We have frequently experienced the lack of correspondence of vancomycin dosages noted on the manufacturer's sheet and the dosage given for renal dysfunction in interview form with the actual dosage. Accordingly, we investigated retrospectively to determine and to estimate via several methods, the initial dosage and dose interval of vancomycin based on renal function, age and body weight. With regard to renal function, dosages estimated by Moellering et al. and by Nielsen et al. greatly differed from that determined by the one-compartment model individualized method. Furthermore, the dose interval estimated by Lake-Peterson's method was significantly different from that generated by individualized method, whereas that derived by Matzke's method did not significantly differ. The indivdualized method produced the most precise prediction follwed in order by Matzke's method and Moellering's method. The elimination rate constant (Kel) and dose interval significantly contracorrelated and correlated with the age in all patients as well as in patients presenting normal renal function and mild renal dysfunction. Thus, for elderly patients, the dose interval should be longer than that for younger patients even if they were not complicated with renal dysfunction. Body weights significantly correlated with vancomycin dosages, specifically indicating that the dosage should be estimated by body weight. As actual body weight did not differ from ideal body weight in our investigtion, the dosage/actual body weight and dosage/ideal body weight expressed almost the same values. This investigation confirmed that initial vancomycin therapy must be determined by body weight. Moreover, for renal dysfuncion patients, Matzke's method should be recommended over those of Moellering, Nielsen and Lake-Peterson. Finaly, the dose interval should be longer for elderly patients than for younger patients.

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A clinical pharmacy service was performed by the pharmacist using therapeutic drug monitoring of methotrexate (MTX) for a patient with malignant fibrous histiocytoma during highdose MTX (HD-MTX) therapy. Serum, urine and saliva concentrations of MTX and its metabolite, 7-hydroxymethotrexate (7-OH-MTX), were measured with the enzyme immunoassay and high-performance liquid chromatography methods. The pharmacokinetic analysis of MTX and 7-0H-MTX was performed based on the 2-compartment model by taking into consideration the kinetics of 7-OH-MTX. In this model, the conversion of MTX to 7-OH-MTX and the pharmacokinetics of 7-0H-MTX were assumed to follow first-order kinetics and the 1-compartment model, respectively. The individual pharmacokinetic parameter values of the patient were estimated using the serum concentrations and urinary excretion rates with this model.
The mean distribution volume of MTX (0.357 L/kg) was 1.5 times larger than that of 7-OHMTX (0.209 L/kg). The mean values of the distribution rate constant (0.0362 h^-1) and elimination rate constant (0.255 h^-1) of MTX were respectively 4.3 and 30 times larger than the mean value of the rate constant associated with the conversion of MTX to 7-OH-MTX (0.0084 h^-1). The mean value of the elimination rate constant of 7-OH-MTX (0.0849 h^-1) was 3.0 times smaller than that of MTX and 2.4 times larger than that of rate constant for the second decay of MTX (0.036 h^-1). As a consequence, the mean half-life of MTX (19.7 h) was longer than that of 7-OH-MTX (8.23 h).
The serum concentration and urinary excretion rate profiles and the serum concentration ratios of 7-OH-MTX/MTX could be simulated used the pharmacokinetic parameter values determined for each treatment. The monitoring of serum and urine levels and pharmacokinetic analysis with compartment model of MTX and 7-OH-MTX improved the understanding of MTX pharmacokinetics and led to minimized side effects of chemotherapy.

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Theophylline clearance was investigated in 91 hospitalized children (aged 0 to 14 years) with asthma or asthmatic bronchitis, and the change in theophylline clearance with growing larger was evaluated in 12 children. The patients were administered durable intravenous of theophylline intravenously. The mean clearance in children from 0 to 1 year old was significantly decreased (P<0.01) over that in children over 2 years old, and a significant relationship between age and theophylline clearance was confirmed in children from 0 to 36 months old (r=0.647, P<0. 01). The clearance was increased with growing larger in children less than 2 years old. Though, no such changes were observed in children over 2 years old. Since these data revealed that the clearance increases with growing larger in children less than 2 years old, when theophylline is to be administered to children less than 2 years old attention should be given to the effect of age on theophylline clearance. Conversely, to determine the initial optimum dosage in babies and infants, we summarize the theophylline dosage based on the above calculated regression equation, with the dosage in infants aged 6, 12, 18 and 24 months being determined to be 10.7, 12.2, 13.6 and 15.1 mg/kg/day, respectively.

