In some cardiac muscles made inexcitable by inactivating the fast sodium channels with elevated potassium, it has been shown that several agents, including catecholamines, induce slow electrical responses with concomitant contractions. The response is considered to be carried through the slow Ca²⁺ or Ca²⁺-Na⁺ channels on the basis of several types of experimental evidence. X-537A produced this type of electrical and mechanical responses in papillary muscles from both normal and reserpinized guinea pigs. A beta-adrenergic blocking agent, sotalol, did not modify this X-537A-induced responses. Tyramine, an agent known to release endogenous catecholamines, produced the same mechanical responses in normal papillary muscles, but it did not in those from the reserpinized animals. Therefore, it can be concluded that X-537A does act, at least at relatively high concentrations, on the cardiac plasma membrane to increase the Ca²⁺ permeability, which can be visualized with the aid of the specially designed experiments as described above.

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A phlogistic agent, carrageenin, was injected into preformed subcutaneous air pouch on the back of rats to induce carrageenin-air-pouch inflammation. After 1.0, 2.0, 3.0, 4.0, 8.0, 10, 12, 16, 24, 48 and 72 hours and 5, 7 and 8 days, vascular permeability of the inflammatory tissue was measured with the aid of radioiodinated human serum albumin. The time course study of the vascular permeability indicated the existence of two separate periods in the course of the vascular permeability change, i.e. acute and chronic stages. The acute stage elevation exhibited a sharp peak over the period of 2-8 hours after the carrageenin injection. After exhibiting the sharp peak of the increased vascular permeability, the vascular leakage declined rapidly coming to a level of 1/5 as low as the peak value during the period of 16-24 hours. This low level of the permeability was maintained for several hours, and then it turned upwards once again increasing slowly along with the formation of granulation tissues. The peak of the permeability in this chronic, proliferative, stage of the inflammation was attained around day 7. Between the acute stage and the chronic, proliferative, stage there was a marked difference in the sensitivity of leaking blood vessels to a non-steroid anti-inflammatory drug indomethacin. In the acute stage the vascular permeability was inhibited considerably in agreement with the data reported in most literatures of indomethacin, whereas in the chronic, proliferative, stage indomethacin was shown to be almost inert. Underlying mechanisms are discussed with special reference to the role of E type prostaglandins considered in connection with the data of our previous reports.

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All nitrofuran derivatives tested, 3-(5-nitro-2-furyl)-2-(2-furyl) acrylic acid [I], 5-nitro-2-furanacrylic acid [II] and 5-nitro-2-furoic acid [III], and their amide and ester derivatives exhibited the mutagenic and antibacterial activities against Salmonella typhimurium TA 100. The amides and esters of [I] and [III] which were more rapidly reduced by intact Salmonella typhimurium TA 100 cells or milk xanthine oxidase showed apparently stronger mutagenicity than the corresponding carboxylic acids ([I] and [III]) which were less susceptible to the reduction. In the case of [II] and its derivatives, the correlation between the mutagenic activity and the reducibility was also observed, but not so clear as in other groups. Furthermore, antibacterial activities of the nitrofuran derivatives in each group were also well correlated to their reduction rates. However, the nitrofuran derivatives highly susceptible to the enzymatic reduction were not always strong mutagenic and antibacterial agents.

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There was good correlation of lipid peroxidation and covalent binding of acetaminophen (AAP) to liver microsomal protein in mice, guinea pigs and rabbits, but not in rats. By increasing concentrations of EDTA which is an inhibitor of lipid peroxidation, the degree of microsomal lipid peroxidation decreased in mice, guinea pigs, rabbits and rats, and the amount of covalent binding of AAP metabolite to liver microsomal protein increased in mice, guinea pigs and rabbits, but no consistent results were observed in rats. GSH depletion caused by AAP metabolite was increased in accordance with increase in the concentration of EDTA in mice and rats. In rats, the metabolism of AAP increased with increasing concentrations of EDTA and, in contrast to liver microsomes, the radioactivity of enzyme-mediated ¹⁴C-AAP metabolite in liver microsomal lipid was not observed. These results indicated that the decrease in covalent binding for AAP metabolite to liver microsomal protein with increasing concentrations of EDTA was not due to the decrease in the amount of AAP metabolite and the binding of ¹⁴C-AAP metabolite to liver microsomal lipid layer.

