Comparison of Animal Models for Premature Ovarian Insufficiency Induced by Different Doses of Cyclophosphamide: a Network Meta‑analysis

IntroductionCyclophosphamide (CTX), is reported to be extensively used to establish POI animal model. But the most effective dose has not been systematically concluded yet. This systematic review and network meta-analysis is aimed to compare and rank the different doses of cyclophosphamide in the CTX-induced POI rat model.MethodsRandomized controlled trials of CTX-induced rat POI model were searched in four databases from inception to December, 2021. A network meta-analysis was conducted to analyze the data of included publications. The quality assessment was assessed by SYRCLE’s risk of bias tool. Data were analyzed with STATA 15.0 and Review Manager 5.3.Result205 records were searched and a total of 14 articles met inclusion criteria, Compared by Ovarian morphological changes, estrous cycle and hormone level (FSH, E2, AMH), the loading dose of 200mg/kg CTX with the maintenance dose of 8mg/kg CTX for consecutive 14 days showed the best efficacy in inducing rat POI model.

Optimized loading dose strategies for bedaquiline when restarting interrupted drug-resistant tuberculosis treatment

Interruption of treatment is common in drug-resistant tuberculosis patients. Bedaquiline has a long terminal half-life therefore, restarting after an interruption without a loading dose could increase the risk of suboptimal treatment outcome and resistance development. We aimed to identify the most suitable loading dose strategies for bedaquiline restart after an interruption. A model-based simulation study was performed. Pharmacokinetic profiles of bedaquiline and its metabolite M2 (associated with QT-prolongation) were simulated for 5000 virtual patients for different durations and starting points of treatment interruption. Weekly bedaquiline area under the concentration-time curve (AUC) and M2 maximum concentration (Cmax) deviation before interruption and after reloading were assessed to evaluate the efficacy and safety respectively of the reloading strategies. Bedaquiline weekly AUC and M2 Cmax deviation were mainly driven by the duration of interruption and only marginally by the starting point of interruption. For interruptions with a duration shorter than two weeks, no new loading dose is needed. For interruptions with durations between two weeks and one month, one month and one year, and longer than one year, reloading periods of three days, one week, and two weeks, respectively, are recommended. This reloading strategy results in an average bedaquiline AUC deviation of 1.88% to 5.98% compared with -16.4% to -59.8% without reloading for interruptions of two weeks and one year respectively, without increasing M2 Cmax. This study presents easy-to-implement reloading strategies for restarting a patient on bedaquiline treatment after an interruption.

Drug Utilization Evaluation of Colistin: A Retrospective Study

Background: Colistin, is used as the last treatment line for infections concluded from multiple drug-resistant gram-negative microorganisms. Increased consumption of colistin leads to resistance to this antibiotic in many countries. This study investigated the usage pattern of colistin administration in a selected hospital in Iran. Methods: This study was conducted in a selected hospital in Ahvaz. Inclusion criteria were all patients who received colistin during this time according to the health information system. Patients who were received less than three doses of colistin were excluded from the study. Prescription of colistin in all patients was evaluated according to the protocol extracted from the last version of Lexicomp written by Wolters Kluwer. The descriptive and analytical statistics were carried out by the R software. Results: Among 27 patients who received colistin, pneumonia (30%) was the main diagnoses. Colistin administration was based on the microbiological culture data in 70% of cases. Considering the involved microorganism, most cases were Acinetobacter spp., followed by Klebsiella spp. Loading dose was prescribed for seven (26%) patients. In only five (19%) cases, colistin dosing, including loading dose, maintenance dose, and the interval of colistin administration, was appropriate during the study time. Increasing in serum creatinine was seen in two (7.4%) patients. In 29.4% of patients, the combination of colistin and carbapenems was observed. Conclusion: Given the lack of appropriate dose adjustment of colistin that may lead to incidence of resistance and adverse effect, applying of the specialist clinical pharmacist will be suggested.

