We investigated the loss of miconazole from solutions into the intravenous delivery system by equilibrium and kinetic approaches. Miconazole concentrations were measured by highperformance liquid chromatography. It was estimated that the loss of miconazole occurred through the mechanism of sorption, or partition and diffusion into the administration set. When the miconazole solution was passed through the administration set 100cm in length at a flow rate 0.81ml/min, and initial concentration 102μg/ml, the miconazole concentration was reduced to 79%in 15min.The factors affecting the loss of miconazole from intravenous solutions were the container materials, the concentration of miconazole injection and the pH of intravenous solutions.And the dissolution of diethylhexyl phthalate (DEHP), used as a plasticizer of the polyvinyl chloride (PVC), into the miconazol injection from the administration set was observed.

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Accompanied by prescriptions spreaded in wide area, there could be a problem of the use of abbreviated drug names as a serious factor which may cause a medication error.In this study, investigation on recognition of abbreviation for drug name by pharmacists was carried out, and further, the result was compared with the abbreviation written in prescriptions.111 abbreviated drug names were selected from books, Chozaishishin and Chozaigyomushishin, which were frequently used by pharmacists and students of pharmacy.96 pharmacists in 4 institutions, and 42 novice intern pharmacists in the University of Tokyo Hospital participated in recognition test.
The average percentages of correct answer in pharmacists and resident pharmacists were 43.8 and 19.8, respectively, and the well-recognized abbreviations were only 9 words. Especially, aq.armen.for apricot kernel water was recognized as 8 incorrect drug names. There was a significant difference in the extents of recognition for abbreviated drug names between age groups (p<0.05).As abbreviated drug names in prescriptions, there were 25 words in selected 111 words.

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The evaluation of valproic acid (VPA) hollow type suppository was carried out by a comparison between rectal and oral administration of VPA in 3 healthy volunteers and 10 patients. The oral dosage form was used as tablet or syrup of sodium valproate (VPA-Na) and a hollow type suppository containing VPA in the form of oily liquid was used for the rectal administration. A single oral dose of VPA-Na 7mg/kg or a single rectal dose of VPA 6.02mg/kg was administered to 3 healthy volunteers by a cross over study, respectively. The peak serum concentration (C_max;45.24±4.84μg/ml) was reached within 1.7 hours after oral administration, while it was reached at 3.09 hours in the case of rectal administration (C_max;41.28±1.21μg/ml). The areas under the curve of serum concentration (AUC) after oral and rectal administration were 887.76±182.03μg·h/ml and 1021.14±200.70μg·h/ml, respectively. Therefore, relative bioavailability (AUC rectal/AUC oral×100) was 115%. In patients after neurosurgical operation, relative bioavailability was over 88%.These data suggested that VPA was efficiently absorbed from the human rectum after the administration of hollow type suppository.Thus, it was concluded that VPA hollow type suppository could be useful for prophylaxis and management of seizure, especially for the patients who were not able to ingest the oral preparations.

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Fungicidal activities of six kinds of disinfectants, such as chlorhexidine digluconate (CHX), benzalkonium chloride (BAC), alkylpolyaminoethylglycine (APE), formalin (FON), cresol soap (CRS) and povidone iodine (PVI) were investigated against 8 clinical isolated fungi, which included 1 Aspergillus niger, 1 Aspergillus terreus, 2 Candida albicans, 2 Candida tropicalis, 1 Candida parapsilosis, 1 Cryptococcus neoformans, 1 Trichophyton rubrum and 1 Rhodotorula glutinis strains. Concentrations of fungal suspensions were adjusted to approximately 10⁷CFU/ ml for A.niger, A.terreus and T.rubrum and 10^8-9CFU/ml for C.albicans (A), (B), C.tropicalis (A), (B), C.parapsilosis, C.neoformans and R.glutinis strains, respectively
The fungal suspensions with the various concentration of disinfectant were incubated at 25°C, for 15, 30, 60min.and 24 hrs, respectively.An aliquot (0.1ml) was inoculated onto the Sabouraud-glucose agar plates, and the growth was observed after 7 days of incubation at 25°C. Among the 5 strains tested, A.niger was the most resistant one to all disinfectants examined, and 0.4% concentration of CHX, APE or CRS was found to be effective against A. niger strain for lhr.It was considered that BAC, FON or PVI was more effective against the fungi tested than CHX, APE or CRS in short time.

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The distribution of highly lipophilic drugs into cerebrospinal fluid (CSF) is thought to be predictable from both assumptions of simple diffusion process and pH partition theory. We tried to predict CSF/plasma concentration ratio (CcsF/Cp) from the fraction of unbound drug in plasma (fp), pKa, and pH of blood and CSF and to compare the predicted C_CSF/C_p values with the observed C_CSF/C_p values collected from literatures.In the case of highly-lipophilic drugs, we found that the penetration into CSF could be predicted from various parameters we above. Since the penetration of more hydrophilic drugs into CSF could not be estimated from those parameters, we tried to predict C_CSF/C_p values by using influx (PS1) rate constant from blood to brain and active efflux (kac) rate constant from brain to blood.The PS1 value was calculated from octanol/buffer partition coefficient (PC) and the diffusion constant across water (Dm) based on Sawada's report (Y.Sawada et al., Am.J.Physiol., 258, H1585 (1990)). The kac value was calculated on pharmacokinetic model considering the active efflux mechanisrr from brain to blood.A significant correlation (r=0.96) between kac and PC of each drug was observed.The predicted C_CSF/C_p values based on this model wes comparable with the observed values.These findings suggested that the C_CSF/C_p value of lipophilic or hydrophilic drugs was predictable from various biochemical, physicochemical and physiological parameters.

