Real-world risk of cardiovascular diseases in patients with type 2 diabetes associated with sodium-glucose cotransporter 2 inhibitors in comparison with metformin: A propensity score-matched model analysis in Japan.

We aimed to compare the effects of cardiovascular disease risk in Japanese patients with type 2 diabetes on sodium-glucose cotransporter 2 inhibitors (SGLT2Is) or metformin. This retrospective, real-world cohort study was carried out using a claims database and propensity score matching; 58,402 eligible patients (29,201 per group) were included. The outcomes included nonfatal myocardial infarction, angina pectoris, nonfatal stroke, hospitalization for heart failure and composite end-points. The hazard ratio (HR) for the composite end-point was 0.79, which was lower for SGLT2Is than for metformin. For male patients (HR 0.76), patients aged <65 years (HR 0.94), patients aged ≥75 years (HR 0.78) and patients with body mass index ≥25 kg/m2 (HR 0.76), the HRs for the composite end-point were significantly lower in the SGLT2I group than in the metformin group. SGLT2Is might be superior to metformin in reducing the composite risk of cardiovascular disease in patients with type 2 diabetes.

A meta-analysis of observational studies on anticholinergic burden and fracture risk: evaluation of conventional burden scales.

BACKGROUND: Anticholinergic burden potentially increases the risk of fracture. Although there are various anticholinergic burden scales, little is known about the inter-scale compatibility regarding the relationship of anticholinergic burden with fracture risk. We performed meta-analysis to examine the association of fracture risk with anticholinergic burden measured using various scales. METHODS: Primary literature was retrieved from PubMed (1966 to March, 2021), the Cochrane Library (1974 to March, 2021), Scopus (1970 to March, 2021), and Ichushi-web (1983 to March, 2021). Cohort and case-control studies that evaluated the association between any fracture and anticholinergic drugs were included. Additionally, we included studies in which patients were administered anticholinergic drugs included on the anticholinergic risk scale (ARS), anticholinergic cognitive burden (ACB), anticholinergic drug scale, or drug burden index-anticholinergic component. Random effects models were used to calculate pooled relative risk (RR) and 95% confidence interval (CI) due to heterogeneity among the studies. Publication bias was examined by funnel plots and the Begg's test. RESULTS: A total of 49 datasets from 10 studies were included in the meta-analysis. Six of the 10 studies included only patients aged over 65 years, who accounted for 93% of the total study population (453,186/487,247). Meta-analysis indicated a positive relationship between use of anticholinergic drugs and fracture risk, regardless of the anticholinergic burden scale used. However, the relationship between anticholinergic burden and fracture risk varied depending on the scale used. Fracture risk increased linearly with increasing anticholinergic burden measured using ARS. ARS 1 point was associated with 28% increase in fracture risk, ARS 1-2 point(s) with 39%, ARS 2 points with 54%, ARS 3 points with 66%, and ARS ≥ 4 points with 77%. On the other hand, ACB 1 point and ACB 2 points were associated with similar fracture risk (pooled RR [95% CI]: overall; 1.28 [1.18-1.39], 1 point; 1.12 [1.06-1.18], 2 points; 1.15 [1.08-1.23]). CONCLUSIONS: This result suggests that the relationship between anticholinergic drug burden and fracture risk may differ depending on the anticholinergic burden scale used.

Population pharmacokinetics of R- and S-carvedilol in Japanese patients with chronic heart failure.

Carvedilol is a beta-adrenoceptor antagonist used for treating chronic heart failure (CHF). Two clinical studies were conducted to evaluate the population pharmacokinetics and pharmacodynamics of R- and S-carvedilol, and associated covariates, in patients with CHF. Fifty-eight patients (male=45, female=13) with New York Heart Association class I-IV CHF were enrolled in two clinical studies. R- and S-carvedilol concentrations were measured using HPLC at steady-state after oral administration of carvedilol at 1.25-20 mg o.d. or b.i.d. The data from both studies were used to estimate the population pharmacokinetic parameters and covariates using the nonlinear mixed effects model program. For 40 patients evaluated in one clinical study, the cytochrome P450 (CYP)2D6 *1, *10, and *5 genotypes were determined using allele-specific primer PCR, and individual patients' oral clearance (CL/F) of both enantiomers were estimated by the empirical Bayes method. A one-compartment model with a first-order absorption rate was established, in which body weight and alpha(1)-acid glycoprotein were significant covariates. Individual CL/F values for carvedilol were significantly lower in Japanese CHF patients with the CYP2D6 *1/*5, *5/*10 and *10/*10 genotypes. Estimation of the population pharmacokinetic parameters and their covariates for each enantiomer in Japanese patients with CHF showed that the CL/F values for R- and S-carvedilol were dependent on body weight, alpha(1)-acid glycoprotein, and CYP2D6 genotype. Prediction of exposure to free plasma carvedilol is important for dosage adjustment of beta-blocker therapy in patients with CHF.