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We examined the effect of the water content in the ointment on the stability of aspirin in an effort to improve the stability of aspirin washable ointment which we previously reported (JJHP 17 335 (1991)). The measurement of water content of ointments showed that the smaller the water content the more stabilized is the aspirin in ointment.
The half-life of aspirin in ointment became longer when polyoxyethylenehydrogenated castor oil 60 was used instead of glyceryl monostearate, and isopropanol instead of crotamiton as the aspirin solvent. The aspirin in the ointment comprising of dehydrated ingredients was found to be stable for at least two months even at room temperature.

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Oxaprozin (OXP) suppositories were prepared and their characteristics were investigated. In vivo rectal absorption studies were carried out in rats by measuring the plasma concentrations of OXP. The amorphous state of OXP with polyvinylpyrrolidone (PVP) was obtained using the dissolving method, and the effect of this solid dispersion on the dissolution of OXP was determined. Enhanced rectal absorption of OXP in the amorphous state was not observed in the OXP-PVP solid dispersion system. By using the pH controlled method, a 6-fold effective increase in C_max was obtained. The increased bioavailability of OXP resulted in a modification of the dissolution characteristics of OXP by an internal buffer system with Na₂HPO₄.

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A sustained release suppository containing progesterone (mixed suppository) was prepared to treat the luteal phase defect. A mixture of ethylene-vinyl acetate copolymer (EVA) and Witepsol-W35 was used as the suppository base. Characteristics of the mixed suppositories using various types of EVA were compared with those of Witepsol-W35 alone (control suppository).
Determined as physical characteristics were hardness, DSC peak temperature, heat of fusion and release profiles of progesterone. Furthermore, the plasma concentration profiles of progesterone observed from suppositories were measured in rabbits. The sustained release of progesterone from the mixed suppository was observed in the beads cylindrical filter method.
When the mixed suppositories were administered to the vagina of rabbits, some part of the suppository remained after 3 hours though nothing remained the control suppository.
The Pharmacokinetic parameters obtained from the plasma concentration profiles suggested the sustained release property of progesterone in the biophase when the mixed suppository was administered. With this mixed suppository, the concentrations of progesterone in the vagina, cervical canal and uterus at 3 hours after the administration were higher than those of the control suppository.
These results suggest that the mixed suppository could be useful as a dosage form for replacement therapy of progesterone.

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Integrity testing of membrane filters was performed using bubble point pressure measurement in order to establish the validation of sterile filtration of intrahospital sterile preparations. The average bubble point values for six 0.2μm hydrophilic and three hydrophobic membrane filters were between 59.5-73.4 psi and 22.4-23.7 psi, respectively, that were satisfied on sterile filtration. No effect of sterilization by autoclaving on the bubble point values of filter was appreciably observed. The bubble point ratio was evaluated on intrahospital sterile preparations. In some of them, the bubble point ratios were below 1.0 because of the decrease in the surface tension of the pharmaceuticals. This suggested that bubble point measurement as an integrity test for sterile filtration was easily done and constituted one of the useful methods for ensuring the quality of intrahospital sterile preparations.

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To investigate the in vitro metabolism of [6]-gingerol, one of the major pharmacological constituents of ginger, in the intestine, [6]-gingerol was added to the jejunal mucosal and muscular tissue homogenates isolated from rats in high (50μg/ml) and low (10μg/ml) concentrations, and the residual [6]-gingerol concentration was periodically determined. In addition, the stability of [6]-gingerol at 20 μg/ml in rat whole blood was also examined in vitro to compare with the metabolic degradation in rat jejunal tissues. In the incubation mixture of rat mucosal layer with the high concentration, the residual [6]-gingerol was 96.5 ± 6.5% following 60 min of incubation. For the low that initial [6]-gingerol concentration, [6]-gingerol concentration was significantly decreased to 81.0 ± 6.1% after 60min (p < 0.001). On the other hand, cumulative amounts of [6]-gingerol decreased in jejunal mucosal homogenates with the high and low initial concentrations for 60min being 0.236 ± 0.449 and 0.231 ± 0.084μg/mg protein, respectively. The residual [6]-gingerol in the incubation mixture of muscular homogenate was about 95-98% at 60 min after the incubation in both the initial concentrations. Furthermore, no change was observed in the [6]-gingerol concentration in the incubation mixture of whole blood. These results suggest that [6]-gingerol may be subject to some metabolic degradation in the mucosal layer of rat jejunum. This first-pass metabolism in the jejunal region would be one of the reasons for the considerable amount which was not recovered as [6]-gingerol in the previous in situ absorption study.

