Kinetic-pharmacodynamic model of warfarin for prothrombin time-international normalized ratio in Japanese patients.

AIMS: Genotype-guided dosing algorithms can explain about half of the interindividual variability in prothrombin time-international normalized ratio (PT-INR) under warfarin treatment. This study aimed to refine a published kinetic-pharmacodynamic model and guide warfarin dosage for an optimal PT-INR based on renal function. METHODS: Using a retrospective cohort of adult patients (>20 years) who were administered warfarin and underwent PT-INR measurements, we refined the kinetic-pharmacodynamic model with age and the genotypes of cytochrome P450 2C9 and vitamin K epoxide reductase complex subunit 1 using the PRIOR subroutine in the nonlinear-mixed-effect modelling programme. We searched the significant covariates for parameters, such as the dose rate for 50% inhibition of coagulation (EDR50 ), using a stepwise forward and backward method. Monte Carlo simulation determined a required daily dose of warfarin with a target range of PT-INR (2.0-3.0 or 1.6-2.6) based on the significant covariates. RESULTS: A total of 350 patients with 2762 PT-INR measurements were enrolled (estimated glomerular filtration rate [eGFR]: 47.5 [range: 2.6-199.0] mL/min/1.73 m2 ). The final kinetic-pharmacodynamic model showed that the EDR50 changed power functionally with body surface area, serum albumin level and eGFR. Monte Carlo simulation revealed that a lower daily dose of warfarin was required to attain the target PT-INR range as eGFR decreased. CONCLUSIONS: Model-informed precision dosing of warfarin is a valuable approach for estimating its dosage in patients with renal impairment.

Development of a therapeutic drug-monitoring algorithm for outpatients receiving voriconazole: A multicentre retrospective study.

AIMS: Although therapeutic drug monitoring (TDM) of voriconazole is performed in outpatients to prevent treatment failure and toxicity, whether TDM should be performed in all or only selected patients remains controversial. This study evaluated the association between voriconazole trough concentrations and clinical events. METHODS: We investigated the aggravation of clinical symptoms, incidence of hepatotoxicity and visual disturbances, change in co-medications and interaction between voriconazole and co-medications in outpatients receiving voriconazole between 2017 and 2021 in three facilities. Abnormal trough concentrations were defined as <1.0 mg/L (low group) and >4.0 mg/L (high group). RESULTS: A total of 141 outpatients (578 concentration measurements) met the inclusion criteria (treatment, 37 patients, 131 values; prophylaxis, 104 patients, 447 values). The percentages of patients with abnormal concentrations were 29.0% and 31.5% in the treatment and prophylaxis groups, respectively. Abnormal concentrations showed 50% of the concentrations at the first measurement in both therapies. Aggravation of clinical symptoms was most frequently observed in the low treatment group (18.2%). Adverse events were most common in the high group for both therapies (treatment, hepatotoxicity 6.3%, visual disturbance 18.8%; prophylaxis, hepatotoxicity 27.9%). No differences were found in changes to co-medications and drug interactions. In the prophylaxis group, prescription duration in the presence of clinical events tended to be longer than in their absence (47.4 ± 23.4 days vs 39.7 ± 21.9 days, P = .1132). CONCLUSIONS: We developed an algorithm based on clinical events for appropriate implementation of TDM in outpatients. However, future interventions based on this algorithm should be validated.

Comparison of clinical efficacy and safety of baloxavir marboxil versus oseltamivir as the treatment for influenza virus infections: A systematic review and meta-analysis.

