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Clinical Pharmacokinetics Aug 2015Tramadol hydrochloride is used worldwide as an analgesic drug with a unique dual function. The metabolic enzymes cytochrome P450 (CYP) 3A4, CYP2B6, and CYP2D6 and the... (Review)
Review
BACKGROUND AND OBJECTIVE
Tramadol hydrochloride is used worldwide as an analgesic drug with a unique dual function. The metabolic enzymes cytochrome P450 (CYP) 3A4, CYP2B6, and CYP2D6 and the various transporters [adenosine triphosphate-binding cassette B1/multidrug resistance 1/P-glycoprotein, organic cation transporter 1, serotonin transporter (SERT), norepinephrine transporter (NET)] and receptor genes (opioid receptor μ 1 gene) give possible genetic differences that might affect the pharmacokinetics and/or pharmacodynamics of tramadol. Therefore, the aim of this review is to present a systematic walkthrough of all possible genetic factors involved in the pharmacology of tramadol.
METHOD
A systematic literature search was conducted in PubMed and EMBASE involving all metabolic enzymes, drug transporters and receptors, as well as SERT and NET that are involved in the pharmacokinetics and pharmacodynamics of tramadol. An additional search on population pharmacokinetics with genetic factors as covariates was performed separately.
RESULTS
A total of 56 studies (45 cohort and case-control studies, three case reports, six in vitro studies, and two animal studies) were included.
CONCLUSION
In this systematic review, the current knowledge on all possible genetic factors that might influence the metabolism or clinical efficacy of tramadol has been collected and summarized. Only the effect of CYP2D6 polymorphisms on the metabolism of tramadol and the consequent effect on pain relief has been thoroughly studied and sufficiently established as clinically relevant.
Topics: Analgesics, Opioid; Animals; Biological Availability; Case-Control Studies; Clinical Studies as Topic; Cohort Studies; Cytochrome P-450 CYP2D6; Humans; Pain; Pharmacogenetics; Tramadol
PubMed: 25910878
DOI: 10.1007/s40262-015-0268-0 -
Phytomedicine : International Journal... Jul 2019Artemisinin was isolated and identified in 1972, which was the starting point for a new era in antimalarial drug therapy. Furthermore, numerous studies have demonstrated...
BACKGROUND
Artemisinin was isolated and identified in 1972, which was the starting point for a new era in antimalarial drug therapy. Furthermore, numerous studies have demonstrated that artemisinin and its derivatives exhibit considerable anticancer activity both in vitro, in vivo, and even in clinical Phase I/II trials. P-glycoprotein (P-gp) mediated multi-drug resistance (MDR) is one of the most serious causes of chemotherapy failure in cancer treatment. Interestingly, many artemisinin derivatives exhibit excellent ability to overcome P-gp mediated MDR and even show collateral sensitivity against MDR cancer cells. Furthermore, some artemisinin derivatives show P-gp-mediated MDR reversal activity. Therefore, the interaction between P-gp and artemisinin derivatives is important to develop novel combination treatment protocols with artemisinin derivatives and established anticancer drugs that are P-gp substrates.
PURPOSE
This systematic review provides an updated overview on the interaction between artemisinin derivatives and P-gp and the effect of artemisinin derivatives on the P-gp expression level.
RESULTS
Artemisinin derivatives exhibit multi-specific interactions with P-gp. The currently used artemisinin derivatives are not transported by P-gp. However, some of novel synthetized artemisinin derivatives exhibit P-gp substrate properties. Furthermore, many artemisinin derivatives act as P-gp inhibitors, which exhibit the potential to reverse MDR towards clinically used anticancer drugs.
