[A case of drug-induced liver injury caused by entecavir for treatment of hepatitis B virus reactivation during RCHOP in a patient with non-Hodgkin lymphoma].

A 49-year-old-man, a healthy carrier of hepatitis B virus (HBV), received chemotherapy with a rituximab/cyclo- phosphamide/doxorubicin/vincristine/prednisolone (R-CHOP) regimen for non-Hodgkin's lymphoma. At the first course of chemotherapy, not only the liver function but the HBV DNA level was elevated. These symptoms were diagnosed as hepatic injury induced by HBV reactivation, and, therefore, entecavir (ETV) was started. As a result, although the treatment with ETV decreased the HBV DNA level, liver function values were remarkably elevated again (over 3 times the levels before beginning ETV). ETV was discontinued because of suspicion regarding the onset of hepatic injury it caused. After switching to lamivudine (LVD), the liver function quickly improved and no problems were observed with renewal of the R-CHOP regimen. In addition, the HBV DNA level decreased and 3 courses of R-CHOP were performed successfully. In our case, the hepatic injury was induced by ETV, although anti-HBV medicine was used for the treatment of HBV reactivation according to the guideline. Therefore, the medical staff must carefully and consistently observe patients with HBV infection after chemotherapy.

The incidence of endophthalmitis or macular involvement and the necessity of a routine ophthalmic examination in patients with candidemia.

BACKGROUND: The incidence of ocular candidiasis (OC) in patients with candidemia varies across different reports, and the issue of whether routine ophthalmoscopy improves outcomes has been raised. This study investigated the incidence of OC and evaluate whether the extent of OC impacts the clinical outcomes. METHODS: This retrospective study included non-neutropenic patients with candidemia who underwent treatment at one of 15 medical centers between 2010 and 2016. Chorioretinitis without other possible causes for the ocular lesions and endophthalmitis was classified as a probable OC. If signs of chorioretinitis were observed in patients with a systemic disease that causes similar ocular lesions, they were classified as a possible OC. RESULTS: In total, 781 of 1089 patients with candidemia underwent an ophthalmic examination. The prevalence of OC was 19.5%. The time from the collection of a positive blood culture to the initial ophthalmic examination was 5.0 ± 3.9 days in patients with OC. The leading isolate was Candida albicans (77.9%). Possible OC was associated with unsuccessful treatments (resolution of ocular findings) (odds ratio: 0.354, 95% confidence interval: 0.141-0.887), indicating an overdiagnosis in patients with a possible OC. If these patients were excluded, the incidence fell to 12.8%. Endophthalmitis and/or macular involvement, both of which require aggressive therapy, were detected in 43.1% of patients; a significantly higher incidence of visual symptoms was observed in these patients. CONCLUSION: Even when early routine ophthalmic examinations were performed, a high incidence of advanced ocular lesions was observed. These results suggest that routine ophthalmic examinations are still warranted in patients with candidemia.

Effects of turmeric extract on the pharmacokinetics of nifedipine after a single oral administration in healthy volunteers.

The effects of turmeric extracts on the pharmacokinetics of nifedipine were examined in 10 healthy volunteers. An open-label and randomized crossover study was performed at 2-week intervals. In the control experiment, after a 10 h overnight fast, 10 mg of nifedipine (Adalat® capsule) was administered orally and blood was collected at 0, 0.5, 1, 2, 3, 4, 5, 6, and 8 h. In the combination experiment, the volunteers were orally administered 10 mg of nifedipine together with six tablets containing concentrated turmeric extract (480 mg of curcuminoid per six tablets), which is the general daily dose, and blood was sampled as above. The time profile of the plasma concentration of nifedipine in the control was comparable to that in combination with turmeric extract, as were the pharmacokinetic parameters: that is, the mean ratio of turmeric extract/control group (90% confidence interval: CI); C(max), 0.98 (0.95, 1.01) and AUC(0 - ∞) 1.00 (0.98, 1.02). In addition, the volunteers all completed the study without any serious adverse events. Consumption of the turmeric extract did not affect the pharmacokinetics of nifedipine after a single oral administration.

Studies on interactions between traditional herbal and western medicines. V. effects of Sho-saiko-to (Xiao-Cai-hu-Tang) on the pharmacokinetics of carbamazepine in rats.

