Risk and Time-to-Onset of Acute Kidney Injury With Vancomycin Plus Piperacillin-tazobactam Combination: Analysis Using JADER.

BACKGROUND/AIM: Pharmacovigilance data and clinical studies have indicated a risk of acute kidney injury (AKI) associated with concomitant administration of vancomycin and piperacillin-tazobactam. However, no pharmacovigilance studies have evaluated time-to-onset and outcomes of AKI related to this combination. Therefore, this study used a pharmacovigilance database to investigate the incidence, time-to-onset, and outcomes of AKI in patients treated with intravenous vancomycin plus piperacillin-tazobactam or other antipseudomonal antibiotics. PATIENTS AND METHODS: From data in the Japanese Adverse Drug Event Report (JADER) database, we calculated the reporting odds ratios (RORs) and 95% confidence intervals (CIs), time-to-onset, and outcomes of AKI following intravenous administration of vancomycin plus piperacillin-tazobactam or other antipseudomonal antibiotics and with other vancomycin regimens, including monotherapy. RESULTS: The JADER database contained 4,471 reports of intravenous vancomycin treatment, including 517 reports of AKI. The adjusted RORs (95%CIs) of AKI in cases with co-administration of intravenous vancomycin and piperacillin-tazobactam was 2.58 (2.06-3.24). The median time-to-onset for AKI in vancomycin plus piperacillin-tazobactam was 6.0 (interquartile range=3.0-10.3). Weibull shape parameter analysis showed that the pattern of onset of AKI in vancomycin plus piperacillin-tazobactam represented a wear out failure, predicting an increasing hazard with time. For the outcome of AKI, there was no significant difference between all vancomycin regimen and the piperacillin-tazobactam combination groups. CONCLUSION: Concomitant use of intravenous vancomycin and piperacillin-tazobactam may increase the incidence of AKI but may not affect the outcome. This combination does not necessarily have to be avoided, but long-term use is not advisable.

Population pharmacokinetics and limited sampling strategy for therapeutic drug monitoring of mycophenolate mofetil in Japanese patients with lupus nephritis.

BACKGROUND: Mycophenolate mofetil (MMF), a prodrug of the immunosuppressive agent mycophenolic acid (MPA), is difficult to administer because of the pharmacokinetic complexity of MPA. Although dosage adjustment according to the 12-h area under the concentration-time curve (AUC0-12) is thought to be desirable, multiple blood samplings for AUC calculation may pose a clinical challenge. A limited sampling strategy (LSS) would provide a solution; however, little is known about MPA pharmacokinetics in lupus nephritis patients, especially in those with Asian backgrounds, or few, if any, LSSs are reported for them. METHODS: Thirty-four adult Japanese patients receiving MMF for lupus nephritis were examined retrospectively. MPA pharmacokinetics were investigated, and a PPK model was developed using Phoenix® NLME™ software. Single and double blood sampling strategies from Bayesian estimation using the PPK model and from multiple linear regression were compared. Tolerability was also evaluated. RESULTS: In the pharmacokinetic analysis, renal function and serum albumin had significant effects on dose-normalized AUC0-12; and serum albumin, concomitant proton pump inhibitor (PPI) and iron/magnesium oxide did on dose-normalized maximum concentration. As a PPK model, a two-compartment model was developed with a transit absorption model and first-order elimination, in which creatinine clearance and serum albumin were covariates for MPA clearance. The double sampling strategy at 1 and 4 h by multiple linear regression showed the best agreement with the observed AUC0-12 (r2 = 0.885). Of the single sampling strategies, the one at 6 h by Bayesian estimation performed best (r2 = 0.769). The tolerability evaluation showed that correlations were suggested for gastrointestinal involvement. CONCLUSIONS: The present study developed the first PPK model of MPA for Japanese lupus nephritis patients. As for LSSs, a double sampling strategy at 1 and 4 h by multiple linear regression would work best; when only a single blood sampling is allowed, a strategy at 6 h by Bayesian estimation using the PPK model developed in this study would be best. The LSSs good enough for clinical use may facilitate safer, more effective, and individualized therapy.

Renin-angiotensin system inhibitors may have an advantage over calcium channel blockers in reducing proteinuria in gastric cancer patients receiving ramucirumab.

