Liposomal-encapsulated superoxide dismutase (L-SOD) was prepared with a view to prolonging the half-life and pharmacodynamic action time. Presome^® was adopted as a phospholipid in the preparation of L-SOD.
L-SOD was sterilized through polycarbonate membrane filters having pore diameters of 0.2 μm and 0.4μm. The liposomal particle size, as measured by the dynamic light scattering method, was 198±40 nm. Effective SOD encapsulation efficiency was approximately 25.8%.
Immediately after the i.v. injection of L-SOD into rats, blood levels of SOD decreased in a bi-exponential manner; the half-lives of the α-and β-phases were 16.6 minutes and 7.8 hours, respectively.
AUC and MRT increased as compared with the i. v. injection of r-hSOD (free SOD), The SOD-activity in plasma was on a low level.
These results suggested that still more L-SOD was trapped in the reticulo-endothelial system (RES), involving such organs as in the liver and spleen.
In an effect to increase the SOD activity in plasma and prolong the circulation time of liposomes in blood, we prepared L-SOD modified with polyethyleneglycol derivatives (L-SOD/PEG. DOPE; L-SOD/PEG·DMG).
After the i. v. injection of L-SOD/PEG·DOPE and L-SOD/PEG·DMG into rats, the SOD activity in plasma became higher and also the circulation time of liposomes in blood became longer as compared with the L-SOD i. v. injection.

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The antihistaminic activity of Artemisiae Folium extract was investigated. In the isolated guinea pig ileum preparation, Artemisiae Folium extract (10 and 20 mg/ml) produced a slight acetylcholine-like contraction. In the presence of atropine (10^-6 M), this extract in a concentration of 40 mg/ml significantly inhibited the histamine-induced contraction of guineapig ileum. The oral administration of this extract (40 g/kg) significantly decreased the lethality in mice intravenously injected with histamine (600 mg/kg) from 83% to 42%. The extract (0.4-20 mg/ml) also dose-dependently inhibited the histamine release from rat peritoneal mast cells induced by compound 48/80 (0.4μg/ml). In the clinical examination, 25 patients suffering from pruritus cutaneus were treated with the lotion of Artemisiae Folium extract. Pruritus cutaneus was well controlled, and the final overall ratings were as follows: remarkable improvement, 15%; moderate improvement, 50%; slight improvement, 15%; unchanged, 15%; aggravation, 5%(1 case). Five cases were dropouts. These results suggest that Artemisiae Folium extract has some antihistaminic and histamine-release-inhibiting activities and that its lotion is effective for some patients with pruritus cutaneus.

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Effects of treatment of cimetidine (CMT) on pharmacokinetic behaviors of chlopropamide (CPA), an oral hypoglycemic agent, were investigated in rabbits with the standard renal clearance method. The renal clearance ratio and the renal tubular secretion volume of CPA were found to be markedly decreased by the treatment of CMT. Furthermore, the results of experiments using renal cortical slices demonstrated that CMT of the cationic drug decreased the accumlation of CPA. Inhibition of uptake by 2, 4-dinitrophenol indicated an energy dependence. Probenecid, a competitor for the anion transport mechanism, moderately inhibited CPA uptake. These observations indicate that the treatment of CMT may depress the renal excretion of CPA by inhibiting the tubular secretion.

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This study was undertaken to ascertain the total indexes of adverse drug reaction and with these indexes to clarify the characteristics of adverse reaction to individual antibiotic. The frequencies of adverse reaction in 14 sites were calculated by the accumulative data of 22 antibiotics obtained from clinical trials and post-marketing surveillance which were reported by the Ministry of Health and Welfare. They were examined by principal component analysis.
The results were as follows: 1. There were strong intercorrelations in the frequencies of adverse reactions which affect the whole body in general inclusive of the hepatobiliary system and blood. 2. The first and second principal components were suggested to reveal the frequencies of adverse drug reaction affecting the whole body, and affecting local regions such as the ear, application site and urinary system, respectively. Their cumulative proportion was 61.4%. 3. The first principal component score tended to be larger in parenteral cephems, whereas the second principal component score tended to be larger in aminoglycosides. 4. The first principal component score of ceftizoxime sodium constituted the largest extreme. 5. The frequency of adverse reaction to fosfomycin which affected the whole body was obserbed to decrease by changing Na salt to Ca salt.

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Implantable collagen-poly (hydroxyethyl methacrylate (HEMA)) hydrogels containing antitumor drugs were prepared and evaluated for use in controlled drug carrier systems. The drugs used were CPT-11 and SN-38 which were derivatives of camptothecin (CPT). The drugs were released from the hydrogels at a constant rate (zero-order release) over about 1 week. The drugs sited in the plasma of mice were detectable for 5 days after subcutaneous injjection of the hydrogels while they were undetectable at 24 hours after the injection of the drug aqueous solutions. Ehrlich solid tumor was developed by subcutaneous inoculation of the tumor-cell suspension in the inguinal region of mice. The hydrogels demonstrated greatly improved antitumor activity over the drug aquenus solutions as evidenced by the gross tumor weight and the survival time assessments. This was attributed to the controlled and slow release of the drugs from the gels.

