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Antimicrobial Agents and Chemotherapy Dec 2016Chagas disease is a neglected parasitic illness affecting approximately 8 million people, predominantly in Latin America. Benznidazole is the drug of choice for... (Meta-Analysis)
Meta-Analysis
Chagas disease is a neglected parasitic illness affecting approximately 8 million people, predominantly in Latin America. Benznidazole is the drug of choice for treatment, although its availability has been limited. A paucity of knowledge of the pharmacokinetic properties of this drug has contributed to its limited availability in several jurisdictions. The objective of this study was to conduct a systematic literature review and a Bayesian meta-analysis of pharmacokinetic studies to improve estimates of the basic pharmacokinetic properties of benznidazole. A systematic search of the Embase, Medline, LILACS, and SciELO (Scientific Electronic Library Online) databases was conducted. Eligible studies reported patient-level data from single-100-mg-dose pharmacokinetic evaluations of benznidazole in adults or otherwise provided data relevant to the estimation of pharmacokinetic parameters which could be derived from such studies. A Bayesian hierarchical model was used for analysis. Secondary data (i.e., data from studies that did not include patient-level, single-100-mg-dose data) were used for the generation of empirical priors for the Bayesian analysis. The systematic search identified nine studies for inclusion. Nine pharmacokinetic parameters were estimated, including the area under the concentration-time curve (AUC), the maximum concentration of drug in plasma (C), the time to C, the elimination rate constant (k), the absorption rate constant (K), the absorption and elimination half-lives, the apparent oral clearance, and the apparent oral volume of distribution. The results showed consistency across studies. AUC and C were 51.31 mg · h/liter (95% credible interval [CrI], 45.01, 60.28 mg · h/liter) and 2.19 mg/liter (95% CrI, 2.06, 2.33 mg/liter), respectively. K and k were 1.16 h (95% CrI, 0.59, 1.76 h) and 0.052 h (95% CrI, 0.045, 0.059 h), respectively, with the corresponding absorption and elimination half-lives being 0.60 h (95% CrI, 0.38, 1.11 h) and 13.27 h (95% CrI, 11.79, 15.42 h), respectively. The oral clearance and volume of distribution were 2.04 liters/h (95% CrI, 1.77, 2.32 liters/h) and 39.19 liters (95% CrI, 36.58, 42.17 liters), respectively. A Bayesian meta-analysis was used to improve the estimates of the standard pharmacokinetic parameters of benznidazole. These data can inform clinicians and policy makers as access to this drug increases.
Topics: Area Under Curve; Chagas Disease; Humans; Nitroimidazoles; Trypanocidal Agents
PubMed: 27550362
DOI: 10.1128/AAC.01567-16 -
Drug Design, Development and Therapy 2022Although tigecycline is widely used in clinical practice, its efficiency and optimal dosage regimens remain controversial. The purpose of this article was to help guide... (Review)
Review
Although tigecycline is widely used in clinical practice, its efficiency and optimal dosage regimens remain controversial. The purpose of this article was to help guide tigecycline dosing in different patient subpopulations through comparing the published population pharmacokinetic models of tigecycline, as well as summarizing and determining the potential covariates that markedly influence tigecycline pharmacokinetics. In this review, literature was systematically searched from the PubMed database from inception to March 2022. The articles focusing on population pharmacokinetics for tigecycline in healthy volunteers or patients were included; finally, a total of eight studies were included in this review. NONMEM methods were used in five studies to generate the population pharmacokinetic models. Tigecycline pharmacokinetics were mostly described by a two-compartment model in these included studies. Estimated clearance and volumes of distribution of tigecycline at steady state () varied widely in different target patient populations, with a range of 7.5-23.1 L/h and 212.7-1087.7 L, respectively. Body-weight and creatinine clearance were the most important predictors of clearance in these studies, while other predictors include age, gender, bilirubin and aspartate aminotransferase. In conclusion, this review showed the large variability of tigecycline population pharmacokinetics, which can provide guide dosing in different target populations. For clinicians, the individual dosing adjustment should be based not only on the indication and pathogen susceptibility but also on the potential important predictors. However, more studies were needed to confirm the necessity of modified dosage regimens in different patient subpopulations.
Topics: Anti-Bacterial Agents; Body Weight; Databases, Factual; Humans; Models, Biological; Tigecycline
PubMed: 35747442
DOI: 10.2147/DDDT.S365512 -
International Journal of Molecular... Jun 2023Ischemic stroke, a significant neurovascular disorder, currently lacks effective restorative medication. However, recently developed nanomedicines bring renewed promise... (Review)
Review
Ischemic stroke, a significant neurovascular disorder, currently lacks effective restorative medication. However, recently developed nanomedicines bring renewed promise for alleviating ischemia's effects and facilitating the healing of neurological and physical functions. The aim of this systematic review was to evaluate the efficacy of nanotherapies in animal models of stroke and their potential impact on future stroke therapies. We also assessed the scientific quality of current research focused on nanoparticle-based treatments for ischemic stroke in animal models. We summarized the effectiveness of nanotherapies in these models, considering multiple factors such as their anti-inflammatory, antioxidant, and angiogenetic properties, as well as their safety and biodistribution. We conclude that the application of nanomedicines may reduce infarct size and improve neurological function post-stroke without causing significant organ toxicity.
