High-dose methotrexate (H-D MTX) therapy followed by citrovorum factor rescue is now widely used for the treatment of childhood malignant tumors. To understand pharmacokinetics and toxicity of H-D MTX (50-300mg/ kg), we measured plasma and urine levels of the subject after a total of 170 infusions to 16 children. The samples were obtained 12, 24 and 48hr after the beginning of 6 hr infusion. Two phases of plasma MTX disappearance were seen after infusion: the first phase (12-24hr) had a half-life 2.28-3.27 hr and the second phase (24-48 hr) 6.96-8.74 hr. Significant correlation was obtained between dosage and plasma levels on concentration curve. With the same dose, the younger patients (under 8 years) had low plasma MTX levels, as compared with the older patients (over 13 years). After H-D MTX infusion, severe toxicities such as myelosuppression, abnormal kidney function and stomatitis were observed in 2 cases. We consider that the maximum allowable plasma MTX levels be 10^-5M at 24hr and 10^-6M at 48hr, on the basis of the finding that the plasma MTX levels in these cases exceeded those levels, respectively, at the same hours. From the beginning of H-D MTX infusion, cumulative urinary excretion in the first 12hr was greater than 50% of the administered dose. Our data suggest that in view of the safety of H-D MTX therapy, monitoring of plasma MTX levels and adequate hydration be important, especially for the older patients.

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In the measurement of a concentration of drug in serum by a method based on the enzymeantibody principle, the effects of serum factors such as hemolysis, chyle and icterus on the measured values were studied. Phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), valproic acid (VPA) and digoxin (DGX) levels in serum were measured by the enzyme multiplied immunoassay technique (EMIT), and PB, PHT and CBZ levels by the substrate labeled fluorescence immunoassay (SLFIA).
The effects somewhat varied by serum factors such as hemolysis, chyle and icterus, testing methods and drug; but as far as those 3 factors remain on the levels ordinarily observed, such effects on the measured values may be almost negligible. However, the DGX level rose more than 10% under the influence of bilirubin (5 mg/ dl).

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The applicability of recently developed instrument, automatic Syva System AC-5000 (EMIT-AC), was evaluated. The concentration of total or free theophylline (TH) in plasma, serum, saliva, and spiked sample was measured by EMIT-AC. The results were compared with those obtained by high performance liquid chromatography (HPLC) or substratelabeled fluorescent immunoassay (SLFIA). There was no significant difference (P>0.05) between the results obtained by EMIT-AC and HPLC method using TH spiked samples. The within-day precision of EMIT-AC method was less than 4.5% as the coefficient of variation (C.V.). The C. V. value for between-day precision was 6.3% for EMIT-AC and 3.7% for HPLC method and no significant difference (P>0.05) was observed between the mean values. A good correlation was obtained between EMIT-AC and HPLC method (n=54, r=0.988, P<0.001 for plasma; n= 22, r= 0.998, P<0.001 for serum) in the assay of total TH level. Similar observation was obtained in the free level assay. It was clarified that saliva level can also be analyzed by EMIT-AC method as well as SLFIA method. These findings show that EMIT-AC method is a satisfactory analytical device for giving correct results and applicable for the determination of TH level in body fluid especially in clinical drug monitoring requiring rapidity.

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Stability on preservation of Ketotifen Eye Drops prepared in our hospital for treatment of conjunctivitis due to Japanese cedar pollinosis was examined. The suitability of its heat sterilization was also studied. After storing for 3 months at room temperature or 6 months in a cold place, no changes were observed in appearance and physical properties of the solution. The rate of residual Ketotifen was more than 90%. After sterilization at 105°C for 15 minutes, coloration, .decrease in content, decomposed products were observed, and sterilization by heating seemed impossible. However, it is considered that Ketotifen Eye Drops be useful if it is prepared in the germ-free conditions and preserved in a cold place.

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To test the irritability of 0.1% Ketotifen Eye Drops, the subject compound was given to the rabbits' eyes, and macroscopic and microscopic observations were made for examination of its effects on the cornea and conjunctiva.
No noticeable abnormalities were observed in the eyes of the rabbits treated with 0.1% Ketotifen Eye Drops and Isotonic Buffer B solution as well as in the control (no treatment).

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Quality tests were made on 10 different commercial gefarnate preparations in fine granules as well as granule, which are drugs for gastric or duodenal ulcer. The availability in handling was evaluated on each preparation by examinations of physical properties, such as angle of repose, loose bulk density, packed bulk density, dispersibility and particle size distribution. The stability was also examined by measuring content, hydrolysis rate, peroxide value, because gefarnate is the ester of geraniol and farnecyl acetate of isoprene structure. In addition study was done on the relation between the results of the examinations and the methods of granulation.
From the results of the physical property tests, all the preparations were within acceptable range in actual dispensing. But in 4 preparations out of 10, the amount of gefarnate decreased on the measurement of the content. Peroxide values of these preparations were remarkably high, whereas hydrolysis rate indicated no significant value when these were compared with other commercial preparations. Therefore, it is concluded that degradation process was mainly due to the oxidation. These 4 preparations were produced by extruding granulation procedure. Gefarnate is degraded easily, and its preparations may show great difference in pharmaceutical quality when produced in different techniques.

