Expert Review of Clinical Pharmacology最新文献

Background: Single nucleotide polymorphisms (SNPs) in the N-acetyltransferase 2 (NAT2) gene as well as several other clinical factors can contribute to the elevation of liver function test values in tuberculosis (TB) patients receiving antitubercular therapy (ATT).

Research design and methods: A prospective study involving dynamic monitoring of the liver function tests among 130 TB patients from baseline to 98 days post ATT initiation was undertaken to assess the influence of pharmacogenomic and clinical variables on the elevation of liver function test values. Genomic DNA was extracted from serum samples for the assessment of NAT2 SNPs. Further, within this study population, we conducted a case control study to identify the odds of developing ATT-induced drug-induced liver injury (DILI) based on NAT2 SNPs, genotype and phenotype, and clinical variables.

Results: NAT2 slow acetylators had higher mean [90%CI] liver function test values for 8-28 days post ATT and higher odds of developing DILI (OR: 2.73, 90%CI: 1.05-7.09) than intermediate acetylators/rapid acetylators.

Conclusion: The current study findings provide evidence for closer monitoring among TB patients with specific NAT2 SNPs, genotype and phenotype, and clinical variables, particularly between the period of more than a week to one-month post ATT initiation for better treatment outcomes.

Background: Concerns regarding statin-related neurocognitive disorders have emerged in recent years. However, previous studies have reported inconsistent results. We evaluated the association between statins and neurocognitive disorders using the FDA Adverse Event Reporting System (FAERS).

Research design and methods: Data from 2004 to 2022 were obtained from the FAERS database. After deduplication and standardization of drug names, we extracted neurocognitive disorder event (NCDE) cases reported with statins as the suspected drugs. The significant association between statins and NCDE was evaluated using the reporting odds ratio (ROR) and information component.

Results: In total, 6,959 NCDE cases with statins as the primary suspected drugs were identified. Signals were detected in pravastatin (ROR, 1.49; 95% CI: 1.32-1.67), atorvastatin (ROR, 1.39; 95% CI: 1.34-1.44), and simvastatin (ROR, 1.31; 95% CI: 1.25-1.38). Age-stratified analysis showed that (1) in the population aged 65 years and older, signals were detected for atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin, fluvastatin, and pitavastatin; and (2) in populations under 65 years of age, signals were detected for atorvastatin, simvastatin, rosuvastatin, pravastatin, and lovastatin.

Conclusions: This study suggests a significant association between the NCDE and statins, including atorvastatin, simvastatin, and pravastatin. The intensity of the association increased with age.

Introduction: Diabetes is a global public health challenge with rising prevalence. This review explores current diabetes understanding, diagnostic and management guidelines, economic impact, and lifestyle modifications as the primary approach.

Areas covered: Focusing on pharmacological interventions, we discuss the roles of GLP-1 agonists and GLP/GIP agonists in diabetes management and cardiovascular risk reduction. Tirzepatide, a novel medication, is highlighted for its unique mechanism of action. Clinical trials demonstrate its effectiveness in glucose control, weight reduction, and its potential impact on diabetes, obesity, NASH, and cardiovascular risks.

Expert opinion: Tirzepatide shows promise in diabetes treatment, offering glucose control and weight loss. It also holds potential for addressing comorbidities. However, cautious use is vital due to potential adverse effects and contraindications, including hypersensitivity reactions, pregnancy, and breastfeeding precautions. This review underscores tirzepatide as a valuable addition to diabetes therapies, with evolving prospects for enhanced patient outcomes as research advances.

Objective: The present network meta-analysis (NMA) was conducted to compare and generate evidence for the most efficacious treatment among available pharmacological interventions for treatment-resistant schizophrenia (TRS).

Methods: Reviewers extracted data from 47 studies screened from PubMed/MEDLINE, Embase, Cochrane databases and clinical trial registries fulfilling the eligibility criteria. Random effects Bayesian NMA was done with non-informative priors. Network geometry was visualized, and node splitting was done for the closed triangles. Standardized mean difference and 95% credible interval(95%CrI) were reported for the reduction in symptom severity scores. The probability of each intervention for each rank was plotted. Meta-regression was done for the duration of the therapy.

Results: Augmentation of antipsychotics with escitalopram (SMD: -1.7[95%CrI: -2.8, -0.70]), glycine (SMD: -1.2 [95%CrI: -2.2, -0.28]) and Yokukansan (SMD: -1.3 [95%CrI: -2.4, -0.24]) shows a statistically significant reduction in symptom severity when compared to clozapine. As per surface under cumulative ranking curve analysis, escitalopram in combination with antipsychotics appeared to be the best intervention with moderate certainty of evidence. There was no significant effect of the duration of therapy on the treatment effects.

Conclusion: Escitalopram augmentation of antipsychotics appears to be the most efficacious treatment with moderate certainty of evidence among the available pharmacological interventions.

Prospero registration: CRD42022380292.

Objective: We assessed pharmacokinetic correlates of treatment response to escitalopram using a large therapeutic drug monitoring database.

