Evaluation for Blood Concentration and Efficacy/Safety of Continuous Administration of Thiamylal in Children.

BACKGROUND: Thiamylal exerts excellent sedative effects. However, it is not routinely used because of its serious adverse effects. This study aimed to clarify the target blood concentration range and infusion rate of thiamylal in children by measuring its blood concentration and evaluating its relationship with efficacy and adverse effects. METHODS: This study was approved by the Ethics Committee of Japanese Red Cross Kumamoto Hospital. The authors included 10 children aged between 1 and 7 years who had received continuous intravenous (IV) infusion of thiamylal for the management of refractory status epilepticus, excluding those who met the exclusion criteria. After a 2 mg/kg bolus injection of thiamylal, continuous IV infusion was initiated at a rate of 2-3 mg/kg/h. Thiamylal concentration in the blood was measured using high-performance liquid chromatography. The State Behavioral Scale and the frequency of bolus injections were used to evaluate efficacy. Blood pressure and heart rate were measured to evaluate adverse effects. Statistical analyses of the time to awakening and the factors affecting it were also conducted. RESULTS: The State Behavioral Scale score during thiamylal administration was -2 or lower in all cases, suggesting that the depth of sedation was sufficient. The frequency of bolus injections decreased in a blood concentration-dependent manner, suggesting that the frequency tended to decrease, especially at thiamylal blood concentrations of 20 mcg/mL or higher. An increase of the infusion rate to 3 mg/kg/h was recommended, because the blood concentration may not reach 20 mcg/mL at an infusion rate of 2 mg/kg/h. There was also a case in which a rapid increase in blood concentration accompanied by a decrease in blood pressure and heart rate was observed when the infusion rate was increased to 4 mg/kg/h. Furthermore, the time to awakening after the end of administration correlated with the highest blood concentration during administration; therefore, delayed awakening was noted when using a high dose of thiamylal. CONCLUSIONS: The target blood concentration of thiamylal in children should be 20-30 mcg/mL, and the infusion rate should be based on 3 mg/kg/h.

Effect of Serum Parathyroid Hormone on Tacrolimus Therapy in Kidney Transplant Patients: A Possible Biomarker for a Tacrolimus Dosage Schedule.

The mechanism responsible for the decreased extra-renal CYP3A activity in chronic kidney disease (CKD) patients remains unknown. Using an animal model, we previously found that elevated levels of serum intact parathyroid hormone (iPTH) caused a reduced CYP3A activity. This retrospective observational study assessed the relationship between serum iPTH levels and the blood concentration or dosage of tacrolimus, a CYP3A substrate, after oral administration in kidney transplant patients. Thirty-four patients were enrolled who had kidney transplants between April 2014 and March 2016 and who had been administrated once- daily prolonged-release tacrolimus (Graceptor®, Astellas Pharm Inc.). Among the 34 patients, 22 had taken a CYP3A inhibitor. These patients were excluded from the study. A significant positive correlation between serum iPTH and tacrolimus trough levels was found at 4 d before kidney transplantation in 12 patients who were not receiving potent CYP3A inhibitor. In addition, serum iPTH levels before transplantation could serve as a factor for the dose of tacrolimus up to 1 year after transplantation. Monitoring serum iPTH levels could predict the trough level for the initial administration of tacrolimus, and may serve as an index for the initial dose of tacrolimus in kidney transplantation patients.

Effects of genetic variants in SLC22A2 organic cation transporter 2 and SLC47A1 multidrug and toxin extrusion 1 transporter on cisplatin-induced adverse events.