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The compressed coating tablet swelling with water was investigated for the purpose of development of a new dosage form for elderly patients. The dry gels of agar, gelatin, and Inaagar-L^® were reduced to powders and used as the coating material.
It was found that the surface of any tablet formed a state of jelly through the addition of water, thus masking the taste of the drug. All tablets satisfied the rules of the disintegration test outlined in JP XII. These tablets demonstrated high moisture absorption due to the stored condition. The water absorption pattern of the tablets varied with the kind of coating material used. The agar coating tablet absorbed water rapidly, with its coating layer then being disintegrated. The differences in water absorption and swelling behavior of these tablets were considered to be caused by the difference in the size of the gap between the gel particles of the coating layer and the swelling ability of the gel particles. The Inaagar-L ^® coating tablet was deemed to be the most desirable one in the volunteer test. Therefore, it seems likely that the texture of the swelled coating layer is an important factor in facilitating swallowing.

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The Mutual relation ship was investigated between ED₅₀ and a reliable method which was previously reported, i. e., the area under the effect vs. time curve (AUE). In comparing AUE, AUC and MIC, AUE was found to be the most closely related with ED₅₀. AUE involves are conversion of time-concentration curves into time-effect curves, and is considered to be a simple and reliable method for definitely demonstrating antibacterial effects.

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The solution stability of copper histidinate, which has been used in place of copper acetate or copper sulfate as an intravenous injection for copper supplement treatment of Menkes disease, has been studied. The solutions with various pH's were prepared and their spectral change was monitored by means of UV-visible spectrometer. Although spectral change was very small in acidic and neutral solutions at 5°C, a large decrease in the absorption peak at 630 nm was observed in the basic solution.
Change in the copper concentration was quantitatively analyzed by both UV-visible and ICPMS spectroscopic techniques. Based on these results, the neutral and acidic copper histidinate solutions were concluded to be stable at least for a month if they are stored at 5°C.

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Numerous reports have appeared concerning compatibility, photo-degradation and adsorption in infusion solutions. Scince no studies have been done, however, on producing hydrogen peroxide in infusion solutions to which added multi-vitamins, we formulated research to focus on this particular aspect.
The production of hydrogen peroxide increased immediately after mixing infusion solutions and multi-vitamins, rising to 11.02 ppm in KN solution 4B combined with M. V. I. and 8.76 ppm or 10.58 ppm in Klinizalz^® B combined with Sohvita^® or Neolamin Multi^® respectively. Removal of soluble oxygen and light remarkably affected the on disturbance of the hydrogen peroxide production, while degradation of ascorbic acid (AsA) was observed immediately after mixture initiation.

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The effects of three anticoagulants, which are heparin sodium, nafamostat mesilate and dalte parin sodium, on paraquat adsorption to activated charcoal (AC) and on paraquat desorption from paraquat-AC complex were studied in vitro. Each 10 ml of anticoagulant solution and 100 mg of AC was added to the 10 ml of paraquat dichloride solutions ranging in concentration from 150 to 1000 μg/ml, and the mixture was incubated at 37°C for 24 hours. The concentrations of paraquat unadsorbed on AC in the presence of nafamostat mesilate were 10-73% higher than that in the isotonic sodium chloride solution (control). Furthermore, the paraquat concentrations in the mixture were increased by the rise in nafamostat mesilate which coexisted with paraquat. However, the paraquat concentrations in the presence of the other two anticoagulants were almost equal to that in the control.
Each 10 ml of nafamostat mesilate solutions was added to the AC pre-equilibrated with 10 ml of paraquat dichloride solutions (200 and 700 μg/ml), and the mixture was incubated at 37°C for 24 hours. The concentrations of paraquat unadsorbed on AC and desorbed from AC in the mixture was 14-54% higher than that in the control.
We concludethat nafamostat mesilate is an unsuitable anticoagulant for the prevention of clotting extracorporeal hemoperfusion with AC in instances of paraquat poisoning, although dalteparin during sodium appears to be an effective anticoagulant because no effect is exhibited on paraquat adsorption and little hemorrhage results in patients.

