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JAMA Network Open Feb 2023Controlled clinical laboratory studies have shown that cannabidiol (CBD) can sometimes attenuate or exacerbate the effects of Δ9-tetrahydrocannabinol (Δ9-THC). No... (Randomized Controlled Trial)
Randomized Controlled Trial
Assessment of Orally Administered Δ9-Tetrahydrocannabinol When Coadministered With Cannabidiol on Δ9-Tetrahydrocannabinol Pharmacokinetics and Pharmacodynamics in Healthy Adults: A Randomized Clinical Trial.
IMPORTANCE
Controlled clinical laboratory studies have shown that cannabidiol (CBD) can sometimes attenuate or exacerbate the effects of Δ9-tetrahydrocannabinol (Δ9-THC). No studies have evaluated differences in pharmacokinetics (PK) of Δ9-THC and pharmacodynamics (PD) between orally administered cannabis extracts that vary with respect to Δ9-THC and CBD concentrations.
OBJECTIVE
To compare the PK and PD of orally administered Δ9-THC-dominant and CBD-dominant cannabis extracts that contained the same Δ9-THC dose (20 mg).
DESIGN, SETTING, AND PARTICIPANTS
This randomized clinical trial was a within-participant, double-blind, crossover study conducted from January 2021 to March 2022 at the Johns Hopkins University Behavioral Pharmacology Research Unit, Baltimore, MD. Eighteen healthy adults completed 3 randomized outpatient experimental test sessions that were each separated by at least 1 week.
INTERVENTIONS
Brownies containing (1) no cannabis extract (ie, placebo); (2) Δ9-THC-dominant extract (20 mg Δ9-THC with no CBD); and (3) CBD-dominant extract (20 mg Δ9-THC + 640 mg CBD) were administered to participants 30 minutes prior to administering a cytochrome P450 (CYP) probe drug cocktail, which consisted of 100 mg caffeine, 20 mg omeprazole, 25 mg losartan, 30 mg dextromethorphan, and 2 mg midazolam.
MAIN OUTCOMES AND MEASURES
Change-from-baseline plasma concentrations for Δ9-THC or Δ9-THC metabolites and scores for subjective drug effects, cognitive and psychomotor performance, and vital signs. The area under the plasma vs concentration vs time curve (AUC) and maximum plasma concentration (Cmax) were determined.
RESULTS
The participant cohort of 18 adults included 11 males (61.1%) and 7 females (38.9%) with a mean (SD) age of 30 (7) years who had not used cannabis for at least 30 days prior to initiation of the study (mean [SD] day since last cannabis use, 86 [66] days). The CYP cocktail + placebo brownie and the CYP cocktail did not affect any PD assessments. Relative to CYP cocktail + Δ9-THC, CYP cocktail + Δ9-THC + CBD produced a higher Cmax and area under the plasma concentration vs time curve for Δ9-THC, 11-OH-Δ9-THC, and Δ9-THC-COOH. The CYP cocktail + Δ9-THC + CBD increased self-reported anxiety, sedation, and memory difficulty, increased heart rate, and produced a more pronounced impairment of cognitive and psychomotor performance compared with both CYP cocktail + Δ9-THC and CYP cocktail + placebo.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial of oral Δ9-THC and CBD, stronger adverse effects were elicited from a CBD-dominant cannabis extract compared with a Δ9-THC-dominant cannabis extract at the same Δ9-THC dose, which contradicts common claims that CBD attenuates the adverse effects of Δ9-THC. CBD inhibition of Δ9-THC and 11-OH-Δ9-THC metabolism is the likely mechanism for the differences observed. An improved understanding of cannabinoid-cannabinoid and cannabinoid-drug interactions are needed to inform clinical and regulatory decision-making regarding the therapeutic and nontherapeutic use of cannabis products.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT04201197.