Methods: A large naturalistic sample of patients receiving escitalopram was analyzed. Responders were defined as 'very much improved' or 'much improved' based on the Clinical Global Impression - Improvement score, CGI-I. We compared responders (n = 83) vs. non-responders (n = 388) with the primary outcome being the escitalopram plasma concentration and concentration corrected by the daily dose (C/D ratio). Effects of age, sex, body-mass-index (BMI), and C/D ratio were assessed in a multivariate logistic regression model predicting response.

Results: There were no statistically significant differences in clinical and demographic characteristics between responders vs. non-responders. There were also no differences between escitalopram daily doses or plasma concentrations, while C/D ratios were significantly higher in non-responders than in responders (1.6 ± 1.7 vs. 1.2 ± 0.9 (ng/mL)/(mg/day), p = 0.007); C/D ratios (odds ratio 0.52, 95% confidence interval 0.34-0.80, p < 0.003) were associated with response to escitalopram, after controlling for age, sex, and BMI.

Conclusions: Patients with low clearance of escitalopram as reflected upon high C/D ratios may be less likely respond to escitalopram. Identifying these patients during dose titration may support clinical decision-making, including switching to a different antidepressant instead of increasing daily dose.

Introduction: Tyrosine kinase inhibitors (TKIs) have revolutionized survival rates of chronic myeloid leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) and replaced hematopoietic stem cell transplantation (hSCT) as the key treatment option for these patients. More recently, the so-called Philadelphia chromosome-like (Ph-like) ALL has similarly benefitted from TKIs. However, many patients shift from the first generation TKI, imatinib, due to treatment-related toxicities or lack of treatment efficacy. A more personalized approach to TKI treatment could counteract these challenges and potentially be more cost-effective. Therapeutic drug monitoring (TDM) has led to higher response rates and less treatment-related toxicity in adult CML but is rarely used in ALL or in childhood CML.

Areas covered: This review summarizes different antileukemic treatment indications for TKIs with focus on imatinib and its pharmacokinetic/-dynamic properties as well as opportunities and pitfalls of TDM for imatinib treatment in relation to pharmacogenetics and co-medication for pediatric and adult Ph+/Ph-like leukemias.

Expert opinion: TDM of imatinib adds value to standard monitoring of ABL-class leukemia by uncovering non-adherence and potentially mitigating adverse effects. Clinically implementable pharmacokinetic/-dynamic models adjusted for relevant pharmacogenetics could improve individual dosing. Prospective trials of TDM-based treatments, including both children and adults, are needed.

Introduction: This systematic review aimed to compare the effect of alternative levothyroxine administration regimens on thyroid hormone levels and patient-reported outcomes (PROs) among adults with hypothyroidism.

Methods: We searched PubMed, Embase, CENTRAL, CINAHL, LILACS, SciELO, Scopus, Web of Science, OpenGrey, ProQuest, ClinicalTrials.gov, and ICTRP from inception to May/2023 for randomized controlled trials (RCTs). We assessed the risk of bias with Cochrane Risk of Bias 2.0 tool. We analyzed TSH levels by pairwise and network meta-analyses (NMA). The FT4 levels and PROs were qualitatively assessed.

Results: We included 14 RCTs (906 participants) comparing different regimens, as bedtime vs. before breakfast. A total of 12 RCTs were at high risk of bias. Seven RCTs were included in the TSH meta-analysis, where the mean difference (MD) and 95% confidence interval (CI) were as follows: bedtime vs before breakfast (4 RCTs) 0.69 (-1.67-3.04), I² = 92%, very low certainty evidence; weekly dose vs before breakfast (2 RCTs) 1.68 (0.94-2.41), I² = 0%, low certainty evidence; and at breakfast vs before breakfast (1 RCT) 0.65 (-1.11-2.41), very low certainty evidence. The NMA showed no evidence of differences in TSH level with different regimens.

Conclusion: The evidence is insufficient to determine the most effective levothyroxine administration regimen for hypothyroidism.

Systematic review registration: PROSPERO - CRD42021279375.

Introduction: Kratom (Mitragyna speciosa) has generated substantial clinical and scientific interest as a complex natural product. Its predominant alkaloid mitragynine and several stereoisomers have been studied for activity in opioid, adrenergic, and serotonin receptors. While awaiting clinical trial results, the pre-clinical evidence suggests a range of potential therapeutic applications for kratom with careful consideration of potential adverse effects.

Areas covered: The focus of this review is on the pharmacology, pharmacokinetics, and potential drug-drug interactions of kratom and its individual alkaloids. A discussion on the clinical pharmacology and toxicology of kratom is followed by a summary of user surveys and the evolving concepts of tolerance, dependence, and withdrawal associated with kratom use disorder.

Expert opinion: With the increasing use of kratom in clinical practice, clinicians should be aware of the potential benefits and adverse effects associated with kratom. While many patients may benefit from kratom use with few or no reported adverse effects, escalating dose and increased use frequency raise the risk for toxic events in the setting of polysubstance use or development of a use disorder.