-
Journal of Clinical Psychopharmacology 2019In clozapine therapeutic drug monitoring (TDM) studies, Chinese reached the same concentrations using half the dosage Caucasians use. Defining clozapine poor...
PURPOSE/BACKGROUND
In clozapine therapeutic drug monitoring (TDM) studies, Chinese reached the same concentrations using half the dosage Caucasians use. Defining clozapine poor metabolizers (PMs) requires stratification by ethnicity, smoking, and sex.
METHODS/PROCEDURES
After sex and smoking stratification in 129 Chinese inpatients (mean, 8.8 TDM samples per patient), we explored the association between the total concentration-dose (C/D) ratio and CYP1A2 (*1C, *1F, and *7) and CYP2C19 alleles (*2 and *3). A systematic literature review identified 22 clozapine TDM prior studies (13 in Caucasians and 7 in East Asians).
FINDINGS/RESULTS
In our Chinese sample, the mean total clozapine C/D ratio (ng/mL per mg/d) was 1.96 for 22 male smokers, 2.07 for 5 female smokers, 2.47 for 36 male nonsmokers, and 2.95 for 66 female nonsmokers. CYP1A2 *1C had no significant effects, and CYP1A2 *1F had small effects. Five clozapine PMs (4%) needed low clozapine doses of 75 to 115 mg/d to get therapeutic concentrations. Using the same methodology in a published Italian sample, we found 5 PMs (3.3% of 152). In the systematic review, the clozapine C/D ratio (ng/mL per mg/d) was higher when comparing: (1) weighted mean values of 1.57 in 876 East Asians versus 1.07 in 1147 Caucasians and (2) ranks of 8 East Asians versus 13 Caucasian samples (P < 0.001).
IMPLICATIONS/CONCLUSIONS
Future TDM studies need to further explore the frequency of clozapine PMs after sex and smoking stratification in East Asian and Caucasian patients. Compared with Caucasians, East Asians appear to have a clinically relevant decrease in clozapine clearance.
Topics: Antipsychotic Agents; Asian People; Clozapine; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2C19; Drug Monitoring; Female; Humans; Male; Pilot Projects; Prevalence; Sex Factors; Smoking; White People
PubMed: 30811372
DOI: 10.1097/JCP.0000000000001018 -
Amino Acids Sep 2016The focus of this review is the effects of creatine supplementation with or without exercise on glucose metabolism. A comprehensive examination of the past 16 years of... (Review)
Review
The focus of this review is the effects of creatine supplementation with or without exercise on glucose metabolism. A comprehensive examination of the past 16 years of study within the field provided a distillation of key data. Both in animal and human studies, creatine supplementation together with exercise training demonstrated greater beneficial effects on glucose metabolism; creatine supplementation itself demonstrated positive results in only a few of the studies. In the animal studies, the effects of creatine supplementation on glucose metabolism were even more distinct, and caution is needed in extrapolating these data to different species, especially to humans. Regarding human studies, considering the samples characteristics, the findings cannot be extrapolated to patients who have poorer glycemic control, are older, are on a different pharmacological treatment (e.g., exogenous insulin therapy) or are physically inactive. Thus, creatine supplementation is a possible nutritional therapy adjuvant with hypoglycemic effects, particularly when used in conjunction with exercise.
Topics: Animals; Carbohydrate Metabolism; Creatine; Diabetes Mellitus, Type 2; Dietary Supplements; Glucose; Humans; Hypoglycemic Agents
PubMed: 27306768
DOI: 10.1007/s00726-016-2277-1 -
Medicine and Science in Sports and... Dec 2011Quercetin is a dietary flavonoid purported to improve human endurance exercise capacity. However, published findings are mixed. (Meta-Analysis)
Meta-Analysis Review
UNLABELLED
Quercetin is a dietary flavonoid purported to improve human endurance exercise capacity. However, published findings are mixed.
PURPOSE
The study's purpose was to perform a systematic review of the literature and meta-analysis to examine whether quercetin ingestion increases endurance exercise capacity.
METHODS
A search of the literature was conducted using the key words quercetin, performance, exercise, endurance, and aerobic capacity. Eleven studies were identified as meeting the inclusion criteria providing data on 254 human subjects. Across all studies, subject presupplementation VO(2max) ranged from 41 to 64 mL·kg(-1)·min(-1) (median = 46), and median treatment duration was 11 d with a median dosage of 1000 mg·d(-1). Effect sizes (ES) were calculated as the standardized mean difference, and meta-analyses were completed using a random-effects model.