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In three children undergoing bone marrow transplantation, the cyclosporine (CyA) regimen was designed by the Bayesian method, and its utility was evaluated.CyA was intravenously infused for the first few weeks after transplantation and thereafter was orally administered. The initial intravenous dose was 3 mg/kg/day, but pharmacokinetic analysis showed that this dose failed to achieve the target through concentration of 100 to 150 ng/ml, and the dose was increased in all three patients.The whole blood concentrations later increased and the dose was decreased again in all three patients.The dose was modified according to the Bayesian feedback method during treatment.To evaluate predictability by the Bayesian method, the mean prediction error (ME) was used as an index of bias, the mean absolute prediction error (MAE) for precision, and the root mean squared error (RMSE) for indicating the discrepancy of the prediction.The ME value was negative because the whole blood levels tended to increase, but the MAE and RMSE values were 22.5 ng/ml and 29.5 ng/ml, respectively, which were considered to be in the permissible range with regard to the target concentration.
To examine the cause of the increase in the CyA concentration, the correlations between trough levels and laboratory findings were studied.A significant relation was noted between ALP and SCr in multiple stepwise regression analysis with the trough levels of CyA as the response variable and GOT, LAP, ALP, BUN, SCr, Hct and TT levels as regressor variables. Since a correlation was recognized between CyA undergoing biliary excretion and ALP an indicator of cholestasis, the possibility of a cholestatic liver disorder was suggested as a cause of the elevation of the CyA concentration.

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Bioavailability and pharmacokinetic study of slow release preparations of sodium valproate (Depakene-R Tablets, NIK-240) were investigated by a cross-over design in six healthy volunteers. When bioavailability parameters were compared between two preparations after a single dose of 600mg of each drug was administered orally, there was difference in maximum serum concentration (C_max), but no difference was found in areas under the serum concentration-time curve (AUC), peak time (T_max), mean residence time (MRT) and variance of residence time (VRT). The pharmacokinetic parameters were estimated according to one-compartment open models with three different absorption steps (first-order or zero-order absorption step with lag time, two first-order input steps) by simultaneous least squares curve fitting method.The firstorder absorption with lag time model fitted better to describe pharmacokinetics of the two preparations than the other models, but pharmacokinetic parameters (Ke, Ka, Vd, lag time) showed no differences in the two preparations.These results indicate that two preparations were comparable to the extent of bioavailability, but not comparable to the rate of bioavailability. NIK-240 was released more slowly than Depakene-R Tablets and predictions regarding multiple dosing show that NIK-240 can provide smaller fluctuations in plasma valproic acid level than Depakene-R Tablets.These results were important for the administration of slowrelease preparations in the drug monitoring and the drug administration regimen.

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Three factor VIII concentrate products (Hemofil-M, Hemate-P, and Confact-F) were examined to characterize the quality of activity.The factor VIII activity of Hemate-P was confirmed to be 6, 500% by comparison with normal serum from humans factor VIII, and the specific activity of this product was about 4, 600%/mg of protein.Hemofil-M had likewise 3, 750% as the activity of factor VIII, and 12, 500%/mg of protein as the specific activity. The factor VIII activity of Confact-F was 4, 250%, and the specific activity was 1, 250%/mg of protein. While Hemate-P and Confact-F were contaminated by impurities such as fibrinogen, fibronectin or IgG, Hemofil-M purified by the monoclonal technique took no notice of those impurities.The light and heavy chains of factor VIII in three products were evaluated as bands by Western blotting, and the molecular weight of factor VIII were observed to be in the range of 90 to 200 KD.The von Willebrand factor involved in Hemate-P and Confact-F on a par level corresponded to 100 times as much as that in Hemofil-M.

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For the topical application to the treatment of candidiasis in oral cavity, four plastibase oral ointments containing amphotericin B (Fungizone oral suspension) were prepared with adhesive bases;carboxymethyl cellulose sodium salt (CMC-Na), CMC-Na: sodium polyacrylate (PANA) (1: 2), CMC-Na: PANA (2: 1) and PANA, respectively.Consistencies of four ointments measured with penetrometer, and spreadabilities measured with spreadmeter were not changed when these ointments were incubated at 5°C, 20°C or 30°C for 21 days.The amphotericin B content in each ointment measured with HPLC was very stable in each ointment at 5°C, 20°C and 30°C for 21 days.
Amphotericin B oral ointments were found to be effective for the therapy of patients with candidiasis in oral cavity.Among the four ointments, the ointment containing only CMC-Na used as adhesive base appeared to be the most useful for clinical application, judging from adhesion tests, several sensory tests and therapeutic effect.