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We investigated the effect of pH and polyoxyethylated castor oil which was used as a solubilizing agent on the sorption rate of miconazole from the buffer solotions to the intravenous administration sets. The leaching of diethylhexyl phthalate which was used as a plasticizer formulated in the preparation of polyvinyl chloride membrane from the intravenous administration sets into the polyoxyethylated caster oil solutions was obverved. The leaching rate was not influenced by the pH in the solutions. Whereas the sorption rate of miconazole was influenced by the polyoxyethylated castor oil concentration and the pH in the solution.
When polyoxyethylated castor oil was not added to the solution, the pH profile of the miconazole sorption rate was pH4. 0<pH5. 0<pH6. O. On the other hand, when polyoxyethylated castor oil was added, this rate was pH4.0<pH7.0<pH5.0 and pH 6.0. It was estimated that the sorption rate of miconazole was dependent on the concentrations of the miconazole ionized form in the aqueous phase, the partition rate from the miconazole molecular form in the micelle to the free molecular form in the aqueous phase, and the partition rate from the free molecular form in the aqueous phase to the molecular form in the organic phase.

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The microbial contamination of burette chambers after clinical use was examined. Sixty-one burette chambers were collected from the gastroenterology ward, the gastroenterological surgery ward and the neurology ward at Kitasato University East Hospital. Each burette chamber was filled with 20 ml of thioglycollate medium (fluid) and incubated at 37°C for 7 days. These burette chambers were investigated for the number of doses and the days of use.
The results on these burette chambers, indicated that only one was contaminated. The isolated bacteria were identified as Propionibacterium spp. In addition, the burette chambere were administered about 13 doses, on average, were used for about 5 days, on average.

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In an attempt to facilitate the counselling for patients on the rational use of suppositories, we surveyed through questionnaire how University of Tokyo Hospital outpatients (range 20-70 years) use suppositories. The collection ratio of the questionnaire was 52%(67 of 146). The suppositories exhibiting a systemic action such as analgesic and antipyretic were used in 60% of patients. The directions for use of suppositories were not well appreciated in 10% of patients. Forty percent of patients experienced trouble when inserting the suppositories. Details of the trouble included “discharge immediately after insertion of the suppository” and “the bowels were evacuated after insertion of suppository” . It was found that patients coped with the trouble in various way such as “suspended the use of the suppository”, “inserted the discharged suppository again” and “inserted a new one” . From these results, further investigationconcerning the problem of the loss of the suppositry from the rectum should be requiredfor to ensure the patients of proper therapy.

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Microbial contamination of 0.025% benzalkonium chloride (BAC), in which the tracheal suction catheter was soaked, was investigated. Six strains of Pseudomonas cepacia were isolated from 30 samples of 0.025% BAC which were used for 24 h. The bactericidal activity of BAC and povidone-iodine (PVP-I) against clinical isolates of P. cepacia was evaluated by logarithmic reduction factors (LRFs). Two strains of P. cepacia isolated from the disinfectant were resistant to BAC, and the LRFs of 0.025% BAC for these strains after 10min exposure were 0 and 0.12, respectively. The LRFs of 0.025% and 0.05% BAC for five strains of P. cepacia isolated from clinical specimens after 1 min exposure were less than 0.94 and 2.09, respectively. On the other hand, 0.1% BAC and 0.2% PVP-I showed antimicrobial activities against P. cepacia isolates tested, and the LRFs after 1 min exposure were more than 3 or 4. The LRFs of 0.025% BAC for P. cepacia were not significantly elevated by the presence of 10^v/v% ethanol. These findings suggest that 0.1% BAC and 0.2% PVP-I are suitable for the disinfection of tracheal suction catheters.

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A few computer systems which monitor and record processes of powder drug dispensing are now commercially available. They have now come into wide use for reconfirming dispensed drugs by monitoring the records which were input into the system by making the barcode reader read the barcode on the bottom of a picked-up stock bottle and by making the electric balance read doses weighed when the pharmacist fills the prescription. The commercial monitoring system for dispensing is usually used stand-alone, but we connected this system to the prescription order system for inpatients in the total computerized hospital information system. With this system, the prescription data ordered by physicians are printed out in the pharmacy, and at the same time, sent directly to the monitoring system device prior to dispensing. In this device this prescription information contributes to dispensing by participating as indexes for filling the proper drugs. When a dispenser picks up a different stock bottle or weighs a dose different from a prescription information, a warning message is sent to the dispenser as an alarm appers on the display, with the next dispensing step not allowed to proceed until the right drug or right dose is determined.
As the result of the practical use of this on-line system, the occurrences of serious dispensing errors such as the wrong drug or dosage of prescriptions could effectively be controlled.

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We examined the stability of intrahospitally prepared β-carotene, which is used for the therapy of cutaneous photosensitivity in patients with erythropoietic protoporphyria. Thirty mg of β-carotene was mixed with 170 mg of sucrose, and stored in wrapping paper or colored or non-colored capsules for 28 days. At room temperature (25±2°C), the β-carotene contents in all preparation decreased to 65-75% and 10-30% of the initial content by 14 and 28 days later, respectively. However, under the lightproof condition at 4°C and 14°C, the β-carotene contents in all preparation remained at 90 and 80%, respectively, 28 days later. It is concluded that β-carotene preparation can be protected against degradation under the lightproof condition at 4°C.

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