RESULTS
The ES calculated for all studies combining VO(2max) and endurance performance measures indicates a significant effect favoring quercetin over placebo (ES = 0.15, P = 0.021, 95% confidence interval = 0.02-0.27), but the magnitude of effect is considered between trivial and small, equating to a ∼2% [corrected] improvement of quercetin over placebo. Using a subgroup meta-analysis comparing quercetin's effect on endurance exercise performance versus VO(2max), no significant difference was found (P = 0.69). Meta-regression of study ES relative to subjects' fitness level or plasma quercetin concentration achieved by supplementation was also not significant.
CONCLUSIONS
On average, quercetin provides a statistically significant benefit in human endurance exercise capacity (VO(2max) and endurance exercise performance), but the effect is between trivial and small. Experimental factors that explain the between-study variation remain to be elucidated.
Topics: Athletes; Athletic Performance; Dietary Supplements; Exercise; Female; Humans; Male; Oxygen Consumption; Physical Endurance; Quercetin
PubMed: 21606866
DOI: 10.1249/MSS.0b013e31822495a7 -
European Journal of Drug Metabolism and... Dec 2016Cyclosporine is an immunosuppressant with narrow therapeutic window, metabolized mainly by cytochrome P450 3A4 (CYP3A4) and minimally by cytochrome P450 3A5 (CYP3A5).... (Comparative Study)
Comparative Study Meta-Analysis Review
INTRODUCTION
Cyclosporine is an immunosuppressant with narrow therapeutic window, metabolized mainly by cytochrome P450 3A4 (CYP3A4) and minimally by cytochrome P450 3A5 (CYP3A5). Citrus juices such as grapefruit juice (GFJ), orange, lemon, pomelo and lime were known to interact with cyclosporine in several randomized controlled trials. The present review is a systematic compilation and quantitative synthesis on the changes of cyclosporine pharmacokinetics with concomitant citrus juice administration.
METHODS
Electronic databases were searched for randomized controlled trials evaluating the effect of any citrus juice on the pharmacokinetics of cyclosporine comparing with water or placebo in healthy volunteers using appropriate search strategies. Percent mean difference with standard error was used to assess the magnitude of difference in the following outcome measures: area under curve from time of drug administration to 24 h (AUC), area under curve from time of drug administration to infinity (AUC), maximum concentration (C ), time to achieve C (T ), elimination half-life (T ), clearance (CL), volume of distribution and frequency for adverse drug reactions following administration of cyclosporine. RevMan 5.3 software was used to assess heterogeneity (by I statistics), use random-effects model and generate pooled results and Forest plot.
RESULTS
A total of 57 studies were obtained with the search strategy, of which seven were found eligible to be included in the present review. The pooled percent mean difference [95 % CI] for GFJ in comparison to controls for AUC, AUC, C and T of cyclosporine was observed to be 53 [43, 64], 53 [45, 62], 24 [12, 36] and 19 [12, 26], respectively. Similarly, pomelo juice was found to significantly increase both AUC and C with the pooled percent mean difference [95 % CI] as 23 [13, 32] and 25 [1, 50], respectively but decrease T {-8 [-15, -1]} of cyclosporine. Orange juice did not alter any of the pharmacokinetic parameter of cyclosporine significantly.
CONCLUSION
Citrus juices especially GFJ and pomelo juice were found to significantly increase the plasma exposure of cyclosporine while orange juice did not exhibit any significant interaction with cyclosporine.
Topics: Biological Availability; Citrus; Citrus paradisi; Cyclosporine; Cytochrome P-450 CYP3A; Evidence-Based Medicine; Fruit and Vegetable Juices; Half-Life; Humans; Immunosuppressive Agents; Metabolic Clearance Rate; Randomized Controlled Trials as Topic
PubMed: 27278683
DOI: 10.1007/s13318-016-0351-4 -
Pharmacology & Therapeutics Jan 2014UDP-glucuronosyltransferases (UGT) catalyze the biotransformation of many endobiotics and xenobiotics, and are coded by polymorphic genes. However, knowledge about the... (Meta-Analysis)
Meta-Analysis Review
UDP-glucuronosyltransferases (UGT) catalyze the biotransformation of many endobiotics and xenobiotics, and are coded by polymorphic genes. However, knowledge about the effects of these polymorphisms is rarely used for the individualization of drug therapy. Here, we present a quantitative systematic review of clinical studies on the impact of UGT variants on drug metabolism to clarify the potential for genotype-adjusted therapy recommendations. Data on UGT polymorphisms and dose-related pharmacokinetic parameters in man were retrieved by a systematic search in public databases. Mean estimates of pharmacokinetic parameters were extracted for each group of carriers of UGT variants to assess their effect size. Pooled estimates and relative confidence bounds were computed with a random-effects meta-analytic approach whenever multiple studies on the same variant, ethnic group, and substrate were available. Information was retrieved on 30 polymorphic metabolic pathways involving 10 UGT enzymes. For irinotecan and mycophenolic acid a wealth of data was available for assessing the impact of genetic polymorphisms on pharmacokinetics under different dosages, between ethnicities, under comedication, and under toxicity. Evidence for effects of potential clinical relevance exists for 19 drugs, but the data are not sufficient to assess effect size with the precision required to issue dose recommendations. In conclusion, compared to other drug metabolizing enzymes much less systematic research has been conducted on the polymorphisms of UGT enzymes. However, there is evidence of the existence of large monogenetic functional polymorphisms affecting pharmacokinetics and suggesting a potential use of UGT polymorphisms for the individualization of drug therapy.
