A study was made to find out how important the role of protein binding was in an admixture of syrups of Alimezine (Ali.) (containing new coccine as a coloring matter), Inolin (Ino.) and Leftose (Lef.), which became discolored during the storage of 5.5 hr at room temperature.The discoloration of new coccine in the Ali.symp from red (λ_max 510nm) to yellow (λ_max445 nm) was monitered at 510 nm nusing a photospectrometer. The acceleration effect on discoloration was found out with Ali. syrup, Ino. syrup and a substitute for Lef. in which lysozyme chloride was replaced by bovine serum albumin (BSA), poly-Llysine and chitosan. The discoloration was reduced with Ali.syrup, Ino.syrup, and water solution of poly-L-glutamic acid and L-lysine, a substitute for Lef. The discoloration of new coccine was not observed in the admixture of 0.01% new coccine, 0.1% Na₂SO₃ and 0.5% lysozyme chloride in the solution of the 0.01% sodium lauryl sulfate and 1M sodium chloride. It is considered that the interaction of ionic binding between sulfonic group on the new coccine molecular and lysine residual group on the lysozyme chloride is an important factor for discoloration process. The reaction rate of discoloration in the syrup admixture is accelerated by protein binding of new coccine to the lysozyme chloride. The enzymatic activity of lysozyme chloride was not decreased with protein binding or discoloration of new coccine. The profile of electrophoresis of lysozyme chloride and BSA obtained after discoloration in the syrup admixture showed the same profile as that of standard samples.

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The mechanism of midazolam loss into a polyvinyl chloride (PVC) bag or an administration set was investigated in equilibrium and kinetic studies.When the buffer solution of midazolam stored in a glass or polypropylene container no drug loss was observed, but in a PVC bag the amount of midazolam remaining in the solution was reduced as storage prolonged.After 24 hrs, nearly 53.8% of midazolam was sorbed into the bag at pH 6.0. A linear relation was found between the amount of midazolam sorbed into an administration set and the equilibrium concentration of midazolam in the range of 4-20μg/ml at 30°C. The amount of midazolam sorbed into an administration set was influenced by the pH of the solution.When the midazolam concentration was 15μg/ml in aqueous solution, it was 0.45mg/g at pH 5.0 and was increased to 5.24mg/g at pH 7.0. The calculated amount of sorbed midazolam, supposing that the equilibrium sorbed amount was in proportion to the apparent partition coefficients [diethylhexyl phthalate (DEHP)/water], was in good accordance with the experimental data. We estimated that midazolam loss into a PVC bag or an administration set occurred through partition and diffusion of midazolam to DEHP used as a plasticizer of PVC.

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We investigated the leaching of diethylhexyl phthalate (DEHP, a plasticizer of polyvinyl chloride) from a polyvinyl chloride container or an administration set into intravenous cyclosporine solutions. The concentration of DEHP was measured by high-performance liquid chromatography. A linear relation was found between the amount of DEHP dissolved from the administration set into the aqueous solution and the concentration of polyoxyethylated castor oil within the range of 2.5-12.5mg/ml. The amount of DEHP dissolved from the polyvinyl chloride bag into solutions increased with time, and after 24 hours at initial cyclosporine concentration of 1.0mg/ml, 76.7μg/ml of DEHP was found in the solution.
When the cyclosporine solution was passed through the administration set with 100cm in length at a flow rate 0.58ml/min and with the initial cyclosporine concentration of 500μg/ml, the concentration of DEHP in the solution was incresed to as much as about 5.8μg/ml in 30 min, and the same level continued till 180min.

