased exposure of CYP2D6-metabolized drugs.
PubMed: 38010591
DOI: 10.1007/s40268-023-00450-6 -
Journal of Psychoactive Drugs Nov 2023Hallucinogen Persisting Perception Disorder (HPPD) is considered rare in hallucinogen users although there are conflicting reports about its incidence and prevalence....
Hallucinogen Persisting Perception Disorder (HPPD) is considered rare in hallucinogen users although there are conflicting reports about its incidence and prevalence. HPPD may be more common in those with trait neuroticism. In this study, we invited hallucinogen and other drug users to complete an online questionnaire about their use of hallucinogens, their experience of HPPD symptoms, and their trait neuroticism and mental health symptoms. We received 802 responses with 415 of these containing adequate data for further analysis. 39.7% of responders reported symptoms corresponding to Type I HPPD, and 4.3% reported symptoms corresponding to Type II HPPD. We found no significant difference between neuroticism scores for participants with or without HPPD. Individuals with Type II HPPD were more likely to report mental health symptoms including anxiety, obsessional thoughts, paranoia, hypochondria and panic attacks ( < .05). We also found that individuals with Type II HPPD were more likely to report the use of 25I-NBOMe, dextromethorphan, nitrous oxide and benzodiazepines ( < .05). 47.3% of participants had never tested their drugs, making the attribution of HPPD severity to specific drugs difficult. Further work into the development of HPPD is required, particularly with the rise of hallucinogens as potential treatments for depression and other mental illnesses.
PubMed: 38009828
DOI: 10.1080/02791072.2023.2287081 -
Pharmaceuticals (Basel, Switzerland) Nov 2023Treatment-resistant depression (TRD) is a term used to describe a particular type of major depressive disorder (MDD). There is no consensus about what defines TRD, with... (Review)
Review
Treatment-resistant depression (TRD) is a term used to describe a particular type of major depressive disorder (MDD). There is no consensus about what defines TRD, with various studies describing between 1 and 4 failures of antidepressant therapies, with or without electroconvulsive therapy (ECT). That is why TRD is such a growing concern among clinicians and researchers, and it explains the necessity for investigating novel therapeutic targets beyond conventional monoamine pathways. An imbalance between two primary central nervous system (CNS) neurotransmitters, -glutamate and γ-aminobutyric acid (GABA), has emerged as having a key role in the pathophysiology of TRD. In this review, we provide an evaluation and comprehensive review of investigational antidepressants targeting these two systems, accessing their levels of available evidence, mechanisms of action, and safety profiles. N-methyl-D-aspartate (NMDA) receptor antagonism has shown the most promise amongst the glutamatergic targets, with ketamine and esketamine (Spravato) robustly generating responses across trials. Two specific NMDA-glycine site modulators, D-cycloserine (DCS) and apimostinel, have also generated promising initial safety and efficacy profiles, warranting further investigation. Combination dextromethorphan-bupropion (AXS-05/Auvelity) displays a unique mechanism of action and demonstrated positive results in particular applicability in subpopulations with cognitive dysfunction. Currently, the most promising GABA modulators appear to be synthetic neurosteroid analogs with positive GABA receptor modulation (such as brexanolone). Overall, advances in the last decade provide exciting perspectives for those who do not improve with conventional therapies. Of the compounds reviewed here, three are approved by the Food and Drug Administration (FDA): esketamine (Spravato) for TRD, Auvelity (dextromethorphan-bupropion) for major depressive disorder (MDD), and brexanolone (Zulresso) for post-partum depression (PPD). Notably, some concerns have arisen with esketamine and brexanolone, which will be detailed in this study.
PubMed: 38004437
DOI: 10.3390/ph16111572 -
Pharmaceuticals (Basel, Switzerland) Oct 2023Huntington's Disease (HD) is a severely debilitating neurodegenerative disorder in which sufferers exhibit different combinations of movement disorders, dementia, and... (Review)
Review
Huntington's Disease (HD) is a severely debilitating neurodegenerative disorder in which sufferers exhibit different combinations of movement disorders, dementia, and behavioral or psychiatric abnormalities. The disorder is a result of a trinucleotide repeat expansion mutation that is inherited in an autosomal dominant manner. While there is currently no treatment to alter the course of HD, there are medications that lessen abnormal movement and psychiatric symptoms. ClinicalTrials.gov was searched to identify drugs that are currently in or have completed phase III drug trials for the treatment of HD. The described phase III trials were further limited to interventional studies that were recruiting, active not recruiting, or completed. In addition, all studies must have posted an update within the past year. PubMed was used to gather further information on these interventional studies. Of the nine clinical trials that met these criteria, eight involved the following drugs: metformin, dextromethorphan/quinidine, deutetrabenazine, valbenazine, Cellavita HD, pridopidine, SAGE-718, and RO7234292 (RG6042). Of these drug treatments, four are already FDA approved. This systematic review provides a resource that summarizes the present therapies for treating this devastating condition that are currently in phase III clinical trials in the United States.
