Cyclosporine-or tacrolimus-induced neurotoxicity was retrospectively evaluated in five patients. Symptoms ranging from mild (tremor, insomnia, visual disturbance) to severe events (convulsion, leukoencephalopathy) were observed. The predisposing risk factors in these patients included hypomagnesemia, liver dysfunction and transient high blood concentrations of the immunosuppressants. Besed on our findings as well as those from other reports, the initial signs and symptoms of immunosuppressant-induced neurotoxicity were as follows ; tremor, headache, anorexia, nausea, vomiting, lethargy, insomnia, anxiety, amnesia, visual disturbance. However, not all of these events correlated with the blood concentrations of the immunosuppressants. The blood cyclosporine concentrations decreased by concomitant use of phenytoin. The blood tacrolimus concentrations varied markedly during the two-week-period after liver transplantation. To prevent patientsfrom developing serious events under immunosuppressant therapy, pharmacists should thus recognize the predisposing risk factors in patients, and carefully monitor the initial signs related to neurotoxicity and the blood concentrations of the patients receiving immunosuppressants.

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We performed a clinical pharmacy based service on the therapeutic drug monitoring (TDM) of cyclophosphamide (CP) during high dose CP chemotherapy in order to mobilize the peripheral blood stem cell in a 42-year-old man with glioblastoma. The patient was infused with 2000 mg CP for 3.75 hours. Samples of blood and of cerebrospinal fluid (CSF) were obtained. Both the CP and active metabolite of CP, nor-mustard (NM), concentrations were measured by the colorimetric assay method used 4-(p-Nitrobenzyl) pyridine (NBP) and the phamacokinetic parameters of CP and NM in plasma and CSF were estimated used a compartment model. The plasma concentration of CP peaked at the end of infusion, and there after decreased in a bi-exponential decay manner. The CSF concentration of CP peaked at the end of infusion, and then decreased in a mono-exponential decay manner. The plasma concentration of NM peaked 2 hours after drug administration and then gradually decreased. NM was not detectable in CSF. The area under the concentration-time curve (AUC) for the CSF of CP comprised only about 16.7% of that found in plasma. Those results suggested that the cytotoxicity of CP and NM in CSF was low because of the permeability of CP and NM into CSF was low.

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Hyperammonemia which is caused by inherited urea cycle enzyme deficiencies, is often fatal when acute symptoms of hyperammonemic coma (vomiting, unconsciousnessf convulsion, respiratory paralysis, et al.) appear and continue without any medical treatment. L-Arginine or sodium benzoate has been used for the treatment of hyperammonemia. However, it is difficult for children to take such reagents orally in powder form due to the bulky dose volume and their offensive bitter taste. A significant decrease in medication compliance has thus led to hyperammonemic coma or liver transplantation.
In this study, we prepared tablets containing a high percentage of L-arginine or sodium benzoate by the wetgranulation method, and administered them to several children with hyperammonemia. Remarkable improvements in the compliance and clinical effects, as well as decreases in the occurance of comas and the serum ammonium levels, have been observed in all patients.

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At our hospital, we recently began to manufacture antifungal creams containing 40% urea to be dispensed to onychomycosis patients who either had griseofulvin-resistant onychomycosis or who could not tolerate griseofulvin treatment for systemic disease. We utilized six commercially available O/W type antifungal creams to manufacture the preparations. By noting whether these preparations could be stocked as intramural preparations and using various methods, we discovered that we could generate the surface active agent in these preparations by adding calcium oxide and oleic acid. The creams prepared using this method were then manufactured under aseptic conditions and stored either at 5°C, room temperature or 40°C for 4 weeks to investigate the base stability of the preparations. Based on naked eye inspections and microscopic examinations of the visual changes with the passage of time, we investigated whether or not the emulsion in these preparations was destroyed. The quantity of the water phase separated by centrifugation, which was employed as an indicator of the destruction of the emulsion, was then measured. We thus found that the base of these preparations remained stable for 4 weeks at room temperature

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Operating conditions affecting the dissolution characteristics of glibenclamide were investigated with the flow-through-cell method (the third method of dissolution test in JP XIII). The partition coefficient of glibenclamide between octanol and phosphate buffer (pH 7.4) was observed to be 24.2, thus suggesting the lipophilic nature of glibenclamide. The flow indicator on the apparatus in the flow-through-cell method did not reflect the real flow rate of the dissolution media.
The dissolution-time curve (ADT) value increased in line with the decrease in the bead's diameter when the flow rate of the indicator was slow (8 ml/min). On the other hand, the ADT value was hardly affected by the bead's diameter when the flow rate was fast (24 ml/min), however, a wide deviation in the ADT values was seen during such conditions. The operating condition of flow rate and bead's diameter was optimized based on the response surface method. As a result, a flow rate of 14 ml/min and a bead diameter of 0.5 mm were estimated as the optimal conditions to obtain the largest ADT and the smallest deviation in the ADT. When using the fl ow-through-cell method, the operating condition should be optimized based on the nature of pharmaceuticals under test.