Topics: Male; Female; Humans; Adult; Dronabinol; Cannabidiol; Cross-Over Studies; Cannabis; Hallucinogens; Cannabinoid Receptor Agonists; Double-Blind Method; Plant Extracts
PubMed: 36780161
DOI: 10.1001/jamanetworkopen.2022.54752 -
Biomedicine & Pharmacotherapy =... Apr 2023Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with high mortality and morbidity rate affecting both upper and lower motor neurons (MN). Muscle force... (Review)
Review
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with high mortality and morbidity rate affecting both upper and lower motor neurons (MN). Muscle force reduction, behavioral change, pseudobulbar affect, and cognitive impairments are the most common clinical manifestations of ALS. The main physiopathology of ALS is still unclear, though several studies have identified that oxidative stress, proteinopathies, glutamate-related excitotoxicity, microglial activation, and neuroinflammation may be involved in the pathogenesis of ALS. From 1995 until October 2022, only Riluzole, Dextromethorphan Hydrobromide (DH) with Quinidine sulfate (Q), Edaravone, and Sodium phenylbutyrate with Taurursodiol (PB/TUDCO) have achieved FDA approval for ALS treatment. Despite the use of these four approved agents, the survival rate and quality of life of ALS patients are still low. Thus, finding novel treatments for ALS patients is an urgent requirement. Masitinib, a tyrosine kinase inhibitor, emphasizes the neuro-inflammatory activity of ALS by targeting macrophages, mast cells, and microglia cells. Masitinib downregulates the proinflammatory cytokines, indirectly reduces inflammation, and induces neuroprotection. Also, it was effective in phase 2/3 and 3 clinical trials (CTs) by increasing overall survival and delaying motor, bulbar, and respiratory function deterioration. This review describes the pathophysiology of ALS, focusing on Masitinib's mechanism of action and explaining why Masitinib could be a promising actor in the treatment of ALS patients. In addition, Masitinib CTs and other competitor drugs in phase 3 CTs have been discussed.
Topics: Humans; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Quality of Life; Seasons
PubMed: 36774721
DOI: 10.1016/j.biopha.2023.114378 -
International Journal of Biological... Apr 2023SARS-CoV-2 Main protease (M) is a well-known drug target against SARS-CoV-2 infection. Identification of M inhibitors is vigorously pursued due to its crucial role in...
SARS-CoV-2 Main protease (M) is a well-known drug target against SARS-CoV-2 infection. Identification of M inhibitors is vigorously pursued due to its crucial role in viral replication. The present study was aimed to identify M inhibitors via repurposing of US-FDA approved drugs by STD-NMR spectroscopy. In this study, 156 drugs and natural compounds were evaluated against M. Among them, 10 drugs were found to be interacting with M, including diltiazem HCl (1), mefenamic acid (2), losartan potassium (3), mexiletine HCl (4), glaucine HBr (5), trimebutine maleate (6), flurbiprofen (7), amantadine HCl (8), dextromethorphan (9), and lobeline HCl (10) in STD-NMR spectroscopy. Their interactions were compared with three standards (Repurposed anti-viral drugs), dexamethasone, chloroquine phosphate, and remdesivir. Thermal stability of M and dissociation constant (K) of six interacting drugs were also determined using DSF. RMSD plots in MD simulation studies showed the formation of stable protein-ligand complexes. They were further examined for their antiviral activity by plaque reduction assay against SARS-CoV-2, which showed 55-100% reduction in viral plaques. This study demonstrates the importance of drug repurposing against emerging and neglected diseases. This study also exhibits successful application of STD-NMR spectroscopy combined with plaque reduction assay in rapid identification of potential anti-viral agents.
Topics: Humans; Antiviral Agents; COVID-19; SARS-CoV-2; Drug Repositioning; Protease Inhibitors; Molecular Docking Simulation; Molecular Dynamics Simulation
PubMed: 36740128
DOI: 10.1016/j.ijbiomac.2023.123540 -
Yakugaku Zasshi : Journal of the... 2023Sinomenine (SIN) is a major component contained in extracts of the Chinese medicinal herb Sinomenium acutum. SIN has various pharmacological properties, including...