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Computerized systems for checking prescriptions issued to OPD patients and the directions for use of the prescribed drugs, which are lined up to work together, have been developed. The prescription checking system has functions to prevent overlapping prescription of same medications from different departments visited by same patient and to warn against drug interactions while giving reasons for the warning as references.
The system for the use directions, when the input of the number of drug envelope, the type of direction and the times of administration are made, automatically prints out the dose, times and precautions for administration and warnings for physiological changes after the administration on the label for the drug. The above systems contribute to improvement of service for safety of medication and sufficient instructions as to the use of drugs, which could not be previously achieved by manual dispensing.

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As an evaluation of sustained release preparations, release patterns of two sustained release preparations of isosorbide dinitrate were examined. Comparisons were made between Nitrol R and Frandol in respect to the effects of stirring methods, rates of stirring and a surfactant on the release patterns of the drug. Dependence of release patterns on stirring methods and rates of stirring was less in Nitrol R than that in Frandol. In both preparations, release rates were higher in a release medium with surfactant and more variable than those without surfactant.

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Three rifampicin (RFP) products (CB, DI and KB) were examined on their dissolution patterns and bioavailability in healthy subjects and tuberculous patients. Dissolution rates of 3 RFP products at 60 min were more than 80% in the first fluid of the Japanese Pharmacopoeia (IX) disintegration test. In the second fluid, the rates of CB, DI and KB at 60 min were 10.0, 72.0 and 73.0%, respectively, and those in a deaerated water were 5.5, 95.0 and 14.0%.
On their bioavailability parameters, DI showed highest plasma RFP concentration and AUC value both in healthy subjects and tuberculous patients. On plasma RFP concentration, statistically significant, higher values were observed in healthy subjects than in tuberculous patients, while in CB, higher values were observed in tuberculous patients at 2 hr after administration (P<0. 05), 4hr (P<0. 02) and 6hr (P<0. 05), in DI at 4 hr (P<0. 05), and in KB at 2hr (P<0.05) and 4hr (P<0. 01).

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Stability of physostigmine (PS) in the presence of sodium pyrosulfite (SPS, Na₂S₂O₅) as antioxidant was examined in aqueous solution by HPLC method. Addition of SPS has no effect on the degradation rate of PS in aqueous buffer solution with pH range of 3.3-5.6 at 93°C under aerobic and anaerobic conditions. When the pH is not adjusted, residual levels of PS in solution of 0.05% and 0.1% SPS were not more than 10% for 8 hours and 141 hours under anaerobic condition, respectively, though these samples were stable for 17 hours under aerobic condition. combination of antioxidant and gas in substitution for air is generally effective for the stabilization of drug. However, PS, when SPS was added, became more stable under aerobic condition than anaerobic condition.

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A new specific high-performance liquid chromatographic method for the determination of theophylline (TPH) in human serum was studied. In this method, TPH in serum was extracted with chloroform-isopropanol (7: 3).; then, an aliquot of the extract was evaporated to dryness in vacuo. TPH was determined by an ion-pairing reversed-phase high-performance liquid chromatography using a Zorbax-ODS column. The mobile phase was a mixture of acetonitrilewater (5: 95 by vol) containing 10mM sodium acetate and 3mM tetrabutylammonium hydrogen sulfate (pH 6.0). Beta-hydroxyethyltheophylline was used as an internal standard.
This method enables to separate TPH and paraxanthine, a metabolite of caffeine which interferes with most TPH assay procedures.

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In oredr to investigate the influence of light on the quality of commercial nifedipine preparations, the light of fluorescent lamp (FL-1.5 SW-G, Hitachi, 860 lux) was irradiated to 3 kinds of tablets and 3 kinds of capsules at a distance of 30 cm from the beam source and then the content of nifedipine was determined every week over 4 weeks by high performance liquid chromatography under the light of infrared lamp. This irradiation was also carried out to pure and fine crystal of nifedipine in a test tube and then the light-degradation product was identified with infrared spectrophotometer.
The results were as follows: 1) In the case of irradiation to the preparations with PTP package, the contents of nifedipine of all the preparations tested remained unchanged after 2 weeks, but those of preparation C (tablet) and E (capsule) decreased after 4 weeks. 2) In the caseof irradiation to the preparations without PTP package, a decrease in the content of nifedipine was observed in preparations C and E after a week and in all the preparations tested after 3weeks, although the decrease varied. 3) In the case of irradiation to the pure and fine crystals, the content of nifedipine [4-(2'-nitropheny1)-2, 6-dimethy1-3, 5-dimethoxycarbonyl-1, 4-dihydro-pyridine] decreased gradually with time and changed completely into 4-(2'-nitrosophenyl)-2, 6-dimethyl-3, 5-dimethoxycarbonyl-pyridine upon exposure to the light for 7 days.

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Compatibility of 4 lactase preparations (Organase powder, Organase granules, Galantase, Lactyme) with 8 drugs was investigated by sensory evaluation method, and residual activity of each lactase in these mixtures was measured by o-nitrophenyl-β-D-galactopyranoside (ONPG) method to study the relation between compatibility and residual activity, respectively. Residual activity and hydrolysis power of lactase against lactose as substrates were measured in mixtures. Residual activity of each lactase was influenced by aspirin, ascorbic acid, dried aluminum hydroxide gel fine granules. When lactose was used as substrate, Galantase showed lowering of residual activity of lactase by aspirin but great. difference was not observed in hydrolysis power of each lactase. It is supposed that the difference of residual activities among lactase preparations correspond to their difference of pH stability. Evident mutual relation was not observed between compatility and residual activity.

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