INTRODUCTION: Baloxavir marboxil (BXM), a newly developed cap-dependent endonuclease inhibitor, is widely used to treat influenza virus infections in inpatients and outpatients. A previous meta-analysis included only outpatients and patients suspected of having an influenza virus infection based on clinical symptoms. However, whether BXM or oseltamivir is safer and more effective for inpatients remains controversial. Therefore, we conducted a systematic review and meta-analysis validating the effectiveness and safety of BXM versus oseltamivir in inpatients with influenza virus. METHODS: The Scopus, EMBASE, PubMed, Ichushi, and CINAHL databases were systematically searched for articles published until January 2023. The outcomes were mortality, hospitalization period, incidence of BXM- or oseltamivir-related adverse events, illness duration, and changes of virus titers and viral RNA load in patients with influenza virus infections. RESULTS: Two randomized controlled trials with 1624 outpatients and two retrospective studies with 874 inpatients were enrolled. No deaths occurred in outpatients treated with BXM or oseltamivir. Among inpatients, BXM reduced mortality (p = 0.06) and significantly shortened hospitalization period (p = 0.01) compared to oseltamivir. In outpatients, BXM had a significantly lower incidence of adverse events (p = 0.03), reductions in influenza virus titers (p < 0.001) and viral RNA loads (p < 0.001), and a tendency to be a shorter illness duration compared with that of oseltamivir (p = 0.27). CONCLUSIONS: Our meta-analysis showed that BXM was safer and more effective in patients than oseltamivir; thus, supporting the use of BXM for the initial treatment of patients with proven influenza virus infection.

Safety and dose-finding trial of tadalafil administered for fetus in labor: A phase I clinical study.

AIM: This study aimed to investigate the safety and efficacy of tadalafil in protecting the fetus from hypoxic stress caused by repeated labor pains during delivery and preventing fetal hypoxic-ischemic encephalopathy. METHODS: The study used a three-case cohort approach. Three patients were administered 10 mg tadalafil and monitored for serious adverse events. In the absence of serious tadalafil-associated adverse events as assessed by the Safety Evaluation Committee, three new patients were added to the study and treated with 20 mg/dose. The blood levels of tadalafil were recorded before and after 2, 4, 8, and 12 h of administration and 2 h after delivery. RESULTS: A total of seven patients were enrolled, and after excluding one patient who delivered before 37 weeks, tadalafil was administered to six patients. Maternal adverse events were considered acceptable from the maternal perspective, with grade 1 headache, anorexia, and myalgia and no obstetrical complications after delivery at both doses. No serious neonatal adverse events were associated with tadalafil. Tadalafil blood levels remained stable at both doses. In addition, the level of soluble fms-like tyrosine kinase-1 did not alter, while that of the placental growth factor differed significantly before and after tadalafil administration. CONCLUSIONS: The study confirmed the safety of tadalafil administration during delivery for both mothers and newborns. The stable tadalafil blood levels confirmed the efficacy of the tested administration regime at 12 h interval. These findings would assist in conducting phase II trials to further verify the optimal dose and safety of tadalafil.

Impact of glycaemic control and CYP3A5 polymorphisms on tacrolimus trough concentrations after adult kidney transplantation.

AIMS: Diabetes mellitus affects the pharmacokinetics of cytochrome P450 3A4/5 (CYP3A4/5) substrates. We evaluated the relationship between haemoglobin A1c (HbA1c) levels and the pharmacokinetics of controlled-release tacrolimus. METHODS: This retrospective observational cohort study included kidney transplant recipients (>18 years) receiving controlled-release tacrolimus orally. CYP3A5 genotypes were categorized as expressers (*1/*1 or *1/*3) and non-expressers (*3/*3). Multiple linear regression analysis determined the predictors for trough concentration/dose-normalized by body weight (C/D) ratio of tacrolimus at 7 days, 6 months and 12 months after administration. Correlations between the C/D ratio and HbA1c levels at baseline, 6 and 12 months after tacrolimus initiation were evaluated with Bonferroni correction. RESULTS: Out of 42 patients (CYP3A5 expressers, n = 17, and non-expressers, n = 25), the multiple linear regression analysis showed that the C/D ratio on Day 7 was marginally higher in CYP3A5 non-expressers than in CYP3A5 expressers (r = .43, P = .028). Factors affecting the elevation of tacrolimus C/D ratio after 6 and 12 months of treatment were male sex and CYP3A5 non-expressers (r = .59, P < .001) and increased HbA1c levels and CYP3A5 non-expressers (r = .62, P < .001), respectively. The C/D ratio and HbA1c levels after 12 months was positively correlated in CYP3A5 non-expressers (y = 54.6x - 194.6, r = .63, P = .004, Bonferroni correction). Furthermore, intra-individual changes in the C/D ratio and HbA1c levels from 6 to 12 months were nearly correlated (y = 54.5x + 20.2, r = .41, P = .036, Bonferroni correction). CONCLUSION: HbA1c and CYP3A5 genotypes might be considered to understand the inter- and intra-individual variability in blood tacrolimus concentrations after 6 months post-kidney transplantation.