A study of cardiovascular function in Tsumura Suzuki obese diabetes, a new model mouse of type 2 diabetes.

Diabetes mellitus is a well known and important risk factor for cardiovascular diseases, including heart failure. A new model of Type 2 diabetes, Tsumura Suzuki Obese Diabetes (TSOD) mice, was introduced recently into the research field of diabetes. The cardiac functions of TSOD mice were studied in comparison with Tsumura Suzuki Non Obesity (TSNO, non-diabetic control) mice, for the first time. In vivo cardiovascular functions were measured by echocardiography and cardiac catheterization at 7, 12 and 18 months old. TSOD mice had no deterioration of cardiac function despite the long-term persistence of severe obesity, hyperglycemia, hyperinsulinemia and hyperlipidemia, including high density lipoprotein (HDL)-cholesterol. No histopathological abnormalities were observed in the heart of TSOD mice, while several histological abnormalities were observed in the pancreas and kidney of TSOD mice. To investigate vascular endothelium function at 7 months old, intravenous injection of acetylcholine (ACh; 1, 3, 10 microg/kg)- and N(G)-nitro-L-arginine methyl ester (L-NAME; 50 mg/kg)-induced mean blood pressure (BP) changes were used. ACh decreased whereas L-NAME increased BP, and no significant differences in BP changes were observed between TSOD and TSNO mice. Moreover, ACh-induced relaxation of the thoracic aortae isolated from TSOD and TSNO mice with intact endothelium were not significantly different. These findings suggest that vascular endothelial cells in TSOD mice are not impaired. It was clearly demonstrated that despite obvious diabetes, cardiac functions of TSOD mice were not impaired even at 18 months old.

[Association between Elimination Half-life of Benzodiazepines and Falls in the Elderly: A Meta-analysis of Observational Studies].

Benzodiazepine receptor agonists (BZDRAs) have been associated with an increased risk of falls in the elderly. However, the association between the elimination half-life (t1/2) of BZDRAs and the difference between benzodiazepines (BZDs) and non-benzodiazepines (Z-drugs) has not been clarified. By conducting a meta-analysis of observational studies, we compared the risk of falls with respect to 1) short-acting BZDRAs (t1/2<12 h) vs. long-acting BZDRAs (t1/2≥12 h) and 2) BZDs vs. Z-drugs in elderly patients. Data were retrieved from MEDLINE, the Cochrane Library, and Igaku Chuo Zasshi. In total, 13 observational studies from 12 articles were included in our study (short-acting BZDRAs, n=12; long-acting BZDRAs, n=9; BZDs, n=13; Z-drugs, n=7). The risk of falls was significantly increased by the use of short-acting BZDRAs [Odds ratio (OR) (95% Confidence interval (CI)): 2.00 (1.46-2.73)], long-acting BZDRAs [OR (95%CI): 2.16 (1.61-2.89)], BZDs [OR (95%CI): 1.67 (1.31-2.13)], and Z-drugs [OR (95%CI): 2.42 (1.35-4.34)] compared to the risk in BZDRAs non-users. The increased risk of falls in elderly patients was similar in each group and unrelated to t1/2. This study suggested that all BZDRAs including Z-drugs should be avoided in elderly patients.

Differences in Warfarin Pharmacodynamics and Predictors of Response Among Three Racial Populations.

