ABSTRACT:The Ministry of Health and Welfare, Japan banned coadministration of carbapenems, such as panipenem/betamipron (PAPM), meropenem (MEPM), and valproic acid (VPA) because clinical reports have indicated that the coadministration caused seizures in epileptic patients due to lowered plasma levels of VPA. In this study, we have clarified the mechanism of the drug-drug interaction using PAPM In vitro experiments using monkey liver slices suggested that the apparent synthetic rate of VPA glucuronide (VPA-G) increased in the presence of carbapenems. However, no such increase was observed in the experiment using monkey liver microsomes. Although no increase of uridine 5-diphosphate Dglucuronic acid was found in monkey liver slices in the presence of carbapenems, potent inhibitory activity of carbapenems for the hydrolysis of VPA-G was found in monkey and rat liver homogenate. In vivo hydrolysis of VPA-G was clearly shown by the existence of VPA in plasma after dosing of VPA-G to rats, and its inhibition by carbapenems was also clearly shown by the negligible levels of VPA in rat plasma after coadministration of carbapenems and VPA-G. These results clearly indicate one of the important causes of drug interaction as follows: carbapenems would inhibit the hydrolytic enzyme, which is involved in the hydrolysis of VPA-G to VPA, resulting in a decrease of plasma concentration of VPA.The increased incidence of convulsions or epileptic fits due to interaction between carbapenem antibiotics, such as panipenem/betamipron (PAPM) and meropenem (MEPM), and the antiepileptic valproic acid (VPA) was first reported clinically in 1997 (Nagai et al., 1997). Both PAPM and MEPM reduced the plasma concentration of concomitantly administered VPA, which resulted in an insufficient concentration to prevent epileptic fit. This led to prohibition of the concomitant use of carbapenem antibiotics and VPA being added to the Information on Adverse Reactions to Drugs from the Ministry of Welfare in Japan in 1996. To clarify the mechanism of this drug interaction, many studies have been conducted, but the mechanism is still not clear. (Fig. 1), is a carbapenem antibiotic newly developed by Shionogi Co. Ltd. Because its structure is similar to that of MEPM, there is a possibility of a similar drug interaction; we therefore studied the drug interactions between carbapenems, including S-4661 and VPA, and their mechanism, using in vivo and in vitro methods with monkeys and rats. Materials and MethodsChemicals. VPA (sodium valproate) was supplied by Sigma-Aldrich (St. Louis, MO). [Carbonyl-14 C]-VPA (55 mCi/mmol, 99% pure by thin-layer chromatography) was supplied by Muromachi Chemical Co. (Tokyo, Japan). Doripenem (S-4661) was synthesized by Shionogi Research Laboratories. PAPM was supplied by Sankyo Co. Ltd. (Tokyo, Japan). MEPM was supplied by Sumitomo Pharmaceutical Co. (Osaka, Japan). All other chemicals were of analytical grade.14 C-VPA-G was extracted with methanol from SEP-PAK C18 in which urine and bile, obtained after intravenous administ...

Expression of cyclooxygenase (COX)-2 protein during rat hepatocarcinogenesis associated with fatty change, fibrosis, cirrhosis and oxidative DNA damage, caused by a choline-deficient, L-amino acid-defined (CDAA) diet were investigated in F344 male rats, along with the chemopreventive efficacy of the specific COX-2 inhibitor, nimesulide (NIM). Nimesulide, which was administered in the diet at concentrations of 200, 400, 600 and 800 p.p.m. for 12 weeks, decreased the number and size of preneoplastic enzyme-altered liver foci, levels of oxidative DNA damage, and the grade and incidence of fibrosis in a dose-dependent manner. A preliminary long-term study of 65 weeks also revealed that 800 p.p.m. NIM decreased the multiplicity of neoplastic nodules and hepatocellular carcinomas and prevented the development of cirrhosis. Western blot analysis revealed that COX-2 protein was barely expressed in control livers and increased approximately 2.9-fold in the livers of rats fed on a CDAA diet for 12 weeks and approximately 4.5-5.4-fold in tumors, with a diameter larger than 5 mm, at 80 weeks. Immunohistochemically, COX-2 protein was positive in sinusoidal and stromal cells in fibrotic septa, which were identified by immunoelectron microscopy as Kupffer cells, macrophages, either activated Ito cells or fibroblasts, after exposure to the CDAA diet for 12 weeks, whereas it was only occasionally weakly positive in sinusoidal, probably Kupffer, cells in control livers. In neoplastic nodules in rats fed on a CDAA diet for 30 and 80 weeks, sinusoidal cells and cells with relatively large round nuclei and scanty cytoplasm were strongly positive for COX-2 protein, with the neoplastic hepatocytes in the minority of the nodules, but not the cancer cells, being moderately positive. These results clearly indicate that rat hepatocarcinogenesis, along with fatty change, fibrosis and cirrhosis, is associated with increased expression of COX-2 protein, and point to the chemopreventive efficacy of a selective COX-2 inhibitor against, at least, the early stages of hepatocarcinogenesis.

Atomically thin films of WSe2 from one monolayer up to 8 layers were deposited on an Al2O3 r-cut (11¯02) substrate using a hybrid-Pulsed Laser Deposition (PLD) system where a laser ablation of pure W is combined with a flux of Se. Specular X-ray reflectivities of films were analysed and were consistent with the expected thickness. Raman measurement and atomic force microscopy confirmed the formation of a WSe2 monolayer and its spatial homogeneity over the substrate. Grazing-incidence X-ray diffraction uncovered an in-plane texture in which WSe2 [101¯0] preferentially aligned with Al2O3 [112¯0]. These results present a potential to create 2D transition metal dichalcogenides by PLD, where the growth kinetics can be steered in contrast to common growth techniques like chemical vapor deposition and molecular beam epitaxy.