Tolerability and effectiveness of (S)-amlodipine compared with racemic amlodipine in hypertension: A systematic review and meta-analysis

AbstractBackground: Amlodipine is a calcium channel blocker prescribed for the management of angina and hypertension. As a racemic mixture, amlodipine contains (R)- and (S)-amlodipine isomers, but only (S)-amlodipine as the active moiety possesses therapeutic activity. Based on pharmacologic research, it remains uncertain if (S)-amlodipine alone has similar efficacy and fewer associated adverse events (AEs) compared with the racemic mixtures.Objective: The aim of this systematic review and meta-analysis was to determine the effectiveness and tolerability of (S)-amlodipine compared with that of racemic amlodipine.Methods: A systematic literature search was performed using MEDLINE (1966–2009), EMBASE (1966–2009), the Cochrane Central Register of Controlled Trials (issue 3, 2009), the Chinese Biomedical Database (1978–2009), and the China National Knowledge Internet (1980–2009). All randomized controlled trials (RCTs) comparing (S)-amlodipine 2.5 mg and racemic amlodipine 5.0 mg in the treatment of hypertension were included in the review. The outcome measures to be collected were cardiovascular events, systolic blood pressure (SBP), diastolic BP (DBP), and AEs. Quality assessments of clinical trials were conducted using a modified Jadad Scale, with trials being rated as low quality (score 0–3) or high quality (score 4–7). Meta-analysis of the included studies was performed using RevMan software.Results: Of the 229 references identified, 214 were excluded after screening the titles, abstracts, or full texts. Fifteen RCTs were included, of which 13 were in Chinese and 2 in English. Based on the Jadad Scale score, 3 of the RCTs were classified as high quality (score 5 or 6) and the remaining 12 as low quality (score 1–3). None of the trials evaluated cardiovascular events beyond 40 weeks. Meta-analysis of the 15 trials indicated that (S)-amlodipine was not significantly different from racemic amlodipine in the effect on BP. When only high-quality studies were included, after 4 weeks' treatment, the weighted mean difference (WMD) of SBP and DBP decrease (1 study) was −2.84 (95% CI, −6.42 to 0.74) with (S)-amlodipine and −1.71 (95% CI, −3.48 to 0.06) with racemic amlodipine. After 8 weeks' treatment, the WMD of SBP and DBP decrease (2 studies) was −1.13 (95% CI, −5.29 to 3.03) and −1.34 (95% CI, −2.67 to −0.01), respectively. The risk difference (RD) for the number of patients who experienced AEs with (S)-amlodipine and racemic amlodipine was found to be −0.04 (95% CI, −0.06 to −0.02). When all the trials were included, (S)-amlodipine treatment was associated with significantly less edema than racemic amlodipine (RD, −0.02; 95% CI, −0.03 to 0.00); however, when only high-quality studies (2 studies) were included, no difference was found between the 2 groups (RD, 0.01; 95% CI, −0.02 to 0.03). One high-quality study found significant differences in increases in aspartate and alanine aminotransferase activities in the 2 groups (RD, 0.08; 95% CI, 0.01 to 0.05). No significant differences between the 2 groups were found in the incidence of headache (RD, 0.00; 95% CI, −0.02 to 0.01) or flushing (RD, −0.01; 95% CI, −0.02 to 0.00).Conclusions: The majority of the clinical trials comparing (S)-amlodipine and racemic amlodipine treatment were low quality (12/15 [80%]). According to the limited evidence, there were no significant differences between (S)-amlodipine 2.5 mg and racemic amlodipine 5.0 mg in controlling BP. When all the trials were considered, (S)-amlodipine treatment was associated with significantly less edema than racemic amlodipine; however, when only high-quality trials were included, no significant difference was found. More long-term, high-quality RCTs with cardiovascular events as the primary outcome are needed to compare the safety and efficacy of (S)-amlodipine and racemic amlodipine

Tetrandrine alleviates oxaliplatin-induced mechanical allodynia via modulation of inflammation-related genes

Oxaliplatin, a platinum-based chemotherapy drug, causes neuropathic pain, yet effective pharmacological treatments are lacking. Previously, we showed that tetrandrine (TET), with anti-inflammatory properties, reduces mechanical allodynia in nerve-injured mice. This study explores the effect of TET on oxaliplatin-induced mechanical allodynia and gene changes in mice. Male C57BL/6J mice received oxaliplatin intraperitoneally to induce mechanical allodynia. Post-treatment with TET or vehicle, the mechanical withdrawal threshold (WMT) was assessed using von Frey filaments. TET alleviated oxaliplatin-induced mechanical allodynia. RNA sequencing identified 365 differentially expressed genes (DEGs) in the Control vs. Oxaliplatin group and 229 DEGs in the Oxaliplatin vs. TET group. Pearson correlation analysis of co-regulated DEGs and inflammation-related genes (IRGs) revealed 104 co-regulated inflammation-related genes (Co-IRGs) (|cor| > 0.8, P < 0.01). The top 30 genes in the PPI network were identified. Arg2, Cxcl12, H2-Q6, Kdr, and Nfkbia were highlighted based on ROC analysis. Subsequently, Arg2, Cxcl12, Kdr, and Nfkbia were further verified by qRCR. Immune infiltration analysis indicated increased follicular CD4 T cell infiltration in oxaliplatin-treated mice, reduced by TET. Molecular docking showed strong binding affinity between TET and proteins encoded by Arg2, Cxcl12, Kdr, and Nfkbia. In summary, TET may alleviate oxaliplatin-induced peripheral neuropathy in clinical conditions