Variations in prothrombin time-international normalized ratio caused by drug-drug interaction in patients receiving warfarin: A retrospective observational study.

OBJECTIVES: Drug-drug interactions between warfarin and cytochrome P450 (CYP) 2C9 inhibitors and inducers are well known. Few studies have clarified the clinical impact of CYP2C9 inhibitors and inducers on warfarin therapy. Here, we evaluated the clinical impact of CYP2C9-mediated interactions on the pharmacodynamics of warfarin. MATERIALS AND METHODS: This retrospective observational study enrolled patients who received warfarin between 2008 and 2020 at Mie University Hospital. We defined prothrombin time-international normalized ratio/daily warfarin dose (PT-INR/dose) as the primary outcome and conducted a multiple linear regression analysis to clarify the factors that affected the primary outcome. Additionally, we examined the clinical features of patients who received CYP2C9 inducers. RESULTS: Out of 1,393 patients, 17 (1.2%) received carbamazepine, rifampicin, phenobarbital, or phenytoin as CYP2C9 inducers. Multiple linear regression analysis indicated that age, body mass index (BMI), serum albumin (Alb), estimated glomerular filtration rate (eGFR), and CYP2C9 inducers were associated with PT-INR/dose. The multiple regression equation was as follows: PT-INR/dose = 1.590 + 0.004 × age - 0.020 × BMI - 0.141 × Alb - 0.001 × eGFR - 0.149 × (if concomitant use of CYP2C9 inducers) (adjusted coefficient of determination = 0.106, Akaike information criterion = 267.3, p < 0.001). In patients receiving CYP2C9 inducers, lower PT-INR/dose values were observed regardless of co-administered CYP2C9 inhibitors. CONCLUSION: In addition to age, BMI, Alb, and eGFR, concomitant use of CYP2C9 inducers should be considered when adjusting the warfarin dose and PT-INR.

A systematic review and meta-analysis of efficacy and safety of isavuconazole for the treatment and prophylaxis of invasive fungal infections.

BACKGROUND: Isavuconazole is a novel triazole antifungal agent. However, the previous outcomes were highlighted by statistical heterogeneity. This meta-analysis aimed to validate the efficacy and safety of isavuconazole for the treatment and prophylaxis of invasive fungal infections (IFIs) compared with other antifungal agents (amphotericin B, voriconazole and posaconazole). METHODS: Scopus, EMBASE, PubMed, CINAHL and Ichushi databases were searched for relevant articles that met the inclusion criteria through February 2023. Mortality, IFI rate, discontinuation rate of antifungal therapy and incidence of abnormal hepatic function were evaluated. The discontinuation rate was defined as the percentage of therapy discontinuations due to adverse events. The control group included patients who received other antifungal agents. RESULTS: Of the 1784 citations identified for screening, 10 studies with an overall total of 3037 patients enrolled. Isavuconazole was comparable with the control group in mortality and IFI rate in the treatment and prophylaxis of IFIs, respectively (mortality, odds rate (OR) 1.11, 95% confidential interval (CI) 0.82-1.51; IFI rate, OR 1.02, 95% CI 0.49-2.12). Isavuconazole significantly reduced the discontinuation rate in the treatment (OR 1.96, 95% CI 1.26-3.07) and incidence of hepatic function abnormalities in the treatment and prophylaxis, compared with the control group (treatment, OR 2.31, 95% CI 1.41-3.78; prophylaxis, OR 3.63, 95% CI 1.31-10.05). CONCLUSIONS: Our meta-analysis revealed that isavuconazole was not inferior to other antifungal agents for the treatment and prophylaxis of IFIs, with substantially fewer drug-associated adverse events and discontinuations. Our findings support the use of isavuconazole as the primary treatment and prophylaxis for IFIs.

Clinical risk factors for severity and prognosis of antiresorptive agent-related osteonecrosis of the jaw: a retrospective observational study.

