Glycosylation is one of the most important post-translational modifications of proteins, which affects biological activities by way of controlling higher order structure. Recently, the novel structure of glycoprotein, namely C-glycosyl protein was identified in various proteins. The first total synthesis of the naturally occurring C-glycosyl amino acid and peptide was achieved. The mannose and tryptophan moiety was connected via ring opening reaction of epoxide by lithiated indole derivative. After functional group conversion and deprotection, the glyco-amino acid was synthesized in a concise and stereoselective manner. To develop the rapid oligosaccharide construction methodology, the soluble polymer supported oligosaccharide was investigated. Due to high polarity of polymer support, the purification of PEG bound compound is achieved quite easily. The real-time monitoring of the glycosylation reaction was performed by MALDI-TOF MS, whereas the deprotection reaction of chloroacetyl group was performed by color test using (p-nitrobenzyl) pyridine. The purification of PEG bound compound which has chloroacetyl group, is achieved by capture-release strategy by use of resin bound cysteine derivative. By combination of these methodologies and novel linker, tetrasaccharides were synthesized.
Recently, the separation between dispensing and prescribing drugs has made rapid progress and the number of pharmacists' jobs at hospitals have increased, which means that pharmacists are contributing more than ever to medical treatment. Thus the relation between the supply of and demand for pharmacists has become a topic in the improvement of pharmacist quality. In this study, we used date on pharmacists including type of job, registration number, etc. to predict the relation between the supply of pharmacists at work and the demand for pharmacists. In addition, we analyzed the working trends of pharmacy pharmacists and predicted the in relation between the supply and demand. Due to progress in the separation of dispensing and prescribing drugs, the supply of pharmacists will nearly equal demand temporarily. Howerer, the supply at work will always exceed demand, and we concluded that no shortage of pharmacists would occur. In addition, after the demand for pharmacists stops increasing, the excess supply of pharmacists will continue to increase. Based on analysis of working trends of pharmacy pharmacists, the in number will increase at the same rate as between 1996 and 1998 (approximately 6000 persons/year). Under this assumption, we concluded that no shortage of pharmacy pharmacists will occur, even if the separation of dispensing and prescribing drugs continues to accur at the rate of 5%/year.
The effect of the intake of 200g of grapefruit pulp (corresponding to one grapefruit) on the pharmacokinetics of the calcium antagonists nifedipine (NF) and nisoldipine (NS) were investigated in 8 healthy Japanese male volunteers. A crossover design was used for the study: group I did not ingest any grapefruit (control group); group II ingested grapefruit 1 h after drug administration; and group III ingested grapefruit 1 h before drug administration. The intake of grapefruit pulp increased the plasma concentrations of both NF and NS, an effect that has previously been reported with grapefruit juice. The increase was most marked when grapefruit was eaten before drug administration. For both NF and NS, subjects who ingested grapefruit 1 h before drug administration exhibited a greater Cmax and AUC0—24 than did subjects in the control group. For NF, the Cmax was 1.4 times higher and the AUC0—24 1.3 times larger in group III than in group I. For NS, the Cmax was 1.5 times higher and the AUC0—24 1.3 times larger in group III than in group I. The increase in the AUC0-24 was significant for both drugs (p<0.05). The finding that the ratios of Cmax and AUC0—24 for unchanged drug and metabolites did not vary greatly among the three groups for either drug suggests that the increase in serum concentration produced by grapefruit intake may be due to other factors than an inhibitory effect on drug metabolism. Also, the increases in Cmax and AUC0—24 of NS produced by grapefruit intake were smaller than those produced by grapefruit juice intake, indicating that grapefruit pulp and juice have different effects on the pharmacokinetics.
Phenytoin (PHT) exhibits nonlinear pharmacokinetics in the therapeutic range. Therefore a slight increase in dose may lead to considerable elevation of the serum PHT level. Although its bioavailability is dependent on the formulation, bioequivalence is considered to be preserved between the three major formulations, of tablet, 97% fine granules, and 10% powder. However, we experienced many cases of increases serum PHT concentration after changes in formulation from 97% fine granules to 97/4% hospital-made fine granules, and from the latter to 10% powder. Retrospective analysis revealed that these alterations were accompanied by 55% and 16% increases in the serum concentration-to-dose ratio of PHT, respectively. We investigated the factors of this increase by analyzing the weight of remaining powder in a package and the PHT content of each formulation. Each package of PHT formulation prepared with 97% fine granules and 10% powder was unsealed, and the contents were weighed to calculate the rate of recovery. The rate of ingestion was estimated by correcting the rate of recovery by PHT strength (i. e., 1.0 for 10% powder and 0.97 for fine granules). The rates of recovery and ingestion for 10% powder were 13% and 16% higher than those for 97% fine granules, respectively (p<0.01). In conclusion, Changing the PHT formulation from 97% fine granules to 10% powder may lead to a considerable increase in the serum PHT concentration and possibly induce PHT toxicity.
In the present study, the induction of drug-metabolizing enzymes and transporters was evaluated by analyzing mRNA expression in human hepatocytes after exposure to various compounds. The compounds tested included typical enzyme inducers, rifampicin and omeprazole, and controls. All experiments were performed in the presence of 0.1% DMSO. Analysis was performed by the real-time reverse-transcription polymerase chain reaction method (RT-PCR) in the presence of TaqMan probes using an ABI PRISM 7700 Sequence Detector system. A new analytic method to quantify mRNA levels in small numbers of human hepatocytes has been developed for phase I enzymes, phase II enzymes, and transporters. The levels of CYP1A1, CYP2B6, CYP2C8, CYP3A4, CYP3A5, ADH3, and ABCG1 mRNA in human hepatocytes increased after exposure to rifampicin. The levels of CYP1A1, CYP2B6, CYP3A4, CYP3A5, and ABCG1 mRNA recovered after a change to media without rifampicin. The levels of CYP1A1, CYP1A2, CYP1B1, ALDH3, and ALDH6 mRNA increased after exposure to omeprazole, and recovered after a change to media without omeprazole. On the other hand, the levels of ADH3 and ABCB4 mRNA decreased after exposure to omeprazole, and recovered after a change to media without omeprazole. In conclusion, these results demonstrate the applicability of quantitative real-time RT-PCR to the evaluation of the gene induction and recovery of drug-metabolizing enzymes and transporters after exposure to drugs in human hepatocytes.