We have developed a computer program (PPMODELS) for the analysis of the physiological pharmacokinetic model in a changed physiological condition by using NeXTSTEP 3.0J. The software was designed to facilitate the process of generating patient-specific drug doses using physiological and biochemical parameters.
System architecture provides an object-oriented and graphical user interface (GUI) within a Windows environment that will link image processing, spreadsheet, text, and graphics software packages into a single operational environment. The software uses the Runge-Kutta-Gill algorithm to approximate numerically the solution curves. The initial values, schedules and routes of administration can be defined on the spreadsheet.
The plasma, brain and adipose tissue biperiden concentrations were simulated by the PPMODELS using the physiological parameters after repeated administration of 3.88 mg of biperiden intramusculary to the patient. This work demonstrates that this program can be a useful tool for simulating the drug disposition in conjunction with the physiological pharmacokinetic model.

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The pharmacokinetic-pharmacodynamic model for ascertaining the antiplatelet effect of aspirin was developed, considering the effect of aspirin on the metabolic turnover of cyclooxygenase in platelets and vessel wall endothelium. All date used for analysis were obtained from the literature. The pharmacodynamic parameters, K, K', ke and ke' as reaction rate constants of aspirin and cyclooxygenase in platelets and that in endothelium, and the turnover rate constants of cyclooxygenase in platelets and that in endothelium, respectively, were calculated based on the plasma aspirin concentration profile, the plasma thromboxane B₂ concentration as the index of inhibition of cyclooxygenase in platelets and the reduction of prostacyclin production of venous tissue as the index of inhibition of cyclooxygenase in vessel wall endothelium.
The values of K and K' were 3.21 and 0.97 ml·μg^-1 · hr^-1, respectively, demonstrating selectivity of aspirin to cyclooxygenase in platelets. The value of ke was 0.00630 hr^-1, which was consistent with the platelet life span. The developed model could explain the long duration of antiplatelet activity of aspirin and may be useful for formulating a rational dosage regimen for effective antiplatelet therapy utilizing aspirin.

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We examined the effect of etoposide on cell cycle progression in L1210 murine ascites tumor. Cell cycle analysis was examined by flow cytometer. At 3 and 6 hr after administration of etoposide, the percentage of the S-phase increased to more than 1.3-fold as compared to that of the control. At 10 hr, cells were piled up in G₂+M Phase, and S-phase decreased. Since ara-C is a drug with a cell cycle S-phase specific action, these results might explain the enhanced incorporation of ara-C by pretreatment with etoposide that we reported previously.

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We investigated the influence of pharmacokinetics on the dilution of isosorbide (ISOBIDE^®) in three healthy male volunteers. They received both undiluted ISOBIDE^® and 5-times-diluted ISOBIDE^®. Gas chromatodraphy was used to measure the serum concentration and excretion rate of isosorbides in urine.
The results showed thet the pharmacokinetic parameters did not significantly differ between to undiluted ISOBIDE^® and 5-times-diluted ISOBIDE^® (elimination rate constant of 0.101 hr^-1 and 0.106 hr^-1, distribution volume of 0.660 1/kg and 0.660 1/kg, half-life of 6.84 hr and 6.57 hr, and excretion amount in urine of 79% and 80%). Therefore, these results indicate that the effect of pharmacokinetics on 5-times-diluted isosorbide remains unchanged.

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A dispensing test of 10% phenytoin powders (10% DPH), which has the same bioavailability as the tablet, was investigated. Pharmaceutical characteristics including an apparent density, a dispersibility, grouping properties and an angle of repose of 10% DPH passed the criteria for dispensing from the hospital pharmacy. Next, according to clinical formulas, we designed the eight standard formulas that consisting 10% DPH with 10% phenobarbital powders, zonisamide powders, carbamazepine granules, sodium valproate granules and lactomin powders. Pharmaceutical characteristics of these standard formulas also passed the criteria required for dispensing from the hospital pharmacy. The particle size of some standard formulas showed twin-peak distribution patterns. In the mixing test of the standard formulas, all of the coefficients of variation (CV) of the phenytion content were under 5% which met the criterion (6.1%) of a guideline of dispensing (9 th Revised Edition) by Japan Pharmasist Association. CV values of net weight and phenytoin content after dividing and packing the standard formulas also met the criterion of the guideline for dispensing. The CV values of the net weight and phenytoin content in formulas exhibiting twin-peak distribution patterns in particle size were not significantly larger than those in formulas exhibiting single-peak distribution patterns of drug particles. This distribution patterns did not demonstrate a relationship to the distribution of net weight in dividing and packaging powder mixtures. The CV values of the phenytoin content showed low values (<5%) independent of the particle distribution of the formulas. These results indicate that the 10% DPH has been distributed uniformly in the mixture with the other powders and that it is an useful preparation for clinical use.

