Effects of co-administration of cimetidine (CMT) on pharmacokinetic behaviors of chlorpropamide (CPA), an oral hypoglycemic agent, after intravenous injection, were investigated in rabbits.The co-administration of CMT enhanced the plasma concentration of CPA, and reduced the amount of cumulative urinary excretion of CPA after intravenous bolus injection.Furthermore, the co-administration of CMT was found to decrease the renal clearance of CPA significantly, but to have no effect on its extrarenal clearance.These clearly indicate that the interaction of CPA with CMT is generated during renal excretion.For the purpose of elucidating the cause, effects of CMT on plasma protein binding of CPA, glomerular filtration rate (GFR), renal tubular secretion of PSP, and urinary pH were investigated.Plasma protein binding of CPA, GFR, and urinary pH were unchanged with and without CMT.But urinary excretion of PSP was decreased by co-administration of CMT.These observations suggest that the co-administration of CMT may depress the renal excretion of CPA by inhibiting the tubular secretion.

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We have developed a totally new dispensing management system for the purpose of improving the quality of medical treatment.This new system employs three sub-systems, i.e.prescription printing system, automatic drug envelope printing system, and systemic packaging of single dose tablets system (via a host computer). The automatic drug envelope printing system offers the patient printed instructions on how to use the drug according to the doctors' instructions.This format allows the doctor to access different printing patterns and to use the one most suitable for the patient's needs.As a result of the new system, case reference time has been reduced, allowing pharmacists to answer outpatient questions more efficiently. The system has the efficiency of reducing the time for printing inpatient prescriptions, and of allowing prescriptions to be dispensed earlier.This system has allowed the pharmacy to eliminate the inputting of the regular inpatient prescriptions with the automatic tablet counter. The efficient printing of outpatient prescriptions has also resulted in earlier dispensation.Because drug envelopes are printed automatically, outpatient waiting time has decreased.The time produced by this system has allowed for the beginning of new clinical work such as ward pharmacist.

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Recently, with the spread of a computer in hospitals a prescription ordering system has been introduced in many hospitals.An automatic dispensing system in which a prescription ordering system and automatic tablet counting and packing system (ATC) are connected by on-line network has been developed and one-dose packing of tablets/capsules has been attempted.However, an automatic dispensing system in which 2 or more sets of ATC are operated efficiently has not been reported and the objects are restricted to a part of prescriptions for inpatients. In Kochi Medical School Hospital an automatic dispensing system in which a prescription ordering system and 5 sets of ATC are interlocking efficiently was developed for the improvement of patient compliance and the increase in efficiency of dispensing and labor-saving in drug-giving for ward nurses.Full operation of the system has been started in June 1990 for all the prescriptions for inpatients as the object.As a result, prescription data were delivered from the host CPU to 5 sets of ATC efficiently by a data communicating system, and one-dose packing of tablets/capsules, which had not been hitherto made, became possible without causing an increase in the required time.The rate of errors of dispensing in tablets/capsules was decreased from 0.22 to 0.04%.In wards the labor of drug-giving by nurses was saved by 19%.Furthermore, printing patient's name on subdivided-pack paper was judged useful for preventing

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The influence of lipids in the food on the bioavailability of nifedipine sustained-release granules (KB-1712P) was examined in healthy subjects.Each of seven male volunteers was given 15mg of nifedipine sustained-release granules with 100ml of water under two conditions, after a low-fat diet and high-fat diet.A crossover method was employed after a two-days washout period. Blood samples were drawn at time zero, and 1, 2, 3, 4, 6, 8, and 10 hours after dosing.Nifedipine assays in plasma were performed by high performance liquid chromatography (HPLC). The maximum plasma concentration of 80.4ng/ml was observed at 3 hours.A mean plasma level was 13.4ng/ml at 10 hours.The area under the concentration-time curve (AUC) from 0 to 10 hours, maximum plasma concentration (C_max), mean residence time (MRT), absorption rate constant (Ka), and elimination rate constant (Ke) were not significantly altered by the content of fat in the diet.The mean time to peak level (T_max) for low-fat and high-fat diets were 3.08hr and 2.33hr, respectively. These results indicate that under a meal containing about 30g and about 60g of fats per day this sustained-release granules is not changed in absorption.

