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Advanced Drug Delivery Reviews 2020Vaccines are one of the most powerful technologies supporting public health. The adaptive immune response induced by immunization arises following appropriate activation...
Vaccines are one of the most powerful technologies supporting public health. The adaptive immune response induced by immunization arises following appropriate activation and differentiation of T and B cells in lymph nodes. Among many parameters impacting the resulting immune response, the presence of antigen and inflammatory cues for an appropriate temporal duration within the lymph nodes, and further within appropriate subcompartments of the lymph nodes- the right timing and location- play a critical role in shaping cellular and humoral immunity. Here we review recent advances in our understanding of how vaccine kinetics and biodistribution impact adaptive immunity, and the underlying immunological mechanisms that govern these responses. We discuss emerging approaches to engineer these properties for future vaccines, with a focus on subunit vaccines.
Topics: Adjuvants, Immunologic; B-Lymphocytes; Drug Carriers; Humans; Immunity, Humoral; Inflammation Mediators; Liposomes; Lymph Nodes; Nanoparticles; Plasmids; RNA, Messenger; T-Lymphocytes; Tissue Distribution; Vaccines
PubMed: 32598970
DOI: 10.1016/j.addr.2020.06.019 -
Reumatologia Clinica 2018To develop recommendations for the use of parenteral methotrexate (MTX) in rheumatic diseases, mainly rheumatoid arthritis, based on best evidence and experience.
OBJECTIVE
To develop recommendations for the use of parenteral methotrexate (MTX) in rheumatic diseases, mainly rheumatoid arthritis, based on best evidence and experience.
METHODS
A group of 21 experts on parenteral MTX use was selected. The coordinator formulated 13 questions about parenteral MTX (indications, efficacy, safety and cost-effectiveness). A systematic review was conducted to answer the questions. Using this information, inclusion and exclusion criteria were established, as were the search strategies (involving Medline, EMBASE and the Cochrane Library). Three different reviewers selected the articles. Evidence tables were created. Abstracts from the European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) were evaluated. Based on this evidence, the coordinator proposed preliminary recommendations that the experts discussed and voted in a nominal group meeting. The level of evidence and grade of recommendation were established using the Oxford Center for Evidence-Based Medicine and the level of agreement with the Delphi technique (2 rounds). Agreement was established if at least 80% of the experts voted yes (yes/no).
RESULTS
Most of the evidence involved rheumatoid arthritis. A total of 13 preliminary recommendations on the use of parenteral MTX were proposed; 11 of them were accepted. Two of the 13 were not voted and are commented on in the main text.
CONCLUSIONS
The manuscript aims to solve frequent questions and help in decision-making strategies when treating patients with parenteral MTX.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Biological Availability; Clinical Decision-Making; Dose-Response Relationship, Drug; Drug Administration Routes; Evidence-Based Medicine; Humans; Medication Adherence; Methotrexate; Patient Education as Topic; Practice Guidelines as Topic; Quality of Life; Randomized Controlled Trials as Topic; Rheumatic Diseases; Self Administration
PubMed: 28082032
DOI: 10.1016/j.reuma.2016.12.001 -
International Journal of Molecular... Apr 2021Chronic kidney disease (CKD) is an important global public health problem due to its high prevalence and morbidity. Although the treatment of nephrology patients has... (Meta-Analysis)
Meta-Analysis Review
Chronic kidney disease (CKD) is an important global public health problem due to its high prevalence and morbidity. Although the treatment of nephrology patients has changed considerably, ineffectiveness and side effects of medications represent a major issue. In an effort to elucidate the contribution of genetic variants located in several genes in the response to treatment of patients with CKD, we performed a systematic review and meta-analysis of all available pharmacogenetics studies. The association between genotype distribution and response to medication was examined using the dominant, recessive, and additive inheritance models. Subgroup analysis based on ethnicity was also performed. In total, 29 studies were included in the meta-analysis, which examined the association of 11 genes (16 polymorphisms) with the response to treatment regarding CKD. Among the 29 studies, 18 studies included patients with renal transplantation, 8 involved patients with nephrotic syndrome, and 3 studies included patients with lupus nephritis. The present meta-analysis provides strong evidence for the contribution of variants harbored in the , , , , and genes that creates some genetic predisposition that reduces effectiveness or is associated with adverse events of medications used in CKD.