Sinomenine (SIN) is a major component contained in extracts of the Chinese medicinal herb Sinomenium acutum. SIN has various pharmacological properties, including cytoprotection, immunosuppression and anti-inflammation effects. Furthermore, recent studies have reported that SIN has anti-tumor and antidepressant effects, which has created a strong need for SIN kinetic studies. This paper reports a simple and sensitive competitive enzyme-linked immunosorbent assay (ELISA) for the pharmacokinetic evaluation of SIN. Anti-SIN serum was obtained by immunizing mice with an antigen conjugated with bovine serum albumin and carboxylic modified SIN using the N-succinimidyl ester method. Enzyme labeling of SIN with horseradish peroxidase was similarly performed using carboxylic modified SIN. Under optimized conditions, this ELISA shows a linear detection range from 40 to 5000 pg/mL, and a limit of detection of 12.1 pg/mL for 50-µL samples. This assay was specific for SIN and showed very slight cross-reactivity with dextromethorphan (0.45%), dimemorfan (0.22%) and codeine (0.01%), but no cross-reactivity with 2-methoxycyclohex-2-enone (<0.001%). Using this ELISA, SIN levels were easily determined in the blood of mice after oral administration of Kampo medicine, Boiogito. The ELISA may be a valuable tool for studies of the biological and pharmacological properties of SIN.
Topics: Mice; Animals; Kinetics; Enzyme-Linked Immunosorbent Assay; Morphinans; Antigens
PubMed: 36724928
DOI: 10.1248/yakushi.22-00164 -
Indian Journal of Pharmacology 2022The concept of listing essential medicines can lead to improved supply and access, more rational prescribing, and lower costs of drugs. However, these benefits hinge on...
Use of drugs not listed in the National List of Essential Medicines: Findings from a prescription analysis by the Indian Council of Medical Research-Rational Use of Medicines Centres Network in tertiary care hospitals across India.
BACKGROUND
The concept of listing essential medicines can lead to improved supply and access, more rational prescribing, and lower costs of drugs. However, these benefits hinge on the prescription of drugs from an Essential Medicines List (EML). Several studies have highlighted the problem of underutilization of EMLs by prescribers. Therefore, as part of prescription research by the Indian Council of Medical Research-Rational Use of Medicines Centres Network, we evaluated the extent of prescription of drugs not listed in the National List of Essential Medicines (NLEM).
MATERIALS AND METHODS
Prescriptions of outpatients from participating centers were included after obtaining verbal/written informed consent as approved by the Ethics Committee, and evaluated for prescription of drugs from the NLEM 2015.
RESULTS
Analysis of 4838 prescriptions from 13 tertiary health-care institutes revealed that 2677 (55.33%) prescriptions had at least one non-NLEM drug prescribed. In all, 5215 (31.12%) of the total 16,758 drugs prescribed were not in NLEM. Of these, 2722 (16.24%) were single drugs and 2493 (14.88%) were fixed-dose combinations (FDCs). These comprised 700 different drug products - 346 single drugs and 354 FDCs. The average number of non-NLEM drugs prescribed per prescription was 1.08, while the average number of all drugs prescribed was 3.35 per prescription. It was also found that some of the non-NLEM drugs prescribed had the potential to result in increased cost (for example, levocetirizine), increased adverse effects (dextromethorphan), and less effectiveness (losartan) when compared to their NLEM counterparts. Nonavailability of an essential drug (oral hydroxocobalamin) was another important finding of our study.
CONCLUSION
This study highlights the extent and pattern of drugs prescribed from outside the NLEM at the tertiary health-care level and the need for training and enhanced awareness among prescribers for greater utilization of the NLEM.
