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Frontiers in Pharmacology 2024The recent exponential increase in legalized medical and recreational cannabis, development of medical cannabis programs, and production of unregulated over-the-counter...
BACKGROUND
The recent exponential increase in legalized medical and recreational cannabis, development of medical cannabis programs, and production of unregulated over-the-counter products (e.g., cannabidiol (CBD) oil, and delta-8-tetrahydrocannabinol (delta-8-THC)), has the potential to create unintended health consequences. The major cannabinoids (delta-9-tetrahydrocannabinol and cannabidiol) are metabolized by the same cytochrome P450 (CYP) enzymes that metabolize most prescription medications and xenobiotics (CYP3A4, CYP2C9, CYP2C19). As a result, we predict that there will be instances of drug-drug interactions and the potential for adverse outcomes, especially for prescription medications with a narrow therapeutic index.
METHODS
We conducted a systematic review of all years to 2023 to identify real world reports of documented cannabinoid interactions with prescription medications. We limited our search to a set list of medications with predicted narrow therapeutic indices that may produce unintended adverse drug reactions (ADRs). Our team screened 4,600 reports and selected 151 full-text articles to assess for inclusion and exclusion criteria.
RESULTS
Our investigation revealed 31 reports for which cannabinoids altered pharmacokinetics and/or produced adverse events. These reports involved 16 different Narrow Therapeutic Index (NTI) medications, under six drug classes, 889 individual subjects and 603 cannabis/cannabinoid users. Interactions between cannabis/cannabinoids and warfarin, valproate, tacrolimus, and sirolimus were the most widely reported and may pose the greatest risk to patients. Common ADRs included bleeding risk, altered mental status, difficulty inducing anesthesia, and gastrointestinal distress. Additionally, we identified 18 instances (58%) in which clinicians uncovered an unexpected serum level of the prescribed drug. The quality of pharmacokinetic evidence for each report was assessed using an internally developed ten-point scale.
CONCLUSION
Drug-drug interactions with cannabinoids are likely amongst prescription medications that use common CYP450 systems. Our findings highlight the need for healthcare providers and patients/care-givers to openly communicate about cannabis/cannabinoid use to prevent unintended adverse events. To that end, we have developed a free online tool (www.CANN-DIR.psu.edu) to help identify potential cannabinoid drug-drug interactions with prescription medications.
PubMed: 38868665
DOI: 10.3389/fphar.2024.1282831 -
The American Journal of Chinese Medicine Jun 2024has been widely used in traditional Chinese medicine for over 1700 years. This plant is known for its heat-clearing, damp-drying, insecticidal, and diuretic properties....
has been widely used in traditional Chinese medicine for over 1700 years. This plant is known for its heat-clearing, damp-drying, insecticidal, and diuretic properties. Phytochemical research has identified prenylated flavonoids as a unique class of bioactive compounds in . Recent pharmacological studies reveal that the prenylated flavonoids from (PFS) exhibit potent antitumor, anti-inflammatory, and glycolipid metabolism-regulating activities, offering significant therapeutic benefits for various diseases. However, the pharmacokinetics and toxicological profiles of PFS have not been systematically studied. Despite the diverse biological effects of prenylated flavonoid compounds against similar diseases, their structure-activity relationship is not yet fully understood. This review aims to summarize the latest findings regarding the chemical composition, drug metabolism, pharmacological properties, toxicity, and structure-activity relationship of prenylated flavonoids from . It seeks to highlight their potential for clinical use and suggest directions for future related studies.
PubMed: 38864547
DOI: 10.1142/S0192415X24500447 -
AAPS PharmSciTech Jun 2024Inclusion complexes require higher concentration of Beta cyclodextrins (βCD) resulting in increased formulation bulk, toxicity, and production costs. This systematic...