INTRODUCTION: The incidence of antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is rare, and its management has not yet been established. This study aimed to investigate the predictors for advanced stage and healing of ARONJ to establish an appropriate treatment strategy. MATERIALS AND METHODS: We retrospectively analyzed patients diagnosed with ARONJ at Kobe City Medical Center General Hospital between April 2014 and March 2020. Outcomes were defined as stage ≥ 2 ARONJ (primary) and healing of ARONJ (secondary). Multivariate logistic regression analysis was used to detect factors associated with the outcomes, and odds ratios (OR) and 95% confidence intervals (CI) were calculated. RESULTS: This study included 143 patients (stage ≥ 2 ARONJ, 51%; healing of ARONJ, 60%). Multivariate logistic regression analysis revealed that advanced age (per year) (OR 1.037; 95% CI 1.003-1.072; p = 0.028) and serum albumin (per g/dL) (OR 0.430; 95% CI 0.213-0.869; p = 0.018) were significantly associated with stage ≥ 2 ARONJ. Furthermore, multivariate logistic regression analysis revealed that cancer (yes) (OR 0.099; 95% CI 0.029-0.339; p < 0.001), conservative surgical treatment (yes) (OR 15.42; 95% CI 5.657-42.0; p < 0.001), C-reactive protein (per mg/dL) (OR 0.599; 95% CI 0.415-0.864; p < 0.001), and vitamin D analog (yes) (OR 0.167; 95% CI 0.034-0.827; p = 0.028) were factors associated with healing. CONCLUSION: Our findings suggest that age and hypoalbuminemia are associated with the severity of ARONJ, and cancer, high inflammation, and vitamin D analog may impair healing. In contrast, conservative surgical treatment can overcome the poor treatment outcomes associated with ARONJ.

Population Pharmacokinetic Model of Amiodarone and N-Desethylamiodarone Focusing on Glucocorticoid and Inflammation.

Some population pharmacokinetic models for amiodarone (AMD) did not incorporate N-desethylamiodarone (DEA) concentration. Glucocorticoids activate CYP3A4 activity, metabolizing AMD. In contrast, CYP3A4 activity may decrease under inflammation conditions. However, direct evidence for the role of glucocorticoid or inflammation on the pharmacokinetics of AMD and DEA is lacking. The pilot study aimed to address this gap using a population pharmacokinetic analysis of AMD and DEA. A retrospective cohort observational study in adult patients who underwent AMD treatment with trough concentration measurement was conducted at Tokyo Women's Medical University, Medical Center East from June 2015 to March 2019. Both structural models of AMD and DEA applied 1-compartment models, which included significant covariates using a stepwise forward selection and backward elimination method. The eligible 81 patients (C-reactive protein level: 0.26 [interquartile range; 0.09-1.92] mg/dL) had a total of 408 trough concentrations for both AMD and DEA. The median trough concentrations were 0.49 [0.31-0.81] µg/mL for AMD and 0.43 [0.28-0.71] µg/mL for DEA during a median follow-up period of 446 [147-1059] d. Three patients received low-dose oral glucocorticoid. The final model identified that AMD clearance was 7.9 L/h, and the apparent DEA clearance was 10.3 L/h. Co-administered glucocorticoids lowered apparent DEA clearance by 35%. These results indicate that co-administered glucocorticoids may increase DEA concentrations in patients without severe inflammation.

External Evaluation of a Bayesian Warfarin Dose Optimization Based on a Kinetic-Pharmacodynamic Model.

Warfarin is a representative anticoagulant with large interindividual variability. The published kinetic-pharmacodynamic (K-PD) model allows the prediction of warfarin dose requirement in Swedish patients; however, its applicability in Japanese patients is not known. We evaluated the model's predictive performance in Japanese patients with various backgrounds and relationships using Bayesian parameter estimation and sampling times. A single-center retrospective observational study was conducted at Tokyo Women's Medical University, Medical Center East. The study population consisted of adult patients aged >20 years who commenced warfarin with a prothrombin time-international normalized ratio (PT-INR) from June 2015 to June 2019. The published K-PD model modified by Wright and Duffull was assessed using prediction-corrected visual predictive checks, focusing on clinical characteristics, including age, renal function, and individual prediction error. The external dataset included 232 patients who received an initial warfarin daily dose of 3.2 ± 1.28 mg with 2278 PT-INR points (median [range] follow-up period of 23 d [7-28]). Prediction-corrected visual predictive checks carried a propensity for underprediction. Additionally, age >60 years, body mass index ≤25 kg/m2, and estimated glomerular filtration rate ≤60 mL/min/1.73 m2 had a pronounced tendency to underpredict PT-INR. However, Bayesian prediction using four prior observations reduced underprediction. To improve the prediction performance of these special populations, further studies are required to construct a model to predict warfarin dose requirements in Japanese patients.