PubMed: 38004378
DOI: 10.3390/ph16111513 -
Neuroscience Bulletin May 2024Neuroinflammation mediated by microglia and oxidative stress play pivotal roles in the development of chronic temporal lobe epilepsy (TLE). We postulated that kainic...
Neuroinflammation mediated by microglia and oxidative stress play pivotal roles in the development of chronic temporal lobe epilepsy (TLE). We postulated that kainic acid (KA)-Induced status epilepticus triggers microglia-dependent inflammation, leading to neuronal damage, a lowered seizure threshold, and the emergence of spontaneous recurrent seizures (SRS). Extensive evidence from our laboratory suggests that dextromethorphan (DM), even in ultra-low doses, has anti-inflammatory and neuroprotective effects in many animal models of neurodegenerative disease. Our results showed that administration of DM (10 ng/kg per day; subcutaneously via osmotic minipump for 4 weeks) significantly mitigated the residual effects of KA, including the frequency of SRS and seizure susceptibility. In addition, DM-treated rats showed improved cognitive function and reduced hippocampal neuronal loss. We found suppressed microglial activation-mediated neuroinflammation and decreased expression of hippocampal gp91 and p47 proteins in KA-induced chronic TLE rats. Notably, even after discontinuation of DM treatment, ultra-low doses of DM continued to confer long-term anti-seizure and neuroprotective effects, which were attributed to the inhibition of microglial NADPH oxidase 2 as revealed by mechanistic studies.
Topics: Animals; Epilepsy, Temporal Lobe; Kainic Acid; Dextromethorphan; Neuroprotective Agents; Male; NADPH Oxidases; Rats, Sprague-Dawley; Microglia; Hippocampus; Rats; Anticonvulsants; Disease Models, Animal; Chronic Disease
PubMed: 37973720
DOI: 10.1007/s12264-023-01140-8 -
Journal of Pharmaceutical and... Jan 2024Fingerprints left at a crime scene are used to connect the crime to a person who may have been present there. Fingerprints can also be used as alternative material in...
Fingerprints left at a crime scene are used to connect the crime to a person who may have been present there. Fingerprints can also be used as alternative material in forensic toxicology. The detection of drugs in fingerprint samples can be used to show that an individual touching an item has consumed specific drugs. The aim of this study was to check the usefulness of fingerprints in drug analyses and detection of some analytes in this material. Fingerprint samples were collected on glass slides from a volunteer who consumed separately tablets containing pseudoephedrine, codeine, dextromethorphan, and used lidocaine spray. Moreover, fingerprints of individuals receiving sertraline, hydroxyzine and trazodone as part of their long-term treatment were analysed. The detection of drugs was conducted using the liquid chromatography tandem mass spectrometry (LC-MS/MS) technique. After administration of single doses of drugs, they were detected up to 36 h (pseudoephedrine), 24 h (codeine), and less than 6 h (dextromethorphan and lidocaine) with maximum concentrations observed at 1-4 h. In fingerprints of a person who has finished treatment with hydroxyzine and sertraline it was possible to detect these drugs even 20 days after last drug administration. Cetirizine (hydroxyzine metabolite) and mCPP (trazodone metabolite) were determined in fingerprints of individuals under long-term treatment. This work has demonstrated that forensic toxicology can use fingerprints as alternative material. Drugs can be detected in fingerprints even after their single doses. Parent compounds predominate over metabolites in the fingerprints. The detection window depends on the type of drug and duration of the treatment.
Topics: Humans; Chromatography, Liquid; Trazodone; Tandem Mass Spectrometry; Dextromethorphan; Pseudoephedrine; Sertraline; Substance Abuse Detection; Pharmaceutical Preparations; Hydroxyzine; Codeine; Lidocaine
PubMed: 37926037
DOI: 10.1016/j.jpba.2023.115835