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The effect of monoolein-bile salts, sodium glycocholate and sodium taurocholate, mixed micellar solutions on the intestinal absorption of heparin was investigated using the in situ closed loop of the rats. It was observed that these mixed micellar solutions extremely enhanced the absorption of heparin and that the mixed micellar solution prepared with distilled water facilitated the intestinal absorption of heparin more markedly than that prepared with pH 6.5 phosphate buffer solution. This difference between mixed micellar distilled water solution and mixed micellar buffer solution was studied by ultrafiltration, pretreatment with the micellar and mixed micellar solutions, and gut exsorption. Enhanced permeability is discussed from the standpoints of intraluminal interaction between the mixed micelles and heparin molecules, and an alternation in the permeability of the mucosal membrane.

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The pharmacokinetics of p-aminohippurate (PAH) was investigated in rabbits by administering the compound intravenously as a bolus or as constant infusion. PAH was measured in plasma and in urine. Appropriate models are formulated, with the overall model describing PAH disposition consisting of 5 compartments.

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Antitumor activity of 1-hexylcarbamoyl-5-fluorouracil (HCFU) against Lewis lung carcinoma and B16 melanoma by long-term oral administration was examined. HCFU was active against the tumors. Increase in life-span in early Lewis lung carcinoma system at optimal dose by the compound was 100%, while those by 1-(2-tetrahydrofuryl)-5-fluorouracil (FT) and 5-fluorouracil (5FU) were 69 and 33%, respectively. HCFU prevented completely lung metastases of the carcinoma. The potency of HCFU was comparable to that of cyclophosphamide. In advanced Lewis lung carcinoma, HCFU was also markedly active, and the tumor growth at inoculation site was suppressed by the compound, whereas it was slightly suppressed by cyclophosphamide, which was the most active compound as already reported. HCFU was also active against B16 melanoma and increase in life-span at optimal dose was 38%. However, those by FT and 5FU in long-term administration were 26 and 9%, respectively. As a result, HCFU was found to be active not only against rapid growing tumors but against early or advanced slow growing tumors such as Lewis lung carcinoma and B16 melanoma.

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Antigenic properties of three new types of estriol 16-glucuronide-bovine serum albumin (BSA) conjugates in which the steroid hapten was linked to a carrier protein through the C-2 or C-4 position have been investigated. All antibodies elicited by immunization with these antigens showed the high affinity (K_a=1.41×10⁹-3.50×10⁹M^-) and the excellent specificity to estriol 16-glucuronide. No significant cross-reactivity was observed with other glucuronides, sulfates and free steroids except for estriol 17-glucuronide (0.78-1.34%). These antisera appear to be useful for direct radioimmunoassay of estriol 16-glucuronide in biological fluids without prior hydrolysis and chromatographic purification.

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Although the presence of free 2'-hydroxyl groups in both strands of a double-stranded RNA complex has been recognized as one of the major requisites for the interferon inducing activity of double-stranded RNAs, we have found a particular analog of (I)_n·(C)_n, in which the 2'-hydroxyls of the purine strand were replaced by azido groups [(dIz)_n·(C)_n], to be exquisitely effective in inducing interferon. Various other 2'-azido analogs, i.e. (dIz)_n·(brC)_n, (I)_n·(dCz)_n, (dAz)_n·(U)_n, (dAz)_n·(rT)_n and (dAz)_n·(dUz)_n were inactive as inducers of interferon. Thus we come to the conclusion that the interferon inducing system recognizes total threedimensional conformation of the double-stranded RNA.

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