CONCLUSION
Therefore, studies on the interaction between artemisinin derivatives and P-gp provide important information for the development of novel anti-cancer artemisinin derivatives to reverse P-gp mediated MDR and for the design of rational artemisinin-based combination therapies against cancer.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Artemisinins; Drug Resistance, Multiple; Humans; Neoplasms
PubMed: 31301971
DOI: 10.1016/j.phymed.2019.152998 -
Clinical Pharmacology and Therapeutics Jul 2023The P-glycoprotein efflux pump, encoded by the ABCB1 gene, has been shown to alter concentrations of various antidepressants in the brain. In this study, we conducted a... (Meta-Analysis)
Meta-Analysis Review
The P-glycoprotein efflux pump, encoded by the ABCB1 gene, has been shown to alter concentrations of various antidepressants in the brain. In this study, we conducted a systematic review and meta-analysis to investigate the association between six ABCB1 single-nucleotide polymorphisms (SNPs; rs1045642, rs2032582, rs1128503, rs2032583, rs2235015, and rs2235040) and antidepressant treatment outcomes in individuals with major depressive disorder (MDD), including new data from the Canadian Biomarker and Integration Network for Depression (CAN-BIND-1) cohort. For the CAN-BIND-1 sample, we applied regression models to investigate the association between ABCB1 SNPs and antidepressant treatment response, remission, tolerability, and antidepressant serum levels. For the meta-analysis, we systematically summarized pharmacogenetic evidence of the association between ABCB1 SNPs and antidepressant treatment outcomes. Studies were included in the meta-analysis if they investigated at least one ABCB1 SNP in individuals with MDD treated with at least one antidepressant. We did not find a significant association between ABCB1 SNPs and antidepressant treatment outcomes in the CAN-BIND-1 sample. A total of 39 studies were included in the systematic review. In the meta-analysis, we observed a significant association between rs1128503 and treatment response (T vs. C-allele, odds ratio = 1.30, 95% confidence interval = 1.15-1.48, P value (adjusted) = 0.024, n = 2,526). We did not find associations among the six SNPs and treatment remission nor tolerability. Our findings provide limited evidence for an association between common ABCB1 SNPs and antidepressant outcomes, which do not support the implementation of ABCB1 genotyping to inform antidepressant treatment at this time. Future research, especially on rs1128503, is recommended.
Topics: Humans; Depressive Disorder, Major; Canada; Antidepressive Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biomarkers; Polymorphism, Single Nucleotide; Genotype; ATP Binding Cassette Transporter, Subfamily B
PubMed: 36681895
DOI: 10.1002/cpt.2854 -
Regulation of gut microbiome by ketogenic diet in neurodegenerative diseases: A molecular crosstalk.Frontiers in Aging Neuroscience 2022The gut taxonomical profile is one of the contributory factors in maintaining homeostasis within the central nervous system (CNS). Of late, the efficacy of diet as a...
The gut taxonomical profile is one of the contributory factors in maintaining homeostasis within the central nervous system (CNS). Of late, the efficacy of diet as a target of treatment, and how various dietary interventions may modulate gut microbiota differently have been an area of focus in research. The role of ketogenic diet (KD) in particular has been well-established in other diseases like intractable epilepsy due to its postulated effects on gut microbiome modulation, resulting in neuronal stability and prevention of epileptogenesis. Therefore, this systematic review aimed to critically evaluate the current available literature investigating the interplay between the three distinct entities: ketogenic diet, neurodegeneration, and gut microbiota, which may serve as a focus guide for future neurodegenerative diseases (ND) therapeutic research. A comprehensive literature search was performed on three databases; PubMed, Scopus, and Ovid Medline. A total of 12 articles were selected for critical appraisal, after subjecting to the inclusion and exclusion criteria in this study. The selected articles revealed that the hopes of KD as a treatment modality for ND are being ventured into as these individuals are said to acquire gut dysbiosis, primarily through increased colonization of phyla and . Although positive effects including restoration of healthy gut microbes such as sp., improvement in cognitive functioning and decline in neuro-inflammatory markers were noted, this systematic review also depicted conflicting results such as decrease in alpha and beta species diversity as well as diminution of healthy gut commensals such as . In addition, positive neuromodulation were also observed, notably an increase in cerebral blood perfusion to ventromedial hippocampal region increased expression of eNOS and clearance of amyloid-beta proteins across the blood-brain-barrier expression of p-glycoprotein. Neuroprotective mechanisms of ketogenic diet also included downregulation of mTOR expression, to prevention acceleration of pathological diseases such as Alzheimer's. Thus due to this conflicting/contrasting results demonstrated by ketogenic diet, such as a decline in gut species richness, diminution in beneficial microbes and decline cognition unless delivered in an intermittent fasting pattern, further studies may still be required before prior recommendation of a ketogenic diet therapeutic regime in ND patients.
PubMed: 36313018
DOI: 10.3389/fnagi.2022.1015837 -
Seminars in Arthritis and Rheumatism Feb 2023To identify reports of colchicine-induced neuropathy and myopathy and ascertain risk factors associated with this toxicity at commonly used doses.
OBJECTIVE
To identify reports of colchicine-induced neuropathy and myopathy and ascertain risk factors associated with this toxicity at commonly used doses.
METHODS
A systematic review of case reports was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA methodology). PubMed and EMBASE were searched through October 2021 for case reports of neuropathy and/or myopathy associated with the use of colchicine at therapeutic doses.