Topics: Azathioprine; Cyclosporine; Humans; Pharmacogenomic Testing; Pharmacogenomic Variants; Polymorphism, Genetic; Prednisolone; Renal Insufficiency, Chronic; Tacrolimus; Treatment Outcome
PubMed: 33923087
DOI: 10.3390/ijms22094480 -
Journal of the American Heart... Oct 2017Time in the therapeutic range (TTR) is associated with the effectiveness and safety of vitamin K antagonist (VKA) therapy. To optimize prescribing of VKA, we aimed to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Time in the therapeutic range (TTR) is associated with the effectiveness and safety of vitamin K antagonist (VKA) therapy. To optimize prescribing of VKA, we aimed to develop and validate a prediction model for TTR in older adults taking VKA for nonvalvular atrial fibrillation and venous thromboembolism.
METHODS AND RESULTS
The study cohort comprised patients aged ≥65 years who were taking VKA for atrial fibrillation or venous thromboembolism and who were identified in the 2 US electronic health record databases linked with Medicare claims data from 2007 through 2014. With the predictors identified from a systematic review and clinical knowledge, we built a prediction model for TTR, using one electronic health record system as the training set and the other as the validation set. We compared the performance of the new models to that of a published prediction score for TTR, SAMe-TTR. Based on 1663 patients in the training set and 1181 in the validation set, our optimized score included 42 variables and the simplified model included 7 variables, abbreviated as PROSPER (Pneumonia, Renal dysfunction, Oozing blood [prior bleeding], Staying in hospital ≥7 days, Pain medication use, no Enhanced [structured] anticoagulation services, Rx for antibiotics). The PROSPER score outperformed SAMe-TTR when predicting both TTR ≥70% (area under the receiver operating characteristic curve 0.67 versus 0.55) and the thromboembolic and bleeding outcomes (area under the receiver operating characteristic curve 0.62 versus 0.52).
CONCLUSIONS
Our geriatric TTR score can be used as a clinical decision aid to select appropriate candidates to receive VKA therapy and as a research tool to address confounding and treatment effect heterogeneity by anticoagulation quality.
Topics: Age Factors; Aged; Analgesics; Anti-Bacterial Agents; Anticoagulants; Area Under Curve; Atrial Fibrillation; Blood Coagulation; Clinical Decision-Making; Databases, Factual; Decision Support Techniques; Drug Monitoring; Electronic Health Records; Female; Hemorrhage; Humans; International Normalized Ratio; Length of Stay; Male; Patient Selection; Predictive Value of Tests; Quality Control; Quality Indicators, Health Care; ROC Curve; Reproducibility of Results; Risk Factors; Time Factors; Treatment Outcome; Venous Thromboembolism
PubMed: 28982676
DOI: 10.1161/JAHA.117.006814 -
Linezolid pharmacokinetics in MDR-TB: a systematic review, meta-analysis and Monte Carlo simulation.The Journal of Antimicrobial... Jul 2018The oxazolidinone linezolid is an effective component of drug-resistant TB treatment, but its use is limited by toxicity and the optimum dose is uncertain. Current... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
The oxazolidinone linezolid is an effective component of drug-resistant TB treatment, but its use is limited by toxicity and the optimum dose is uncertain. Current strategies are not informed by clinical pharmacokinetic (PK)/pharmacodynamic (PD) data; we aimed to address this gap.