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Content uniformity test of six commercial salbutamol sulfate tablets as well as their stability after pulverization was undertaken, and it was found that Venetlin is the most suitable tablet for the large scale preparation of triturated powders.
On the basis of these findings, Venetlin was subjected to pulverization, and was triturated with corn starch to give powders (10mg/g as salbutamol).The studies on content uniformity test, stability, and compatibility on the triturated powders exhibited satisfactory quality for practical use.

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We prepared the standards to evaluate the compliance instructions for patients, who were hospitalized in the Second Department of Surgery.In addition, we examined whether the use of inpatient medicine diary produced any changes or improvements in the patients'attitudes in taking medicine.The patients' attitudes were discussed from the following three points.
(1) conditions in taking medicine: To what degree do patients observe the instructions when they receive medicine? How many cups of water or lukewarm water do they use when taking medicine? (2) interest in medicine: To what degree do they want to know about medicine and do they ask any questions on medicine? (3) knowledge and understanding on medicine: To what degree do they know and understand medicine?
From the above, the following results were obtained.1) The patients'attitudes before the receipt of inpatient medicine diaries were evaluated as (1) 3.2 (very good), (2) 2.5 (good) and (3) 2.5 (good).This indicates that most of patients before admission had good attitudes toward the conditions, but there is room for improvement as to the items (2) and (3). 2) The patients' attitudes after the receipt of inpatient medicine diaries were markedly improved. The evaluation scores increased (1) from 3.2 to 3.5, (2) from 2.5 to 3.2 and (3) from 2.5 to 3.2.In addition, the total evaluation point increased from 2.7 to 3.5.These suggest that the use of inpatient medicine diary is quite useful for giving patient compliance instructions.

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Lisinopril tablets in the shape of a butterfly have been marketed. This unique tablet shape is the first of its kind. We evaluated the butterfly-shaped tablet, with respect to its distinguishability especially in appearance and its adaptability to the automatic tablet packaging machine equipped with a computer.The results showed that this tablet presents several advantages with regard to drug inspection, in giving instructions to patients for taking the drug and obtaining patients'compliance with such instructions.Moreover, this tablet could be put into small packages smoothly with the automatic tablet packaging machine.However, since the shape of the tablet is not a perfect butterfly, simply referring to the “butterfly-shaped medicine” may not be enough to convey the intended information.Therefore, some care should be taken.

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In order to increase our service for outpatients, characteristics of waiting time at pharmacy was investigated on the number of prescriptions, dispensing cases, and drug items every 30minutes, and was imvestigated on the number of pharmacists with weight in experiences and of clinical departments for outpatients. Multiple regression analysis using 3 factors was carried out.The obtained standard partial regression coefficients showed that waiting time depended on the number of prescriptions every 30 minutes and of pharmacists with weight in experiences. The number of patients who failed to receive medicines was independent of waiting time.
As the result that we inquired of outpatients how about waiting time at pharmacy, many outpatients voiced their discontent.The source of their discontent was, however, not their waiting time in itself, but it was revealed that they had been discontented because of the lack of understanding of dispensing.

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The number of trade name of the sustained release (SR) dosage form as existing trade name+suffix has increased. Physicians frequently leave out the suffix in prescribing, so that pharmacists may lead to recognize as another trade name.We investigated the nomenclature for SR dosage form for avoidance of medication error.

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I investigated the change in volume of prescription orders at Tatebayashi Kosei Hospital pharmacy between 1978 and 1989, during this period, the volume showed considerable increase. The number of prescription order sheets doubled, but the number of prescriptions and prescribed days tripled, indicating an increase in multiple drug prescription and drug medication period.The number of prescriptions perpharmacist doubled, whereas the number of pharmacists showed smaller increase. Of types of medications prescribed during the entire period, tablets, capsules and powder preparations constituted approximately 70% to 80%, liquids and mixtures about 10% to 20%, and those for external use about 4% to 6%.

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In Shinshu University Hospital, prescription ordering system by physicians for outpatients and inpatients has been introduced at the same time since April 1st, 1991. We adopted distribution system by personal computer FMR 50 with LAN using optical data highway as the host machine, FACOM M770/8.Using this system, physicians can prescribe medicines for intrahospital, extra-hospital and narcotic prescriptions. Extra-hospital and narcotic prescriptions are printed out at the medical office, while informations for intra-hospital prescriptions are directly transmitted to the hospital pharmacy, and prescriptions and drug envelopes are formed using by the printing machines.
Drug information system is constructed using MEDIS-DC tape.Drug information retrieval on this system is classified in four parts; 1) usage and dosage, 2) contraindications, 3) effect and efficacy, and 4) adverse reactions.Physicians can make the prescriptions through the all time in a day except 9-10 p.m.from Monday to Thursday and 9-10: 30 p.m. at Friday. This system has the advantage of reducing both prescription making time and patient waiting time.

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