BACKGROUND: Susceptibility to cisplatin (CDDP) nephrotoxicity is known to vary between individuals, but the basis of this variation has not been fully elucidated. In the kidney, CDDP is taken up into the renal proximal tubular cells mainly via SLC22A2 organic cation transporter 2 (OCT2) and secreted into lumen via other transporters including SLC47A1 multidrug and toxin extrusion 1 (MATE1). Here, we explore the effect of single-nucleotide polymorphisms (SNPs) at 808G>T in OCT2 and at rs2289669 G>A in MATE1 on CDDP-induced adverse events. METHODS: Fifty-three patients who had been treated with CDDP were enrolled. The plasma concentration of CDDP was measured on days 4 and 7 after treatment. The grade of hematology and nephrotoxicity was evaluated by Common Terminology Criteria for Adverse Events. RESULTS: In the first treatment cycle, serum creatinine (SCr) levels in the patients with OCT2 808GG and 808GT were increased by 1.43- and 1.19-fold, respectively. In the total treatment cycles, 12 patients (27 %) with 808GG experienced over grade 2 SCr elevation, whereas those with 808GT did not show any apparent nephrotoxicity. The hematological toxicity and plasma concentrations of CDDP showed no difference between patients in both groups. The rs2289669 G>A SNP in MATE1 was not associated with adverse effects and disposition of CDDP. CONCLUSION: The 808G>T SNP in OCT2 ameliorated CDDP-induced nephrotoxicity without alteration of disposition, whereas the rs2289669 G>A SNP in MATE1 had no effect on CDDP toxicity.

The relationship between treatment time of gemcitabine and development of hematologic toxicity in cancer patients.

Although gemcitabine is frequently used in the treatment of cancer, it is associated with myelosuppression. An animal study showed that the tolerability of gemcitabine varied with changes in treatment time; however, no clinical data have verified this finding. The purpose of this study was to determine the relationship between treatment time and development of hematologic toxicity in patients treated with gemcitabine. Gemcitabine-induced hematologic toxicity was retrospectively investigated in 77 patients. Patients were divided into two treatment-time groups: 9:00 and 15:00. Hematologic toxicity was evaluated on day 8 and 15 after treatment. On day 8 and 15, the changing count of white blood cells was significantly reduced in patients treated at 15:00 compared with those treated at 9:00 (p<0.01 and p<0.05, respectively). On days 8 and 15, the changing count of platelet was significantly reduced in patients treated at 15:00 compared with those treated at 9:00 (p<0.05). The incident of over common terminology criteria for adverse events (CTCAE) grade 2 white blood cell decreased was significantly reduced in patients treated at 15:00 compared with those treated at 9:00 (p=0.048, odds ratio=2.92). In conclusion, this cohort study demonstrated that gemcitabine-induced hematologic toxicity could be alleviated by treating patients at 9:00.

Parathyroid hormone contributes to the down-regulation of cytochrome P450 3A through the cAMP/PI3K/PKC/PKA/NF-κB signaling pathway in secondary hyperparathyroidism.

Chronic kidney disease (CKD), which affects, not only renal clearance, but also non-renal clearance, is accompanied by a decline in renal function. Although it has been suggested that humoral factors, such as uremic toxins that accumulate in the body under CKD conditions, could be involved in the changes associated with non-renal drug clearance, the overall process is not completely understood. In this study, we report on the role of parathyroid hormone (PTH), a middle molecule uremic toxin, on the expression of drug metabolizing or transporting proteins using rats with secondary hyperparathyroidism (SHPT) as models. In SHPT rats, hepatic and intestinal CYP3A expression was suppressed, but the changes were recovered by the administration of the calcimimetic cinacalcet, a PTH suppressor. Under the same experimental conditions, a pharmacokinetic study using orally administered midazolam, a substrate for CYP3A, showed that the AUC was increased by 5 times in SHPT rats, but that was partially recovered by a cinacalcet treatment. This was directly tested in rat primary hepatocytes and intestinal Caco-2 cells where the expression of the CYP3A protein was down-regulated by PTH (1-34). In Caco-2 cells, PTH (1-34) down-regulated the expression of CYP3A mRNA, but an inactive PTH derivative (13-34) had no effect. 8-Bromo-cyclic adenosine monophosphate, a membrane-permeable cAMP analog, reduced mRNA expression of CYP3A whereas the inhibitors of PI3K, NF-κB, PKC and PKA reversed the PTH-induced CYP3A down-regulation. These results suggest that PTH down-regulates CYP3A through multiple signaling pathways, including the PI3K/PKC/PKA/NF-κB pathway after the elevation of intracellular cAMP, and the effect of PTH can be prevented by cinacalcet treatment.