METHODS
We defined linezolid PK/PD targets for efficacy (fAUC0-24:MIC >119 mg/L/h) and safety (fCmin <1.38 mg/L). We extracted individual-level linezolid PK data from existing studies on TB patients and performed meta-analysis, producing summary estimates of fAUC0-24 and fCmin for published doses. Combining these with a published MIC distribution, we performed Monte Carlo simulations of target attainment.
RESULTS
The efficacy target was attained in all simulated individuals at 300 mg q12h and 600 mg q12h, but only 20.7% missed the safety target at 300 mg q12h versus 98.5% at 600 mg q12h. Although suggesting 300 mg q12h should be used preferentially, these data were reliant on a single centre. Efficacy and safety targets were missed by 41.0% and 24.2%, respectively, at 300 mg q24h and by 44.6% and 27.5%, respectively, at 600 mg q24h. However, the confounding effect of between-study heterogeneity on target attainment for q24h regimens was considerable.
CONCLUSIONS
Linezolid dosing at 300 mg q12h may retain the efficacy of the 600 mg q12h licensed dosing with improved safety. Data to evaluate commonly used 300 mg q24h and 600 mg q24h doses are limited. Comprehensive, prospectively obtained PK/PD data for linezolid doses in drug-resistant TB treatment are required.
Topics: Anti-Bacterial Agents; Humans; Linezolid; Microbial Sensitivity Tests; Monte Carlo Method; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 29584861
DOI: 10.1093/jac/dky096 -
European Journal of Drug Metabolism and... Jan 2022BACKGROUND AND OBJECTIVE: Vancomycin is often used in the ICU for the treatment of Gram-positive bacterial infection. In critically ill children, there are...
UNLABELLED
BACKGROUND AND OBJECTIVE: Vancomycin is often used in the ICU for the treatment of Gram-positive bacterial infection. In critically ill children, there are pathophysiologic changes that affect the pharmacokinetics of vancomycin. A systematic review of vancomycin pharmacokinetics and pharmacodynamics in critically ill children was performed.
METHODS
Pharmacokinetic studies of vancomycin in critically ill children published up to May 2021 were included in the review provided they included children aged > 1 month. Studies including neonates were excluded. A search was performed using the PubMed, Scopus, and Google Scholar databases. The Risk of Bias Assessment Tool for Systematic Reviews (ROBIS) was used to check for quality and reduce bias. Data on study characteristics, patient demographics, clinical parameters, pharmacokinetic parameters, outcomes, and study limitations were collected.
RESULTS
Thirteen studies were included in this review. A wide variety of dosing and sampling strategies were used in the studies. Methods for estimating vancomycin pharmacokinetics, especially the area under the curve over 24 h, varied. Vancomycin doses of 20-60 mg/kg were given daily. This resulted in high variability in pharmacokinetic parameters. Vancomycin trough level was less than 15 μg/mL in most of the studies. Vancomycin clearance ranged from 0.05 to 0.38 L/h/kg. Volume of distribution ranged from 0.1 to 1.16 L/kg. Half-life was between 2.4 and 23.6 h. Patients in the study receiving continuous vancomycin infusion had AUC < 400 µg·h/mL.
CONCLUSION
There is large variability in the pharmacokinetics of vancomycin among critically ill patients. Studies to assess the factors responsible for this variability in vancomycin pharmacokinetics are needed.