RESULTS
A total of 143 cases of neuromyopathy from 99 articles were identified as having a "definite" or "probable" association with colchicine usage, as assessed by the Naranjo algorithm. Most of these cases presented with features of both neuropathy and myopathy (n=72, 51%) but symptoms of myopathy were predominant. The mean total daily dose was 1.25±0.60 mg and 48% had been taking colchicine for more than 12 months before presenting with neuromyopathy. A total of 117 (82%) of all reports had either a significant co-morbidity or possible colchicine drug-drug interaction, while 57 (40%) had both risk factors. A total of 26 cases (18%) had no significant risk factor but only 15 of these reports contained complete descriptions of the patient's co-morbidities and co-medications. Cessation of colchicine generally led to complete resolution of symptoms in 70% of cases within a median of 21 days. There were 3 deaths reported which were due to multi-organ failure despite cessation of colchicine and medical management. Colchicine was restarted at reduced doses in 15 cases and 73% had no symptom recurrence.
CONCLUSION
Neuromyopathy is an uncommon but reported adverse effect of colchicine. Cases generally present with proximal myopathy symptoms. Cases of colchicine neuromyopathy are largely reported in patients on commonly used doses. Renal and hepatic dysfunction and medications that inhibit cytochrome P450 3A4 isozyme (CYP3A4) and P-glycoprotein (P-gp) appear to be the most significant risk factors. Fortunately, cessation of colchicine generally leads to complete resolution of symptoms. Recommencement of colchicine at reduced doses appeared to be usually safe.
Topics: Humans; Colchicine; Neuromuscular Diseases; Muscular Diseases; Peripheral Nervous System Diseases; Risk Factors
PubMed: 36512928
DOI: 10.1016/j.semarthrit.2022.152150 -
Pharmacotherapy Apr 2022Colchicine and statins are frequently co-prescribed for prevention and treatment of cardiovascular diseases, auto-inflammatory diseases, and gout. Both are substrates... (Review)
Review
Colchicine and statins are frequently co-prescribed for prevention and treatment of cardiovascular diseases, auto-inflammatory diseases, and gout. Both are substrates and inhibitors of the cytochrome P-450 (CYP) 3A4 isozyme and P-glycoprotein so that taken together, they represent a clinically significant interaction. Data suggest the interaction may be associated with potentially life-threatening myopathies and rhabdomyolysis. The purposes of this systematic review (SR) were to gather and appraise evidence surrounding the statin-colchicine drug interaction and discuss related risk-mitigation strategies. An electronic literature search was performed. Twenty-one articles met the protocol to be included in the qualitative analysis: 18 case reports/series, 2 retrospective observational cohort studies, and 1 retrospective case-control study. Thirty-eight patients developed an adverse drug event (ADE) receiving statin-colchicine combination therapy; 25 (66%) patients developed myopathy; 10 (26%) patients developed rhabdomyolysis, and three (8%) patients developed neuromyopathy. Over 70% of patients developed ADEs on simvastatin or atorvastatin, and 80% of studies reported moderate-to-high intensity statins. Colchicine dosing varied but ranged between 0.5 to 1.5 mg daily. Sixty-two percent of patients in the case reports/series had comorbid renal disease. Seven studies (33% of all included studies) reported patients taking concomitant interacting medications at the CYP3A4 and/or P-glycoprotein efflux pump. Seventeen studies (81% of all included studies) reported ADEs leading to hospitalization. A multivariate analysis from one case-control study identified risk factors prognosticating myopathy ADEs in patients taking statin-colchicine therapy: comorbid renal disease and/or cirrhosis, colchicine doses 1.2 mg daily or greater, and concomitant interacting medications. Clinicians must be cognizant that the statin-colchicine drug interaction may lead to patient harm and thus should employ risk-mitigation strategies for statin-associated muscle symptoms. Future studies are warranted to validate clinically relevant risk factors that are strongly associated with the complications owing to the statin-colchicine drug interaction.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Case-Control Studies; Colchicine; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Muscular Diseases; Retrospective Studies; Rhabdomyolysis
PubMed: 35175631
DOI: 10.1002/phar.2674 -
Cardiovascular Drugs and Therapy Aug 2023Non-vitamin K antagonist oral anticoagulants (NOACs) are excreted by P-glycoprotein (P-gp) and some are metabolized by CYP450 enzymes such as CYP3A4. Although fewer drug... (Meta-Analysis)
Meta-Analysis Review
Non-vitamin K Antagonist Oral Anticoagulants (NOACs) Versus Warfarin in Patients with Atrial Fibrillation Using P-gp and/or CYP450-Interacting Drugs: a Systematic Review and Meta-analysis.
