The biosynthesis of rat gastric glycoproteins with or without sulfate was investigated in rats subjected to restraint and water immersion stress. Studies were carried out in vitro in rat glandular stomach using ³H-glucosamine and ³⁵S-sulfate. Labeled glycoproteins were extracted with 2% Triton X-100 and fractionated on Bio Gel A-1.5 m. Radioactivity incorporated into glycoproteins was estimated in the tissue as well as in the medium. The incorporation of ³H-glucosamine into the tissue was unchanged during the experimental period, while the release of ³H-labeled glycoproteins into the medium was markedly increased at 12 h after the onset of stress. The incorporation of ³⁵S-sulfate into the tissue was decreased at 6 h and increased at 12 h. The release of ³⁵S-labeled glycoproteins into the medium was not changed significantly. However, the change in the total radioactivity (tissue plus medium) of ³H was similar to that of ³⁵S. These results suggest that the remarkable increase in the biosynthesis of glycoproteins and sulfated glycoproteins was closely related to reinforcement of defensive response. Furchermore, we investigated the effect of anti-ulcer agents on the biosynthesis of mucus glycoproteins. Cimetidine and atropine decreased the incorporation of radioactive precursors and the release of labeled glycoproteins into the incubation medium in vitro. AAHA (N-(N-acetly-β-alanyl)-L-histidine aluminum complex) and sofalcone (SU-88; 2-carboxymethoxy-4, 4'-bis (3-methyl-2-butenyloxy) chalcone) increased the incorporation of radioactive precursors and the release of labeled glycoproteins into the medium. These observations indicate that anti-ulcer agents having different modes of action show different effects on the glycoprotein biosynthesis.

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A nonlinear multiple regression analysis program MULTI2 (BAYES) was developed for microcomputers. The Bayesian algorithm which is incorporated in MULTI2 (BAYES) combines the insufficient individual patient data (individual data) with the pharmacokinetic parameters published in literatures (population parameters) to predict the plasma time course of the patient. The program is written in the minimum Microsoft BASIC commands alone to be executable on many personal computers without any modification. The numbers of parameters to estimate, independent variables and dependent variables are not restricted in use of MULTI2(BAYES). The pharmacokinetic models are defined as one pleases by the user. The four nonlinear least squares algorithms, i.e. Gauss-Newton method, damping Gauss-Newton method, modified Marquardt method by Fletcher and simplex method can be selected at user's option. MULTI2(BAYES) calculates the confidence limits of time courses at 95% significant level

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The effects of coumarins on anaphylactic mediator release from rat mast cells were investigated. Since Pd-Ia (3'-angeloyloxy-4'-acetoxy-3', 4'-dihydroseselin) causes relaxation of smooth muscle unhibiting calcium influx, and since mediator release is a calcium-dependent process, studies were made on whether coumarins block calcium influx into rat mast cells stimulated by concanavalin A. Pd-Ia isolated from Peucedanum praeruptorum DUNN and related compounds, named Pd-C-II, Pd-C-III and Pd-C-IV, from Peucedanum decursivum MAXIM., (Angelica decursiva FR. et SAV.) inhibited mediator release from purified mast cells induced by concanavalin A with phosphatidylserine; their IC₅₀ values were 79, 100, 102 and 73 μM, respectively. Pd-III, decursidin and water-soluble analogues of Pd-Ia (Pd-Ia-OH, Pd-Ia-OCH₂CH₃) did not inhibit the release. Thus the inhibitory actions of coumarins on calcium influx seemed to depend on the chemical structures of these compounds ; an acetoxyl residue at position 3' or 4' on the seselin or xanthyletin skeleton might be essential for an inhibitory. Furthermore, Pd-Ia and Pc-C-III caused more than 40% reduction in ⁴⁵Ca uptake induced by concanavalin A, whereas decursidin had little effect on it. Therefore, the inhibitions of mediator release of mast cells by some of coumarins from "Qian-Hu" seem to depend on their effect in blocking calcium influx.