Topics: Analgesics; Anti-HIV Agents; Antihypertensive Agents; Antineoplastic Agents; Glucuronosyltransferase; Humans; Pharmaceutical Preparations; Pharmacokinetics; Polymorphism, Genetic; Psychotropic Drugs; Uridine Diphosphate
PubMed: 24076267
DOI: 10.1016/j.pharmthera.2013.09.002 -
Journal of Neuromuscular Diseases 2021Metabolic myopathies are a heterogenous group of muscle diseases typically characterized by exercise intolerance, myalgia and progressive muscle weakness. Effective...
BACKGROUND
Metabolic myopathies are a heterogenous group of muscle diseases typically characterized by exercise intolerance, myalgia and progressive muscle weakness. Effective treatments for some of these diseases are available, but while our understanding of the pathogenesis of metabolic myopathies related to glycogen storage, lipid metabolism and β-oxidation is well established, evidence linking treatments with the precise causative genetic defect is lacking.
OBJECTIVE
The objective of this study was to collate all published evidence on pharmacological therapies for the aforementioned metabolic myopathies and link this to the genetic mutation in a format amenable to databasing for further computational use in line with the principles of the "treatabolome" project.
METHODS
A systematic literature review was conducted to retrieve all levels of evidence examining the therapeutic efficacy of pharmacological treatments on metabolic myopathies related to glycogen storage and lipid metabolism. A key inclusion criterion was the availability of the genetic variant of the treated patients in order to link treatment outcome with the genetic defect.
RESULTS
Of the 1,085 articles initially identified, 268 full-text articles were assessed for eligibility, of which 87 were carried over into the final data extraction. The most studied metabolic myopathies were Pompe disease (45 articles), multiple acyl-CoA dehydrogenase deficiency related to mutations in the ETFDH gene (15 articles) and systemic primary carnitine deficiency (8 articles). The most studied therapeutic management strategies for these diseases were enzyme replacement therapy, riboflavin, and carnitine supplementation, respectively.
CONCLUSIONS
This systematic review provides evidence for treatments of metabolic myopathies linked with the genetic defect in a computationally accessible format suitable for databasing in the treatabolome system, which will enable clinicians to acquire evidence on appropriate therapeutic options for their patient at the time of diagnosis.
Topics: Glycogen; Glycogen Storage Disease Type II; Humans; Lipid Metabolism; Metabolism, Inborn Errors; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Muscle Weakness; Mutation
PubMed: 33720849
DOI: 10.3233/JND-200621 -
Journal of Controlled Release :... Jul 2019The idea of using extracellular vesicles (EVs) for targeted drug delivery was first introduced in 2011 and has since then gained increasing attention as promising new...
The idea of using extracellular vesicles (EVs) for targeted drug delivery was first introduced in 2011 and has since then gained increasing attention as promising new candidates in the field. Targeting EVs to areas of disease can be achieved through a complex process of designing and inserting a targeting ligand to the surface of the EVs. Although this can be obtained via chemical conjugation, the most important strategy has been to transfect or modulate the EV-producing cell to endow the EVs with the desired targeting capabilities. However, since EVs are harvested from biological sources, their composition is highly heterogeneous, which makes it difficult to control the purity and quality of the resulting EV-based drug delivery vehicles. In this review, we present a detailed account of EVs in targeted drug delivery based on a systematic literature search. We discuss the potential advantages of EVs compared to synthetic lipid-based nanocarriers, and the methodological and biological limitations associated with their use as targeted drug delivery vehicles.
Topics: Animals; Drug Delivery Systems; Extracellular Vesicles; Humans; Liposomes; Tissue Distribution
PubMed: 31175896
DOI: 10.1016/j.jconrel.2019.06.006 -
Molecules (Basel, Switzerland) May 2022Bile acids (BAs) are important steroidal molecules with a rapidly growing span of applications across a variety of fields such as supramolecular chemistry, pharmacy, and... (Review)
Review
Bile acids (BAs) are important steroidal molecules with a rapidly growing span of applications across a variety of fields such as supramolecular chemistry, pharmacy, and biomedicine. This work provides a systematic review on their transport processes within the enterohepatic circulation and related processes. The focus is laid on the description of specific or less-specific BA transport proteins and their localization. Initially, the reader is provided with essential information about BAs' properties, their systemic flow, metabolism, and functions. Later, the transport processes are described in detail and schematically illustrated, moving step by step from the liver via bile ducts to the gallbladder, small intestine, and colon; this description is accompanied by descriptions of major proteins known to be involved in BA transport. Spillage of BAs into systemic circulation and urine excretion are also discussed. Finally, the review also points out some of the less-studied areas of the enterohepatic circulation, which can be crucial for the development of BA-related drugs, prodrugs, and drug carrier systems.