Drug-drug interaction between remdesivir and immunosuppressant agents in a kidney transplant recipient.

A 60-year-old man was treated with a regimen of controlled-release tacrolimus (2 mg once daily), everolimus (0.5 mg twice daily), methylprednisolone (4 mg once daily), and mizoribine (100 mg twice daily) as an anti-rejection regimen following living-donor kidney transplantation. One year after transplantation, the recipient was admitted to Mie University Hospital (day X; admission date) to treat coronavirus disease 2019 pneumonia. The latest trough concentrations of tacrolimus and everolimus before admission (day X-65) were 4.5 ng/mL and 4.4 ng/mL, respectively. Since tacrolimus concentration was 4.2 ng/mL on day X+3, the dose was adjusted to 1.5 mg once daily to reach the target concentration of 3.0 ng/mL due to the introduction of remdesivir. After starting remdesivir on day X+4, the increased trough concentrations of tacrolimus on day X+6 (6.9 ng/mL) and everolimus on day X+7 (9.2 ng/mL) were observed, which resulted in dose reduction of tacrolimus (0.5 mg once daily) and discontinuation of everolimus. After discontinuation of remdesivir on day X+9, dose titration of controlled-release tacrolimus and restart of everolimus (0.5 mg twice daily) were performed from day X+15. The dose of controlled-release tacrolimus was titrated and fixed to 2 mg once daily at discharge (day X+21). There was no toxicity due to immunosuppressive agents during hospitalization. This case report indicated that remdesivir might interact with cytochrome P450 3A4 substrates, such as tacrolimus and everolimus, and elevate their blood concentrations under high inflammatory conditions.

Systematic review and meta-analysis for impacts of oral antibiotic treatment on pregnancy outcomes in chronic endometritis patients.

BACKGROUND: Chronic endometritis is a persistent inflammatory condition of the endometrium that negatively affects pregnancy outcomes. The Centers for Disease Control and Prevention guidelines recommend oral antibiotic treatment for chronic endometritis. However, a recent randomized controlled trial concluded that it was unclear whether antibiotic treatment improved pregnancy outcomes. Hence, we performed a systematic review and meta-analysis to validate the impact of oral antibiotic treatments on pregnancy outcomes among patients with chronic endometritis. METHODS: We systematically searched the PubMed, Scopus, Ichushi, CINAHL, and EMBASE databases until May 2021. We compared the pregnancy outcomes in patients with chronic endometritis with and without antibiotic treatment. We then focused on the implantation rate, intrauterine pregnancy rate, and live birth rate to evaluate pregnancy outcomes. RESULTS: Seven studies were included in the meta-analysis. Three hundred seventy-two patients were treated with antibiotics, while 1024 patients were not treated with antibiotics. Various antibiotic regimens were administered during the study period [14-21 days]. Antibiotic treatments for chronic endometritis did not increase the implantation rate (odds ratios [OR] 1.02, 95% confidence interval [CI], 0.78-1.33), intrauterine pregnancy rate (OR 1.08, 95% CI 0.72-1.63), or live birth rate (OR 1.13, 95% CI 0.65-1.97). CONCLUSIONS: Our meta-analysis proved that oral antibiotic treatment did not improve pregnancy outcomes in patients with chronic endometritis. Accordingly, further studies are needed to elucidate the treatment to improve pregnancy outcomes.

Evaluation of bleeding and anticoagulation markers by edoxaban and low-dose cyclosporine: A case series study.