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Anti-tumor activity of 1-acetyl-3-o-toluyl-5-fluorouracil (A-OT) against MH134 solid tumors in mice was studied following subcutaneous and oral administration and compared with that of 5-fluorouracil (5-FU) administered subcutaneously at doses of 0.2, 0.4 and 0.6 mmol/kg/d. Oral administration of A-OT demonstrated a remarkable effect on MH134 solid tumors, the effect being more marked than that of subcutaneous administration of A-OT. Anti-tumor activity of oral administration of A-OT at a dose of 0.2 mmol/kg/d was comparable to that of subcutaneous administration of 5-FU at the same dose. The level of decrease in thymus weight and the magnitude of increase of spleen weight following oral administration of A-OT at any dose were smaller than those by subcutaneous administration of 5-FU (0.2 mmol/kg/d).

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Microencapsulation of ampicilin, an orally administered antibiotic, with different viscosity grades of ethyl cellulose was studied. The preparation of microcapsules was done as follows ; the mixture of ethyl cellulose-CH₂Cl₂-ampicillin was dispersed in purified water containing 0.5% (w/w) sodium lauryl benzenesulfonate, and then CH₂Cl₂ was dried out by elevating the temperature. The dissolution curves for the release of ampicillin from microcapsules prepared using the four different viscosity grades of ethyl cellulose were quite different. The release of ampicillin increased with decreasing ethyl cellulose viscosity. The evaluation of prepared microcapsules was made using gastric-emptying-controlled rabbits. The plasma concentration of ampicillin obtained by the administration of microcapsules showed a significant sustained-release pattern. The area under the plasma concentration curve (AUC ) of ampicillin obtained after a single oral administration of microcapsules prepared using 10 cps ethyl cellulose was 1.8 times greater than that obtained after double oral administration of powder. This fact will be caused by the delaying of gastric-emptying, intestinal-transit and dissolution of ampicillin there. It was confirmed that a large number of microcapsules still remained in the stomach and each microcapsules still contained ampicilli at 24 h after dosing from the experiment using gasntric-emptying-controlled rabbits.

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The absorption mechanisms of γ-butyrolactone-γ-carbonyl-L-histidyl-L-prolinamide citrate (DN-1417) and thyrotropin-releasing hormone (TRH) were studied in the rat. In situ absorption experiments were carried out by radioimmunoassay, and experiments using everted sacs of small intestine were by radioactivity measurements with ¹⁴C-labeled DN-1417 or ³H-labeled TRH in the low concentration range of drug and by a high pressure liquid chromatography in the rather high concentration range of drug. The site specificity of absorption in the small intestine of rats could not be found with DN-1417 whereas TRH-T was absorbed from only the upper part of small intestine. Dose-proportional absorption of of DN-1417 was observed in experiments of in situ as well as in vitro. Dose-proportional transfer of DN-1417 through the everted small intestine was also found within the concentration range from 120 ng/ml to 27 mg/ml, whereas the transfer ratio of TRH decreased with increase in the concentration of TRH. DN-1417 transfer from mucosal to serosal fluid was not inhibited by the replacement of medium Na ions by K ions, pretreatment of intestinal mucosa with HgCl₂, the existence of an oligopeptide, or the existence of β-lactam antibiotics which had been reported to be absorbed by active transport or carrier-mediated transport systems. While, TRH transfer was inhibited by the replacement of medium Na ions by K ions, pretreatment of intestinal mucosa with HgCl₂, the existence of an oligopeptide, and the existence of β-lactam antibiotics. From these results, it was concluded that DN-1417 transfer through the small intestine was mainly due to the simple diffusion, and the contribution of the carrier-mediated transport to TRH transfer through the small intestine was not disregarded

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The effect of medium chain glyceride (MCG) on the intestinal absorption of cefmetazole sodium (CMZ) was investigated in rats and dogs. In rats, MCG containing glyceryl mono-, di-and tri-caprylate enhanced the intestinal absorption of CMZ after intraduodenal administration, though the promoting effect of MCG was less than that after rectal administration. The promoting effect of MCG was found to be mainly due to glycerylmonocaprylate and dependent on the dosage of MCG. The plasma CMZ levels after intraduodenal administration as MCG solution tended to be slightly higher than those observed after administration as MCG emulsion, though the differences were found to be statistically insignificant. Moreover, the intestinal absorption of CMZ after intraduodenal administration as MCG emulsion was decreased significantly by increasing the amount of water in the emulsion. The promoting effect of MCG in dogs was more clearly demonstrated in the lower intestine than in the upper intestine. Furthermore, the oral bioavailability of pharamceutical of CMZ was also investigated in dogs. When enteric coated capsules filled with MCG solution were administered to dogs, the bioavailability of CMZ was enhanced significantly.