PURPOSE
Non-vitamin K antagonist oral anticoagulants (NOACs) are excreted by P-glycoprotein (P-gp) and some are metabolized by CYP450 enzymes such as CYP3A4. Although fewer drug interactions are present with NOACs, it is unclear whether NOACs should also be preferred over vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) using pharmacokinetically interacting drugs. Therefore, the benefit-risk profile of NOACs versus VKAs was investigated in AF patients treated with P-gp and/or CYP450-interacting drugs.
METHODS
Using PubMed and Embase, randomized controlled trials and observational studies on the effectiveness and safety of NOACs versus VKAs in AF patients using P-gp and/or CYP450-interacting drugs were included. A meta-analysis was performed, calculating relative risks (RR) and 95% confidence intervals (CI) with the Mantel-Haenszel method.
RESULTS
Twelve studies were included, investigating 10,793 NOAC and 10,096 VKA users treated with P-gp/CYP3A4 inhibitors, whereas no studies on P-gp and/or CYP450-inducing drugs were identified. Compared to VKAs, NOACs were associated with a borderline non-significantly lower stroke or systemic embolism (stroke/SE) risk (RR 0.85, 95%CI (0.72-1.01)), significantly lower intracranial bleeding (RR 0.47, 95%CI (0.34-0.65)) and all-cause mortality risks (RR 0.87, 95%CI (0.79-0.95), but significantly higher gastrointestinal bleeding risk (RR 1.74, 95%CI (1.06-2.86)). Among AF patients using amiodarone, NOACs were associated with significantly lower stroke/SE (RR 0.71, 95%CI (0.54-0.93)) and intracranial bleeding risks (RR 0.51, 95%CI (0.29-0.88)), but significantly higher gastrointestinal bleeding risk (RR 2.15, 95%CI (1.24-3.72)) than VKAs.
CONCLUSION
The benefit-risk profile of NOACs compared to VKAs was preserved in AF patients using P-gp/CYP3A4 inhibitors, including amiodarone.
Topics: Humans; Warfarin; Anticoagulants; Atrial Fibrillation; ATP Binding Cassette Transporter, Subfamily B, Member 1; Administration, Oral; Cytochrome P-450 CYP3A Inhibitors; Stroke; Intracranial Hemorrhages; Gastrointestinal Hemorrhage; Embolism; Amiodarone
PubMed: 34637052
DOI: 10.1007/s10557-021-07279-8 -
Research and Practice in Thrombosis and... Mar 2023Direct oral anticoagulants (DOACs) are widely used in patients with atrial fibrillation and venous thromboembolism. However, DOACs have important potential drug-drug... (Review)
Review
BACKGROUND
Direct oral anticoagulants (DOACs) are widely used in patients with atrial fibrillation and venous thromboembolism. However, DOACs have important potential drug-drug interactions (DDIs) with several classes of drugs. In particular, antiepileptic (AE) drugs may induce cytochrome P450 3A4 or P-glycoprotein. Co-administration of DOACs and AE drugs may result in lower DOAC drug levels and reduced DOAC efficacy. However, the clinical significance of such DDIs is uncertain.
OBJECTIVES
The aim of this systematic review was to generate an updated review of these DDIs and their clinical relevance, given the rapidly evolving knowledge relating to DOAC and AE DDIs.
METHODS
We searched the MEDLINE and Embase databases for studies reporting clinical adverse outcomes (thrombotic events, bleeding events, and all-cause mortality) in patients concomitantly taking DOACs and AE drugs.
RESULTS
We retrieved 874 studies of which 15 were deemed eligible for this review, including 4 congress abstracts, 3 case reports, 2 letters to the editor, 5 retrospective cohorts, and 1 prospective cohort study. No randomized clinical trials were found. Most of the included studies reported thrombotic events, 3 studies reported major bleeding, and one study reported all-cause mortality associated with DOAC and AE drug administration. Substantial differences in the study designs did not allow for a meta-analysis to be performed.
CONCLUSION
The current literature assessing these adverse clinical outcomes from DOAC and AE drug co-administration is limited. Although the available data point to a possible increased risk of thrombotic events, they are insufficient to draw definitive conclusions. Well-designed clinical studies are of utmost importance.
