The effect of methylprednisolone (MP) of high dosage on not only surfactant lipids but also other phospholipid components of adult rat lungs was studied. In spite of the decrease in body weight after one and two intraperitoneal injections of MP of 50 and 100 mg/kg, the increase in content of phospholipids of post-lavaged lung tissue, alveolar white layer, and alveolar macrophages occurred. Although the phospholipid content in the lung tissue and white layer started to decrease by following MP treatment of higher doses, its amount in the white layer and macrophages continued to increase by 25 mg/kg of MP. These changes in the phospholipid content with MP treatment was mainly a consequence of the changes in the content of phosphatidylcholine, especially disaturated phosphatidycholine, as a main component of lung surfactant. The changes in percentages of other phospholipid components, except for phosphatidylglycerol among total phospholipid in the white layer were not significant. Changes in the content and composition of phospholipid of the isolated epithelial type II cells from adult rat lung after one and two injections of MP (50 mg/kg) were similar to those shown in the lung tissue. Our results indicate that, in the adult rat lung, not only the biosynthesis of phospholipid including surfactant lipids but also its secretion into alveolar space are greatly stimulated by administration of MP of high does.

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The percutaneous absorption of drugs was investigated in rats by measuring plasma levels, using mainly 6-carboxyfluorescein (CF) as a model of poorly absorbable drugs. Azone^【○!R】 (AZ), a new useful promoter for the percutaneous absorption of drugs, was used instead of dimethylsulfoxide. We have examined the effects of the solubilized state and concentration of AZ on the percutaneous absorption of CF. AZ was dissolved with the aid of surface-active agents, β-cyclodextrin (CD) or dimethyl-β-cyclodextrin (DMCD). When AZ (2 v/v%) was dissolved completely by a surface-active agent (HCO-60 : polyoxyethylene hardened castor oil derivative), plasma CF levels showed the highest value. Plasma CF levels following the administration of CF with AX which formed a complex with CD or DMCD were scarcely increased as compared to that of CF alone. In the case of fluorescin (FL), which has a higher partition coefficient than CF, the percutaneous absorption of FL was more enhanced by the addition of AZ than in the case of CF.

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The effects of twenty-three natural cytochalasans and sixteen synthetic derivatives on actin-distribution and alteration in morphology of C3H-2K cells, inhibition of lymphocyte capping, and inhibition of actin filament elongation were compared. The effects on cellular level and the in vitro effects showed positive correlation and the structure-activity relationship observed is discussed.

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Selectivities were examined between α₁ and α₂-adrenolytic activities of two apogalanthamine analogs (dibenzazocine derivatives), 6-methyl-5, 6, 7, 8-tetrahydrodibenz [c, e]-azocine (DA-VIII-Me) and its N-allyl analog (DA-VIII-allyl), and two dibenzazepine derivatives, azapetine (DA-VII-allyl) and its N-methyl analog (DA-VII-Me). The α⁽adrenolytic activites were evaluated as inhibitory effects against the response to norepinephrine of isolated was deferens and anococcygeus muscle of rats. The pA₂ values for DA-VIII-Me, DA-VIII-allyl, DA-VII-Me and azapetine on the isolated rat vas deferens were 7.32, 7.76. 6.61 and 7.78 respectively, which were similar to those on the anococcygeus muscle. The α₂-adrenolytic activities of these compounds against the twitch-inhibitory response to clonidine in transmurally stimulated rat vas deferens and guinea-pig ileum were less potent than those against the above α₁-adrenoceptors. In addition, their inhibitory activities on the aggregation of human platelets induced by norepinephrine were weaker than those of phentolamine and yohimbine. These results indicate that the apogalanthamine and azapetine analogs tested are more selective in blocking α₁-adrenoceptors than α₂-adrenoceptors.

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The change of disposition kinetics for p-aminohippuric acid (PAH) was studied following intravenous administration of p-[glycyl-1-¹⁴C] aminohippuric acid to 1-day-old, 1-week-old, 3-week-old and 8-week-old mice. The expiratory excretion of ¹⁴CO₂ in 24 h following the administration was almost negligible in 1-day-old and 1-week-old mice in contrast to 3-week-old (6.8±1.8%) and 8-week-old (8.8±1.9%) mice. The ability to metabolize PAH may not be developed in these infant mice.The elimination of blood radioactivity following the administration was considerably delayed in 1-day-old and 1-week-old mice, especially in 1-day-old mice, suggesting that the renal trubular secretory function for PAH might not have been developed in the infant mice. Whole-body autoradiographic data showed that the transfer of PAH form blood to muscle was enhanced in 1-day-old and 1-week-old mice, especially in 1-day-old mice, compared to 3-week-old and 8-week-old mice. The enhanced muscular cell membrane permeability to PAH in 1-day-old and 1-week-old mice was considered to be the most plausible explanation for this result.