The possibility of pharmacokinetic interactions between Sho-saiko-to extract powder (TJ-9), the most widely used traditional Chinese herbal (Kampo) medicine in Japan, and carbamazepine (CBZ), an important anti-epileptic drug, was examined in rats. There was no significant difference in the protein binding of CBZ in serum obtained before and after the single oral administration of TJ-9. The addition of TJ-9 to normal hepatic microsomes inhibited CBZ-10,11-epoxylase activity in a concentration-dependent manner. Liver weight, amounts of P450 and cytochrome b(5) in hepatic microsomes and the formation of carbamazepine-10,11-epoxide (CBZ-E), an active metabolite of CBZ, by microsomes were not influenced by 2-week repeated oral pretreatment with TJ-9 (1 g/kg/d), although pretreatments with phenobarbital (80 mg/kg/d, i.p.) significantly increased these parameters. The simultaneous oral administration of TJ-9 (1 g/kg) significantly decreased the peak plasma concentration of CBZ and the area under the concentration-time curve of CBZ-E, and lengthened the time to reach the peak concentration of CBZ after oral administration of CBZ. Two-week repeated oral pretreatment with TJ-9, however, did not affect the plasma concentration-time profile or any pharmacokinetic parameter of CBZ or CBZ-E. Also, a single oral administration of TJ-9 (1 g/kg) significantly delayed gastric emptying. These results indicated that the simultaneous oral administration of TJ-9 with CBZ to rats decreased the gastrointestinal absorption of CBZ, at least in part, by delaying gastric emptying, without affecting the metabolism of CBZ.

Studies on interactions between functional foods or dietary supplements and medicines. III. Effects of ginkgo biloba leaf extract on the pharmacokinetics of nifedipine in rats.

The effects of Ginkgo biloba leaf extract (GBE), one of the most widely used herbal dietary supplements in Japan and the United States, on the pharmacokinetics of nifedipine (NFP), a typical probe of P450 (CYP) 3A, but not a substrate of the multidrug transporter P-glycoprotein (P-gp), were studied using rats. Simultaneous oral treatment with GBE (20 mg/kg) did not affect the pharmacokinetics after intravenous administration of NFP (2.5 mg/kg). However, the maximal plasma NFP concentration, the area under the concentration-time curve and absolute bioavailability after oral administration of NFP (5 mg/kg) were significantly increased by simultaneous oral treatment with GBE, approximately 1.6-fold, 1.6-fold and 2.1-fold, respectively. These results suggest that the concomitant oral use of GBE appeared to reduce the first-pass metabolism of orally administered NFP, by inhibiting CYP3A, possibly but not P-gp, in rats.

Studies on interactions between functional foods or dietary supplements and medicines. IV. Effects of ginkgo biloba leaf extract on the pharmacokinetics and pharmacodynamics of nifedipine in healthy volunteers.

The effects of Ginkgo biloba leaf extract (GBE), a widely used herbal dietary supplement in Japan, on the pharmacokinetics and pharmacodynamics of nifedipine (NFP), a calcium-channel blocker, were studied using 8 healthy volunteers. Simultaneous oral ingestion of GBE (240 mg) did not significantly affect any of the mean pharmacokinetic parameters of either NFP or dehydronifedipine, a major metabolite of NFP, after oral administration of NFP (10 mg). However, the maximal plasma NFP concentrations in 2 subjects were approximately doubled by GBE, and they had severer and longer-lasting headaches with GBE than without GBE, with dizziness or hot flushes in combination with GBE. The mean heart rate after oral administration of NFP with GBE tended to be faster than that without GBE at every time point. Accordingly, it was concluded that GBE and NFP should not be simultaneously ingested as much as possible, and careful monitoring is needed when administering NFP concomitantly with GBE to humans.

Studies on interactions between functional foods or dietary supplements and medicines. I. Effects of Ginkgo biloba leaf extract on the pharmacokinetics of diltiazem in rats.

The effects of Ginkgo biloba leaf extract (GBE), one of the most widely used herbal dietary supplements in Japan, on the pharmacokinetics of diltiazem (DTZ), a typical probe of cytochrome P450 (CYP) 3A, were examined in rats. The simultaneous addition of GBE to small intestine and liver microsomes inhibited the formation of N-demethyl DTZ (MA), an active metabolite of DTZ produced by CYP3A, in a concentration-dependent manner, with an IC(50) of about 50 and 182 microg/ml, respectively. This inhibition appeared to be caused, at least in part, by a mechanism-based inhibition. Both the rate of formation of MA and total amount of CYP in intestinal or hepatic microsomes after a single oral pretreatment with GBE (20 mg/kg) decreased transiently. The pretreatment significantly decreased the terminal elimination rate constant and increased the mean residence time, after intravenous administration of DTZ (3 mg/kg). Furthermore, it significantly increased the area under the concentration-time curve and absolute bioavailability after oral administration of DTZ (30 mg/kg). These results indicated that the concomitant use of GBE in rats increased the bioavailability of DTZ by inhibiting both intestinal and hepatic metabolism, at least in part, via a mechanism-based inhibition for CYP3A.