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The mechanism of the loss of diltiazem hydrochloride in the solutions in polyvinyl chloride (PVC) containers or intravenous administration set was investigated. Diltiazem hydrochloride was quantified by high-performance liquid chromatography. When the diltiazem hydrochloride solution for injection (pH 8.0) was passed through the intravenous administration set 100cm in length at a flow rate 0.52m1/min., the diltiazem hydrochloride concentration was reduced to about 83.3% in 5 minutes, and gradually returned to the initial level with time.
This decrease in the diltiazem hydrochloride content in the PVC membrane was speculated to occur due to hydrolysis of diltiazem hydrochloride in the solutions and its sorption in to the PVC membrane.

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The utility of a newly designed closed-system sterile reconstitution kit was compared with three other reconstitution methods for sterile injectable solid preparations:(1) a needle and syringe, (2) a double-ended needle, and (3) a connecting tube. A questionnaire on the utility of the newly designed kit was presented to nurses and pharmacists at Kitasato Institute Hospital. In addition, the microbial contamination of the sterile injectable solid preparations was investigated after reconstitution on each method. The newly designed kit showed a significantly better utility (p<0.001) than the three other reconstitution methods. The number of contaminated vials with each reconstitution method was 0/120 for the kit, 0/120 for methods (1) and (3), and 2/120 for method (2).

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The long-term compatibility of sodium valproate (VPA) and pyridoxal phosphate calcium (PAL-P) was examined. Mixtures of VPA and PAL-P in heat-sealed packages (polyethylenelaminated glassine paper) were stored under various conditions for 90 days. Under the most severe condition (30°C and 90% relative humidity), the color of the mixture changed to dark yellow and the weight increased by 20-35%. Although the VPA content in the mixture did not change, the PAL-P content decreased by approximately 15%. When the mixture was stored in the paper bag at 20-30°C and in the air-tight receptacle at 25°C and 50% relative humidity, the decrease in the VPA or PAL-P content was less than 7%. Therefore, when preserved over a long-term period, the mixture of these medicines should be avoided in high-temperature and high-humidity condition.

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When suppositories were prescribed for pediatric patients, they are inserted into the rectum of the patient by the mother in most cases. Therefore, counselling on the proper use of suppositories is essential. In an attempt to facilitate counselling for drug use, we surveyed via questionnaire how the mothers (ranging 26-39 years) of pediatric inpatients (2.5 months-15 years) of the University of Tokyo Hospital use suppositories. The collection ratio of the questionnaire was 100%(42 of 42). The suppositories exhibiting a systemic action such as antipyretic were used in 80% of patients. The directions for use of suppositories were not well appreciated in 15% of mothers. Twenty percent of mothers experienced trouble when inserting the suppositories into their children, and 54% of the trouble was “discharge after insertion of the suppository” . Most of this discharge occurred within 30 minutes after insertion. When the discharge occurred with a stool, 64% of the mothers coped with the trouble as “suspended the use of the suppository” and 36% as “inserted a new one”, and so on. Our results indicate that the study dealing with the problem of the loss of suppositories from the rectum is essential for the proper therapy of patients.

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We surveyed the amount of morphine preparations used at our hospital, the Hospital of Toyama Medical and Pharmaceutical University, including both marketed preparations and the sustained release suppository which we prepare here at our pharmacy. For oral dosage, the amount of controlled release morphine tablet used rapidly increased, while morphine HC1 powder decreased dramatically. As for the amount of suppositories being used, the morphine HCl suppository as well as that of the sustaind release suppository tends toward a slight increase. Since more morphine is expected to be used, it is essential for pharmacists to contribute to a more appropriate clinical use of morphine.

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Prior to enforcement of the revised GPMSP from April 1994, we conducted similar questionnaires as we did the previous year in September 1993. We attempted to ascertain some changes in awareness of companies by comparing the two sets of ansewers.
Examination of the answers from 76 pharmaceutical companies led us to consider that it doubtful whether or not the meaning of GPMSP will be conveyed to the smallest unit of the organization in entire company structures and whether or not doctors will sufficiently understand the necessity and significance of GPMSP. We should contend with these present difficulties.

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A suspension of aluminum hydroxide and magnesium hydroxide is frequently prescribed to treat gastric ulcer and gastritis. The proper dosage was investigated using the 1126 prescriptions from eight general hospitals and two university hospitals.
The number of prescription increased along with the patient age. The ratio of prescription in the population aging over 65 years reached 41.1%. The patients were instructed to take the prescription 3 or 4 times every day; between meals or before meals and at bed time. The dosage per time was 5 ml for the ratio of 1.7% in all prescription, 10 ml at 75.7%, 15 ml at 8.1%, and 20 ml at 11.7%.
The single-dose package containing 10 ml of the aluminum hydroxide and magnesium hydroxide suspension is considered advisable as a suitable dosage form for elderly patients.

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