BACKGROUND: Population differences in warfarin dosing requirement have been reported; however, unlike the pharmacokinetics (PK) of warfarin, the quantitative influences of pharmacodynamic (PD) factors on the anticoagulation response to warfarin in different ethnic populations are totally unknown. METHODS: Using population PK/PD analysis, we attempted to identify predictors of S-warfarin clearance [CL(S)] and half maximal effective concentration (EC50) to quantify racial differences in both PK and PD parameters, and to assess the contribution of these parameters to the international normalized ratio (INR) and over-anticoagulation response (INR ≥ 4) in a cohort of 309 White, Asian and African American patients. RESULTS: Similar to our previous findings, the median CL(S) was 30% lower in African American patients than Asian and White patients (169 vs. 243 and 234 mL/h, p < 0.01). EC50 showed a greater racial difference than CL(S) [1.03, 1.70 and 2.76 µg/mL for Asian, White and African American patients, respectively, p < 0.01). Significant predictors of INR included demographic/clinical (age, body weight, creatinine clearance and sex) and genotypic (CYP2C9*3,*8 and VKORC1 -1639G>A) factors, as well as African American ethnicity. In all three racial groups, genetic predictors of INR appeared to have greater influence than demographic/clinical predictors. Both CL(S) and EC50 contributed to the over-anticoagulation response to warfarin. Patients having VKORC1 -1639 G>A and/or factors associated with reduced CYP2C9 activity were more likely to have an INR ≥ 4. CONCLUSIONS: Although there were contrasting racial differences in CL(S) and EC50 that impacted on the INR, the racial difference in EC50 was greater than that for CL(S), thus explaining the higher warfarin requirement for African American patients.

Stereoselective first-pass metabolism of verapamil in the small intestine and liver in rats.

Verapamil (VP) is used as a racemate but shows stereoselective pharmacokinetics and pharmacodynamics. It undergoes extensive first-pass metabolism. Stereoselective first-pass metabolism in the intestine and liver was investigated in vivo and in vitro to determine its impact on the disposition of VP and its main metabolite, norverapamil (NVP). VP racemate was administered to rats i.v., p.o., and via the portal vein. The formation rates of the main metabolites of the VP enantiomers were estimated in an in vitro intestinal microsomal study. The hepatic bioavailability of VP showed saturable metabolism, and the hepatic bioavailability of R-VP was higher than that of S-VP. Conversely, the intestinal bioavailability of R-VP was lower than that of S-VP, resulting in a higher systemic bioavailability of S-VP. The pharmacokinetics of the NVP enantiomers was similar. These results suggest that the stereoselectivity of the total bioavailability of VP is determined by first-pass metabolism in the small intestine and liver, and that the NVP enantiomers observed in the systemic circulation after p.o. administration of VP racemate originate mainly from the liver in rats.

Safety of human papillomavirus vaccines in healthy young women: a meta-analysis of 24 controlled studies.

BACKGROUND: Human papillomavirus (HPV) vaccines have been shown to be effective for the eradication of HPV and prevention of cervical cancer. However, the number of women who receive HPV vaccinations has decreased over the last several years in Japan, due to concerns about adverse reactions associated with the vaccines. We evaluated the safety of three types of HPV vaccines separately in young women and the difference in the risk of adverse reactions between HPV and other vaccines by conducting a meta-analysis. METHODS: Primary literature was retrieved from MEDLINE, the Cochrane Central Register of Controlled Trials, and Japana Centra Revuo Medicina. Prospective controlled studies with participants consisting exclusively of healthy women who received bivalent, quadrivalent, or 9-valent HPV (2vHPV, 4vHPV or 9vHPV) vaccines were included. Primary safety outcome was the incidence of solicited local and systemic symptoms, and unsolicited symptoms. When two or more studies were found for the same analysis, a meta-analysis was applied. RESULTS: A total of 24 controlled studies from 22 articles were included in our study. Of the 24 studies, 16 were placebo-controlled and eight were active-controlled (different HPV vaccine or hepatitis vaccine). Average ages of the participants ranged from 12 to 37 years. A significantly higher incidence of solicited local symptoms was observed following injection of HPV vaccines (2vHPV and 4vHPV) compared to placebo, but there was no difference between HPV vaccines [risk ratio (RR) for 2vHPV: 1.25, 95% confidence interval (CI): 1.09 to 1.43, RR for 4vHPV: 1.16, 95% CI: 1.11 to 1.20]. The incidence of solicited systemic symptoms was not different between HPV vaccines and placebo (RR: 1.04, 95% CI: 0.99 to 1.09). The incidence of unsolicited symptoms was significantly higher for 2vHPV vaccine compared to placebo (RR: 1.28, 95% CI: 1.01 to 1.63), but was not significantly different between 2vHPV and hepatitis B vaccines. CONCLUSIONS: HPV vaccines had significantly higher risk of any injection site symptom compared to placebo or other vaccines (hepatitis A and B vaccines), and the incidence of solicited local symptoms was no difference between 2vHPV vaccination and 4vHPV vaccination. However, the most adverse reactions were transient.