This study aimed to investigate whether renin-angiotensin system inhibitors (RAS-I) have an advantage over calcium channel blockers (CCB) for suppression of proteinuria in hypertensive patients with gastric cancer receiving ramucirumab (RAM) treatment. Adult Japanese patients with gastric cancer who were outpatients at Asahikawa Medical University Hospital, National Hospital Organization Hokkaido Cancer Center, and Iwate Medical University Hospital between July 1, 2015, and March 31, 2021, were included in this study. Of these patients, those who had received first-time RAM treatment, and those treated with antihypertensive agents including RAS-I or a CCB at initial RAM administration were included. A total of 36 patients were analyzed in this study. Of these patients, 17 patients were classified into the RAS-I group and the remaining 19 into the CCB group. After 12 weeks of RAM administration, the prevalence of proteinuria in the RAS-I group was significantly lower than that in the CCB group. Additionally, Kaplan-Meier analysis showed that the cumulative occurrence of proteinuria in the RAS-I group over 12 weeks following RAM administration was significantly lower than that in the CCB group. Furthermore, simulation of the time course of RAM blood concentrations based on the O'Brien model showed that there may not be differences in the RAM blood concentration profiles over 12 weeks between the two groups. RAS-I may have an advantage over CCB for suppressing proteinuria in hypertensive patients with gastric cancer treated with blood pressure antihypertensive agents. Our results provide useful information to healthcare professionals involved in the administration of RAM treatment.

Population Pharmacokinetics of Teicoplanin and Its Dosing Recommendations for Neutropenic Patients With Augmented Renal Clearance for Hematological Malignancies.

BACKGROUND: Plasma teicoplanin concentrations do not reach the therapeutic range in several patients with hematological malignancies. Nevertheless, the characteristics of the population pharmacokinetic (PPK) models have not been clarified for malignancy. The decrease in the teicoplanin concentration in patients with cancer has been attributed to augmented renal clearance (ARC). It is essential to identify the causative factors of ARC to construct a PPK model to optimize the administration method. The authors aimed to establish a PPK model and develop an appropriate dosing regimen for teicoplanin in patients with hematological malignancies. METHODS: PPK analysis was performed using therapeutic drug monitoring (TDM) data from 119 patients with hematological malignancies. The developed model was verified by predictive performance. RESULTS: The covariates affecting systemic clearance were serum creatinine, presence or absence of neutropenia (<500/µL), and body size descriptor. Patients with hematologic malignancies and neutropenia showed a 25% increase in clearance compared with those with a normal neutrophil count. The PPK model was constructed based on the presence or absence of neutropenia. This model allowed the selection of the most appropriate dosage regimen out of those recommended by the TDM guidelines for patients with eGFR of >60 mL/min/1.73 m2. The PPK model predicted a dosing regimen for achieving a 10% improvement in the coverage probability of the target concentration range during the loading and maintenance phases. CONCLUSIONS: The PPK model may help optimize dose regimens and evaluate dosing methods, using comparative simulations, in patients with hematological malignancies.

Multiwall Carbon Nanotube Composites as Artificial Joint Materials.

Because ultrahigh-molecular-weight polyethylene (UHMWPE) is susceptible to frictional wear when used in sliding members of artificial joints, it is common practice to use cross-linked UHMWPE instead. However, cross-linked UHMWPE has low impact resistance; implant breakage has been reported in some cases. Hence, sliding members of artificial joints pose a major trade-off between wear resistance and impact resistance, which has not been resolved by any UHMWPE. On the other hand, multiwall carbon nanotubes (MWCNTs) are used in industrial products for reinforcement of polymeric materials but not used as biomaterials because of their unclear safety. In the present study, we attempted to solve this trade-off issue by complexing UHMWPE with MWCNTs. In addition, we assessed the safety of these composites for use in sliding members of artificial joints. The results showed the equivalence of MWCNT/UHMWPE composites to cross-linked UHMWPE in terms of wear resistance and to non-cross-linked UHMWPE in terms of impact resistance. In addition, all MWCNT/UHMWPE composites examined complied with the requirements of biosafety testing in accordance with the ISO10993-series specifications for implantable medical devices. Furthermore, because MWCNTs can occur alone in wear dust, MWCNTs in an amount of about 1.5 times that contained in the dust produced from 50 years of wear (in the worst case) were injected into rat knees, which were monitored for 26 weeks. Although mild inflammatory reactions occurred in the joints, the reactions soon became quiescent. In addition, the MWCNTs did not migrate to other organs. Furthermore, MWCNTs did not exhibit carcinogenicity when injected into the knees of mice genetically modified to spontaneously develop cancer. The MWCNT/UHMWPE composite is a new biomaterial expected to be safe for clinical applications in both total hip arthroplasty and total knee arthroplasty as the first sliding member of artificial joints to have both high wear resistance and high impact resistance.

Oral administration of porcine liver decomposition product for 4 weeks enhances visual memory and delayed recall in healthy adults over 40 years of age: A randomized, double-blind, placebo-controlled study.

