Katsuyoshi Nakajima

Discovery of CS-0777: A Potent, Selective, and Orally Active S1P1 Agonist.

CS-0777 (3) is phosphorylated in vivo, and the phosphate of CS-0777 (CS-0777-P) (4) acts as a selective S1P receptor-1 (S1P1) modulator. We report herein the synthesis of CS-0777 and CS-0777-P, pharmacological effects such as S1P1 and S1P3 agonist activity in vitro, peripheral blood lymphocyte lowering effects and the suppressive effect on experimental autoimmune encephalomyelitis (EAE), and also the pharmacokinetics in rats. CS-0777-P had ∼320-fold greater agonist activity for human S1P1 (EC50; 1.1 nM) relative to S1P3 (EC50; 350 nM). Following administration of single oral doses of 0.1 and 1 mg/kg of CS-0777 in rats, lymphocyte counts decreased significantly, with a nadir at 12 h postdose and recovery to vehicle control levels by 5 days postdose. In the EAE model compared to the vehicle-treated group, significant decreases in the cumulative EAE scores were observed for the 0.1 and 1 mg/kg CS-0777 groups in rats. CS-0777 is currently in clinical trials for the treatment of multiple sclerosis (MS).

Combined tachykinin receptor antagonist: synthesis and stereochemical structure–activity relationships of novel morpholine analogues

We report herein the synthesis and stereochemical structure-activity relationships of novel morpholine analogues 12 and 13 with regards to NK1, NK2 and NK3 tachykinin receptor binding affinity. An essential requirement for more potent binding affinities was controlled by absolute configuration. (S,R)-12 and (S,R)-13 exhibited high binding affinities for NK1, NK2 and NK3 receptors.

Results of the Tokyo Trial of Prevention of Post-ERCP Pancreatitis with Risperidone-2: a multicenter, randomized, placebo-controlled, double-blind clinical trial

BACKGROUND Our previous study suggested that a combination of ulinastatin and risperidone reduced post-ERCP pancreatitis (PEP) compared with ulinastatin alone. OBJECTIVE The aim of this study was to evaluate the efficacy of risperidone alone for prevention of PEP. DESIGN A multicenter, randomized, placebo-controlled, double-blind clinical trial. SETTING Two academic hospitals and 5 referral hospitals in Tokyo and Saitama, Japan. PATIENTS Patients undergoing therapeutic or interventional-diagnostic ERCP. INTERVENTION The patients were randomized to receive 2 mg of oral risperidone or oral placebo at 0.5 to 2 hours before ERCP. MAIN OUTCOME MEASUREMENTS The primary endpoint was the incidence of PEP. Secondary endpoints were the incidence of hyperenzymemia and enzyme levels (amylase, pancreatic amylase, lipase). Risk factors for PEP were evaluated. RESULTS We initially enrolled 500 patients in the study (250 in the risperidone group and 250 in the placebo group), but 17 (11 in the risperidone and 6 in the placebo group) were excluded after randomization. PEP developed in 24 patients (10.0%) in the risperidone group and 21 patients (8.6%) in the placebo group (P = .587). Serum amylase levels at 3 hours after ERCP were lower in the risperidone group (P = .007 in a single test of hypothesis, significance removed by Bonferroni correction for multiple testing). In multivariate analysis, a small papilla of Vater, total procedure time ≥40 minutes, and stenosis of the intrahepatic duct were significantly associated with PEP. LIMITATIONS Multiplicity of study centers and a relatively wide time range of drug administration time. CONCLUSION Risperidone did not show a benefit in prevention of PEP in this trial. ( CLINICAL TRIAL REGISTRATION NUMBER NCT000004592.).