Population pharmacokinetic and pharmacodynamic analysis of a class IC antiarrhythmic, pilsicainide, in patients with cardiac arrhythmias.

Population pharmacokinetics (PK) of a sodium channel-blocking antiarrhythmic, pilsicainide, was studied using the nonlinear mixed-effects modeling technique in 91 patients with cardiac arrhythmias (80 suspected Brugada syndrome [BrS] and 11 with atrial fibrillation) who received an intravenous infusion of 10 mg of the drug. Population pharmacodynamic (PD) analysis was also performed using an effect compartment model. PD responses were assessed by changes in electrocardiogram (ECG) pattern (BrS-like elevation of ST-segment) and conduction parameters. The final PK model showed that gender (values were 50% lower in women than in men) and creatinine clearance were significant (P < .01) covariates of weight-normalized systemic clearance of pilsicainide. Patients who showed a BrS-like ECG pattern after the drug administration also showed a significantly (P < .01) greater prolongation in His-Purkinje conduction compared to the remaining patients. In conclusion, female gender, renal dysfunction, and the drug-induced BrS-like ECG morphology may be associated with augmented ECG responses to pilsicainide.

Enantioselective and highly sensitive determination of carvedilol in human plasma and whole blood after administration of the racemate using normal-phase high-performance liquid chromatography.

A highly sensitive HPLC method for enantioselective determination of carvedilol in human whole blood and plasma was developed. Carvedilol and S-carazolol as an internal standard extracted from whole blood or plasma were separated using an enantioselective separation column (Chiralpak AD column; 2.0 diameter x 250 mm) without any chiral derivatizations. The mobile phase was hexane:isopropanol:diethylamine (78:22:1, v/v). The excitation and emission wavelengths were set at 284 and 343 nm, respectively. The limits of quantification for the S(-)- and R(+)-carvedilol enantiomers in plasma and blood were both 0.5 ng/ml. Intra- and inter-day variations were less than 5.9%. As an application of the assay, concentrations of carvedilol enantiomer in plasma and blood samples from 15 patients treated with carvedilol for congestive heart failure were determined.

Predictors of the therapeutic effect of sivelestat in patients with acute lung injury associated with systemic inflammatory response syndrome.

BACKGROUND: Sivelestat, a neutrophil elastase inhibitor, was previously approved in Japan for the treatment of acute lung injury associated with systemic inflammatory response syndrome. However, sivelestat produced inconsistent therapeutic benefits. This study aimed to identify factors predicting the therapeutic effects of sivelestat. METHODS: We enrolled 53 mechanically ventilated patients who received sivelestat. The patients were classified as effective (n = 28) if they were weaned from the ventilator within 28 days, or as ineffective groups (n = 25). Patient characteristics were compared between these groups and multivariate logistic regression analysis was used to identify predictive factors. A validation study was then conducted in sivelestat-free patients. RESULTS: A high red blood cell count and low hydrogen ion concentration were significantly associated with a higher ventilator weaning rate in patients receiving sivelestat. The validation study revealed that the hydrogen ion concentration value also significantly associated with ventilator weaning in patients who did not receive sivelestat. CONCLUSIONS: Although hydrogen ion concentration was inversely associated with the ventilator weaning rate, it did not predict sivelestat efficacy. This study indicated that acute lung injury patients with a high red blood cell count would derive the most benefit from sivelestat administration.

[Effectiveness of anti-emetics for the prophylaxis of cisplatin-induced delayed emesis: a systematic review].

We performed a systematic review of the effectiveness of anti-emetics for prophylaxis of cisplatin-induced delayed emesis using meta-analysis. We selected 12 reports of randomized controlled trials from MEDLINE (1966-2003. 4) and The Cochrane Library Issue 1, 2003. Nine of these reports were evaluated as high quality and the others as low quality according to the evaluation criteria of Jadad et al., and only the high-quality reports were subjected to meta-analysis. The statistical results obtained from all 12 reports were also compared with those obtained from the 9 reports of high quality. Corticosteroids significantly reduced the occurrence of delayed emesis. Metoclopramide tended to reduce the occurrence of delayed emesis, although not to a significant extent. In contrast, 5-HT3 receptor antagonists did not show a significant prophylactic effect on delayed emesis. Combination treatments using corticosteroids with metoclopramide or 5-HT3 receptor antagonists did not show significant additional benefits over corticosteroids alone. In conclusion, treatment with corticosteroids without additional metoclopramide or 5-HT3 receptor antagonists appears to be preferable for the prevention of delayed emesis induced by cisplatin.