Inclusion complexes require higher concentration of Beta cyclodextrins (βCD) resulting in increased formulation bulk, toxicity, and production costs. This systematic review offers a comprehensive analysis using Quality by design (QbD) as a tool to predict potential applications of Polyvinylpyrrolidone (PVP) as a ternary substance to address issues of inclusion complexes. We reviewed 623 documents from 2013 to 2023 and Eighteen (18) research papers were selected for statistical and meta-analysis using the QbD concept to identify the most critical factors for selecting drugs and effect of PVP on inclusion complexes. The QbD analysis revealed that Molecular weight (MW), Partition coefficient (Log P), and the auxiliary substance ratio directly affected complexation efficiency (CE), thermodynamic stability in terms of Gibbs free energy (ΔG), and percent drug release. However, Stability constant (K) remained unaffected by any of these parameters. The results showed that low MW (250), median Log P (6), and a βCD: PVP ratio of 2:3 would result in higher CE, lower G, and improved drug release. PVP improves drug solubility, enhances delivery and therapeutic outcomes, and counteracts increased drug ionization due to decreased pH. In certain cases, its bulky nature and hydrogen bonding with CD molecules can form non-inclusion complexes. The findings of the study shows that there is potential molecular interaction between PVP and β-cyclodextrins, which possibly enhances the stability of inclusion complexes for drug with low MW and log P values less than 9. The systematic review shows a comprehensive methodology based on QbD offers a replicable template for future investigations into drug formulation research.
Topics: beta-Cyclodextrins; Chemistry, Pharmaceutical; Cyclodextrins; Drug Liberation; Excipients; Molecular Weight; Pilot Projects; Povidone; Solubility; Thermodynamics
PubMed: 38862663
DOI: 10.1208/s12249-024-02845-3 -
CNS & Neurological Disorders Drug... Jun 2024The association between carbamazepine (CBZ) metabolism and resistance in epilepsy and the genetic polymorphisms of CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480,...
BACKGROUND AND OBJECTIVE
The association between carbamazepine (CBZ) metabolism and resistance in epilepsy and the genetic polymorphisms of CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480, rs2740574, rs35599367, rs12721627, and rs28371759) has been the subject of previous investigations with controversial results. We conducted a systematic review to assess the potential link between these polymorphisms and CBZ metabolism and resistance.
METHODS
Identifying relevant studies, was carried out bay searching PubMed, Scopus, PharmGKB, EPIGAD, and PHARMAADME databases up until June 2023. The studies included in our analysis investigated the connection between CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480, rs2740574, rs35599367, rs12721627, and rs28371759) polymorphisms and CBZ metabolism and resistance.
RESULTS
This review included a total of 23 studies and more than 2177 epilepsy patients. As a result the CYP3A4 (rs12721627 and rs28371759) polymorphisms are associated with reduced catalytic activity, where the CYP3A4 (rs2740574) polymorphism is linked to lower levels of CBZ-diol and decreased activity. It's been found also that the CYP3A5 (rs776746) polymorphism influences the dose-adjusted plasma levels of CBZ.
CONCLUSION
Although these findings highlight the impact of genetic variations in the CYP3A4 and CYP3A5 genes on CBZ pharmacokinetics and pharmacodynamics, further studies across diverse populations are essential to enhance personalized epilepsy therapy in clinical settings.
PubMed: 38859787
DOI: 10.2174/0118715273298953240529100325 -
Naunyn-Schmiedeberg's Archives of... Jun 2024Due to the inevitable differences in physiological and/or genetic factors between genders, the possibility that differences in pharmacokinetics between genders may occur... (Review)
Review
Due to the inevitable differences in physiological and/or genetic factors between genders, the possibility that differences in pharmacokinetics between genders may occur when exposed to the same dose of the same drug is subject to reasonable inference and suspicion. Nevertheless, a significant number of medicines still rely on empirical usage and uniform clinical application without consideration of inter-individual diversity factors. In particular, in the pharmacokinetic diversity of medicines related to central nervous system (CNS) activity, consideration of gender factors and access to comparative analysis are very limited. The purpose of this study was to conduct an integrated analysis and review of differences in pharmacokinetics between genders that have not been specifically reported to date for medicines related to CNS effects, which are a group of drugs with relatively significant concerns about systemic side effects. This study was accessible through extensive data collection and analyzes using a web-based scientific literature search engine of pharmacokinetic results of CNS-related drugs performed on humans, taking gender into account. As a result, significant differences in pharmacokinetics between genders were identified for many drugs related to CNS. And most of the pharmacokinetic differences between genders suggested a higher in vivo exposure in females. This study suggests that consideration of gender factors cannot be ignored and will be an important point of interest in the precision medicine application of CNS-related medicines.