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The inhibitory effects of mexiletine hydrochloride (MEX), an antiarrhythmic agent, on a monooxygenase system in mouse hepatic microsomes were studied. In vitro, MEX inhibited aniline hydroxylase and aminopyrine N-demethylase activities.The modes of inhibitions of these enzymes by MEX (mixed type) were similar to those cimetidine, while there was a great difference between inhibition constants (K_i) of MEX for aniline hydroxylase (0.05mM) and aminopyrine N-demethylase (1.26mM), in contrast to cimetidine which has a close similarity between K_i values of these enzymes.The effects of MEX on the stereospecific hydroxylations of testosterone were also measured.MEX exhibited the inhibitory activities for 6β-and 7α-hydroxylations, while a little effect of MEX on 16α-hydroxylase activity was found.Aspectrophotometric study revealed that MEX interacted directly with cytochrome P-450, but not with reduced nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome c reductase.MEX inhibited competitively the binding of theophylline to cytochrome P-450 and its inhibitory potency was about 5-fold greater than that of cimetidine.These results indicated that MEX is a selective potent inhibitor of some cytochrome P-450-mediated drug-metabolism in hepatic microsomes.

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Tumor sensitivity assays have been widely reported, and we have been performed SDI (succinic dehydrogenase inhibition) test using MTT.In this paper we have studied this test fundamentally by the use of a new synthesized tetrazolium salt, XTT.The assay is performed with 96-well microplates.In the assay using XTT, addition of appropriate concentration of PMS (phenazine methosulfate) to XTT results in a marked increase in optical density and continues to increase with reaction time, which means XTT is less toxic to cells than MTT. Therefore, we have studied from time to time the possibility of evaluation with a little number of cells comparing with MTT assay.Tumor cells used in this experiment are Sarcoma 180, Ehrlich carcinoma, NUGC4 and SW13 as human cell lines.
In result, when we incubate tumor cell over 20-h with XTT, we are able to evaluate sufficiently with a little number of cells, and we studied I.I.(Inhibition Index) of each drug (MMC, ADM, CDDP). XTT assay is easy to be influenced by pH and requires the use of medium contained buffer.Formazan formed from XTT is soluble in water, so that XTT assay does not require DMSO (dimethyl sulf oxide), but the problem is the measure of colored drugs for example ADM etc.It is thought that XTT is a useful tetrazolium salt and the assay is simple and able to evaluate with a little number of cells.

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We prepared experimentally the polyvinyl chloride (PVC) membrane with the DEHP content of 15.0-33.3% in order to investigate the mechanism of the leaching of diethylhexyl phthalate (DEHP, a plasticizer of polyvinyl chloride) from a PVC membrane into the solution.The dissolved amount of DEHP was influenced by the content of DEHP in the prepared PVC membrane. The DEHP leaching was not observed at the DEHP content below 20%, but at above 20%, the dissolved amount of DEHP was increased as the DEHP content in the PVC membrane was risen (Fig.3). The similar phenomenon was observed on the diazepam sorption.It was not occurred at the DEHP content below 20%, while at above 20% diazepam sorbed to the PVC membrane (Fig.4). These results suggested that the DEHP in the PVC membrane interacted with a PVC molecule at DEHP content below 20%, and at above 20% it was a mixture of a interaction state and a free liquid, and the DEHP dissolution was occurred by the liquid part in the PVC membrane.

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The evaluation of morphine hydrochloride (MOR) hollow type suppository was carried out by a comparison between rectal and intravenous administrations of MOR in rabbits.The hollow type suppository containing three doses of MOR (1mg/kg, 3mg/kg, 10mg/kg) was used for the rectal administration, and the aqueous solution of MOR (20mg/ml) was used for the intravenous administration (3mg/kg).The serum concentration of MOR was measured with gas chromatography-mass spectrometer by selected ion monitoring method.The absorption constant of MOR from suppository had dose-dependent characteristics, although the peak serum concentrations (1mg/kg;38.8ng/ml, 3mg/kg;61.9ng/ml, 10mg/kg;137.1ng/ml) were reached within 0.4 hours, respectively The area under the curve of serum concentration (AUC) after rectal administration were compaired with the AUC after intravenous administration.The bioavailability (AUC_rectl/AUC_iv×Dose_iv/Dose_rectal×100) were 90%(1mg/kg), 62%(3mg/kg) and 53%(10mg/kg), respectively.These data suggested that the absorption of MOR had dose-dependency. We used hollow type supporitory of MOR for the pain control of patients with cancer for 6 years.It was required to administer every 4-6 hours for pain control.Thus, it was concluded that MOR hollow type suppository could be useful for the pain control of patients with cancer, especially for the patients who were not able to ingest the oral preparations and the patients who need individual dosage adjustment.