Topics: Animals; Tissue Distribution; Stroke; Ischemic Stroke; Anti-Inflammatory Agents; Nanoparticles; Brain Ischemia
PubMed: 37445979
DOI: 10.3390/ijms241310802 -
Acta Clinica Belgica Apr 2017Pharmacokinetic parameters of drugs are widely investigated under normothermic conditions and normal hemodynamic parameters. The European Resuscitation Council... (Review)
Review
OBJECTIVE
Pharmacokinetic parameters of drugs are widely investigated under normothermic conditions and normal hemodynamic parameters. The European Resuscitation Council recommends the use of targeted temperature management (TTM) with a target temperature of 34 °C in cardiac arrest (CA) patients. The aim of this literature review is to investigate the influence of CA combined with TTM on the pharmacokinetics of drugs. Results of preclinical and clinical studies are compared with each other. Only the most important drugs, administered during CA in emergency setting, were studied.
METHODS
A literature search was conducted within PubMed and Google Scholar. The search terms included 'therapeutic hypothermia', 'TTM', 'drug metabolism', 'pharmacokinetics during hypothermia', 'cardiac arrest/etiology'. In Pubmed, MeSH-terms were also included: 'myocardial infarction/therapy', 'heart arrest/complications' and 'hypothermia'. To search for preclinical studies: the search terms 'pigs' and 'swine' were used. After the primary shift of relevant findings, further articles were found through references of these (snowballing method), as well as through related articles as suggested by the databases.
RESULTS
Due to the reduced cardiac output during TTM, most of the distribution volume ([Formula: see text]) of drugs included in this literature study is decreased. Only the [Formula: see text] of chlorzoxazone in CA rats and midazolam in non-CA patients are significantly increased during respectively deep and mild hypothermia. The renal, hepatic and biliary clearance of drugs administered during CA/TTM/hypothermia are decreased.
DISCUSSION
The combination of a decreased [Formula: see text] and a decrease in the metabolization/excretion of drugs during CA/TTM result in higher plasma concentrations compared to the plasma concentrations during CA without TTM.
Topics: Animals; Cardiovascular Agents; Heart Arrest; Humans; Hypothermia, Induced
PubMed: 28220713
DOI: 10.1080/17843286.2017.1291782 -
European Review For Medical and... Apr 2015Chlorhexidine (CHX) is one of the most widely used antiseptic, especially in dentistry. At low concentrations CHX is bacteriostatic and at high concentrations acts... (Review)
Review
OBJECTIVES
Chlorhexidine (CHX) is one of the most widely used antiseptic, especially in dentistry. At low concentrations CHX is bacteriostatic and at high concentrations acts bactericidal causing cell death by cytolysis. In this study, we performed a systematic review of pharmaco-biological activity and application of CHX.
MATERIALS AND METHODS
Articles for inclusion in this review were retrieved from online databases PubMed/Medline. The selected papers were included in the present manuscript according to their relevance for the topic.
RESULTS
Totally 75 papers were enrolled in this research. CHX has strong biocidal activity against Gram-positive bacteria and weaker activity against Gram-negative bacteria. It is also active against yeasts, some dermatophytes and some lipophilic viruses. The most widely application CHX has found in dentistry and antisepsis. Numerous studies have confirmed the beneficial effects of CHX in reducing of plaque accumulation, in tooth caries, gingivitis, periodontitis and in alveolar osteitis. Unfortunately, CHX exhibits cytotoxic activity on human cells, can cause colorization of teeth and fillings, and its activity depends on the pH of the environment and the presence of organic substances.
CONCLUSIONS
CHX play a valuable role in the dentistry and antisepsis. However, it can also cause side effects, limiting its application time.