PubMed: 38850303
DOI: 10.1007/s00210-024-03190-9 -
Scientific Reports Jun 2024Accurate prognostic tools for mortality in patients with healthcare-associated pneumonia (HCAP) are needed to provide appropriate medical care, but the efficacy for... (Meta-Analysis)
Meta-Analysis
Accurate prognostic tools for mortality in patients with healthcare-associated pneumonia (HCAP) are needed to provide appropriate medical care, but the efficacy for mortality prediction of tools like PSI, A-DROP, I-ROAD, and CURB-65, widely used for predicting mortality in community-acquired and hospital-acquired pneumonia cases, remains controversial. In this study, we conducted a systematic review and meta-analysis using PubMed, Cochrane Library (trials), and Ichushi web database (accessed on August 22, 2022). We identified articles evaluating either PSI, A-DROP, I-ROAD, or CURB-65 and the mortality outcome in patients with HCAP, and calculated the pooled sensitivities, specificities, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the summary area under the curves (AUCs) for mortality prediction. Additionally, the differences in predicting prognosis among these four assessment tools were evaluated using overall AUCs pooled from AUC values reported in included studies. Eventually, 21 articles were included and these quality assessments were evaluated by QUADAS-2. Using a cut-off value of moderate in patients with HCAP, the range of pooled sensitivity, specificity, PLR, NLR, and DOR were found to be 0.91-0.97, 0.15-0.44, 1.14-1.66, 0.18-0.33, and 3.86-9.32, respectively. Upon using a cut-off value of severe in those patients, the range of pooled sensitivity, specificity, PLR, NLR, and DOR were 0.63-0.70, 0.54-0.66, 1.50-2.03, 0.47-0.58, and 2.66-4.32, respectively. Overall AUCs were 0.70 (0.68-0.72), 0.70 (0.63-0.76), 0.68 (0.64-0.73), and 0.67 (0.63-0.71), respectively, for PSI, A-DROP, I-ROAD, and CURB-65 (p = 0.66). In conclusion, these severity assessment tools do not have enough ability to predict mortality in HCAP patients. Furthermore, there are no significant differences in predictive performance among these four severity assessment tools.
Topics: Humans; Healthcare-Associated Pneumonia; Severity of Illness Index; Prognosis; Area Under Curve
PubMed: 38839837
DOI: 10.1038/s41598-024-63618-3 -
Drug Design, Development and Therapy 2024Several population pharmacokinetic (PPK) models of B cell lymphoma-2 (BCL-2) venetoclax (VEN) have been developed and published to characterize the influencing factors... (Review)
Review
Several population pharmacokinetic (PPK) models of B cell lymphoma-2 (BCL-2) venetoclax (VEN) have been developed and published to characterize the influencing factors of pharmacokinetics in hematologic malignancies. This review described PPK models of VEN examining the magnitude and types of covariate effects in PK parameters, as well as identified areas that require further investigation in order to facilitate their use. Currently, there are six analyses on PPK models of VEN summarized in this review. Most analyses described the pharmacokinetics of VEN with a two-compartment model and all covariates are categorical. The median estimated apparent clearance (CL/F) was 446 L/Day and apparent volume of distribution of the central compartment (V/F) was 114.5 L. The median IIV of CL/F reported was 39.5% and V/F was 46.7%. Most commonly, CYP3A inhibitors, OATP1B3 inhibitors and rituximab co-administration were found to be significant covariates on CL/F. In addition, sex and population were influential covariates on V/F. A detailed description of the characteristics of PPK models of VEN is provided in this review, as well as the effects of covariates on the PK parameters. For future development of the VEN PPK model, CYP3A inhibitors, rituximab co-administration, OATP1B1 transporter inhibitors, sex, population, and food might be considered. Further research and comprehensive investigations should be undertaken to explore reference ranges for therapeutic drug monitoring, define the potential role of patients with cerebrospinal fluid complications, and assess new or potential covariates. These endeavors will facilitate the development of personalized VEN therapy.