It was reported that high-dose cyclosporine at 500 mg daily increases edoxaban exposure. We investigated whether cyclosporine <500 mg daily leads to edoxaban-induced bleeding in the clinical setting. This case series study included patients receiving edoxaban and cyclosporine at Mie University Hospital. The outcomes were bleeding and anticoagulant markers, including activated partial thromboplastin time (APTT), prothrombin time (PT), and the international normalized ratio of prothrombin time (PT-INR). We examined the genotypes of cytochrome P450 3A5 (CYP3A5), multidrug resistance 1 (ABCB1), and solute carrier organic anion transporter 1B1 (SLCO1B1). Trends in anticoagulant markers were analyzed. Thirteen patients received edoxaban (standard dose; n = 3 and reduced dose; n = 10) and cyclosporine (1.94 ± 1.42 mg/kg). A bleeding event occurred in one patient receiving a standard dose of edoxaban plus cyclosporine of 25 mg daily (HAS-BLED score of 2 and genotypes; CYP3A5*3/*3, ABCB1 3435CT, and SLCO1B1*1a/*1b). After edoxaban treatment, anticoagulant markers were prolonged (APTT; 27.95 ± 3.64 s vs. 31.11 ± 3.90 s, p < 0.001, PT; 11.53 ± 1.01 s vs. 13.03 ± 0.98 s, p = 0.002, PT-INR; 0.98 ± 0.09 vs. 1.11 ± 0.11, p = 0.007). In summary, the genotypes of CYP3A5, ABCB1, and SLCO1B1 and the dosage of edoxaban may affect the risk of bleeding by edoxaban when co-administered with cyclosporine, even at low doses.

A systematic review and meta-analysis of decontamination methods to prevent hospital environmental contamination and transmission of Clostridioidesdifficile.

The current guidelines suggest that hospital rooms previously occupied with Clostridioides difficile infection (CDI) patients should be decontaminated with recommended decontamination methods because C. difficile can persist on surfaces despite adherence to the recommended procedures. Recently, ultraviolet (UV) light and hydrogen peroxide have increasingly been used as innovative decontamination methods. Hence, we conducted a systematic review and meta-analysis to investigate which decontamination methods are effective in reducing environmental C. difficile contamination. We systematically searched the EMBASE, PubMed, CINAHL, Scopus, and Ichushi until March 11, 2021. We evaluated the efficacy of decontamination methods in terms of the frequency of C. difficile contamination on high-touch surfaces in hospital rooms and the incidence of hospital-acquired C. difficile infection. Among the 15 studies retrieved in our meta-analysis, eight evaluated decontamination methods with the frequency of C. difficile detection among samples after disinfection procedures, and eight reported the number of hospital-acquired CDI cases. Pooled analysis indicated that hydrogen peroxide significantly reduced the frequency of environmental C. difficile contamination, compared with hypochlorite (odds ratios [OR]: 0.12; 95% confidence interval [CI]: 0.07-0.23). Additionally, hydrogen peroxide reduced the incidence of hospital-acquired CDI compared to other methods (OR: 0.52; 95% CI: 0.28-0.96). Decontamination with UV significantly reduced the incidence of hospital-acquired CDI compared to hypochlorite (OR 0.52, 95% CI 0.28-0.96). The use of hydrogen peroxide and UV can help prevent environmental C. difficile contamination and transmission in healthcare facilities.

Investigation of Biomarkers and Handling Strategy of Erlotinib-Induced Skin Rash in Rats.

Skin rash is a common adverse event associated with erlotinib therapy. In severe conditions, the rash could affect patients' QOL. If the rash occurrence can be predicted, erlotinib treatment failures can be prevented. We designed an in vivo study that applied erlotinib regimens resembling its clinical application to evaluate possible erlotinib-induced skin rash biomarkers for humans and simultaneously observe the effects of erlotinib discontinuation, followed with or without dose reduction, on rash development. Rats were divided into four groups: placebo, constant (erlotinib 35 mg/kg on d1-d21), intermittent (erlotinib 70 mg/kg on d1-d7 and d15-d21), and mimic (erlotinib 70 mg/kg on d1-d7 and erlotinib 35 mg/kg on d15-d21). Blood sampling was performed on d1, d8, d15, and d22. The samples were used to measure erlotinib concentrations, the level of hepatic and renal function markers, immune cell percentages, and immune cells' CD45 expression levels. Erlotinib 70 mg/kg generated high mean circulating erlotinib concentrations (>1800 ng/mL) that led to severe rashes. Erlotinib dose reduction following rash occurrence reduced circulating erlotinib concentration and rash severity. After the treatment, the escalation of neutrophil percentages and reduction of neutrophils' CD45 expression levels were observed, which were significantly correlated with the rash occurrence. This study is the first to show that erlotinib-induced skin rash may be affected by the reduction of neutrophils' CD45 expression levels, and this is a valuable finding to elucidate the erlotinib-induced skin rash formation mechanism.