Effects of Dexmedetomidine on Perioperative Serum Potassium and Postoperative Rehabilitation of Patients Undergoing Radical Resection of Gastrointestinal Malignancy

Background: To investigate the effects of dexmedetomidine on perioperative potassium and postoperative rehabilitation. Methods: Totally 124 patients scheduled for elective radical resection of gastrointestinal malignant tumor under general anesthesia were included. and randomly assigned to four groups (n=31): groups D1, D2 and D3 received dexmedetomidine loading dose 1, 1 and 0.5 μg/kg and maintenance dose 0.25, 0.5 and 0.5 μg/kg/h, respectively, group C received normal saline 50 ml/h for 10 min and maintenance dose 10 ml/h. Serum potassium and lactate changes were recorded at 5 min after arteriovenous puncture (T1), 1 h after surgery beginning (T6), surgery ending (T7) and 1 h into the post-anesthesia care unit (PACU) (T10). Serum potassium was examined at 48 h after surgery (T11). Perioperative rehabilitation indicators were recorded.Results: Compared with basal values, serum potassium concentration in groups C, D1 and D2 increased significantly at T11 (P=0.003, 0.002, and ˂0.001, respectively) and at T7 (P=0.008), T10 (P=0.015) and T11 (P˂0.001) in group D3. Serum potassium at T11 in group D2 was significantly lower than group C (P=0.032). Serum potassium at T7 in group D3 was significantly higher than group D2 (P=0.036). There were no significant differences in perioperative rehabilitation indicators in all groups. Conclusions: Dexmedetomidine did not decrease perioperative potassium significantly in patients undergoing radical resection of gastrointestinal malignancy, while its loading dose 0.5 μg/kg and maintenance dose 0.5 μg/kg/h can elevate potassium slightly with no adverse effect on perioperative rehabilitation.Trial registration: This study was retrospectively registered on the clinicaltrials.gov website (registration number: NCT04771637).

Clinical Efficacy and Nephrotoxicity of the Loading Dose Colistin for the Treatment of Carbapenem-Resistant Acinetobacter baumannii in Critically Ill Patients

Carbapenem-resistant Acinetobacter baumannii (CRAB) is one of the most common causes of nosocomial infections in critically ill patients. Colistin methanesulfonate (CMS), an inactive prodrug, has been considered as a last-resort treatment for CRAB infection in critically ill patients. The objective of this study was to assess 30-day survival and nephrotoxicity in critically ill patients who received non-loading dose (LD) versus LD of CMS for CRAB infection treatment. Between 2012 and 2017, this retrospective cohort analysis was performed at Chiang Mai University Hospital (CMUH), focusing on critically ill patients with CRAB infection who received either non-LD or LD of CMS. A total of 383 patients met the criteria for inclusion. At the 30th day of treatment, the survival rate of patients in the LD CMS group was 1.70 times (adjusted HR) of those in the non-LD group (95% CI = 1.17–2.50, p = 0.006). Clinical response was significantly higher in the LD CMS group than non-LD CMS group (aHR, 1.35, 95% CI, 1.01–1.82, p = 0.046). In addition, a microbiological response—eradication of pre-treatment isolated pathogens in post-treatment cultures—in patients with LD CMS was 1.57 times that of patients with non-LD CMS (95% CI, 1.15–2.15, p = 0.004). Additionally, there was a significant difference in nephrotoxicity between LD CMS and non-LD CMS (aHR, 1.57, 95% CI, 1.14–2.17, p = 0.006). Based on these results, LD CMS should be used to increase the opportunity of patients to achieve favourable outcomes. However, LD CMS was found associated with an increase in nephrotoxicity, so renal function should be closely monitored when LD colistin was administered.