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The effect of atropine (ATR), a parasynpatholytic agent, on the intestinal absorption of salicylamide (SAM) was studied using the absorption kinetic model proposed by Winne et al. The disappearance of SAM from perfusate and the appearance in intestinal blood were determined using perfused intestinal loop of the rat in vivo. The results showed that the absorption of SAM was simulated by the four compartment model consisting of luminal, interstitial, blood and serosal compartments. The model was assumed to have three rate determining factors, namely mucosal membrane permeability, clearance by blood flow and serosal membrane permeability. ATR decreased the absorption of SAM by decreasing the clearance factor relating to intestinal blood flow and increased the fraction of the transported amount of SAM from interstitia1 space to serosal compartment.

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Mixed micelles (MM) composed of polyoxyethylated (60 mol) hydrogenated castor oil (HCO60) as a harmless surfactant and linoleic acid (LA) as an essential fatty acid potentiated the antitumor activity of bleomycin (BLM). In the in vivo experiment, intraperitoneal administration of BLM with MM significantly prolonged the survival time of male ddY mice bearing Ehrlich ascites tumor and male Donryu rats bearing ascites hepatomas AH 66 inoculated intraperitoneally, compared with that of animals treated with BLM alone, BLM with HCO60, and BLM with LA, respectively, wheares MM had no antitumor effect to both tumors. Also in Winn-type tumor-neutralizing assay in which 10 male ddY mice were innoculated intraperitoneally with Ehrlich ascites tumor cells preincubated with a test material, BLM with showed a more marked enhancing activity with 3 surviving tumorfree mice than did BLM alone.

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Dibucaine, a local anaesthetic, reversilbly suppressed growth and differentiation of cultured chick myogenic cells. In the presence of 10 μM dibucaine, chick myoblasts multiplied and fused to form myotubes. However, myotubes did not increase their size. Accumulation of creatine kinase (CK) activity per culture dish was also suppressed, showing that myotube growth was suppressed. Concomitantly, myofibril formation and developmental transition of CK isozymes were retarded. The myotubes remained immature. When dibucaine was removed from the culture medium and cells were further incubated, the accumulation of CK activity, especially of muscle type isoform, and formation of myofibrils took place ; eventually the myofibrils were organized similarly to those in the control culture. The concentration of dibucaine enough to exert these effects was about one-hundredth of the concentration used in clinical anaesthesia.

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The absorption of an immunosuppressive drug, cyclosporin A (CsA), with the aid of lipid-surfactant mixed micelles from the rat gastrointestinal (GI) tract and lymphatic delivery were studied. The administration of CsA in oily solution, sesame oil or linolic acid, into the rat duodenum indicated a small amount of CsA both in the plasma and lymph for about 6 h. the administration of CsA in the mixed micellar solution composing of linolic acid and HCO-60, polyoxyethylated (60 mol) hydrogenated castor oil, accelerated the absorption of CsA from the GI tract, and CsA was delivered into the lymphatics with an extremely high selectivity.

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The exsorption of theophylline into the small intestinal lumen after intravenous administration of aminophylline was studied by in situ single-pass perfusion technique. As the concentrations of the drug in the serum and the bile juice were dicreased, the exsorption rate of the drug into the perfusate decreased obeying the apparent first-order kinetics. The half-lives of the drug concentrations in the serum and the bile juice were 2.13 and 2.58 h for pH 6.0 isotonic phosphate buffer, and were 2.71 and 2.32 h for pH 8.0 isotonic phosphate buffer, respectively. The amounts of theophylline excreted in the perfusate and the bile juice were 12.08% and 0.17% of dose for pH 6.0 isotonic phosphate buffer, and were 13.81% and 0.20% of dose for pH 8.0 isotonic phosphate buffer. These results demonstrated that a considerable amount theophylline was exsorbed into the intestinal lumen. The mechanism by which oral activated charcoal enhanced clearance of theophylline administered intravenously may be adsorption of the drug transported into the gastrointestinal by the charcoal.

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