Topics: Bile Acids and Salts; Bile Ducts; Carrier Proteins; Enterohepatic Circulation; Liver
PubMed: 35566302
DOI: 10.3390/molecules27092961 -
Phytotherapy Research : PTR May 2024It is suggested that supplementation with silymarin (SIL) has beneficial impacts on kidney and liver functions. This systematic review and dose-response meta-analysis... (Meta-Analysis)
Meta-Analysis Review
It is suggested that supplementation with silymarin (SIL) has beneficial impacts on kidney and liver functions. This systematic review and dose-response meta-analysis assessed the impact of SIL administration on certain hepatic, renal, and oxidative stress markers. A systematic search was conducted in various databases to identify relevant trials published until January 2023. Randomized controlled trials (RCTs) that evaluated the effects of SIL on kidney and liver markers were included. A random-effects model was used for the analysis and 41 RCTs were included. The pooled results indicated that SIL supplementation led to a significant reduction in serum levels of alkaline phosphatase, alanine transaminase, creatinine, and aspartate aminotransferase, along with a substantial elevation in serum glutathione in the SIL-treated group compared to their untreated counterparts. In addition, there was a nonsignificant decrease in serum levels of gamma-glutamyl transferase, malondialdehyde (MDA), total bilirubin, albumin (Alb), total antioxidant capacity, and blood urea nitrogen. Sub-group analyses revealed a considerable decline in MDA and Alb serum values among SIL-treated participants with liver disease in trials with a longer duration (≥12 weeks). These findings suggest that SIL may ameliorate certain liver markers with potential hepatoprotective effects, specifically with long-term and high-dose supplementation. However, its nephroprotective effects and impact on oxidative stress markers were not observed. Additional high-quality RCTs with longer durations are required to determine the clinical efficacy of SIL supplementation on renal and oxidative stress markers.
Topics: Silymarin; Humans; Kidney; Liver; Dietary Supplements; Oxidative Stress; Antioxidants; Randomized Controlled Trials as Topic; Dose-Response Relationship, Drug; Biomarkers
PubMed: 38475999
DOI: 10.1002/ptr.8173 -
Advances in Therapy Jan 2012Lipid profile is an important determinant of cardiovascular risk in type 2 diabetic patients. Available glucose-lowering agents can affect lipid levels. Dipeptidyl... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Lipid profile is an important determinant of cardiovascular risk in type 2 diabetic patients. Available glucose-lowering agents can affect lipid levels. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to reduce total cholesterol, but results are inconsistent across trials. The present metaanalysis was designed to assess the effect of DPP-4 inhibitors on blood lipids, verifying possible differences across compounds of this class.
METHODS
An extensive search of Medline and the Cochrane Library (any date up to December 31, 2010, restricted to randomized clinical trials, published in English) was performed for all trials containing, in any field, the words "sitagliptin," "vildagliptin," "saxagliptin," "alogliptin," "linagliptin," and/or "dutogliptin." Completed but unpublished trials were identified through a search of the ClinicalTrials.gov website, using the same keywords as above. Differences in the endpoint levels and absolute or percent variations of lipids were assessed. A metaregression was performed on the trials specified above to assess the effect of putative moderators on the effect of DPP-4 inhibitors on plasma lipids, considering all drugs together and each one separately.
RESULTS
Although the number of trials of appropriate size and duration was high (n=53), only a small fraction of those (n=17) reported data on endpoint total, high-density lipoprotein, and low-density lipoprotein cholesterol, and triglyceride. The difference-in-means for endpoint versus baseline total cholesterol in patients on DPP-4 inhibitors treatment was significantly higher in comparison with controls, meaning that treatment with DPP-4 inhibitors is associated with a significant reduction in total cholesterol (-0.18 [-0.29; -0.06] mmol/L (-7.0 [-11.2; -2.50] mg/dL); P=0.002).
CONCLUSIONS
This meta-analysis suggests a possible beneficial effect of DPP-4 inhibitors on cholesterol, which, although small, could contribute to the reduction of cardiovascular risk.
Topics: Cardiovascular Diseases; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Humans; Lipid Metabolism; Lipoproteins, HDL; Lipoproteins, LDL; Triglycerides
PubMed: 22215383
DOI: 10.1007/s12325-011-0088-z