-
Clinical Drug Investigation Jun 2024The absence of a definitive cure for amyotrophic lateral sclerosis (ALS) emphasizes the crucial need to explore new and improved treatment approaches for this fatal,... (Review)
Review
The absence of a definitive cure for amyotrophic lateral sclerosis (ALS) emphasizes the crucial need to explore new and improved treatment approaches for this fatal, progressive, and disabling neurodegenerative disorder. As at the end of 2023, five treatments - riluzole, edaravone, dextromethorphan hydrobromide + quinidine sulfate (DHQ), tofersen, and sodium phenylbutyrate-tauroursodeoxycholic acid (PB-TUDCA) - were FDA approved for the treatment of patients with ALS. Among them PB-TUDCA has been shown to impact DNA processing impairments, mitochondria dysfunction, endoplasmic reticulum stress, oxidative stress, and pathologic folded protein agglomeration defects, which have been associated with ALS pathophysiology. The Phase 2 CENTAUR trial demonstrated significant impact of PB-TUDCA on the ALS Functional Rating Scale-Revised (ALSFRS-R) risk of death, hospitalization, and the need for tracheostomy or permanent assisted ventilation in patients with ALS based on post hoc analyses. More recently, contrasting with the CENTAUR trial results, results from the Phase 3 PHOENIX trial (NCT05021536) showed no change in ALSFRS-R total score at 48 weeks. Consequently, the sponsor company initiated the process with the US FDA and Health Canada to voluntarily withdraw the marketing authorizations for PB-TUDCA. In the present article, we review ALS pathophysiology, with a focus on PB-TUDCA's proposed mechanisms of action and recent clinical trial results and discuss the implications of conflicting trial data for ALS and other neurological disorders.
PubMed: 38909349
DOI: 10.1007/s40261-024-01371-1 -
JMIR Public Health and Surveillance Jan 2024Drug-induced suicide (DIS) is a severe adverse drug reaction (ADR). Although clinical trials have provided evidence on DIS, limited investigations have been performed on... (Review)
Review
BACKGROUND
Drug-induced suicide (DIS) is a severe adverse drug reaction (ADR). Although clinical trials have provided evidence on DIS, limited investigations have been performed on rare ADRs, such as suicide.
OBJECTIVE
We aimed to systematically review case reports on DIS to provide evidence-based drug information.
METHODS
We searched PubMed to obtain case reports regarding DIS published until July 2021. Cases resulting from drugs that are no longer used or are nonapproved, substance use, and suicidal intentions were excluded. The quality of each case report was assessed using the CASE (Case Reports) checklist. We extracted data regarding demographics, medication history, suicide symptoms, and symptom improvement and evaluated the causality of DIS using the Naranjo score. Furthermore, to identify the potential suicidal risk of the unknown drugs, we compared the results of the causality assessment with those of the approved drug labels.
RESULTS
In 83 articles, we identified 152 cases involving 61 drugs. Antidepressants were reported as the most frequent causative drugs of DIS followed by immunostimulants. The causality assessment revealed 61 cases having possible, 89 cases having probable, and 2 cases having definite relationships with DIS. For approximately 85% of suspected drugs, the risk of suicidal ADRs was indicated on the approved label; however, the approved labels for 9 drugs, including lumacaftor/ivacaftor, doxycycline, clozapine, dextromethorphan, adalimumab, infliximab, piroxicam, paclitaxel, and formoterol, did not provide information about these risks.
CONCLUSIONS
We found several case reports involving drugs without suicide risk information on the drug label. Our findings might provide valuable insights into drugs that may cause suicidal ADRs.
Topics: Humans; Doxycycline; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Suicidal Ideation; Suicide; Case Reports as Topic
PubMed: 38289650
DOI: 10.2196/49755 -
Orphanet Journal of Rare Diseases Apr 2024We aim to describe the behavioral phenotype of children and adolescents with the good to intermediate attenuated form of non-ketotic hyperglycinemia (NKH) and to explore...
AIM
We aim to describe the behavioral phenotype of children and adolescents with the good to intermediate attenuated form of non-ketotic hyperglycinemia (NKH) and to explore associations between the behavioral phenotype and age, sex, plasma glycine levels and drug treatment.
METHOD
Parents of children with attenuated NKH completed questionnaires assessing maladaptive behavior, adaptive behavior, social communication, speech/language development and motor development in addition to demographic and medical questions.
RESULTS AND INTERPRETATION
Twelve children, age 6 to 21y, functioned at mild to severe intellectual disability levels. Their speech/language development was in line with their developmental quotient. Relative to their intellectual functioning, their motor development and communication were weaker in comparison to their general development. Their adaptive behavior, however, appeared a relative strength. There was no evidence for autism spectrum disorder occurring more frequently than expected, rather social skills, except for communication, were rated as a relative strength. Maladaptive behaviors with ADHD-like characteristics were present in more than two thirds of children. Maladaptive behaviors were significantly related to female sex and to taking dextromethorphan, but no significant relation between plasma glycine levels and behavior was found. Future studies will need to evaluate causality in the observed relation between dextromethorphan use and maladaptive behaviors. Clinicians should reconsider the benefit of dextromethorphan when presented with disruptive behaviors in children with attenuated NKH.