Topics: Humans; Hematologic Neoplasms; Sulfonamides; Bridged Bicyclo Compounds, Heterocyclic; Antineoplastic Agents; Models, Biological
PubMed: 38828021
DOI: 10.2147/DDDT.S458927 -
Therapeutic Advances in Medical Oncology 2024Compared with anti-infective drugs, immunosuppressants and other fields, the application of therapeutic drug monitoring (TDM) in oncology is somewhat limited. (Review)
Review
BACKGROUND
Compared with anti-infective drugs, immunosuppressants and other fields, the application of therapeutic drug monitoring (TDM) in oncology is somewhat limited.
OBJECTIVE
We aimed to provide a comprehensive understanding of TDM guidelines for antineoplastic drugs and to promote the development of individualized drug therapy in oncology.
DESIGN
This study type is a systematic review.
DATA SOURCES AND METHODS
This study was performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement. Databases including PubMed, Embase, the official websites of TDM-related associations and Chinese databases were comprehensively searched up to March 2023. Two investigators independently screened the literature and extracted data. The methodological and reporting quality was evaluated using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) and the Reporting Items for Practice Guidelines in Healthcare (RIGHT), respectively. Recommendations and quality evaluation results were presented by visual plots. This study was registered in PROSPERO (No. CRD42022325661).
RESULTS
A total of eight studies were included, with publication years ranging from 2014 to 2022. From the perspective of guideline development, two guidelines were developed using evidence-based methods. Among the included guidelines, four guidelines were for cytotoxic antineoplastic drugs, three for small molecule kinase inhibitors, and one for antineoplastic biosimilars. Currently available guidelines and clinical practice provided recommendations of individualized medication in oncology based on TDM, as well as influencing factors. With regard to methodological quality based on AGREE II, the average overall quality score was 55.21%. As for the reporting quality by RIGHT evaluation, the average reporting rate was 53.57%.
CONCLUSION
From the perspective of current guidelines, TDM in oncology is now being expanded from cytotoxic antineoplastic drugs to newer targeted treatments. Whereas, the types of antineoplastic drugs involved are still small, and there is still room for quality improvement. Furthermore, the reflected gaps warrant future studies into the exposure-response relationships and population pharmacokinetics models.
PubMed: 38812991
DOI: 10.1177/17588359241250130 -
Clinical Pharmacokinetics Jun 2024Managing drug-food interactions is essential for optimizing the effectiveness and safety profile of quinolones. Following PRISMA guidelines, we systematically reviewed... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVE
Managing drug-food interactions is essential for optimizing the effectiveness and safety profile of quinolones. Following PRISMA guidelines, we systematically reviewed the influence of dietary interventions on the bioavailability of 22 quinolones.
METHODS
All studies describing or investigating the impact of food, beverages, antacids, and mineral supplements on pharmacokinetic parameters or pharmacokinetic/pharmacodynamic indices of orally taken quinolones were considered for inclusion. We excluded reviews, in vitro and in silico studies, studies performed on animals, and those involving alcohol. We performed the search in Medline (via PubMed), Embase, and Cochrane Library, covering reports from database inception to December 2022. We used the following tools to assess the risk of bias: version 2 of the Cochrane risk-of-bias tool for parallel trials, the Cochrane risk-of-bias tool for cross-over studies, and the NIH quality assessment tool for before-after studies. We performed quantitative analyses for each quinolone if two or more food-effect studies with specified and comparable study designs were available. If meta-analyses were not applicable, we qualitatively summarized the results.