Guidelines for Therapeutic Drug Monitoring of Vancomycin: A Systematic Review

<div><p>Background and Objective</p><p>Despite the availability of clinical practice guidelines (CPGs) for therapeutic drug monitoring (TDM) of vancomycin, vancomycin serum concentrations still do not reach therapeutic concentrations in many patients. Thus, we sought to systematically review the quality and consistency of recommendations for an international cohort of CPGs regarding vancomycin TDM.</p><p>Methods</p><p>PubMed, Embase, guidelines' websites and Google were searched for CPGs for vancomycin TDM. Two independent assessors rated the quality of each CPG using the Appraisal of Guidelines for Research & Evaluation II (AGREEII) instrument and data were independently extracted.</p><p>Results</p><p>Twelve guidelines were evaluated and the overall quality of guidelines for vancomycin TDM was moderate. The highest score was recorded in the domain of clarity of presentation, and the lowest score was recorded in the domain of rigor of development and stakeholder involvement. The specific recommendations for vancomycin TDM were moderately consistent and guidelines varied in trough concentration monitoring, frequency of TDM, and serum concentration targets.</p><p>Conclusion</p><p>The overall guideline quality for vancomycin TDM was not optimal and effort is needed to improve guideline quality, especially in the domain of rigor of development and stakeholder involvement.</p></div

Association between the AUC0-24/MIC Ratio of Vancomycin and Its Clinical Effectiveness: A Systematic Review and Meta-Analysis.

A target AUC0-24/MIC ratio of 400 has been associated with its clinical success when treating Staphylococcus aureus infections but is not currently supported by state-of-the-art evidence-based research.This current systematic review aimed to evaluate the available evidence for the association between the AUC0-24/MIC ratio of vancomycin and its clinical effectiveness on hospitalized patients and to confirm the existing target value of 400.PubMed, Embase, Web of Sciences, the Cochrane Library and two Chinese literature databases (CNKI, CBM) were systematically searched. Manual searching was also applied. Both RCTs and observational studies comparing the clinical outcomes of high AUC0-24/MIC groups versus low AUC0-24/MIC groups were eligible. Two reviewers independently extracted the data. The primary outcomes were mortality and infection treatment failure. Risk ratios (RRs) with 95% confidence intervals (95%CIs) were calculated.No RCTs were retrieved. Nine cohort studies were included in the meta-analysis. Mortality rates were significantly lower in high AUC0-24/MIC groups (RR = 0.47, 95%CI = 0.31-0.70, p<0.001). The rates of infection treatment failure were also significantly lower in high AUC/MIC groups and were consistent after correcting for heterogeneity (RR = 0.39, 95%CI = 0.28-0.55, p = 0.001). Subgroup analyses showed that results were consistent whether MIC values were determined by broth microdilution (BMD) method or Etest method. In studies using the BMD method, breakpoints of AUC0-24/MIC all fell within 85% to 115% of 400.This meta-analysis demonstrated that achieving a high AUC0-24/MIC of vancomycin could significantly decrease mortality rates by 53% and rates of infection treatment failure by 61%, with 400 being a reasonable target

Effects of the <i>CYP3A4*1B</i> Genetic Polymorphism on the Pharmacokinetics of Tacrolimus in Adult Renal Transplant Recipients: A Meta-Analysis