PubMed: 37122531
DOI: 10.1016/j.rpth.2023.100137 -
Oxidative Medicine and Cellular... 2016Cancer is a leading cause of death worldwide. We aim to provide a systematic review about the roles of reactive oxygen species (ROS) in anticancer therapy with Salvia... (Review)
Review
Cancer is a leading cause of death worldwide. We aim to provide a systematic review about the roles of reactive oxygen species (ROS) in anticancer therapy with Salvia miltiorrhiza Bunge (Danshen). Danshen, including its lipophilic and hydrophilic constituents, is potentially beneficial for treating various cancers. The mechanisms of ROS-related anticancer effects of Danshen vary depending on the specific type of cancer cells involved. Danshen may enhance TNF-α-induced apoptosis, upregulate caspase-3, caspase-8, caspase-9, endoplasmic reticulum stress, P21, P53, Bax/Bcl-2, DR5, and AMP-activated protein kinase, or activate the p38/JNK, mitogen-activated protein kinase, and FasL signaling pathways. Conversely, Danshen may downregulate human telomerase reverse transcriptase mRNA, telomerase, survivin, vascular endothelial growth factor/vascular endothelial growth factor receptor 2, CD31, NF-κB, Erk1/2, matrix metalloproteinases, microtubule assembly, and receptor tyrosine kinases including epidermal growth factor receptors, HER2, and P-glycoprotein and inhibit the PI3K/Akt/mTOR or estrogen receptor signaling pathways. Therefore, Danshen may inhibit cancer cells proliferation through antioxidation on tumor initiation and induce apoptosis or autophagy through ROS generation on tumor progression, tumor promotion, and tumor metastasis. Based on the available evidence regarding its anticancer properties, this review provides new insights for further anticancer research or clinical trials with Danshen.
Topics: Animals; Antineoplastic Agents; Drugs, Chinese Herbal; Humans; Hydrophobic and Hydrophilic Interactions; Neoplasms; Reactive Oxygen Species; Salvia miltiorrhiza
PubMed: 27579153
DOI: 10.1155/2016/5293284 -
Cardiovascular Drugs and Therapy Oct 2019To study whether polypharmacy or drug-drug interactions have differential effect on safety and efficacy in patients treated with direct oral anticoagulants (DOACs)... (Meta-Analysis)
Meta-Analysis
PURPOSE
To study whether polypharmacy or drug-drug interactions have differential effect on safety and efficacy in patients treated with direct oral anticoagulants (DOACs) versus warfarin.
METHODS
We performed a systematic review and meta-analysis of studies that randomized patients with atrial fibrillation to DOACs or warfarin stratified by the number of concomitant drugs. Outcomes included stroke or systemic embolism (SE), all-cause mortality, major bleeding, and intracranial hemorrhage. Risk ratios (RR) were calculated and Mantel-Haenszel random effects were applied.
RESULTS
Two high-quality studies were eligible, including 32,465 participants who received apixaban, rivaroxaban, or warfarin, with a median follow-up of 1.9 years. Of participants, 29% used < 5 drugs, 55% used 5-9 drugs, and 16% used ≥ 10 drugs. Drugs interacting with DOACs (P-glycoprotein/CYP3A4) were used by 6460 (20%) of patients. Patients with higher number of drugs (0-4 vs 5-9 vs ≥ 10) had higher rates of mortality (5.8%, 7.9%, 10.0%) and major bleeding (3.4%, 4.8%, 7.7%). Comparative efficacy or safety of DOACs versus warfarin was not affected by polypharmacy status or P-glycoprotein/CYP3A4 inhibitor use. However, the presence of polypharmacy (p = 0.001) or glycoprotein/CYP3A4-modulating drugs (p = 0.03) was correlated with increased risk of major bleeding when compared with warfarin. Overall, DOAC use was associated with a lower risk of stroke/SE (RR, 0.84; 95%CI, 0.74-0.94), all-cause mortality (RR, 0.91; 95%CI, 0.84-0.98), and intracranial hemorrhage (RR, 0.51; 95%CI, 0.38-0.70) compared with warfarin.
CONCLUSIONS
DOACs were more effective than warfarin, and at least as safe. Polypharmacy was associated with adverse outcomes and attenuated the advantage in risk of major bleeding among rivaroxaban users, particularly in the presence of P-glycoprotein/CYP3A4-modulating drugs.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Female; Hemorrhage; Humans; Male; Middle Aged; Polypharmacy; Risk Assessment; Risk Factors; Stroke; Treatment Outcome
PubMed: 31520256
DOI: 10.1007/s10557-019-06907-8