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The interaction of gentamicin with renal cortex of rats has been studied in vitro by means of a binding assay to brush border and basolateral membranes. Gentamicin specifically bound to plasma membrane fractions, compared to other subcellular fractions. Gentamicin binding to brush border and basolateral membranes was markedly inhibited by polycations such as spermine, and was slightly inhibited by high concentrations of tetraethylammonium. The treatment of phospholipase A₂ to both types of membranes increased gentamicin binding, although the treatments by proteolytic enzymes and sulfhydryl reagent did not affect the binding. Gentamicin binding was increased in the brush border membranes treated with acidic phospholipids, whereas it was decreased in the membranes treated wich calcium. Judging from the determination of membrane surface charge by metachromasy of cationic dye, basolateral membranes seemed to contain more anionic sites than brush border membranes. The alterations of gentamicin binding described above correlated with the changes of anionic charge on the membranes, indicating a charge interaction between gentamicin and anionic binding sites on the membranes. The addition of other aminoglycoside antibiotics to the incubation mixture induced significant reductions in the binding of gentamicin in the order of aminoglycosides according to their positive charge. The present results suggest that the characteristics of gentamicin binding to brush border and to basolateral memobranes are essentially similar, and therefore the renal accumulation of gentamicin may be regulated by the transport of gentamicin across both plasma membranes.

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Protective activity of an acidic fraction of bakers' yeast mannan containing protein and phosphorus, designated as WAM025, against infection of Staphylococcus aureus βH 248 strain in mice was investigated. WAM025 elicited a marked increase in the survival ration of mice challenged with viable cells of the S.aureus strain, 5×10⁸ cells per mouse, when the fraction was administered to mice 150 mg/kg/d, 5 times, intraperitoneallyl. The effect was stronger than that of WNM, a neutral fraction of mannan obtained from the same bakers' yeast. The difference seemed to correlate with the strength of activating effects of WAM025 and WNM on the reticuloendotherial system of the host animal. WAM025 induced higher activities of serum lysozyme and carbon clearance in mice than WNM. Also, mice treated with WAM025 showed a greater increase in number and activity of oxygengenerating blood polymorphonuclear leucocytes than mice treated with WNM.

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Pretreatment of male Wistar rats wuth 3, 4, 5, 3', 4'-pentachlorobiphenyl (PenCB), a potent 3-methylcholanchrene-type inducer, increased selectively 7α-but strongly repressed 2α-, 6β-and 16α-hydroxylations of testosterone in the liver microsomes. To understand this unique phenomenon, the testosterone metabolism by three isozymes (P-452, P-448 L and P-448 H) of cytochrome P-450 purified from Wistar rats treated with PenCB was studied in a reconstituted system. For comparison 4 other iozymes (P-451 I, P-451 II, P-450 II and P-450 III) of cytochrome P-450 from untreated and phenobarbital-treated rats were also studied. In addition, the contribution of cytochrome P-450's to testosterone hydroxylation was ecamined by an immune complex inhibition of the activity and by a determination of the individual cytochrome P-450 in microsomes using antibodies. In the reconstituted system, 7α-hydroxylation of testosterone was catalyzed almost exclusively by P-452, with the exception of P-451 I. On the other hand, the 6β- hydroxylation was catalyzed by most of the cytochrome P-450's tested at considerably lower rates. Among the seven forms, P451 II was the most effective catalyst for 2α- and 16α-hydroxylations, with equally high turnover numbers, while other forms showed only low or no activity for either or both hydroxylations. The microsomal activity of 7α- hydroxylation in PenCB-treated rats was inhibited almost completely by anti-P-452. A partial inhibition of the 16α-hydroxylation was achieved by anti-P-451 II and anti-P-452 while the 6β-hydroxylation was insensitive to anti-P-451 II but slightly sensitive to anti-P-452. The activity of 2α-hydroxylation was not detected in the liver microsomes from PenCB-treated rats. Immunochemical quantitation showed that in the microsomes from PenCB-treated rats, P-451 II, P-452, P-448 L and P-448 H accounted for 4.1, 3.6, 31.6 and 62.8%, respectively, of the total cytochrome P-450 (2.69 nmol/mg protein). On the other hand, the microsomal cytochrome P-450 in untreated rat livers (0.83 nmol/mg protein) consisted of 62.7% as P-451 II, less than 1% as P-452 and the remainder as P-451 I and other unknown forms. The results indicate that the unique change of the testosterone metabolism caused by PenCB-treatment might be due to both the considerable increase of P-452 as shown by 7α-hydroxylase and the marked decreases of other constitutive forms such as P-451 II and unknown form (s) involved in the 2α-, 6β- and 16α-hydroxy1ations.