Determinants of the over-anticoagulation response during warfarin initiation therapy in Asian patients based on population pharmacokinetic-pharmacodynamic analyses.

UNLABELLED: To clarify pharmacokinetic-pharmacodynamic (PK-PD) factors associated with the over-anticoagulation response in Asians during warfarin induction therapy, population PK-PD analyses were conducted in an attempt to predict the time-courses of the plasma S-warfarin concentration, Cp(S), and coagulation and anti-coagulation (INR) responses. In 99 Chinese patients we analyzed the relationships between dose and Cp(S) to estimate the clearance of S-warfarin, CL(S), and that between Cp(S) and the normal prothrombin concentration (NPT) as a coagulation marker for estimation of IC50. We also analyzed the non-linear relationship between NPT inhibition and the increase in INR to derive the non-linear index λ. Population analyses accurately predicted the time-courses of Cp(S), NPT and INR. Multivariate analysis showed that CYP2C9*3 mutation and body surface area were predictors of CL(S), that VKORC1 and CYP4F2 polymorphisms were predictors of IC50, and that baseline NPT was a predictor of λ. CL(S) and λ were significantly lower in patients with INR≥4 than in those with INR<4 (190 mL/h vs 265 mL/h, P<0.01 and 3.2 vs 3.7, P<0.01, respectively). Finally, logistic regression analysis revealed that CL(S), ALT and hypertension contributed significantly to INR≥4. All these results indicate that factors associated with the reduced metabolic activity of warfarin represented by CL(S), might be critical determinants of the over-anticoagulation response during warfarin initiation in Asians. TRIAL REGISTRATION: ClinicalTrials.gov NCT02065388.

Computer-based evolutionary search for a nonlinear conversion function for establishing in vitro-in vivo correlation (IVIVC) of oral drug formulations.

Establishment of in vitro-in vivo correlation (IVIVC) accelerates optimization of desirable drug formulations and/or modification of the manufacturing processes in the scale-up and post-approval periods. This article presents a method of finding the optimal conversion function for establishing Level A point-to-point IVIVC, based on a computer-based evolutionary search technique. Gene expression programming (GEP) is a technique for optimizing a mathematical expression tree with the help of a genetic algorithm. A parameter optimization routine, which minimizes the number of parameters in the mathematical expression trees and estimates the best-fit parameter values, was implemented in the GEP algorithm. Feasibility of the computer program was investigated using the in vitro and in vivo data for sustained release diltiazem formulations. It provided a mathematical equation that, from their in vitro dissolution profiles, successfully predicts the plasma concentration profiles of three different formulations of diltiazem following oral administration. Because the present approach does not use intravenous injection data like conventional IVIVC analyses, it is widely applicable to the evaluation of various oral formulations.

Inter-individual differences in baseline coagulation activities and their implications for international normalized ratio control during warfarin initiation therapy.