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After a mixed solution of epinephrine and prednisolone succinate for inhalation (Nebulizer No.1 solution) was prepared in the hospital and was allocated into 50m1 sterilized bottles, Nebulizer No.1 solution was stored for 4 weeks under the following 3 conditions i.e.at room temperature with room lighting (25±2°C, 500 lux), at room temperature with prevention of room light transmittance (25±2°C, covered with brown light-resistant bag), and in a cool and dark place (5-10°C, covered with brown light-resistant bag). After the storage, the observation of appearances, pH measurement, the measurement of contents and the identification and quantification of decomposed products by high-performance liquid chromatography (HPLC) were performed.
In storage at room temperature under room lighting or prevention of room light transmittance, Nebulizer No.1 solution was markedly colored; contents of epinephrine and prednisolone succinate in the mixed solution were decreased; and adrenochrome and prednisolone were detected as decomposed products.In cool and dark storage, there were no changes in appearances, even after storage for 4 weeks, and epinephrine and prednisolone succinate remained by 86% and 92%, respectively.

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Mutants derived from Enterobacter cloacae ATCC 23355 and Serratia marcescens ATCC 8100 by treatment with ceftizoxime were found to be resistant to various newer beta-lactam antibiotics, except for imipenem. E.cloacae ATCC 23355M as a mutant showed no changes in beta-lactamase production and activity during serial passages of the, strain, indicating that its acquisition of resistance was due to chromosomal mutation.In contrast, there was no change in beta-lactamase production by S.marcescens ATCC 8100M in comparison with S.marcescens ATCC 8100 as a parent strain.Mutants of both S. marcescens ATCC 8100 and E.cloacae ATCC 23355 showed changes in their major outer membrane proteins. These findings suggested that the acquisition of resistance to the newer beta-lactam antibiotics by S.marcescens and E.cloacae was dependent on changes of their major outer membrane proteins or changes of beta-lactamase production.

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Antimicrobial activity of acrinol was studied for 16 bacterial and one yeast-like fungal strains. Acrinol exhibited a lower minimal inhibitory concentration (1.56-100μg/ml) against Grampositive cocci and Candida, but exhibited a higher concentration (200->3200μg/ml) against Enterobacteriaceae and glucose nonfermentative Gram-negative bacilli. On the other hand, 0.1 % acrinol produced no more than 2-log reduction of Gram-positive cocci and glucose nonfermentative Gram-negative bacilli except for Pseudomonas aeruginosa after ten minutes exposure, while did more than 2-log reduction of most of Enterobacteriaceae, P.aeruginosa, and Candida. It has been shown that the static effect of acrinol is greater against Gram-positive cocci than Gram-negative bacilli such as E. coli and P. aeruginosa, but the cidal activity of acrinol is contrary to the case of static effect.

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A new method to determine serum mexiletine (MX) concentrations using high-performance liquid chromatography (HPLC) was established.This method could reduce a sample volume to 100μ1 of serum and could shorten the pretreatment time to less than 10 minutes by using Chem Elut minicolumn. The results obtained by this method (n=28) correlated well with those obtained by gas chromatography method (r=0.997).Moreover, this method had a good recovery and reproducibility, suggesting that it is an excellent method for determining serum MX concentrations.
Using this HPLC method, serum protein binding of MX was studied in healthy subjects and patients with chronic renal failure (CRF). The protein binding of MX was 60.83±4.37% in healthy subjects (n=6) and 52.45±6.22% in CRF (n=9).The protein binding of MX in CRF was significantly decreased, compared with healthy subjects, indicating an apparent elevation of free drug concentrations.
In general, dose adjustment of MX in CRF is considered to be unnecessary. However, free drug concentrations may participate in the appearance of effects and adverse reactions. The possibility of enhanced pharmacological effects and increased adverse reactions due to such variations of protein binding in CRF should be also considered.