Topics: Anti-Infective Agents, Local; Antisepsis; Biological Availability; Chlorhexidine; Dental Plaque; Humans
PubMed: 25912596
DOI: No ID Found -
Frontiers in Immunology 2023Cytokines are pivotal mediators of cell communication in the tumor microenvironment. Multiple cytokines are involved in the host antitumor response, but the production... (Review)
Review
Cytokines are pivotal mediators of cell communication in the tumor microenvironment. Multiple cytokines are involved in the host antitumor response, but the production and function of these cytokines are usually dysregulated during malignant tumor progression. Considering their clinical potential and the early successful use of cytokines in cancer immunotherapy, such as interferon alpha-2b (IFNα-2b; IntronA) and IL-2 (Proleukin), cytokine-based therapeutics have been extensively evaluated in many follow-up clinical trials. Following these initial breakthroughs, however, clinical translation of these natural messenger molecules has been greatly limited owing to their high-degree pleiotropic features and complex biological properties in many cell types. These characteristics, coupled with poor pharmacokinetics (a short half-life), have hampered the delivery of cytokines via systemic administration, particularly because of severe dose-limiting toxicities. New engineering approaches have been developed to widen the therapeutic window, prolong pharmacokinetic effects, enhance tumor targeting and reduce adverse effects, thereby improving therapeutic efficacy. In this review, we focus on the recent progress and competitive landscape in cytokine engineering strategies and preclinical/clinical therapeutics for cancer. In addition, aiming to promote engineered cytokine-based cancer immunotherapy, we present a profound discussion about the feasibility of recently developed methods in clinical medicine translation.
Topics: Humans; Cytokines; Neoplasms; Immunotherapy; Tumor Microenvironment
PubMed: 37483629
DOI: 10.3389/fimmu.2023.1218082 -
Journal of Nanobiotechnology Jan 2024Exosomes are nanoscale extracellular vesicles secreted by cells and enclosed by a lipid bilayer membrane containing various biologically active cargoes such as proteins,... (Review)
Review
Exosomes are nanoscale extracellular vesicles secreted by cells and enclosed by a lipid bilayer membrane containing various biologically active cargoes such as proteins, lipids, and nucleic acids. Engineered exosomes generated through genetic modification of parent cells show promise as drug delivery vehicles, and they have been demonstrated to have great therapeutic potential for treating cancer, cardiovascular, neurological, and immune diseases, but systematic knowledge is lacking regarding optimization of drug loading and assessment of delivery efficacy. This review summarizes current approaches for engineering exosomes and evaluating their drug delivery effects, and current techniques for assessing exosome drug loading and release kinetics, cell targeting, biodistribution, pharmacokinetics, and therapeutic outcomes are critically examined. Additionally, this review synthesizes the latest applications of exosome engineering and drug delivery in clinical translation. The knowledge compiled in this review provides a framework for the rational design and rigorous assessment of exosomes as therapeutics. Continued advancement of robust characterization methods and reporting standards will accelerate the development of exosome engineering technologies and pave the way for clinical studies.
Topics: Humans; Exosomes; Tissue Distribution; Drug Delivery Systems; Extracellular Vesicles; Neoplasms; Pharmaceutical Preparations
PubMed: 38172932
DOI: 10.1186/s12951-023-02259-6 -
Bulletin of the World Health... Aug 2011To systemically review the evidence in support of World Health Organization guidelines recommending broad-spectrum antibiotics for children with severe acute... (Review)
Review
OBJECTIVE
To systemically review the evidence in support of World Health Organization guidelines recommending broad-spectrum antibiotics for children with severe acute malnutrition (SAM).
METHODS
CENTRAL, MEDLINE, EMBASE, LILACS, POPLINE, CAB Abstracts and ongoing trials registers were searched. Experts were contacted. Conference proceedings and reference lists were manually searched. All study types, except single case reports, were included.
FINDINGS
Two randomized controlled trials (RCTs), one before-and-after study and two retrospective reports on clinical efficacy and safety were retrieved, together with 18 pharmacokinetic studies. Trial quality was generally poor and results could not be pooled due to heterogeneity. Oral amoxicillin for 5 days was as effective as intramuscular ceftriaxone for 2 days (1 RCT). For uncomplicated SAM, amoxicillin showed no benefit over placebo (1 retrospective study). The introduction of a standardized regimen using ampicillin and gentamicin significantly reduced mortality in hospitalized children (odds ratio, OR: 4.0; 95% confidence interval, CI: 1.7-9.8; 1 before-and-after study). Oral chloramphenicol was as effective as trimethoprim-sulfamethoxazole in children with pneumonia (1 RCT). Pharmacokinetic data suggest that normal doses of penicillins, cotrimoxazole and gentamicin are safe in malnourished children, while the dose or frequency of chloramphenicol requires adjustment. Existing evidence is not strong enough to further clarify recommendations for antibiotic treatment in children with SAM.
CONCLUSION
Large RCTs are needed to define optimal antibiotic treatment in children with SAM with and without complications. Further research into gentamicin and chloramphenicol toxicity and into the pharmacokinetics of ceftriaxone and ciprofloxacin is also required.