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In order to clarify the problem of medication counseling for outpatients by plural pharmacistsworking in rotation, we studied the state of utilization of our “Medication Counseling Corner” from July 1993 to April 1994, especially taking notice of the patients who made repeated use of this corner. During this period, 814 outpatinnts consulted with the pharmacists on how to use their medicinal drugs (33.4%), their pharmacological effect (30.3%), their adverse reactions and interactions (15.0%), and other reasons (21.3%). The number of patients who consulted with the pharmacists at less twice was 97 (11.9% of all users of the corner), with 13 of them (1.6% of all) repeated the same question more than one. The elderly and psychiatric patients showed a tendency to use the corner repeatedly. In more than 80% of these cases, although a different pharmacist advised the patient who queried about the same matter as asked the last pharmacist, the advice given was almost identical for each pharmacist. The categories of the repeated questions put forword by the patients were concerned with their medications, the pharmacological effects (76.9 %), adverse reactions (15.4%), and how to use (7.7%) the prescribed drugs.
These findings suggest that a risk arises in the possibility of giving a different answer to the same question from the same patient by a different pharmacist working in this rotational counseling system. When the plural pharmacists take charge of medication counseling for outpatients in rotation, it is therefor necessary to maintain each patients counseling record carefully.

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We investigated the effect of drip conditions on the loss of isosorbide dinitrate (ISDN) or nitroglycerin (GTN) solution contens in practice injection of precision continuous drip infusion. When ISDN or GTN solutions for injection were passed through an intravenous administration tube 100cm in length and 2.1mm inside diameter, at a flow rate of 5.0ml/h, the ISDN or GTN concentrations were reduced to about 30.6% or 10.8% in 60 minutes respectively, and gradually returned to the initial level with time.
It was found that the factors affecting the percentage of remaining ISDN were the length and the inside diameter of the administration tube, the drip rate of the solution, and the tube materials used. Moreover, it was suggested that the amount of ISDN remaining after passage through the administration tube was closely related with the time in which the administration tube was used.

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We participated in the development of a one-month curriculum for clinical pharmacy training for fourth-year undergraduates studying at Kanazawa University. Students learned about 81 diseases and the drug therapy through integrating an up-to-date electronic textbook. The pharmacists surveyed the education problem offered at the university by giving the lectures and attending a conference on drug therpy.

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A method for predicting pH changes in multiple admixtures was designed on the basis of the acid-base equilibrium theory. The pH's of transfusions mixed with the various injections were estimated by solving a general theoretical equation for proton concentrations in the multicomponents-blended aquaous solution obtained using a dichotomy as the algorithm. Eighty-two transfusions and parenteral solution mixture combinations were examined for the efficacy of the predicted equation. As a result, the estimated pH was in good agreement with the measured pH in all examinations, and a good corelation existed between the measured and calculated values of pH. Furthermore, the incompatibility of the parenteral admixture can be easily predicted using the present estimation-program for pH changes without any preliminary pH titration tests. These results suggest that this prediction method will be a useful tool for constructing and handling database incompatibility.

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A computer system for prescription ordering that prevents hazardous drug interactions has been introduced at Hokkaido University Hospital. About 180 items indicated with the caution “avoid coadministration” in the information leaflet are entered in this system with their about 460 corresponding incompatible items. If overlapping prescriptions are intended to be administered to the same patient, the hazardous drugs are ascertained and shown on the display along with a explanation as to why the drugs will interact. This system can also print out the ID number, daily dose and the administration date of a patient treated with a certain drug. Evidence thus far suggests that this system provides a well-controlled prescribing process and thus a safer treatment.

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The effect of grinding on the coloration of the isoniazid sodium methanesulfonate (IHMS) and pyridoxal calcium phosphate (PAL-P-Ca) compound was investigated using three types of mixers, namely a twin-shell mixer, a ball mill, or a chaser mill. The color of the compound powder became an intense yellow with increase in the mixing time when the ball or chaser mill was employed. Conversely, mixing using the twin-shell mixer did not significantly affect the color of the compoud powder. The color difference before and after mixing, ΔE, of PAL-P-Ca itself increased with prolonged mixing by the ball mill.
The results of X-ray powder diffraction analysis of the ground PAL-P-Ca powder suggested that the crystallinity of the drug decreased.The dehydration temperature of the ground PAL-P-Ca decreased with the increase in grinding time by mechanochemical stress, while the chemical stability of the drug was not affected. These results suggest that the coloration of PAL-P-Ca crystals under mechanical stress are closely related to a change in physicochemical properties (water content, dehydration temperature and crystallinity).

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The required forces for opening the safety closures of three reclosable packagings were measured at initial and after 60 opening and closing, and child resistant characteristics of those packagings were estimated by sequential test method, which reduces test subjects without changing the statistical parameters while permitting the same prediction accuracy with the PPPA (Poison Prevention Packaging Act) test method. As the results of the sequential tests, these packagings were statistically confirmed as child resistant materials under given conditions.
Trials had shown that people in the age group over 61 had not great difficulty in opening child resistant packagings. Then it seemed that there was no need for the age group (61-65 years) to be tested specially.

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