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A local anesthetic preparation to be applied on skin surface, 7% lidocaine cream, was prepared and was stored for one year under a room temperature (25±2°C) to test the stability. The appearance was visually inspected, lidocaine content was determined by high-performance liquid chromatography (HPLC), and water content was measured according to the Karl Fisher method described in the Japanese Pharmacopeia.The transdermal absorption and the anesthetic effect were also compared between the 7% lidocaine cream and EMLA cream (ASTRA) which is used in Europe.The transdermal absorption was estimated from the remaining drug in the cream one hour after application. The anesthetic effect was assessed according to the pinprick method.
Little changes in both lidocaine content and water content of the 7% lidocaine cream were observed one year after the preparation, which proved its satisfactory stability.Although it was estimated that the amount of drug absorbed was smaller with 7% lidocaine cream than that with EMLA cream, both creams had an almost equivalent anesthetic effect.

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We investigated the loss of nicardipine hydrochloride from solutions to the intravenous administration set. Nicardipine hydrochloride concentrations were measured by high-performance liquid chromatography. It was found that the factors affecting the loss of nicardipine hydrochloride were the container materials, the pH of the intravenous solutions and the flow rate. When the injection diluted with isotonic sodium chloride solution stored in a glass or a polypropylene container no drug loss was observed, while in a polyvinyl chloride bag nicardipine hydrochloride concentration was reduced to 83.8% in 24 hr. When the nicardipine hydrochloride solution (pH 6.0) was passed through the administration set at a flow rate of 2.43 ml/min, initial concentration 32.3 μg/ml and the length of administration set 100 cm for 90 minutes, 18.1% of nicardipine hydrochloride was sorbed to the administration set.

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Interaction of admixtures between recombinant human erythropoietin (rHuEPO) injection and 38 kinds of injectable preparations including 13 kinds of antibiotics was investigated on pH, appearance, and EPO activity which was measured by radioimmunoassay method using antirecombinant erythropoietin antibody.Although the EPO activity remained unchanged in majority of admixtures, it was reduced by Ferricon, Fesin, Cefmetazon, Gentacin, Kefrin, Sulperazon, Hydrocortone phosphate, and Stronger Neo-Minophagen C. The present study clearly showed that the drastic change of pH and admixing with injectable preparations containing sodium bisulfite as a stabilizer may result in the decrease of EPO activity.

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The chemical stability and the microbial numbers of non-sterilized and sterilized 0.1% allopurinol gargle (allopurinol gargle) were studied.Furthermore, studied the efficacy for some patients who were afflicted with oral mucositis.Allopurinol gargle (0.1%) was chemically stable under the storage in the room temperature or in the refrigerator at least for 15 days. Bacterial numbers in the non-sterilized samples increased at regular interval, while the sterilized sample wasn't detected the bacterial colonies for 15 days. On the therapeutical efficacy of allopurinol gargle for 8 patients, all 8 cases were judged effective.However, we think that more modification to the allopurinol gargle preparation and more clinical data would be needed.

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We compared the drug resistance patterns of clinical isolates of Enterobacter cloacae and Serratia marcescens in 1983 and 1990 at Nagasaki University Hospital. Furthermore, beta-lactamase production by drug-resistant strains of several organisms was investigated. In 1990, the number of E.cloacae or S. marcescens strains isolated was about half of that in 1983. Most of the E.cloacae strains were isolated from the respiratory tract in both years. A large proportion of S. marcescens strains were isolated from the urinary tract in 1983, but in 1990 these strains were isolated from the respiratory tract. An increase in E. cloacae strains and S. marcescens strains resistant to ceftizoxime or to latamoxef was not noted when comparing 1990 with 1983. The beta-lactamase prepared from resistant strains isolated in 1990 showed a higher potency than that from susceptible strains isolated in the same year, and a larger amount of betalactamase was produced by the resistant strains. Beta-lactamase production by resistant strains of E. cloacae, Citrobacter freundii, and S. marcescens was found to be due to derepression. These strains resistant to beta-lactams were susceptible to imipenem.