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Immunoglobulin E (IgE) antibody production against Dermatophagoides farinae extract (mite antigen) was studied in female BALB/c mice. When mice were immunized with mite antigen and aluminium hydroxide gel (alum) intraperitoneally at intervals of 30 d, good primary, secondary and tertiary IgE antibody responses were observed. In the absence of adjubant, a subcutaneous injection of mite antigen failed to induce the primary IgE antibody response. However, good IgE antibody responses were observed after the secondary immunization given 30 d after the primary immunization. Furthermore, 5 weekly injections of mite antigen alone also induced the IgE antibody production. Intranasal administrations of mite antigen alone also induced the IgE antibody production in mice. Two exposures to mite antigen, intranasally, were sufficient for eliciting low IgE antibody production. The response was significantly potentiated by the administration of islet-activating protein obtained from cculture fluids of Bordetella pertussis. These results indicate that the intranasal administration of mite antigen is very effective for eliciting the IgE antibody production.

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We studied the effects of propranolol on infarct size and hemodynamic impairment induced by 24 h-coronary ligation. The myocardial infarction produced by the left circumflex coronary artery ligation was more consistent than that induced by the left anterior descending coronary artery ligation, suggesting that the former is a more appropriate experimental model for pharmacological evaluations. Oral treatment with propranolol, 3-30 mg/kg, reduced infarct size and reduced the elevated left ventricular end-diastolic pressure, which was shown to be most closely related with infarct size, in dogs with circumflex coronary artery ligation extending over 24 h. In conclusion, our results indicate that propranolol protects against the enlargement of infarct size and improves the impaired hemodynamics observed in myocardial infarcted dogs with occlusions extending over 24 h, as well as in dogs with less than 24 h-occlusions reported by numerous investigators.

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Aqueous extracts (macromolecule fractions in particulr) of 25 species of well-known marine animals were tested for their antitumor activity against transplanted sarcoma 180 solid from in ICR mice. All of the macromolecule fractions from the extracts of animals in the shellfish category except that of Mytilus edulis inhibited the growth of sarcoma 180. The use of aqueous extracts from Strongylocentrotus nudus, Halocynthia hilgendorfi f. ritteri, Styela plicata, Ecteinascidia turbinata, and Megabalanus rosa also revealed relatively high inhibition ratios of over 60%.

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Enkephalin analogues of tyrosyl group on the N-terminal and Phe-ol or phenyl-ethylamine (PHA) group on the C-terminal which are connected with different chain length were tested for their activities in vitro and in vivo. The inhibitory effect of the synthetic peptides on the electrically evoked contractions of isolated longitudinal muscle strips of guinea pig ileum were weaker than that of morphine or Leu-enkephalin and tended to decrease by increasing the number of methylene group, -(CH₂)_n^-, n=1-5, between N-and C-terminal. Compounds with PHA group on the C-terminal, n=4 and 5, showed the least activity. The effect of peptides with short chains of methylene groups, n=1 or 2, and Phe-ol on the C-terminal were antagonized by naloxone but others were insensitive to naloxone. Differing from in vitro activity, compounds with PHA on the C-terminal with a chain of 4 methylene groups produced short lasting analgesia after i.c.v. injection as well as the compounds with Phe-ol on the C-terminal and 1 or 2 methylene groups. The analgesic effect of these compounds were completely antagonized by naloxone. At a high i.c.v. dose all the synthetic peptides, except the one with PHA on the C-terminal with a chain of 4 methylene group, produced convulsions and/or ipsilateral rotation to the injection side. These behavioral effects were not antagonized by naloxone. Thus, minor alterations in the chemical structure of enkephalin analogues resulted in the changes of their receptor selectivity and potencies in vitro and in vivo.

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The biliary excretions of latamoxef and N-methyltetrazolethiol (NMTT) were studied in patients with T-tubes inserted in their common bile ducts, and in bile fistulated male rats. The highest concentrations of latamoxef and NMTT in 6 patients with cholelithiasis were obtained 1-2 h after intravenous injection of a single 1-g dose, and the mean peak values were 66.2 and 0.85 μg/ml, respectively. The values in patients with gallbladder carcinoma or pancreas head carcinoma were much lower than those with cholelithiasis. The biliary excretions of latamoxef and NMTT in rats were much higher and faster than in humans, with the highest levels being obtained within 30 min after injection. About 20% of the injected dose was recovered as latamoxef and 4% as decomposed materials in 2.5 h after injection. Latamoxef was not decomposed in human or rat bile when kept at-20°C for 4 weeks if the pH was adjusted to 6 ; some decomposition occurred (10-20%) if the pH was not adjusted.

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