BACKGROUND AND OBJECTIVES: Porcine liver decomposition product (PLDP) contains neurofunctional phospholipids. We previously reported that PLDP enhances cognitive function in healthy adult humans, based on clinical evaluations using Hasegawa's Dementia Scale-Revised. In this study, we evaluated the effect of PLDP on memory indicators of the Wechsler Memory Scale-Revised (WMS-R), an internationally recognized battery for memory assessment. METHODS: We conducted a double-blind parallel-group placebo-controlled trial to evaluate the effect of PLDP on memory. Fifty-eight participants competed the trial: 28 participants were in the PLDP group and 30 participants were in the placebo group. Each group was administered PLDP (4 capsules) or a placebo (4 capsules) for 4 continuous weeks. WMS-R was administered before and 4 weeks after PLDP or placebo intake. The data were also subdivided by age for participants under 40 years (N = 15 in PLDP; N = 15 in placebo) and over 40 years (N = 13 in PLDP, N = 15 in placebo). Changes in Verbal Memory, Visual Memory, Attention/Concentration, and Delayed Recall were analyzed. RESULTS: No significant differences were found in any memory indicators between the PLDP group and the placebo group in pooled participants and in participants under 40 years of age. However, for participants over 40 years of age, PLDP administration resulted in a significant enhancement than placebo administration in Delayed Recall (14.1 ± 7.1 points vs. 7.1 ± 6.8 points) (P < 0.05), Visual Recall I (20.1 ± 23.1 percentile vs 1.9 ± 22.8 percentile) (P < 0.05), and Visual Recall II (24.2 ± 25.8 percentile vs 6.7 ± 19.0 percentile) (P < 0.05), respectively. The composition ratio of men to women in each group was imbalanced but no significant difference existed between the two groups. LIMITATIONS: A modest sample size, single-center design, and a fairly short follow-up period. CONCLUSION: PLDP enhanced Visual Memory and Delayed Recall in healthy adults over 40 years of age but not in healthy adults under 40 years of age. Therefore, PLDP may represent a promising nutraceutical that could improve cognitive function in healthy adults over 40 years of age. Further studies are required to evaluate if long term PLDP administration can prevent or delay cognitive dysfunction in healthy adults over 40 years of age.

[Influence of temperature and humidity on physico-pharmaceutical characteristics of Rasilez(®) tablets].

Rasilez(®) tablets (RTs) contain the active ingredient aliskiren, which is a direct renin inhibitor of the renin-angiotensin system and used for the treatment of hypertension. We examined the influence of temperature and humidity on the physico-pharmaceutical characteristics (mass, volume, hardness, elution) of RTs. The RTs were preserved under conditions in which the temperature and humidity were altered using the second-order spherical composite experimental design for multi-objective problems. The characteristics of RTs were influenced more by the humidity than temperature, and differed markedly with over 55% relative humidity (RH). The mass and volume were increased with increasing humidity, and the tablets swelled. The hardness after vacuum-drying of the tablets, which preserved moisture conditions, was increased. Semitransparent particles were observed in the cross-section of the drying tablets in which aliskiren crystal forms were changed to amorphous forms. The mean dissolution time (MDT) of tablets was reduced with increasing humidity. The critical relative humidity (CRH) of the tablets was 36.1%RH at 30°C. These results suggest that RTs, on moisture absorption, showed changes in not their appearance and hardness, but also in crystal forms and the elution characteristics of aliskiren.

Suppression of free radical-induced DNA strand breaks by linoleic acid and low density lipoprotein in vitro.

The results of the present study have shown that unoxidized linoleic acid (LA) and low density lipoprotein (LDL) suppressed free radical-induced supercoiled plasmid DNA strand breaks. Unoxidized LA suppressed DNA strand breaks induced by free radicals generated from hydrogen peroxide/Fe(II) ion, 2'-azobis(2-amidinopropane)hydrochloride (AAPH), and 4-(hydroxymethyl)benzene diazonium salt. Thiobarbituric acid reactive substances (TBARS) of LA were increased on treatment with the radical generators. The intensities of the electron spin resonance (ESR) signals of the spin adducts of the radicals were reduced by unoxidized LA. Although LA hydroperoxide caused DNA strand breaks as has already been shown, its strand breaking activity was observed only at the higher concentrations. Unoxidized LDL inhibited ascorbic acid/Cu(II) ion-, ascorbic acid/Fe(II) ion-, peroxynitrite- and AAPH-induced DNA strand breaks. The TBARS of LDL were increased by treatment with the agents. LDL oxidized with Cu(II) ion did not cause DNA strand breaks. The results indicate that the potency of the free radicals to cause DNA strand breaks was attenuated by the fatty acid and the lipoprotein through lipid peroxidation.