エトポシド(VP-16)注射液の持続注入時に発生したポリウレタン製カテーテル亀裂の要因に関する検討

We studied the cause of cracking of a clinically used polyurethane (PU) catheter during the constant infusion of etoposide (VP-16) injection (Lastet), administered without dilution to patients as a part of combination high-dose chemotherapy. After VP-16 injection was infused into the PU catheter at a constant infusion rate (30 ml/h) for 24 h, a decrease in the elasticity (36% of untreated) and on increase in the length of the catheter (3.7%) were observed. These changes were significantly higher than those treated with the control saline. The similar changes of the PU catheter were observed after treatment with a basal solution containing polyethylene glycol 400 (PEG 400), polysorbate 80 and ethanol, which is the vehicle of the VP-16 injection, and with ethanol alone. Moreover, obvious degeneration of the internal wall (occurrence of spots like melting) and cutting face (micro-cracking) of the catheter was observed with an electron microscope after treatment with the vehicle. On the other hand, the elasticity or extension of the PU catheter were not changed after treatment with saline or PEG 400. From these findings, it was suggested that the degeneration and subsequent cracking of the PU catheter during the infusion of VP-16 injection was caused by ethanol contained in its injection solution. No cracking or morphological changes of polyvinyl chloride (PVC) and silicone catheters were found after treatment with the vehicle solution. However, since it has been reported in previous reports that di(2-ethylhexyl)phthalate was leached from PVC bags, the high dose chemotherapy with the dilution-free VP-16 injection should be achieved safely and effectively using a silicon catheter, rather than the PU catheter.

Development and Evaluation of a Medication Management System for Rational Inventory Control of Medicine.

In the University of Tokyo Hospital, the reentry of data, the re-output of documents, the transfer of data by hand writing, etc. has to be routinely carried out in each department, because there is no compatibility in the related work between the systems and generated information.In this study, we developed a medication management system to share drug-requesting information generated inside the hospital with medical wholesalers who introduced the Value Added Network (VAN) -ordering system, and evaluated the usefulness of this system by sending questionnaires to those who are working in the wholesale, clinical wards, and office work sections.The developed medication management system unified a series of information on the request-to-order processing of medicine between the hospital and wholesalers, the warehousing processing in the pharmacy department, the supply processing for the clinical wards, and the expenditure processing of purchased medical supplies. In addition, the system was designed to work with the LAN of our hospital information system under the environment of Windows NT®.In the investigation on the introduction situation of the computer for the drug wholesalers, 14 out of 16 companies (88%) introduced a computerized system to receive orders. Moreover, 12 out of 14 companies (86%) replied with “it is useful” regarding the usefulness of the system. On the other hand, in clinical wards, 41 out of 55 (75%) replied with “the requesting process has become more convenient by using this system”. In office sections, the time needed to process orders was drastically shortened from approximately 20 to 5 minutes on average.By utilizing this newly developed medication management system, it became possible to share the drug-requesting information originally generated in the clinical wards with the pharmacy department and office work section in the hospital and the medical wholesalers ; therefore, we find this system to be a useful supporting system for the proper management not only for hospitals but for medical wholesalers as well.

Running-state Analysis of the Outpatient Consultation for Drug Compliance and Development of a Management System of the Consultation Records Based on an In-hospital LAN.

Since we started both active and passive consultation regarding drug compliance for outpatients at the department of pharmacy, University of Tokyo Hospital in 1991, the records of such consultation have been carefully kept on ‘drug consultation sheets’. In the present study, we analyzed the consultation records from April to September in 1998. The case number of consultation during this period was 627; among them, active instructions were given to 409 cases (65%) while passive instructions were given to the others. The analysis showed that 28 cases (14patients) out of 627 cases experienced our consultation more than once; 13 (93%) of such patients were advised by different pharmacists and 10 (71%) were advised regarding the same drug, thus suggesting the need for a quick retrieval of past records. As a result, we designed a software system to integrate an electronic database for consultation records, including the contents of consultations, a list of the prescribed drugs and any OTC drugs which have been taken, the patients characteristics, and a history of using a medication diary (so-called ‘Okusuri Techo’). We set up a local area network (LAN) using the database inside the hospital so that all accumulated information could be easily retrieved from any hospital terminal. The intranet-based management system of outpatient consultation records has now enabled a high consistency and efficiency in consultations by different pharmacists while also allowing for a quick compilation of all medical records.