Topics: Anti-Bacterial Agents; Child; Child, Preschool; Critical Illness; Female; Humans; Infant; Infant, Newborn; Male; Vancomycin
PubMed: 34750740
DOI: 10.1007/s13318-021-00730-z -
Clinical Pharmacology and Therapeutics Sep 2013Metoprolol, a commonly prescribed β-blocker, is primarily metabolized by cytochrome P450 2D6 (CYP2D6), an enzyme with substantial genetic heterogeneity. Several smaller... (Meta-Analysis)
Meta-Analysis Review
Metoprolol, a commonly prescribed β-blocker, is primarily metabolized by cytochrome P450 2D6 (CYP2D6), an enzyme with substantial genetic heterogeneity. Several smaller studies have shown that metoprolol pharmacokinetics is influenced by CYP2D6 genotype and metabolizer phenotype. To increase robustness of metoprolol pharmacokinetic estimates, a systematic review and meta-analysis of pharmacokinetic studies that administered a single oral dose of immediate-release metoprolol were performed. Pooled analysis (n = 264) demonstrated differences in peak plasma metoprolol concentration, area under the concentration-time curve, elimination half-life, and apparent oral clearance that were 2.3-, 4.9-, 2.3-, and 5.9-fold between extensive and poor metabolizers, respectively, and 5.3-, 13-, 2.6-, and 15-fold between ultrarapid and poor metabolizers (all P < 0.001), respectively. Enantiomer-specific analysis revealed genotype-dependent enantio-selective metabolism, with nearly 40% greater R- than S-metoprolol metabolism in ultrarapid and extensive metabolizers. This study demonstrates a marked effect of CYP2D6 metabolizer phenotype on metoprolol pharmacokinetics and confirms enantiomer-specific metabolism of metoprolol.
Topics: Adrenergic beta-Antagonists; Cytochrome P-450 CYP2D6; Gene Dosage; Humans; Metoprolol; Phenotype; Stereoisomerism
PubMed: 23665868
DOI: 10.1038/clpt.2013.96 -
Journal of Medical Internet Research Oct 2023Frailty syndrome (FS) is one of the most common noncommunicable diseases, which is associated with lower physical and mental capacities in older adults. FS diagnosis is... (Review)
Review
BACKGROUND
Frailty syndrome (FS) is one of the most common noncommunicable diseases, which is associated with lower physical and mental capacities in older adults. FS diagnosis is mostly focused on biological variables; however, it is likely that this diagnosis could fail owing to the high biological variability in this syndrome. Therefore, artificial intelligence (AI) could be a potential strategy to identify and diagnose this complex and multifactorial geriatric syndrome.
OBJECTIVE
The objective of this scoping review was to analyze the existing scientific evidence on the use of AI for the identification and diagnosis of FS in older adults, as well as to identify which model provides enhanced accuracy, sensitivity, specificity, and area under the curve (AUC).
METHODS
A search was conducted using PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines on various databases: PubMed, Web of Science, Scopus, and Google Scholar. The search strategy followed Population/Problem, Intervention, Comparison, and Outcome (PICO) criteria with the population being older adults; intervention being AI; comparison being compared or not to other diagnostic methods; and outcome being FS with reported sensitivity, specificity, accuracy, or AUC values. The results were synthesized through information extraction and are presented in tables.
RESULTS
We identified 26 studies that met the inclusion criteria, 6 of which had a data set over 2000 and 3 with data sets below 100. Machine learning was the most widely used type of AI, employed in 18 studies. Moreover, of the 26 included studies, 9 used clinical data, with clinical histories being the most frequently used data type in this category. The remaining 17 studies used nonclinical data, most frequently involving activity monitoring using an inertial sensor in clinical and nonclinical contexts. Regarding the performance of each AI model, 10 studies achieved a value of precision, sensitivity, specificity, or AUC ≥90.
CONCLUSIONS
The findings of this scoping review clarify the overall status of recent studies using AI to identify and diagnose FS. Moreover, the findings show that the combined use of AI using clinical data along with nonclinical information such as the kinematics of inertial sensors that monitor activities in a nonclinical context could be an appropriate tool for the identification and diagnosis of FS. Nevertheless, some possible limitations of the evidence included in the review could be small sample sizes, heterogeneity of study designs, and lack of standardization in the AI models and diagnostic criteria used across studies. Future research is needed to validate AI systems with diverse data sources for diagnosing FS. AI should be used as a decision support tool for identifying FS, with data quality and privacy addressed, and the tool should be regularly monitored for performance after being integrated in clinical practice.
