In vivo inhibition of acylpeptide hydrolase by carbapenem antibiotics causes the decrease of plasma concentration of valproic acid in dogs

1.?Our previous in vitro studies suggest that inhibition of the acylpeptide hydrolase (APEH) activity as valproic acid glucuronide (VPA-G) hydrolase by carbapenems in human liver cytosol is a key process for clinical drug–drug interaction (DDI) of valproic acid (VPA) with carbapenems. Here, we investigated whether in vivo DDI of VPA with meropenem (MEPM) was caused via inhibition of APEH in dogs.

2.?More rapid decrease of plasma VPA levels and increased urinary excretion of VPA-G were observed after co-administration with MEPM compared with those after without co-administration, whereas the plasma level and bile excretion of VPA-G showed no change.

3.?Dog VPA-G hydrolase activity, inhibited by carbapenems, was mainly located in cytosol from both the liver and kidney. APEH-immunodepleted cytosols lacked VPA-G hydrolase activity. Hepatic and renal APEH activity was negligible even at 24?h after dosing of MEPM to a dog.

4.?In conclusion, DDI of VPA with carbapenems in dogs is caused by long-lasting inhibition of APEH-mediated VPA-G hydrolysis by carbapenems, which could explain the delayed recovery of plasma VPA levels to the therapeutic window even after discontinuation of carbapenems in humans.     

Effect of simulated pulpal pressure on all-in-one adhesive bond strengths to dentine

OBJECTIVES: To evaluate the durability of all-in-one adhesive systems bonded to dentine with and without simulated hydrostatic pulpal pressure (PP). METHODS: Flat dentine surfaces of extracted human molars were prepared. Two all-in-one adhesive systems, One-Up Bond F (OBF) (Tokuyama Corp., Tokyo, Japan), and Fluoro Bond Shake One (FBS) (Shofu Co., Kyoto, Japan) were applied to the dentine surfaces under either a PP of 0 or 15cm H(2)O. Then, resin composite build-ups were made. The specimens bonded under pressure were stored in 37 degrees C water for 24h, 1 and 3 months under 15cm H(2)O PP. Specimens not bonded under pressure were stored under zero PP. After storage, the specimens were sectioned into slabs that were trimmed to hourglass shapes and subjected to micro-tensile bond testing (muTBS). The data were analysed using two-way ANOVA and Holm-Sidak HSD multiple comparison tests (alpha=0.05). RESULTS: The muTBS of OBF fell significantly (p<0.05) when PP was applied during bonding and storage, regardless of storage time. In contrast, although the muTBS of OBF specimens bonded and stored without hydrostatic pressure storage fell significantly over the 3 months period, the decrease was less than half as much as specimens stored under PP. In FBS bonded specimens, although there was no significant difference between the muTBS with and without hydrostatic pulpal pressure at 24h, by 1 and 3 months of storage under PP, significant reductions were seen compared with the control group without PP. CONCLUSION: The muTBS of OBF bonded specimens was lowered more by simulated PP than by storage time; specimens bonded with FBS were not sensitive to storage time in the absence of PP, but showed lower bond strengths at 1 and 3 months in the presence of PP.     

Venous sac embolization of pulmonary arteriovenous malformation: Preliminary experience using interlocking detachable coils

Purpose: To evaluate the indication and advantages of venous sac embolization of pulmonary arteriovenous malformations (PAVMs) using interlocking detachable coils (IDCs). Methods: We performed percutaneous embolization in 12 PAVMs in four patients using IDCs, initially placed in the venous sac or at the feeding artery to prevent systemic migration of additional coils. We placed the IDCs in the venous sac in PAVMs with the following vascular architecture: the draining vein was larger than the feeding arteries and both vessels were interposed with the venous sac or there were short feeding arteries. Results: Complete occlusion was achieved in all 12 PAVMs without significant complications. We deployed IDCs in the venous sac in eight PAVMs and in the feeding artery in four. Conclusion: Venous sac embolization may be beneficial in PAVMs with large out-flow vessels or short feeding arteries. IDCs are suitable for this procedure.     

Ultrasensitive determination of NE-100, a novel sigma ligand, in human plasma by liquid chromatography and electrospray ionization tandem mass spectrometry combined with a column-switching technique.

For the highly sensitive and selective determination of NE-100, a novel sigma ligand, at levels of low picogram per milliliter of human plasma, a method with excellent reliability employing liquid chromatography (LC)-electrospray ionization (ESI) tandem mass spectrometry (MS-MS) combined with a column-switching technique has been developed. The method involves the use of a stable isotope labeled compound as the internal standard (I.S.), liquid-solid extraction of a plasma specimen with a C8 cartridge, automated on-line clean-up on a short trapping column, subsequent separation on a micro-bore C18 column and detection with ESI-MS-MS using m/z 356 ([M+H]+) as a precursor ion and m/z 105 as a product ion in a selected reaction monitoring mode. The detection and the quantification limits of NE-100 in plasma were 0.5 pg/ml with a signal-to-noise ratio (S/N) of 3 and 2.3 pg/ml, respectively, with an S/N of 21. The good linearity of the calibration graph was obtained in the range of 2.3 to approximately 907.0 pg/ml with excellent reliability. The developed method was applied to the determination of NE-100 in plasma obtained from the clinical trail.     

Usefulness of measurement of lens culinaris agglutinin-reactive fraction of α-fetoprotein as a marker of prognosis and recurrence of small hepatocellular carcinoma

OBJECTIVE: Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3%) is a recently described marker of hepatocellular carcinoma (HCC), and its usefulness has been demonstrated in many studies. We evaluated the usefulness of serial measurement of AFP-L3% as a marker of prognosis and recurrence after treatment of small HCC. METHODS: AFP-L3% was measured before and after initial treatment in 60 patients with small HCC (maximum diameter < or = 2 cm). AFP-L3% was taken as the ratio of AFP-L3 to total AFP and multiplied by 100%, and levels > or = 10% were considered positive. Outcomes and recurrence were compared between patients AFP-L3%-negative after initial treatment (Group A, n = 43) and patients who were AFP-L3%-positive after initial treatment (Group B, n = 17). RESULTS: Before treatment, AFP-L3% was positive in 14 (23.3%) of the 60 patients. The cumulative survival rate of Group A was significantly longer (p = 0.0091) than that of Group B. The recurrence rate was significantly higher in Group B (p = 0.0104) than in Group A. When recurrence was limited to intrahepatic metastasis, the recurrence rate was significantly higher in Group B (p = 0.0064). However, the recurrence rate of multicentric occurrence did not differ significantly between Groups A and B. CONCLUSIONS: Measurement of AFP-L3% after treatment may be useful for understanding prognosis and recurrence of HCC.