Effect of high-dose sulfamethoxazole/trimethoprim and glucocorticoid use on hyperkalemic event: A retrospective observational study.

INTRODUCTION: Sulfamethoxazole/trimethoprim causes hyperkalemia; however, the effect of sulfamethoxazole/trimethoprim dose and co-administered glucocorticoids on hyperkalemia has not been clarified. METHODS: This single-center, retrospective, observational cohort, chart review study involving patients (>20 years) who were treated with sulfamethoxazole/trimethoprim was conducted at Tokyo Women's Medical University, Medical Center East from June 2015 to May 2019. Multivariate Cox proportional hazard model was used to identify risk factors for hyperkalemia (serum potassium level > 5.5 mEq/L). Additionally, Kaplan-Meier curve analyzed the cumulative incidence of hyperkalemia focusing on sulfamethoxazole/trimethoprim dose and concomitant use of glucocorticoids with mineralocorticoid activity. RESULTS: Among 333 patients, 44 (13%) patients developed hyperkalemia associated with sulfamethoxazole/trimethoprim use for over 49 (interquartile range; 17-233) days. We found associations between the time to hyperkalemia development and sulfamethoxazole/trimethoprim dose (hazard ratio 1.238, 95% confidence interval 1.147-1.338, p < 0.001) and glucocorticoid use (hazard ratio 0.678, 95% confidence interval 0.524-0.877, p = 0.003). Interestingly, the Kaplan-Meier curves revealed that the concomitant use of glucocorticoids did not attenuate the risk of hyperkalemia in patients receiving high-dose sulfamethoxazole/trimethoprim (p = 0.747), whereas concomitant use of glucocorticoids significantly reduced the risk of hyperkalemia in patients receiving non-high dose sulfamethoxazole/trimethoprim (p < 0.001). CONCLUSIONS: High-dose sulfamethoxazole/trimethoprim is a significant predictor of hyperkalemia. The effect of glucocorticoids on hyperkalemia varies depending on the sulfamethoxazole/trimethoprim dose.

Comparison of mortality between echinocandins and polyenes for an initial treatment of candidemia: A systematic review and meta-analysis.

BACKGROUND: Current guidelines recommend echinocandins for the initial treatment of candidemia. However, polyenes are often chosen in clinical settings because of their fungicidal and anti-biofilm effects. Therefore, we performed a systematic review and meta-analysis to evaluate whether echinocandins are superior to polyenes in terms of mortality for the initial treatment of candidemia. METHODS: We systematically searched the Scopus, EMBASE, Cochrane Central Register of Controlled Trials, PubMed, and CINAHL databases until July 1, 2020. We compared the mortality rates of patients who received echinocandins and polyenes. As a subgroup analysis, we compared the mortality rates following the use of echinocandins versus liposomal amphotericin B. RESULTS: Fifteen studies involving 854 patients were included. Various Candida species were detected, and the rates of resistance of echinocandins and polyenes against the overall detected isolates were 1.0% and 0%, respectively. The overall mortality recorded in 15 studies was 41.0%, and the mortality was significantly higher for polyenes than echinocandins (odd ratios [OR] 1.68, 95% confidential interval [CI] 1.17-2.42). Furthermore, liposomal amphotericin B showed higher mortality in the initial treatment than echinocandins (OR 1.42; 95% CI 0.84-2.39). CONCLUSIONS: We revealed an association between echinocandin treatment and reduced mortality in the initial treatment of candidemia when causative fungi were not considered. Our findings partially support current guidelines recommending echinocandins for the treatment of candidemia.

[Observation of Child Development in a Uterine Cervical Cancer Patient Who Received Chemotherapy during Pregnancy].

This report describes the case of a 36-year-old woman with stage ⅠB1 cervical adenocarcinoma that was diagnosed when her fetus was at 19 weeks of gestation. Both she and her family strongly hoped that her pregnancy could continue. After approval by the Ethics Committee of our hospital, she was treated with paclitaxel and carboplatin. At 32 weeks of gestation, the patient delivered a 1,518 g female newborn via cesarean section. A radical hysterectomy with pelvic lymphadenectomy was performed after delivery. The newborn had Apgar scores of 3 at 1 minute and 5 at 5 minutes. No external malformations were observed. The Kyoto Scale of Psychological Development 2001 was used for cognitive assessment. Although the Language-Social Developmental Quotient score was 65 and developmental delay was observed at 1 year 8 months, the score improved to 98 at 3 years 5 months. The child was followed up until the age of 6 years 2 months and showed no developmental delay. Presentation of this case is important because there are few reports in Japan about the development of children of cancer patients who are exposed to anticancer drugs during pregnancy.