RESULTS
We included 109 studies from 101 reports. Meta-analyses were conducted for 12 antibiotics and qualitative synthesis was employed for the remaining drugs. Of the studies, 60.5% were open-label, cross-over, as recommended by FDA. We judged 46% of studies as having a high risk of bias and only 4% of having a low risk of bias. Among 19 quinolones with available food impact data, 14 (74%) had potentially clinically important interactions. For nalidixic acid, oxolinic acid, and tosufloxacin, food exerted a high positive impact on bioavailability (AUC or C increased by > 45%), whereas, for all the remaining drugs, postprandial absorption was lower. The most significant negative influence of food (AUC or C decreased by > 40%) occurred for delafloxacin capsules and norfloxacin, whereas the moderate influence (AUC or C decreased by 30-40%) occurred for nemonoxacin and rufloxacin. All 14 analysed quinolones showed a substantial reduction in bioavailability when co-administered with antacids and mineral supplements, except for calcium preparations. The impact of beverages was evaluated for 10 quinolones, with 50% experiencing significantly reduced absorption in the presence of milk (the highest negative impact for ciprofloxacin). Moreover, both ciprofloxacin and levofloxacin demonstrated compromised bioavailability when consumed with orange juice, particularly calcium-fortified.
DISCUSSION
Several factors may influence interactions, including the physicochemical characteristics of quinolones, the type of intervention, drug formulation, and the patient's health status. We assessed the quality of evidence as low due to the poor actuality of included studies, their methodological diversity, and uneven data availability for individual drugs.
Topics: Quinolones; Humans; Food-Drug Interactions; Biological Availability; Dietary Supplements; Anti-Bacterial Agents; Antacids; Diet; Administration, Oral
PubMed: 38807006
DOI: 10.1007/s40262-024-01377-0 -
Acta Neurologica Belgica May 2024Chronic subdural hematoma (CSDH) is a prevalent type of intracranial hemorrhage. Surgical interventions, such as Twist Drill Craniostomy and Burr Hole Craniostomy, are... (Review)
Review
BACKGROUND
Chronic subdural hematoma (CSDH) is a prevalent type of intracranial hemorrhage. Surgical interventions, such as Twist Drill Craniostomy and Burr Hole Craniostomy, are employed for its treatment. However, limited information exists regarding the impact of postoperative head position (supine vs. elevated) on clinical outcomes. We aim to assess whether patients' head position after surgery influences their prognosis.
METHOD
We conducted a PRISMA-compliant systematic review and meta-analysis. Our search encompassed PubMed, Cochrane CENTRAL, Scopus, Web of Science, and Embase databases to identify relevant published studies. Data were meticulously extracted, pooled using a fixed model, and reported as risk ratios (RR) with 95% confidence intervals (CI). Statistical analysis was performed using R and Stata MP v.17.
RESULTS
Five studies involving 284 patients were included in our meta-analysis. We focused on three primary clinical outcomes, comparing the supine and elevated header positions. Notably, there was no statistically significant difference between the supine and elevated positions in terms of recurrence rate (RR 0.77, 95% CI [0.44, 1.37]), second intervention for recurrence (RR 1.07, 95% CI [0.42, 2.78]) and postoperative complications (RR 1.16, 95% CI [0.70, 1.92]).
CONCLUSION
Current studies have proved no difference between supine and elevated bed header positions regarding recurrence rate, second intervention for recurrence, and postoperative complications. Future RCTs with long-term follow-ups are recommended.
PubMed: 38802719
DOI: 10.1007/s13760-024-02571-4