Topics: Child; Humans; Female; Adolescent; Young Adult; Adult; Hyperglycinemia, Nonketotic; Autism Spectrum Disorder; Dextromethorphan; Phenotype; Glycine
PubMed: 38589924
DOI: 10.1186/s13023-024-03172-3 -
Academic Forensic Pathology Mar 2024Limited case reports have been published regarding serotonin syndrome due to the combined effects of supratherapeutic levels of dextromethorphan and selective serotonin...
Limited case reports have been published regarding serotonin syndrome due to the combined effects of supratherapeutic levels of dextromethorphan and selective serotonin reuptake inhibitor. We report a case of an adolescent with postmortem findings suggestive of a diagnosis of serotonin syndrome-induced psychosis associated with a double homicide and suicide. Postmortem toxicology of the suicide victim was remarkable for elevated serotonergic metabolites of fluoxetine and dextromethorphan in a 14-year-old male.
PubMed: 38505641
DOI: 10.1177/19253621231224531 -
Neurochemical Research Jul 2024N-methyl-D-aspartate receptor-dependent excitotoxicity is one of the most important mechanisms underlying stroke injury and the resulting neuronal death. In the present...
N-methyl-D-aspartate receptor-dependent excitotoxicity is one of the most important mechanisms underlying stroke injury and the resulting neuronal death. In the present study, in order to reduce post-stroke brain injury and improve behavioral performance, a new molecule named IC87201, which acts as an inhibitor of PSD95/nNOS interaction in the intracellular signaling pathway of NMDA receptors, was administered. Using the middle cerebral artery occlusion (MCAO) technique, 24 adult male rats were subjected to one hour of cerebral ischemia. Animals were randomly divided into sham, MCAO, MCAO + DXM, and MCAO + IC87201 groups, and in the last two groups, intraperitoneal injection of dextromethorphan hydrobromide monohydrate (DXM), as an NMDA antagonist, and IC87201 was performed after ischemia. Neurobehavioral scores were evaluated for seven days, and on the last two days, the rats' memory performance was appraised using the passive avoidance test. On seventh day, the brain tissue was properly prepared for stereological analysis. Stereological studies of the hippocampus CA1 and CA3 regions revealed that changes in the total and infarcted volumes, total number of neurons, non-neurons, and dead neurons are the consequences of cerebral ischemia. Also, following cerebral ischemia, neurobehavioral and memory function impairments which were assessed by modified neurological severity scores (mNSS) and passive avoidance test, were observed. The aforementioned impairments were recovered after administration of IC87201 significantly and more potently than DXM. Based on our findings, IC87201 successfully attenuated post-ischemia damages. Therefore, this molecule can be considered as a new therapeutic approach in future research.
Topics: Animals; Male; Disks Large Homolog 4 Protein; Infarction, Middle Cerebral Artery; Rats; Neuroprotective Agents; Rats, Wistar; Stroke; Rats, Sprague-Dawley
PubMed: 38656691
DOI: 10.1007/s11064-024-04140-w -
The American Journal of Emergency... Oct 2023
Topics: Humans; Bupropion; Dextromethorphan; Antidepressive Agents; Drug Overdose; Drug-Related Side Effects and Adverse Reactions; Antidepressive Agents, Second-Generation
PubMed: 37633741
DOI: 10.1016/j.ajem.2023.08.026 -
Membranes Sep 2023High levels of oxidative stress are implicated in hypoxia, a physiological response to low levels of oxygen. Evidence supports a connection between this response and...
High levels of oxidative stress are implicated in hypoxia, a physiological response to low levels of oxygen. Evidence supports a connection between this response and depression. Previous studies indicate that tryptophan hydroxylase can be negatively affected in hypoxia, impairing serotonin synthesis and downstream pathways. Some studies also hypothesize that increasing hypoxia-inducible factor-1 (HIF-1) levels may be a new therapeutic modality for depression. Hence, this study delved into the influence of hypoxia on the cellular response to drugs designed to act in depression. By the induction of hypoxia in SH-SY5Y cells through a hypoxia incubator chamber or Cobalt Chloride treatment, the effect of Mirtazapine, an antidepressant, and other drugs that interact with serotonin receptors (TCB-2, Dextromethorphan, Ketamine, Quetiapine, Scopolamine, Celecoxib, and Lamotrigine) on SH-SY5Y cellular viability and morphology was explored. The selection of drugs was initially conducted by literature search, focusing on compounds with established potential for employment in depression therapy. Subsequently, we employed in silico approaches to forecast their ability to traverse the blood-brain barrier (BBB). This step was particularly pertinent as we aimed to assess their viability for inducing potential antidepressant effects. The effect of these drugs in hypoxia under the inhibition of HIF-1 by Echinomycin was also tested. Our results revealed that all the potential repurposed drugs promoted cell viability, especially when hypoxia was chemically induced. When combined with Echinomycin, all drugs decreased cellular viability, possibly by the inability to interact with HIF-1.