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A detailed analysis was performed on dispensing errors made by resident pharmacists in the initial step of practice training at the Osaka University Hospital Pharmacy during 1989.Based on the results, the education program was improved to prevent the dispensing errors as possible. The newly established program was effectively applied to the education of resident pharmacists in the pharmacy in the following year 1990: the dispensing errors 16.9% during the first week in 1989 was reduced to 10.9% in 1990.

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To develop the checking system for prescription of injections by pharmacists, a questionnaire of intravenous admixture on nurses of 7 hospitals in Yamaguchi Prefecture was carried out.It became clear that nurses had many problems in the ward which is not clean.It seems dengerous for the nurses to mix many injections, because they must perform with various other works. The nurses strongly expected pharmacists admix injections.The information such as easily incompatible injections, adverse reaction for injections when those are administered, has been required.

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Ethanolamine oleate (EO) injection containing a contrast medium has been used as an agent for sclerosing treatment (endoscopic embolization) of esophageal varix.We tested the compatibility of 10% ethanolamine oleate injection [Oldamin for Injection (OD)] with 3 kinds of contrast media [Iopamiron 300 (IP300), Omnipaque 300 (0P300), Isovist 240 (IV240)] and water for injection.The sterilized samples were stored for three months at 6° and 25°, and the unsterilized samples for a week at 25° and 40°.The changes in appearance, pH, viscosity, osmotic pressure, and contents of the contrast medium, oleic acid and benzyl alcohol, and the concentration of iodide (contaminant) were examined at intervals.In all samples, no significant changes were observed in each test item except the concentration of iodide and appearance. After sterilization, OD-0P300 showed the highest concentration of iodide (206μg/ml, while ODIP300 and OD-IV240 showed 36μg/ml and 105μg/ml, respectively) and yellow coloration.The concentration of iodide in OD-OP300 and OD-IV240 increased during the storage at 25° and 40°, while the concentration in OD-1P300 did not change for the storage.These results suggest that Iopamiron 300 is the most appropriate contrast medium which is combined with 01-damin for Injection among the 3 kinds of contrast media.

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We investigated the effect of the drip condition on the leaching of diethylhexyl phthalate (DEHP, a plasticizer of polyvinyl chloride) from a parenteral infusion set into the intravenous, cyclosporine solutions.The concentration of DEHP was measured by high-performace liquid hromatography.The factors effecting on the leaching of DEHP during infusion were the drip rate and the concentration of injection.When the cyclosporine solutions were passed through the administration set, 100cm in length at a flow rate of 0.58ml/min, and initial cyclosporine concentration of 500μg/ml, the total amount of DEHP released up to 180 minutes was 578μg.

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Drug advertisements in six major journals published in Japan and U. S. A.for physicians and pharmacists have been surveyed. Japanese advertisements showed considerable difference from those of America in the fair balance between the safety and effectiveness, one of the most important concepts in the advertising regulations. It was indicated that such a difference reflected the characteristics of the package insert in each country and the occupying area of each advertisement. Drug advertisement is valuable as a convenient and rapid source of information about prescription drugs, but it is needed in Japan to refer to the other DI sources for details of drug's adverse reactions such as their frequency and dangerousness.