Topics: Drugs, Essential; Tertiary Care Centers; India; Biomedical Research; Prescriptions
PubMed: 36722552
DOI: 10.4103/ijp.ijp_878_21 -
Nature Genetics Feb 2023Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide...
Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.
Topics: Humans; Transcriptome; Drug Repositioning; Genome-Wide Association Study; Tobacco Use; Biology; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease
PubMed: 36702996
DOI: 10.1038/s41588-022-01282-x -
Clinical and Experimental Hepatology Sep 2022Hepatic encephalopathy (HE) is a serious clinical problem leading to severe neurological disorders and death. No specific treatment is available for the management of...
INTRODUCTION
Hepatic encephalopathy (HE) is a serious clinical problem leading to severe neurological disorders and death. No specific treatment is available for the management of HE-associated neurological damage. This study aimed to evaluate the effect of dextromethorphan (DXM) on oxidative stress and disturbed locomotor activity in an animal model of HE.
MATERIAL AND METHODS
In the current study, BALB/c mice received acetaminophen (APAP; 1000 mg/kg, intraperitoneally [IP]). Dextromethorphan (0.5, 1, 5, 10 mg/kg, subcutaneously [SC]) was injected in three doses (every 6 h), starting two hours after acetaminophen. Animals' locomotor activity, brain and plasma ammonia levels, as well as biomarkers of oxidative stress and inflammatory cytokines in the brain tissue, were assessed 24 hours after acetaminophen injection.
RESULTS
It was found that APAP administration was significantly associated with liver damage and increased plasma biomarkers of liver injury. Ammonia levels in plasma and brain tissue of APAP-treated mice also increased significantly. There was also a significant difference in motor activity between the control and APAP-treated animals. The acute liver injury also increased the brain level of pro-inflammatory cytokines (tumor necrosis factor a [TNF-a], interleukin 6 [IL-6], and interleukin 1b [IL-1b]). It was found that DXM could significantly improve the motor activity of animals in all doses and decrease the biomarkers of inflammation and oxidative stress in the brain tissue of animals with hyperammonemia.
CONCLUSIONS
The effect of dextromethorphan on oxidative stress and inflammation seems to be a major mechanism for its neuroprotective properties in HE. Based on these data DXM could be applied as an effective pharmacological option against HE-associated brain injury.
PubMed: 36685267
DOI: 10.5114/ceh.2022.118299 -
Biomedicines Jan 2023Psychosis is known as a broad term of symptoms that cause serious disorganization of behavior, thinking, and perception of reality. One of the medicines that recently... (Review)
Review
Psychosis is known as a broad term of symptoms that cause serious disorganization of behavior, thinking, and perception of reality. One of the medicines that recently gained much attention in terms of its psychotic potential is dextromethorphan (DXM). DXM, a widely used antitussive drug, is a commonly abused drug because of its euphoric, hallucinogenic, and dissociative properties. To date, DXM is a legally marketed cough suppressant that is neither a controlled substance nor a regulated chemical under the Controlled Substances Act. The management of DXM-related psychosis is dependent on the type of psychotic symptoms. Atypical neuroleptics (i.e., olanzapine, risperidone, quetiapine) and typical haloperidol have been used in symptomatic treatment due to their efficacy, especially in positive symptoms (hallucinations and delusions). These agents are also recognized as the preferred option in the symptomatic treatment of DXM-related psychosis due to their better efficacy and safety profile than typical haloperidol in the short-term course. The focus of the present review concerns the current stage of knowledge about DXM psychotic potency as well as the management of DXM-related psychoses with a special emphasis on atypical antipsychotic drugs (i.e., olanzapine, risperidone, quetiapine, and haloperidol).