PubMed: 37755222
DOI: 10.3390/membranes13090800 -
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 -
Molecules (Basel, Switzerland) Oct 2023Lekethromycin (LKMS) is a synthetic macrolide compound derivative intended for use as a veterinary medicine. Since there have been no in vitro studies evaluating its...
Lekethromycin (LKMS) is a synthetic macrolide compound derivative intended for use as a veterinary medicine. Since there have been no in vitro studies evaluating its potential for drug-drug interactions related to cytochrome P450 (CYP450) enzymes, the effect of the inhibitory mechanisms of LKMS on CYP450 enzymes is still unclear. Thus, this study aimed to evaluate the inhibitory effects of LKMS on dog CYP450 enzymes. A cocktail approach using ultra-performance liquid chromatography-tandem mass spectrometry was conducted to investigate the inhibitory effect of LKMS on canine CYP450 enzymes. Typical probe substrates of phenacetin, coumarin, bupropion, tolbutamide, dextromethorphan, chlorzoxazone, and testosterone were used for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4, respectively. This study showed that LKMS might not be a time-dependent inhibitor. LKMS inhibited CYP2A6, CYP2B6, and CYP2D6 via mixed inhibition. LKMS exhibited mixed-type inhibition against the activity of CYP2A6 with an inhibition constant (K) value of 135.6 μΜ. LKMS inhibited CYP2B6 in a mixed way, with K values of 59.44 μM. A phenotyping study based on an inhibition assay indicated that CYP2D6 contributes to the biotransformation of LKMS. A mixed inhibition of CYP2D6 with K values of 64.87 μM was also observed. Given that this study was performed in vitro, further in vivo studies should be conducted to identify the interaction between LKMS and canine CYP450 enzymes to provide data support for the clinical application of LKMS and the avoidance of adverse interactions between other drugs.
Topics: Dogs; Animals; Tandem Mass Spectrometry; Chromatography, Liquid; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2D6; Microsomes, Liver; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Liver
PubMed: 37894672
DOI: 10.3390/molecules28207193 -
Clinical Drug Investigation May 2024Viloxazine extended-release (ER) [Qelbree] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for...
Impact of Viloxazine Extended-Release Capsules (Qelbree) on Select Cytochrome P450 Enzyme Activity and Evaluation of CYP2D6 Genetic Polymorphisms on Viloxazine Pharmacokinetics.
BACKGROUND AND OBJECTIVE
Viloxazine extended-release (ER) [Qelbree] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for viloxazine to inhibit cytochrome 450 (CYP) enzymes 1A2, 2B6, 2D6 and 3A4. This clinical study therefore evaluated viloxazine ER effects on index substrates for CYP1A2, 2D6, and 3A4, and secondarily evaluated the impact of CYP2D6 polymorphisms on viloxazine pharmacokinetics.
METHODS
Thirty-seven healthy subjects received a modified Cooperstown cocktail (MCC; caffeine 200 mg, dextromethorphan 30 mg, midazolam 0.025 mg/kg) on Day 1, viloxazine ER 900 mg/day on Days 3-5, and a combination of viloxazine ER 900 mg and MCC on Day 6. Viloxazine ER effects on MCC substrates were evaluated using analysis of variance. The impact of CYP2D6 genetic polymorphisms on steady-state viloxazine plasma concentrations was evaluated using Student's t test assessing pharmacokinetic parameter differences between poor versus extensive metabolizers.
RESULTS
The least squares geometric mean ratio [GMR%] (90% CI) of MCC substrate + viloxazine ER/MCC substrate alone for caffeine maximum concentration (C), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC) was 99.11 (95.84-102.49), 436.15 (398.87-476.92), and 583.35 (262.41-1296.80), respectively; 150.76 (126.03-180.35), 185.76 (155.01-222.61), and 189.71 (160.37-224.42) for dextromethorphan C, AUC and AUC, respectively; and 112.81 (104.71-121.54), 167.56 (153.05-183.45), and 168.91 (154.38-184.80) for midazolam C, AUC and AUC, respectively. At steady state, viloxazine least squares GMR (90% CI) for poor/extensive CYP2D6 metabolizers were C 120.70 (102.33-142.37) and area under the plasme concentration-time curve from time 0 to 24 hours (AUC 125.66 (105.36-149.87)).
CONCLUSION
Viloxazine ER is a strong CYP1A2 inhibitor and a weak CYP2D6 and CYP3A4 inhibitor. CYP2D6 polymorphisms did not meaningfully alter the viloxazine ER pharmacokinetic profile.
Topics: Female; Humans; Male; Caffeine; Capsules; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme System; Delayed-Action Preparations; Dextromethorphan; Healthy Volunteers; Midazolam; Polymorphism, Genetic; Viloxazine
PubMed: 38598106
DOI: 10.1007/s40261-024-01356-0