BACKGROUND AND OBJECTIVE: Genetic polymorphisms of cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) and patient demographic characteristics are responsible for inter-individual differences in warfarin maintenance dosage requirements. At present, however, the factors associated with over-anticoagulation responses, especially before achieving the maintenance phase, have not been completely clarified. In this study, we investigated the effects of baseline coagulation activity assessed in terms of the level of fully carboxylated plasma normal prothrombin (NPT) on international normalized ratio (INR) control during the induction phase of warfarin therapy. Our objectives were to (1) identify factors associated with inter-patient variability in baseline NPT (NPT(0)); (2) estimate the therapeutic NPT (NPT(tx)) levels that can achieve an INR of 2-3; and (3) investigate the influence of NPT(0) on the INR response to warfarin by employing modelling and simulation techniques. METHODS: We measured NPT before (NPT(0)) and during the introduction of warfarin therapy for up to 3 months and analysed functional single nucleotide polymorphisms (SNPs) of VKORC1 and CYP4F2 in 179 Chinese patients. The patients were classified into tertile groups according to NPT(0) values (i.e. high, intermediate and low groups), and in each group the NPT(tx) achieving therapeutic INR, the absolute reduction of NPT from NPT(0) to NPT(tx), and the percentage inhibition of NPT(0) [{(NPT(0) - NPT(tx))/NPT(0)} × 100] were obtained. The nonlinear relationship between NPT and INR was modelled on the basis of the INR value before warfarin treatment (INR(0)) added by the nonlinear increase in INR after warfarin initiation, which was predicted using the percentage inhibition of NPT(0) and a nonlinear coefficient (λ). The population parameter λ and its inter-individual variability and intra-individual variability in INR in the NPT-INR model were estimated by nonlinear mixed-effect modelling software NONMEM(®). RESULTS: Multivariate analysis identified age and liver disease as covariates of NPT(0), but none of the SNPs had a significant influence. Although the mean absolute NPT reduction necessary to achieve NPT(tx) was dependent on NPT(0) (i.e. the higher the NPT(0), the larger the reduction in NPT), the percentage inhibition was within the narrow range of 67-72 % of NPT(0), irrespective of NPT(0). However, a significantly higher percentage inhibition (80 % on average) was observed in patients with INR values exceeding 4.0. As the nonlinear coefficient λ in the developed model was dependent on NPT(0) (i.e. the higher the NPT(0), the larger the nonlinear λ value), the simulated nonlinear NPT-INR curves were superimposable in the three respective NPT(0) groups, and the only difference was the starting median NPT(0) level. As a result, a steeper increase in the slope of the nonlinear NPT-INR curve might be expected in patients with a lower NPT(0) after initiation of warfarin. CONCLUSIONS: The present study suggests that INR may be prolonged by warfarin nonlinearly as a function of the percentage inhibition of NPT(0). Furthermore, these results indicate that NPT(0) may contribute to inter-individual variability in the INR response, and that patients with low NPT(0) may have the potential to show a sharp increase in INR during initiation therapy with warfarin.

Evaluation of Bayesian estimation of pharmacokinetic parameters.

The validity of pharmacokinetic parameters estimated by the maximum a posteriori probability (MAP) Bayesian method was investigated by simulation studies. A 1-compartment model with bolus intravenous administration was used as a pharmacokinetic model, and the coefficients of variation for the parameters and residual error were set at 30% and 10%, respectively. The accuracy of the posterior modes of pharmacokinetic parameters estimated by the MAP Bayesian method was assessed by the difference between the true value and the estimated value. The results showed that the accuracy of the Bayesian estimation depended on sampling times and on the differences between the prior means and individual true parameter values. For assessing the reliability and accuracy of the Bayesian estimation, the authors suggest using the whole posterior distribution of the pharmacokinetic parameters to describe the 95th percentile range for predicted blood concentration profiles. The authors believe that the proposed procedures provide helpful information for evaluating the Bayesian estimation of pharmacokinetic profiles.

Pharmacokinetics and preventive effects of targeted catalase derivatives on hydrogen peroxide-induced injury in perfused rat liver.

PURPOSE: To investigate the pharmacokinetics and preventive effects of liver-targeted catalase (CAT) derivatives on hepatic injury caused by reactive oxygen species. METHODS: The hepatic uptake of 111In-CAT, galactosylated (Gal-), mannosylated (Man-) and succinylated (Suc-) CAT was investigated in isolated perfused rat livers in a single-pass constant infusion mode. Then, pharmacokinetic parameters were obtained by fitting equations derived from a one-organ pharmacokinetic model to the outflow profile. Their effects in preventing hydrogen peroxide-induced injury were determined by lactate dehydrogenase (LDH) release from the perfused liver. RESULTS: The extraction of CAT derivatives by the liver was dose-dependent, and increased by the chemical modifications described. After being bound to the cell surface, chemically modified CAT derivatives were internalized by the liver faster than CAT. Preperfusion of a CAT derivative significantly reduced LDH release by hydrogen peroxide at least for 30 min, and Man-CAT and Suc-CAT effectively inhibited this release. CONCLUSIONS: Internalized CAT derivatives are also effective in degrading hydrogen peroxide and targeted delivery of CAT to liver nonparenchymal cells by mannosylation or succinylation is a useful method for the prevention of hepatic injury caused by reactive oxygen species.