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The purpose of this study is to establish the methodology of individualized medication consultation. We studied a Scale for Discriminating the Self-Regulation of Medication, which was an instrument of discriminating whether a patient was more likely to do a self-regulation of medication. Items of this scale are composed of principal factors related to self-regulation ofmedication age, degree of understanding common information for medication, and the patient's concept of what is important in taking medicines without anxiety. These items were extracted by multivariate analysis. For this analysis, we interviewed 73 patients. About 85 percent of subjects were discriminated correctly with this scale.
This scale enables us: 1) to classify patients according to the discriminant values, where we can select the menu of consultation based on the classification, 2) to understand the reasons why a patient does self-regulation of medication. Consequently, it becomes easier to make an individualized medication consultation plan. To establish and validate this scale, further assessment is needed more in patients with various diseases.

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The susceptibility to antiseptics and intercalating dyes was determined-for 103 clinical isolates of Enterococcus species, 42 isolates of methicillin-resistant Staphylococcus aureus (MRSA) and 49 isolates of methicillin-sensitive Staphylococcus aureus (MSSA). Twelve antiseptic-resistant strains were detected among the isolates of MRSA but none were found among the isolates of MSSA and. Enterococcus. Two and ten of the antiseptic-resistant strains of MRSA were resistant to triclosan and ethidium bromide, respectively. The tested strains of MSSA were more sensitive to antiseptics and intercalating dyes than were the strains of MRSA and Enterococcus. The susceptibility to antiseptics and intercalatng dyes of Enterococcus spp. was similiar to that of MRSA. These results suggest that the Enterococcus spp. might therefore survive in a manner similar to that of MRSA under normal hospital conditions.

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We investigated the effects of metoclopramide and propantheline bromide on the bioavailability of carvedilol in rats. To determine the concentration-time profile of plasma carvedilol, the blood samples were obtained from the tail vein after the simultaneous administration of 20mg/ kg carvedilol either with or without 5 mg/kg metoclopramide and 15 mg/kg propantheline bromide. The plasma carvedilol concentrations were significantly higher than the controls at 15 min.
-1 hr and 3, 4 hr, and the drug pharmacokinetic parameters time to C_max (Tmax) was 0.45 time shorter, while the absorption rate constant (Ka) and area under the concentration-time curve
(AUC0-24) were 2.5 and 1.5 times higher after the oral administration of carvedilol with metoclopramide. The rate of bioavailability for carvedilol was accelerated by metoclopramide which stimulates gastric emptying. In contrast, the plasma carvedilol concentrations and T_max., A UC₀-24 did not change after the single intraperitoneal administration of carvedilol with the oral administration of metoclopramide. Conversely, propantheline bromide, which delays gastric emptying, slowed absorption, but not according the AUC₀-24 of carvedilol.
Other similar pharmacokinetic interaction probably occur since carvedilol are poorly absorbed from the stomach and numerous therapeutic agents influence gastrointestinal motility.

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A sensitive and specific enzyme immunoassay (EIA) for a secretin-like immunoreactive substance (secretin-IS) was developed using a synthetic carboxy-terminal (C-terminal) fragment (residue 5-27) of a porcine secretin conjugated with β-D-galactosidase and an anti-rabbit lgG coated immunoplate. The activity of the enzyme on the plate was fluorometrically determined. The present immunoassay allows the detection of 1.7 to 67 fmol/ml (0.068 to 2.7 fmol/well) of secretin. Using the present EIA, the secretin-ISs in human plasma were determined.
Moreover, significant changes in the plasma secretin-IS levels were found after the oral administration of famotidine (vs.placebo).

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A simple and sensitive reversed-phase high-performance liquid chromatographic method was developed for the analysis of warfarin (WF) in both human serum and serum ultrafiltrate. WF and internal standard (I.S.) were extracted from the serum by simple deproteinization and filtration with a membrane filter. The Column-switching system utilized the short polymer-coated mixed-function (PCMF) phase deproteinization column coupled with a C₁₈ semi-micro analytical column using a mobile phase of acetonitrile, water and NH₄H₂PO₄, followed by a post-column photochemical reaction and fluorimetric detection. The extraction recovery was greater than 80% and the WF and I. S. were separated from the endogenous components in the serum and serumultrafiltrate. The calibration curve was linear from 5 to 1000 ng/mL of serum and 1 to 150 ng/ mL of the serum ultrafiltrate. The limit of quantification was 5 and 1 ng/mL for found to be the serum and serum ultrafiltrate, respectively. The inter and intra-day coefficients of variation for the serum and serum ultrafiltrate ranged less than 10%, respectively. WF was found to be the stable in the serum for a 4-month period during storage at -20°C.