Assessing Nephrotoxicity Associated With Different Vancomycin Dosing Modalities in Obese Patients at a Community Hospital

Background: Vancomycin requires therapeutic drug monitoring (TDM) based on its pharmacokinetic properties, and guidelines have shifted to analyzing area under the curve over 24 hours (AUC24) rather than trough concentrations due to nephrotoxicity concerns and correlation to efficacy. Obesity is an established risk factor for vancomycin-induced nephrotoxicity due to increased drug exposure based on dosing calculations and volume of distribution estimation. The aim of this study is to assess the relationship between AUC-based versus trough-based dosing and nephrotoxicity among obese patients receiving vancomycin. Methods: This research project was conducted as a retrospective, observational, single-centered study which included obese adults who received at least 48 hours of vancomycin. The electronic medical record provided data for patients with vancomycin pharmacokinetic consults either evaluated with trough-only or AUC-based dosing. The primary objective was to compare the development of nephrotoxicity after vancomycin initiation, while secondary objectives included vancomycin loading dose exposure, total daily dose of vancomycin, and whether target TDM was attained. Nominal data were evaluated utilizing the chi-square test and continuous data using the independent samples t-test or Mann-Whitney test. The a priori level of significance was .05. Data analysis was performed using Microsoft Excel and SAS statistical software. Results: Two hundred fifty-four patients were included in the primary analysis. Four patients in the AUC cohort (6.3%) developed nephrotoxicity compared to 32 (17.4%) in the trough cohort ( P = .035). Both cohorts received a median of 4 days of therapy; however, the median loading dose per actual body weight in the AUC cohort was 20 mg/kg as compared to 16 mg/kg in the trough cohort. Of the 130 patients with available TDM in the trough cohort, 97 (74.6%) did not meet target attainment as compared to 15 of the 57 in the AUC cohort (26.3%) ( P < .001). Conclusions: AUC dosing was associated with a statistically significant reduction in AKI occurrence despite overall higher loading dose exposure as compared to the trough cohort. Though maintenance dose exposure was similar between both cohorts, patients in the AUC cohort maintained therapeutic concentrations at a higher percentage than the trough cohort.

Exploring population pharmacokinetic models in patients treated with vancomycin during continuous venovenous haemodiafiltration (CVVHDF)

Background Therapeutic antibiotic dose monitoring can be particularly challenging in septic patients requiring renal replacement therapy. Our aim was to conduct an exploratory population pharmacokinetic (PK) analysis on PK of vancomycin following intermittent infusion in critically ill patients receiving continuous venovenous haemodiafiltration (CVVHDF); focussing on the influence of dialysis-related covariates. Methods This was a retrospective single-centre tertiary level intensive care unit (ICU) study, which included patients treated concurrently with vancomycin and CVVHDF between January 2015 and July 2016. We extracted clinical, laboratory and dialysis data from the electronic healthcare record (EHR), using strict inclusion criteria. A population PK analysis was conducted with a one-compartment model using the PMetrics population PK modelling package. A base structural model was developed, with further analyses including clinical and dialysis-related data to improve model prediction through covariate inclusion. The final selected model simulated patient concentrations using probability of target attainment (PTA) plots to investigate the probability of different dosing regimens achieving target therapeutic concentrations. Results A total of 106 vancomycin dosing intervals (155 levels) in 24 patients were examined. An acceptable 1-compartment base model was produced (Plots of observed vs. population predicted concentrations (Obs–Pred) R2 = 0.78). No continuous covariates explored resulted in a clear improvement over the base model. Inclusion of anticoagulation modality and vasopressor use as categorical covariates resulted in similar PK parameter estimates, with a trend towards lower parameter estimate variability when using regional citrate anti-coagulation or without vasopressor use. Simulations using PTA plots suggested that a 2 g loading dose followed by 750 mg 12 hourly as maintenance dose, commencing 12 h after loading, is required to achieve adequate early target trough concentrations of at least 15 mg/L. Conclusions PTA simulations suggest that acceptable trough vancomycin concentrations can be achieved early in treatment with a 2 g loading dose and maintenance dose of 750 mg 12 hourly for critically ill patients on CVVHDF.