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...
Abstract:The Japanese macaque (Macaca fuscata), along with rhesus and long-tailed macaques, is one of the macaca species. In Japan, it has been preferred for use as a laboratory animal, particularly in the field of neuroscience, because of its high level of intelligence and its gentle nature. In addition, the species has a relatively homogeneous genetic background and field researchers have accumulated abundant information on the social behavior of wild Japanese macaques. As future neuroscience research will undoubtedly be more focused on the higher cognitive functions of the brain, including social behavior among multiple individuals, the Japanese macaque can be expected to become even more valuable as a laboratory animal in the near future. The Ministry of Education, Culture, Sports, Science and Technology has launched a National BioResource Project (NBRP) to establish a stable breeding and supply system for Japanese macaques for laboratory use. The project is in progress and should lead to the establishment of a National Primate Center in Japan, which will support the supply of monkeys as well as social outreach and handling of animal welfare issues.
ABSTRACT. A large bolus of hairs found in the feces of an adult wild chimpanzee in the Budongo Forest, Uganda, was identified as belonging to a chimpanzee below the age of 3 yrs. This represents the second case of infant-eating recorded in the Budongo Forest.Key Words: Chimpanzee; Infant-eating; Electron microscopy; Feces; Hair. OBSERVATIONSOn September 23, 1991 at 10:00, C. BAKUNEETA came across nine adult-sized fecal boluses underneath a Ricinodendron heudelottii tree 800m to the north of the Sonso camp in the Budongo Forest. The basis of the identification of the feces (see MCGREW et al., 1988, Discussion) was as follows.Chimpanzees had been seen feeding under this tree the previous day. The tree had abundant large fruits on which the chimpanzees had been feeding. The feces were fresh when found, having been dropped the same day. The form of the fecal boluses was that of adult chimpanzees, llcm in length and llcm in circumference. The feces were routinely collected in polythene bags for contents analysis.During analysis (by washing and sieving the samples) it was found that one fecal sample contained 6 seeds of Cordia millennii, 2 seeds of Caloncoba crepinia, and in addition a bolus consisting of approximately 500 black hairs together with a small piece of bone and cartilage. No hair was found in the other eight fecal samples. One or two hairs are often found in chimpanzee feces and this is probably the result of grooming activity. Grooming alone would not lead to the presence of 500 hairs in feces. The hairs were collected and dried. A sample was subsequently identified by electron microscopy by H. INAGAKI as belonging to a chimpanzee infant below the age of 3 yrs. Scale patterns of the hairs were wavy (Fig. 1) and the medulla was rich in granules with the appearance of ants' eggs (Fig. 2). Such characteristics corresponded with those of the chimpanzee hairs observed in a previous study (|NAGAKI, 1993). In addition, the hairs are considered to belong to a young animal below the age of 3 yrs since they were relatively fine, and younger chimpanzees have thinner hairs than adults do (INAGAKI, pers. obs.).It would thus appear from this circumstantial evidence that part of an infant chimpanzee may have been eaten by an adult chimpanzee on this occasion. From the absence of hairs in the other feces, it appears that the infant was not eaten by other group members at that time and place.
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