Topics: Humans; Aged; Artificial Intelligence; Frail Elderly; Frailty; Machine Learning; Area Under Curve
PubMed: 37862082
DOI: 10.2196/47346 -
Biology Dec 2022Tamoxifen is useful in managing breast cancer and it is reported to have significant variability in its pharmacokinetics. This review aimed to summarize reported... (Review)
Review
BACKGROUND
Tamoxifen is useful in managing breast cancer and it is reported to have significant variability in its pharmacokinetics. This review aimed to summarize reported population pharmacokinetics studies of tamoxifen and to identify the factors affecting the pharmacokinetics of tamoxifen in adult breast cancer patients.
METHOD
A systematic search was undertaken in Scopus, Web of Science, and PubMed for papers published in the English language from inception to 20 August 2022. Studies were included in the review if the population pharmacokinetic modeling was based on non-linear mixed-effects modeling with a parametric approach for tamoxifen in breast cancer patients.
RESULTS
After initial selection, 671 records were taken for screening. A total of five studies were selected from Scopus, Web of Science, PubMed, and by manual searching. The majority of the studies were two-compartment models with first-order absorption and elimination to describe tamoxifen and its metabolites' disposition. The CYP2D6 phenotype and CYP3A4 genotype were the main covariates that affected the metabolism of tamoxifen and its metabolites. Other factors influencing the drug's pharmacokinetics included age, co-medication, BMI, medication adherence, CYP2B6, and CYP2C19 genotype.
CONCLUSION
The disposition of tamoxifen and its metabolites varies primarily due to the CYP2D6 phenotype and CYP3A4 genotype. However, other factors, such as anthropometric characteristics and menopausal status, should also be addressed when accounting for this variability. All these studies should be externally evaluated to assess their applicability in different populations and to use model-informed dosing in the clinical setting.
PubMed: 36671744
DOI: 10.3390/biology12010051 -
European Journal of Hospital Pharmacy :... Jul 2023Updated European Committee on Antimicrobial Susceptibility Testing (EUCAST) amikacin breakpoints for Enterobacterales and included revised dosing recommendations of... (Review)
Review
BACKGROUND
Updated European Committee on Antimicrobial Susceptibility Testing (EUCAST) amikacin breakpoints for Enterobacterales and included revised dosing recommendations of 25-30 mg/kg to achieve key pharmacokinetic/pharmacodynamic parameters, higher than recommended in the British National Formulary. The objectives of this review were to identify clinical evidence for high-dose amikacin regimens and to determine drug exposures that are related to adverse events and toxicity.
METHODS
The literature search was conducted in October 2021 and updated in May 2022 using electronic databases for any study reporting adult participants treated with amikacin at doses ≥20 mg/kg/day. Reference lists of included papers were also screened for potential papers. Data were extracted for pharmacokinetic parameters and clinical outcomes, presented in a summary table and consolidated narratively. Meta-analysis was not possible. Each study was assessed for bias before, during and after the intervention using the ROBINS-I tool.
RESULTS
Nine studies (total 501 participants in 10 reports) were identified and included, eight of which were observational studies. Assessment of bias showed substantial flaws. Dosing regimens ranged from 25 to 30 mg/kg/day. Six studies adjusted the dose in obesity when participants had a body mass index of ≥30 kg/m. Target peak serum concentrations ranged from 60 mg/L to 80 mg/L and 59.6-81.8% of patients achieved these targets, but there was no information on clinical outcomes. Two studies reported the impact of high-dose amikacin on renal function. No studies reporting auditory or vestibular toxicity were identified.
CONCLUSION
All included papers were limited by a significant risk of bias, while methodological and reporting heterogeneity made drawing conclusions challenging. Lack of information on the impact on renal function or ototoxicity means high-dose regimens should be used cautiously in older people. There is a need for a consensus guideline for high-dose amikacin to be written.
TRIAL REGISTRATION NUMBER
PROSPERO (CRD42021250022).
Topics: Adult; Aged; Humans; Amikacin; Clinical Protocols
PubMed: 36344247
DOI: 10.1136/ejhpharm-2022-003421