Treatment of triethylene tetramine with anhydrous methanolic hydrogen chloride solution derived from acetyl chloride and methanol at 0°C, followed by recrystallization provided pure triethylene tetramine dihydrochloride (trien) which turned out to be less hygroscopy than that prepared by the preceeding procedure. Examination of its stability and drug activity under various conditions suggests that an aqueous solution of trien could also be useful for the treatment of Wilson's disease.

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The stability and the vasoconstrictor effect of fluocinonide in admixtures of fluocinonide ointment with other ointments were studied and the following results were obtained. No change in color on the appearance, in apparent pH and in contents of fluocinonide was observed until 4 weeks after the combination. In admixtures of fluocinonide ointment with ointments used emulsion bases, however, the separation of liquid and the decrease of the release of fluocinonide through the cellulose membrane were observed for 1-4 weeks after the combination.
when these admixtures were applied on skin of human, furthermore, a tendency of the decrease of the vasoconstrictor effect was showed with the lapse of time. In conclusion, it is desirable to avoid mixing fluocinonide ointment with other ointments used emulsion bases beforehand and giving patients as admixtures.

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The dissolution behavior of fifteen commercial extended-release articles was examined by the dissolution test in order to characterize their behavior in vitro. The articles were classified into six groups according to the formation types. The paddle method for six hours was used for tests, and the media were the first solution (pH 1.2) and the second solution (pH 6.8) in JP XI.
Five articles showed different patterns in the above two media, so that their dissolution seemed to depend on pH. A few articles were also effected by pH on the dissolution although they showed time-dependent behavior. The others showed pH-independent (time-dependent) dissolution. The dissolution curves of time-dependent articles approximated to zero-order or firstorder kinetic model. There was, however, no significant relation between the formation type of articles and their dissolution behavior.
In addition, for time-dependent articles, simulation curves of dissolution were calculated by using “Weibull function” with the data obtained from the dissolution test up to six hours. Since most of all curves conformed to the observed curves, the parameters of the simulation curves were re-calculated only with the data up to three hours to obtain the prediction curves. The predicted rate fitted well to the observed rate after six hours in many articles. Therefore the prediction curves could be applicable to shorten time for the dissolution test.

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Plasma concentration, urinary excretion of theophylline and sodium excretion were investigated in 4 healthy adult volunteers after a single oral dose of 300mg theophylline in a solution form and in sustained-release tablets (Theodur). On the average plasma level curve for Theodur tablets, the peak level was reduced from 10μg/ml to 7μg/ml compared with that of an oral solution, but the prolonged effect for plasma level was observed and the absorption from dosage form was reliable.
The renal clearance of theophylline increased initially after a single dose due to its urine flow rate dependence and after a single dose in a solution form the increase in urine flow rate was higher, thereby the initial increase in renal clearance became larger compared with those of sustained-release tablets.
Furthermore, the urinary sodium excretion rate after a single dose increased as sigmoidshaped relationship with increasing the renal clearance of theophylline. And the natriuretic effect for oral solution was relatively potent, whereas that for sustained-release tablets appeared to be very weak.

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Serum concentrations of phenytoin and phenobarbital which were administered as the tablet or the powder in epileptic patients were determined by the fluorescence polarization immunoassay method. The serum concentrations of phenytoin administered as the tablet (Hydantol^®) were higher than those as the powder (Aleviatin ^® fine granules). To investigate the differences in serum levels following administration of each preparation, compliance, dissolution characteristics of the preparations and losses of the powder after operating the dividing and packing machines were investigated. Since phenytoin dissolved from the Hydantol ^® tablet more slowly than from the Aleviatin ^® fine granules, the differences in dissolution rates of both preparations do not seem to be the cause of higher serum concentrations in patients taking the Hydantol ^® tablet.
The amount of the powder after operating three types of dividing and packing machines was decreased about 2-8% of the original amount of the powder by adhesion to various dividing sites of the machine. Accordingly, the lower serum concentrations of phenytoin after the administration of the powder may be due to losses of the powder by the adhesion to dividing and packing machine and due to non-compliance.
Although there was no significant difference in the serum concentrations of phenobarbital between the tablet (Phenobal ^®) and the powder (JP X phenobarbital powder), large variations in the serum concentrations were observed following administration of the powder. In view of the result of questionnaire and bitterness of the drug, a possibility of non-compliance of the powder was considered. Thus, it may be suggested that these factors should be concerned invariations of the serum concentrations.