Topics: Anti-Bacterial Agents; Child; Child Nutrition Disorders; Child, Preschool; Humans; Severity of Illness Index; Treatment Outcome
PubMed: 21836758
DOI: 10.2471/BLT.10.084715 -
International Journal of Molecular... Oct 2017Maxim. (Rutaceae) is a popular food additive and traditional Chinese herbal medicine commonly named in China. This plant is widely distributed in Asian countries. The... (Review)
Review
Maxim. (Rutaceae) is a popular food additive and traditional Chinese herbal medicine commonly named in China. This plant is widely distributed in Asian countries. The aim of this paper is to provide a systematic review on the traditional usages, botany, phytochemistry, pharmacology, pharmacokinetics, and toxicology of this plant. Furthermore, the possible development and perspectives for future research on this plant are also discussed. To date, over 140 compounds have been isolated and identified from , including alkaloids, terpenoids, flavonoids, and free fatty acids. The extracts and compounds have been shown to possess wide-ranging biological activity, such as anti-inflammatory and analgesic effects, antioxidant and anti-tumor effects, antibacterial and antifungal effects, as well as regulatory effects on the gastrointestinal system and nervous system, and other effects. As a traditional herbal medicine, has been widely used to treat many diseases, especially digestive disorders, toothache, stomach ache, and diarrhea. Many traditional usages of this plant have been validated by present investigations. However, further research elucidating the structure-function relationship among chemical compounds, understanding the mechanism of unique sensation, as well as exploring new clinical effects and establishing criteria for quality control for should be further studied.
Topics: Animals; Drugs, Chinese Herbal; Humans; Zanthoxylum
PubMed: 29057808
DOI: 10.3390/ijms18102172 -
Frontiers in Oncology 2023To provide a systematic review of existing meta-analysis on the efficacy, safety and pharmacokinetics of the novel Polo-like kinase-1 (Plk1) inhibitors in various tumor...
OBJECTIVE
To provide a systematic review of existing meta-analysis on the efficacy, safety and pharmacokinetics of the novel Polo-like kinase-1 (Plk1) inhibitors in various tumor treatments, and assess the methodological quality and the strength of evidence of the included meta-analysis.
METHODS
The Medline, PubMed, Embase, etc. were searched and updated on 30 June 2022. 22 eligible clinical trials involving a total of 1256 patients were included for analyses. Randomised controlled trials (RCTs) compared the efficacy or safety, or both of any Plk1 inhibitors with placebo (active or inert) in participants. To be included, studies had to be RCTs, quasi-RCTs, and nonrandomized comparative studies.
RESULTS
A meta-analysis of two trials reported progression-free survival (PFS) of the overall population (effect size (ES), 1.01; 95% confidence intervals (CIs), 0.73-1.30, 0.0%, <0.001) and overall survival (OS) of the overall population (ES, 0.91; 95% CIs, 0.31-1.50, 77.6%, =0.003). 18 adverse events (AEs) reflected that the possibility of occurrence of AEs in the Plk1 inhibitors group was 1.28 times higher than in the control group (odds ratios (ORs), 1.28; 95% CIs,1.02-1.61). The results of meta-analysis showed that the incidence of AEs in the nervous system was the highest (ES, 0.202; 95% CIs, 0.161-0.244), followed by blood system (ES, 0.190; 95% CIs, 0.178-0.201) and digestive system (ES, 0.181; 95% CIs, 0.150-0.213). Rigosertib (ON 01910.Na) was associated with a decreased risk of AEs in digestive system (ES, 0.103; 95% CIs, 0.059-0.147), but BI 2536 and Volasertib (BI 6727) increased risk of AEs in blood system (ES, 0.399; 95% CIs, 0.294-0.504). Five eligible studies reported the pharmacokinetic parameters of the low dosage (100 mg) cohort and the high dosage (200 mg) cohort, and there was no statistical difference in the total plasma clearance, terminal half-life and apparent volume of distribution at steady state.
CONCLUSIONS
Plk1 inhibitors work better in improving OS and they are well tolerated, effective and safe in reducing the severity of illness while improving the quality of life, especially in patients with non-specific tumors, respiratory system tumors, musculoskeletal system tumors, and urinary system tumors. However, they fail to prolong the PFS. From the vertical whole level analysis, compared to other systems in the body, Plk1 inhibitors should be avoided as far as possible for the treatment of tumors related to the blood circulatory system, digestive system and nervous system, which were attributed to the intervention of Plk1 inhibitors associated with an increased risk of AEs in these systems. The toxicity caused by immunotherapy should be carefully considered. Conversely, a horizontal comparison of three different types of Plk1 inhibitors suggested that Rigosertib (ON 01910.Na) might be relatively suitable for the treatment of tumors associated with the digestive system, while Volasertib (BI 6727) might be even less suitable for the treatment of tumors associated with the blood circulation system. Additionally, in the dose selection of Plk1 inhibitors, the low dose of 100 mg should be preferred, and meanwhile, it can also ensure the pharmacokinetic efficacy that is indistinguishable from the high dose of 200 mg.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier CRD42022343507.
PubMed: 36845678
DOI: 10.3389/fonc.2023.1062885