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The present study was designed to investigate on administration schedule practice of hypnotic drugs for outpatients.One hundred and sixty-three outpatients were interviewed at the dispensing counter.They consisted of 53 males (range of 46-86 years) and 110 females (range of 33-88 years).Of the 53 male group, 27 were given triazolam, and 11 were given zopiclone.Of the 110 female group, 69 were given triazolam, and 16 were given estazolam.All outpatients were classified as the following 4 patterrs according to the administration schedule practice of the drugs:(1) who have been taking hypnotic drugs as directed, (2) who have reduced a dose of it and have been taking it as directed, (3) who have sometimes been taking as directed, and (4) who have reduced a dose and have sometimes been taking.As the result of this study, about 36% of male and 53% of female outpatients have been taking hypnotic drugs under the circumctances that they only felt in need at bedtime and 34% of male and 44% of female outpatients have reduced a dose and have been taking at bedtime.

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Incompatibility of solutions for internal use in the admixtures was studied as to 19 kinds of commercial products.Two of them were mixed each other, and the incompatibilities of the 171 kinds of combinations were examined. Admixtures were stored at 4°, room temperature (25-29°), and partly 35°.Visual changes in the admixtures were observed in 19 kinds of combinations whereas no changes were observed in the other 152 kinds of combinations.When admixtures were stored at room temperature, visual changes meaning modifiable incompatibility were observed in 14 kinds of combinations.When they were stored at 4°, changes meaning modifiable incompatibility were observed in 4 kinds of cases and changes meaning tolerable incompatibility were observed in 6 kinds of cases.The cases of combinations inducing modifiable incompatibility in storage at 4°, were Transamin+Bisolvon, Bisolvon+Medicon, Flavitan+Leftose and Brocin+Berotec.Therefore the mixing of these medicines should be avoided in dispensing, even if these medicines would be stored at 4°.

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In order to guarantee more effective and safer parenteral therapy for inpatients, the checking system for prescription of injections using personal computer were developed in Yamaguchi University Hospital.
The system is formed by the following three components.(1) First checking system offers epitomized information of incompatibility, stability, administration routes and methods on the display of personal computer.(2) Second checking system offers the detailed information of each medication, if necessary, on the first checking system.(3) Message delivering system prints out information of stability and adverse reaction for doctors and nurses.We believe that the system has contributed to dispensing injections.

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In Shinshu University Hospital, prescription ordering system by physicians for outpatients and inpatients has been introduced since April 1st, 1991.This system has been linked to printing system of prescriptions and drug envelopes since July, 1991.This system can be used all day. Prescription and designed informations were automatically printed out on the prescription paper and drug envelope paper according to physician's prescribing data, respectively. These papers were sealed by heat and were cut from the continuous rolling paper, and then were transported into printing machines by order of prescriptions. Printing colors of drug envelope are as follows: 1) letters of internal medicine is cyanine color, 2) letters of draft medicine is green color, 3) letters of external medicine is magenta color, 4) letter of patient's name is dark blue color.In this time, our developed system was very useful for making drug envelopes and labor-saving at preparation of medicine.

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In the hospital pharmacy, the analysis of the ingredients in a mixed powder and the codeless tablets or capsules is important pharmaceutical service, but the complete analysis is currently almost impossible because a drug in the mixture is mainly deduced from its characteristic odor or taste and/or color. In this article, the application of X-ray powder diffractometry to the analysis of the ingredients was studied.Each ingredient was identified by comparing the intensity and number of the diffraction peaks with those of the standard substances. The ingredients in the mixture were determined successively by subtracting the peaks of the identified ingredient from the whole peaks of the mixture. For the purpose of this diffractometric analysis, four data bases such as the powder of organic medicines, the granule of organic medicines and the pulverized tablet and capsule were newly constructed.
Since these data bases identify the whole peaks pattern of the preparation containing many constituents as a pattern of a certain drug, each drug, even in the complicated mixed powder containing granules (and/or fine granules) and tablets (and/or capsules) pulverized, could be easily analyzed. However, in the complicated mixture containing fine granules or granules, the concentration of the ingredients was necessary to raise analytic precision for this diffractometry. Each ingredient in the mixture could be qualitatively determined by the combined use of these data bases and the rough sieving through No 30 and 80 screens.It proved that the ingredients of codeless tablets or capsules were identified by using these data bases.In conclusion, the results presented suggests that this X-ray powder diffractometry can be applied to the routine DI and dispensing services in hospital pharmacy.

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