<div><p>Background and Objective</p><p>The association between the <i>CYP3A4*1B</i> single nucleotide polymorphism (SNP) and tacrolimus pharmacokinetics in different studies is controversial. Therefore, a meta-analysis was employed to evaluate the correlation between the <i>CYP3A4*1B</i> genetic polymorphism and tacrolimus pharmacokinetics at different post-transplantation times in adult renal transplant recipients.</p><p>Methods</p><p>Studies evaluating the <i>CYP3A4*1B</i> genetic polymorphism and tacrolimus pharmacokinetics were retrieved through a systematical search of Embase, PubMed, the Cochrane Library, ClinicalTrials.gov and three Chinese literature databases (up to Sept. 2014). The pharmacokinetic parameters (weight-adjusted tacrolimus daily dose and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio) were extracted, and the meta-analysis was performed using Stata 12.1.</p><p>Results</p><p>Seven studies (involving 1182 adult renal transplant recipients) were included in this meta-analysis. For the weight-adjusted tacrolimus daily dose, in all included renal transplant recipients (European & Indian populations), <i>CYP3A4*1/*1</i> recipients required a significantly lower weight-adjusted tacrolimus daily dose than did <i>CYP3A4*1B</i> carriers at 7 days (WMD -0.048; 95% CI -0.083 ~ -0.014), 6 months (WMD -0.058; 95% CI -0.081 ~ -0.036) and 12 months (WMD - 0.061; 95% CI -0.096 ~ -0.027) post-transplantation. In light of the heterogeneity, the analysis was repeated after removing the only study in an Indian population, and <i>CYP3A4*1/*1</i> European recipients (mostly Caucasian) required a lower weight-adjusted tacrolimus daily dose within the first year post-transplantation. The tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio (C₀/Dose ratio) was significantly higher in <i>CYP3A4*1/*1</i> recipients than in <i>CYP3A4*1B</i> carriers at 6 months (WMD 52.588; 95% CI 22.387 ~ 82.789) and 12 months (WMD 62.219; 95% CI 14.218 ~ 110.221) post-transplantation. When the only study in an Indian population was removed to examine European recipients (mostly Caucasian), the significant difference persisted at 1 month, 6 months and 12 months post-transplantation.</p><p>Conclusion</p><p>Based on our meta-analysis, the <i>CYP3A4*1B</i> genetic polymorphism affects tacrolimus dose requirements and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio within the first year post-transplantation in adult renal transplant recipients, especially in European recipients (mostly Caucasian).</p></div

Benefits of Therapeutic Drug Monitoring of Vancomycin: A Systematic Review and Meta-Analysis

<div><p>Background and Objective</p><p>The necessity of therapeutic drug monitoring (TDM) for vancomycin is controversial. The objective of the current review was to evaluate the available evidence for the necessity of TDM in patients given vancomycin to treat Gram-positive infections.</p><p>Methods</p><p>Medline, Embase, Web of Sciences, the Cochrane Library and two Chinese literature databases (CNKI, CBM) were searched. Randomized controlled studies and observational studies that compared the clinical outcomes of TDM groups vs. non-TDM groups were included. Two reviewers independently extracted the data. The primary outcome was clinical efficacy of therapy. Secondary outcomes included vancomycin associated nephrotoxicity, duration of vancomycin therapy, length of hospital stay, and mortality. Meta-analysis was performed using the Mantel-Haenszel fixed effect method (FEM). Odds ratios (ORs) or weighted mean differences (WMD) with 95% confidence intervals (95%CIs) were calculated for categorical and continuous outcomes, respectively.</p><p>Results</p><p>One randomized controlled trial (RCT) and five cohort studies were included in the meta-analysis. Compared with non-TDM groups, TDM groups had significantly higher rates of clinical efficacy (OR = 2.62, 95%CI 1.34–5.11 P = 0.005) and decreased rates of nephrotoxicity (OR = 0.25, 95%CI 0.13–0.48 P<0.0001). Subgroup analyses showed that TDM group had significantly higher rates of clinical efficacy in both cohort studies subgroup (OR = 3.04, 95%CI 1.34–6.90) and in Asian population subgroup (OR = 3.04, 95%CI 1.34–6.90). TDM group had significantly decreased rates of nephrotoxicity in all subgroup. There was no significant difference in duration of vancomycin therapy (WMD = −0.40, 95%CI −2.83–2.02 P = 0.74) or length of stay (WMD = −1.01, 95%CI −7.51-5.49 P = 0.76) between TDM and non-TDM groups. Subgroup analyses showed there were no differences in duration of vancomycin therapy. Only one study reported mortality rates.</p><p>Conclusions</p><p>Studies to date show that TDM significantly increases the rate of clinical efficacy and decreases the rate of nephrotoxicity in patients treated with vancomycin.</p></div

Recommendations from CPGs.

<p>NR: not reported.</p>a<p>Higher levels may be required in specific situations as directed by the microbiologist.</p

Characteristics of clinical practice guideline.

<p>AME: American; ASHP: American Society of Health-System Pharmacists; IDSA: Infectious Diseases Society of America; SIDP: Society of Infectious Diseases Pharmacists; LOS: Los Angeles; VAGLAHS: VA Greater Los Angeles Healthcare System; JAP: Japanese; JSC: Japanese Society of Chemotherapy; JSTDM: Japanese Society of Therapeutic Drug Monitoring. VAN: Vancouver; VCH: Vancouver Costal Health; PHC: Providence Health Care; AHS: ALB: Alberta; Alberta Health Services; NHS: National Health Services; File NHS ADTC: File National Health Services Board Area Drugs and Therapeutics Committee; CAL: Calderdale; CHNHS: Calderdale and Huddersfield NHS; DEV: Devon; RDENHS: Royal Devon and Exeter NHS; COR: Cornwall; RCHNHS: Royal Cornwall Hospitals NHS; BAT: Bath; RUHBNHS: Royal United Hospitals Bath NHS; SAP: Scottish Antimicrobial Prescribing; SAPG: Scottish Antimicrobial Prescribing Group; WOR: Worcestershire; WAHNHS: Worcestershire Acute Hosptials NHS; NR: not reported.</p

Flow chart for the systematic review.

<p>Flow chart for the systematic review.</p