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We evaluated the particle-enhanced turbidimetric inhibition immunoassay (PETINIA) for the measurement of theophylline in serum. The coefficients of variation in both within-day (n= 10) and between-day (n=10) precision studies were less than 4 %, and the analytical recoveries were 98-103% at the concentrations of 5, 10 and 20μg/ml of theophylline. Good correlations were observed among assay results by PETINIA, high-performance liquid chromatography (HPLC) and fluorescence polarization immunoassay (FPIA) for 120 serum specimens cbllected from patients with chronic obstructive pulmonary disease receiving theophylline therapy.
The regression lines obtained were: PETINIA =1.034 x HPLC -0.404 (r =0.994, Sy/x=0. 57μg/ ml), PETINIA =1.037 x FPIA-0.539 (r=0.995, Sy/x=0.51μg/ml). The cross reactivity in PETINIA was also studied with 11 compounds structurally related to theophylline. None of these compounds exhibited significant cross reactivity (less than 5 %) except for 1, 3-dimethyluric acid (11%). From these results, we could conclude that PETINIA is a useful method for therapeutic monitoring of serum theophylline having good precision and accuracy, and high specificity.

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Wagner proposed a new and simple method to predict dosage of drugs obeying simple Michaelis-Menten elimination kinetics. The prediction performance of the Wagner's method was evaluated with respect to accuracy and precision on the basis of 148 predictions in 42 outpatients treated with phenytoin (PHT).
Mean error (ME), mean absolute error (MAE) and root mean squared error (RMSE) served as a measure of accuracy and precision. The MAE and RMSE were 36. Omg/day, 45. 4mg/day, respectively. Therefore, the Wagner's method seemed to be simple and accurate in making routine PHT dosage adjustments.

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Influence of fat emulsion on stability of vitamins in intravenous fluids was examined on vitamin A. A high performance liquid chromatography (HPLC) was employed for the determination of vitamin A. Vitamin A was hydrolyzed, extracted and then chromatographed as vitamin A alcohol by using Develosil ODS-5 reverse phase column. The amount of vitamin A was determined by measuring its peak area. The coefficients of variation at within-run and between-run for 2.5 I.U. are 4.46%(n= 5) and 9.58%(n= 3).
Decomposition of vitamin A under reflection light of 1000 lux was prevented by intravenous fluids containing fat emulsion, and then residual percent of vitamin A was increased with increasing fat emulsion concentration. Decomposition of vitamin A was prevented by use of light-resistant cover all the more, but effect of it used in this experiments was not enough. At cold place, vitamin A in intravenous fluids could be stored up to 7 days.

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The recovery of the adrenocortical function was investigated after the long-term (1-3 years) administration of prednisolone in kidney transplant recipients. The adrenocortical function was estimated by measuring endogenous serum cortisol (F) levels by high-performance liquid chromatography. F levels promptly decreased to less than 10ng/ ml in a week after the administration of prednisolone (minimum static stage). Low level of F continued until 50-600 days after the transplantation, and then recovered thereafter (recovery stage). The mean F level recovered to 68% of the control (before the operation) at 800 days. However, the coefficient of variation between each patient was 85%. Moreover, no recovery was observed 800 days after the transplantation in one case.
These results suggest that the dosage adjustment of prednisolone at the recovery stage should be carried out by monitoring the adrenocortical function in each patient.

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The specially shaped polypropylene bottle has been devised for sterilization of the chlorhexidine gluconate solution by an autoclave. The shape transformation ratio of the bottles and the concentration of the chlorhexidine gluconate solution in the bottles were investigated after autoclaving. The bottles have two characteristic features, concaving on the sides and strengthening of the bottom, which are expected to reduce the transformation during and after sterilization. Bottles were filled with 500ml of the chlorhexidine gluconate solution and sterilized under four conditions, at 100° C for 60 minutes, at 110°C for 40 minutes, at 115°C for 30 minutes and at 120°C for 20 minutes, and the shape transformation ratios were estimated.
These different conditions generated almost the same results of 8.3% expansion of the sides of the bottles. There was no problem with the shape transformation. The remaining ratios of 0.05% and 0.1% of the chlorhexidine gluconate solution in the bottles after sterilization were 100.2%, 99.9% at 100°C for 60 minutes, 99.0%, 99.3% at 110°C for 40 minutes and 95.8%, 98.0% at 115°C for 30 minutes, respectively. These results indicated that there was no decrease of chlorhexidine gluconate by using the bottles. It was suggested that the specially shaped polypropylene bottle was very useful for sterilization of the chlorhexidine gluconate solution by an autoclave.

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The effect of simple syrup dilution in Berotec ^® Syrup with other liquids was investigated with regard to changes in appearance and pH value. These changes were tested immediatly and 3 and 7 days after admixing at 30°C and 5°C. The decrease of redistribution occured in admixture with Pontal^® Syrup and Asverin^® Syrup. A cotton-like substance was observed in all cases of admixtures tested within 7 days at 30°C and identified by IR Spectrum UV Spectrum and high-performance liquid chromatography as Hydroxypropylmethylcellulose (HPMC) which was the additive in Berotec^® Syrup.

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