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Sodium Ferrous Citrate formulatio, Ferromia^®granule was originally supplied as film-coated granules. However, some problems have been pointed out with this formulation regarding awkwardness in handling and unpleasantness during consumption.
Therefore, corrigent was added while the film conting was removed in order to improve it.
We investigated influence of changing the formilative method, and carry out the incompatibility test and hygroscopic test on 29 powders which can be admixed together. Furthermore, we also carried out a ferrous ion dissolution test on 11 powders which are likely to have an ionic interaction with iron. As a result, the modified granuls were incompatible when combined with ascorbic acid powder, Cinal ^®granule, sodium bicarbonate and fblic acid powder (10%).The modified granules demonstrated no water-vapor sorption at 25°C, 75% RH at 30 days. Hygroscopicity was not considered to be related to incompatibility, and no noticeable difference was found due to the modification of the formulation.
In the compounding the sample, dissolution property demonstrated only a slight difference in the ferrous ion elution.

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The practical management regarding trial drugs according to the previous GCP system was analyzed between 1992 and 1996 to provide important information regarding the developmental status of new drugs or preparations under a newly revised revised system in our hospital. These findings helped to clarify the present status regarding the management of trial drugs especially regarding each specific drug.

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The new Good Clinical Practice (new GCP) guidelines which conform to the international standard based on ethics and science (ICH-GCP) were applied to clinical drug research in Japan in April 1997. However some problems still exist regarding clinical drug research based on the new GCP guidelines. One of the maior problems is the management of massive information regarding adverse events supplied from sponsors (drug company) in various styles.
To solve this problem, we tried to make a database of the adverse events supplied by the manufacturers to determine the essential headings of information regarding adverse events, the questionnaire survey was performed on both doctors (n=20) and manufacturers (n=25). Based on the results of the survey, 17 standard information heads (including concomitant drugs, severity, relation of cause and effect, etc.) were determined. In the future the information on the adverse events consisting of 17 standard heading in the electronic medium (ex. floppy disk) should thus be supplied by sponsors to use in all hospitals which take an active role in the clinical drug research.

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We conducted a questionnaire surver of 164 outpatient; who had been prescribed either voglibose or acarbose as an α-glucosidase inhibitor (α-GI) about their knowledge of the medicine, the conditions for taking this medicine, the adverse reactions and symptoms, and also of patient who took another medicine to lower blood sugar level together with α-GI. Regarding the patients knowledge regarding the name of the medicine, α-GI, was low, namely 23.8%. But 82.9% of them complier with the prescription by taking it just before meals. About 71% of them complained of the digestive symptoms such as fletulation. The symptoms also different between the two medicines. Of the 135 patients who took the medicine three times a day, 78.5% toox it at noon. The rate was more than 10% lower than that of the patients who took it in the morning and the evening.
A total of 119 patients (72.6%) took another medicine to lower their blood sugar together with it. Half of them took sulfonyl ureas, and of the patients who took the two medicines, 42.9 % against lowering blood sugar while 28.8% of them correct glucose substitutes. In addition 33.9% of them had a history of low blood sugar. In this investigation, the two α-GI medicines produced differences in both the use and the occurrence of adverse reactions.

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As a general hospital that is aiming to provide regional medical care, our hospital has been actively involved in trying to establish a unified system for providing information on drugs to patients, through close cooperation with the Regional Pharmacists Association. We have been involved in promoting the spread of prescriptions to be filled at outside phrmacies, training pharmacists working in pharmacies, and providing information on drugs to patients through the issuance of a “medicine guidebook” and “drug-record pocketbook”, and thus have established a system for exchanging of information on drugs in order to monitor the side effects in patients, and thereby establish a system to exchange information among patients treated at home. The results of our efforts in these areas have indicated that, hospital pharmacists, in cooperation with pharmacists working at pharmacies, can therefore partitively contribute to the treatment of outpatients and to regional medical care.

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As a general hospital that plays a supporting role in regional medical care, our hospital has been addressing the problems regarding the “Study Project for Cooperation Between Pharmacies in Medical Institutions Offering Home Medical Care and Private Pharmacies” initiated by the Ministry of Health and Welfare in 1997. In this cooperative system, efforts have been made by hospital pharmacists and private pharmacists to interlink such systems as the system for instructing patients being discharged regarding their medications and the delivery system. In this regard there has been an increased exchange of information between pharmacists on patients requiring medical care at home. This system of cooperation between hospital and private pharmacists in home medical care is thought to be an effective way to improve the quality of treatment, and thereby enhane the quality of life for such patients.

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