PubMed: 36672631
DOI: 10.3390/biomedicines11010123 -
IBRO Neuroscience Reports Jun 2023Alzheimer's disease (AD) is the most common cause of dementia worldwide. Because Alzheimer's disease has no known treatment, sufferers and their caregivers must... (Review)
Review
Alzheimer's disease (AD) is the most common cause of dementia worldwide. Because Alzheimer's disease has no known treatment, sufferers and their caregivers must concentrate on symptom management. Astrocytes and microglia are now known to play distinct physiological roles in synaptic function, the blood-brain barrier, and neurovascular coupling. Consequently, the search for drugs that can slow the degenerative process in dementia sufferers continues because existing drugs are designed to alleviate the symptoms of Alzheimer's disease. Drugs that address pathological changes without interfering with the normal function of glia, such as eliminating amyloid-beta deposits, are prospective treatments for neuroinflammatory illnesses. Because neuron-astrocytes-microglia interactions are so complex, developing effective, preventive, and therapeutic medications for AD will necessitate novel methodologies and strategic targets. This review focused on existing medications used in treating AD amongst which include Donepezil, Choline Alphoscerate, Galantamine, Dextromethorphan, palmitoylethanolamide, citalopram, resveratrol, and solanezumab. This review summarizes the effects of these drugs on neurons, astrocytes, and microglia interactions based on their pharmacokinetic properties, mechanism of action, dosing, and clinical presentations.
PubMed: 36593897
DOI: 10.1016/j.ibneur.2022.11.005 -
Frontiers in Pharmacology 2022Community pharmacists are uniquely positioned to identify and address the issue of misuse and abuse of over-the-counter (OTC) medicines. To date, no study has explored...
Community pharmacists are uniquely positioned to identify and address the issue of misuse and abuse of over-the-counter (OTC) medicines. To date, no study has explored the Saudi community pharmacists' views and experiences regarding aspects of OTC medicines' misuse and abuse. To explore the views and experiences of the Saudi community pharmacists towards OTC medicines misuse and abuse. Furthermore, we aimed to identify frequently misused and abused medicines, the reasons and contributing factors, the role of pharmacists, and potential risk-mitigating strategies. Semi-structured interviews were conducted with a convenient sample of sixteen community pharmacists recruited from community pharmacies across the AL-Baha region, Saudi Arabia. Interviews were conducted using a pilot-tested interview guide in the Arabic language. All interviews were audio-recorded, transcribed verbatim, translated from Arabic into English, and then thematically analysed. Analysis of interviews generated five main themes, including the commonly misused and abused OTC medicines, reasons and factors contributing to misuse and abuse of OTC medicines, pharmacists' interventions to manage misuse and abuse, challenges and barriers to pharmacists' interventions in misuse and abuse issues; and potential strategies to reduce the risk of OTC medicines misuse and abuse and improve pharmacists' practice. Sedative antihistamines, cough products containing dextromethorphan, codeine-based analgesics, and non-codeine-based analgesics were commonly misused and abused OTC medicines. Managing ongoing medical conditions was the main reason for misusing OTC analgesics while recreational use and inducing sleep were the common reasons for abuse. Several factors contributing to misuse and abuse were reported, including unprofessional advice sought from other people, lack of awareness about medicines, and commercial advertisement of OTC products. Community pharmacists identified misuse and abuse among customers by judging their behaviours and attitudes and using structured questioning techniques. Counselling customers on the appropriate use of medicines, providing safe alternatives, and refusing to sell products were among the commonly used actions of pharmacists to address misuse/abuse. Pharmacists proposed several strategies to reduce the risk of OTC medicines misuse/abuse but believed that rescheduling OTC medicines with abuse potential to prescription-only medicine was the best option. Community pharmacists believed that the misuse and abuse of OTC medicines amongst pharmacy customers was common. A multidimensional strategy consisting of upskilling community pharmacists, a comprehensive review of OTC medicines sale regulations, and patient education to limit the risks of OTC medicines misuse/abuse is required.
PubMed: 36518676
DOI: 10.3389/fphar.2022.997342