Significant improvement in portal-systemic liver failure symptoms and successful management of portal-splenic venous hemodynamics by the combination of interventional radiology and pharmacotherapy.

This study describes a case of hepatitis C virus-related decompensated cirrhosis with portal-systemic liver failure and refractory encephalopathy. It was successfully managed with a combination of interventional radiology and pharmacotherapy, to improve hepatic function, including hyperammonemia and to control portal-splenic venous hemodynamics with hepatic venous pressure gradient (HVPG) monitoring. A man in his late 50s presented with a Child-Pugh score of 13, Model for End-Stage Liver Disease-sodium (MELD-Na) score of 19 and blood ammonia level of 185 µg/dL. He underwent balloon-occluded retrograde transvenous obliteration (BRTO) followed by partial splenic embolization (PSE) and non-selective beta-blocker (NSBB) administration. BRTO induced drastic changes in the portal-splenic venous hemodynamics, resulting in dramatically improved hepatic function and reduced hyperammonemia. However, the procedure resulted in increased HVPG from 13.6 mmHg at baseline to 23.5 mmHg at 1-month post-BRTO, accompanied by ascites retention and development of portal hypertensive gastropathy. Thereafter, PSE was performed, followed by NSBB administration, to control the elevated portal venous pressure following BRTO. Postoperatively, the patient's ascites and portal hypertensive gastrophy improved after splenic artery embolization, which eventually disappeared after the additional administration of NSBBs 1 month later. The HVPG finally decreased to 16.9 mmHg; the Child-Pugh score, MELD-Na score and blood ammonia level improved to 7, 11 and 22 µg/dL, respectively, after all therapies. BRTO significantly improved the symptoms of portal-systemic liver failure with refractory encephalopathy. PSE and NSBB administration could contribute to additional amelioration of hepatic function and successful management of complications induced by portal hemodynamic changes following BRTO.

Concomitant lansoprazole ameliorates cisplatin-induced nephrotoxicity by inhibiting renal organic cation transporter 2 in rats.

Cisplatin is used widely for the treatment of multiple solid tumors. Cisplatin-induced nephrotoxicity is caused by renal accumulation of cisplatin via human organic cation transporter 2 (hOCT2). As lansoprazole, a proton pump inhibitor, is known to inhibit hOCT2 activity, lansoprazole might ameliorate cisplatin-induced nephrotoxicity. A previous study showed that concomitant lansoprazole administration ameliorated nephrotoxicity in patients receiving cisplatin. However, the detailed mechanism remains to be clarified. In the present study, the drug-drug interaction between lansoprazole and cisplatin was examined using hOCT2-expressing cultured cells and rat renal slices. Moreover, the effect of lansoprazole on cisplatin-induced nephrotoxicity and the pharmacokinetics of cisplatin in rats was investigated. In the uptake study, lansoprazole potently inhibited the uptake of cisplatin in hOCT2-expressing cultured cells and rat renal slices. The in vivo rat study showed that concomitant lansoprazole significantly ameliorated cisplatin-induced nephrotoxicity and reduced the renal accumulation of platinum up to approximately 60% of cisplatin alone at 72 h after cisplatin intraperitoneal administration. Furthermore, the renal uptake of platinum at 3 min after intravenous cisplatin administration in rats with cisplatin and lansoprazole decreased to 78% of rats with cisplatin alone. In addition, there was no significant difference in the plasma platinum concentration between rats treated with and without lansoprazole at 3 min after cisplatin intravenous administration. These findings suggested that concomitant lansoprazole ameliorated cisplatin-induced nephrotoxicity by inhibiting rOCT2-mediated cisplatin uptake in rats, thus decreasing cisplatin accumulation in the kidney. The present findings provided important information for the establishment of novel protective approaches to minimize cisplatin-induced nephrotoxicity.