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In Pseudomonas aeruginosa strains treated with ceftizoxime and latamoxef, the frequency of appearance of highly resistant strains from parent strains was 10^-5 to 10^-8. In the case of ceftazidime, highly resistant strains developed from moderately resistant strains at a frequency of about 10^-8. On the other hand, no strain acquired a high resistance to imipenem or aztreonam, but moderately resistant strains developed from parent strains at a frequency of 10^-5 to 10^-8. In a study of the mechanisms of resistance, strains highly resistant to ceftizoxime, latamoxef and ceftazidime had derepressed production of beta-lactamase, while parent strains produced inducible beta-lactamase. Imipenem-resistant strains had unchanged patterns of beta-lactamase production, but these strains had an outer membrane protein with a different molecular weight from that of the parent strain (48, 000 daltons). Cross-resistance was not observed between imipenem-resistant strains and other beta-lactam-resistant strains.

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Antituberculosis chemotherapy still requires a long duration of over several months or more than a year, though it has become shorter in recent times than before, and discontinuance of chemotherapy may be occasionally seen during this long course. A retrospective study was carried out with the aid of the pharmacist-conducted medication profiles, in order to find out the reasons for discontinuance of chemotherapy and to know whether pharmacists can assist continuity of long-term chemotherapy in tuberculous patients.
From the medication profile, it was found that among 714 cases to whom antituberculous drugs were prescribed in our hospital from March 1988 to January 1990, 179 cases were likely to be involved in some adverse reaction.When these cases were referred to doctor's medication charts, 144 cases were revealed to develop adverse reactions, among which 65 cases had skin rash, 26 cases had drug fever, 41 cases had liver function abnormality, 35 cases had miscellaneous reactions such as gastrointestinal, neurological and haematological disorders. Desensitization was carried out in 66 cases with success in 46 cases.As a whole, the antituberculous chemotherapy was either discontinued or a new drug (s) was given, in 44 out of 714 cases (5.9%) due to adverse reactions. The major reason for discontinuance of drug intake was adverse reactions, followed by self-stopping or delayed hospital visit and change of drug due to appearance of resistance, retreatments of tuberculosis or surgical operation.
Pharmacists can counsel patients effectively by reading medication profile carefully, recognizing their drug intake conditions, identifying the reason for discontinuance of medication and being aware of adverse reactions, and can contribute to improvement of the patient compliance with chemotherapy in long-term tuberculosis treatment.

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Pharmaceutical manufacturers are obliged to report results of clinical application of a new drug for six years after its approval.These clinical results, together with the data obtained before the approval, are comprehensively carried in “Reporting of Adverse Drug Reactions” issued from the Ministry of Health and Welfare. Post marketing surveillance (PMS) data have a significant value because they provide information on adverse reactions in cases which cannot be obtained during development of the drug.We attempted to analyze the data primarily on the basis of the incidence of adverse reactions, in order to use the data as an important information source on drugs.
We put the data from No.27 (October, 1977) to No.109 (July, 1991) into a computer and examined them. When the incidence of adverse reactions was compared before approval (A) and after approval (B), the incidence B was lower in 91.3%(316 of 346) of the cases.All the remaining 8.7%(30 of 346) of the cases had some special reasons. One of the reasons for decrease in the incidence B is increase in the number of patients observed.In PMS, pharmaceutical manufacturers are required to report approximately 10 times as many patients as during the development of drugs. Another reason is that some cases of adverse reactions may not be reported depending on individual physicians' judgement.Moreover, some physicians may not be aware of the adverse reactions.
From our analysis of the results, it is impossible to regard A and B as equivalent.In Japan, incidence of adverse reactions listed in package inserts is expressed as a total average of A and B. Because of the above-mentioned reasons, however, we think that A and B should be indicated separately.

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A novel method for the demand forecasting of drugs in a hospital pharmacy was developed. The method, a weighted moving average method incorporated with the frequency of prescription, was produced more useful reordering point and ordering quantity for the drugs with lowfrequency prescription in comparison with a traditional first-order exponential smoothing method.

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