The writhing reaction in mice induced by kaolin, a factor XII activator, was studied. An intraperitoneal injection of kaolin clearly induced a writhing reaction in a dose-dependent fashion, and the reaction disappeared about 10-15 min later. The writhing reaction reached a peak at 5-10 min after the injection of kaolin (0.5 ml/mouse, i.p. ; 5 mg/ml saline). A simultaneous intraperitoneal injection of soybean trypsin inhibitor (SBTI, 2.5 mg/mouse) almost completely suppressed the writhing reaction caused by kaolin (2.5 mg/mouse) for the first 10 min. The kaolin-induced writhing reaction was markedly potentiated by a simultaneous intraperitoneal injection of captopril (50μg/mouse). At 60 min after kaolin injection during the disappearance of the writhing reaction, the reaction reappeared when captopril was injected, but reactions observed at this later stage were completely blocked by SBTI. Indomethacin, ibuprofen and alminoprofen inhibited the writhing reaction dose-dependently. Kaolin thus induces a clear and reproducible writhing reaction, which might be mainly dependent on the action of bradykinin via activation of factor XII, and should prove to be a simple and convenient model of bradykinin-induced pain for the assessment of analgesic actions.

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Salivary excretion profiles of 5-fluorouracil (5-FU) were investigated following simultaneous bolus intravenous injection of a loading dose and constant-rate intravenous infusion of a maintenance dose of at one of three dose levels in rats. By stimulating salivation with pilocarpine infused intravenously, mandibular (M) and parotid (Pr) saliva samples were periodically collected separately via cannulas inserted into the ducts. Simultaneously, salivary pH and salivary flow rate were determined. (1) There was a good correlation between plasma concentration and each of the saliva concentrations of 5-FU with regard to the pooled data of the three doses (p<0.01). (2) A gland type difference between M and Pr in the saliva/plasma concentration ratio (S/P ratio) of 5-FU was observed. This difference seemed to result from that in salivary pH. These findings were similar to the results following bolus intravenous administration of 5-FU in rats. (3) The fluctuations of the S/P ratio and salivary clearance of 5-FU were smaller than those following the bolus intravenous administration. (4) The S/P ratio and salivary clearance were larger at higher dose and higher plasma concentration of 5-FU. It was confirmed that non-linear kinetics might be involved in the salivary excretion of 5-FU in rats, and it was speculated that 5-FU excreted into primary saliva might be reabsorbed partly through some saturable process.

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The metabolism and excretion of trimethadione (TMO) following an oral dose of 4 mg/kg has been examined in patients with percutaneous transhepatic biliary drainage (PTBD) and renal dysfunction. Biliary excretion as the total amount of TMO and its metabolite, dimethadione (DMO) was 2.0% of the dose during 0 to 48 h after TMO administration in patients with PTBD. Total urinary excretion (0-48 h) was 2.8% and 3.0% of the dose in healthy volunteers and patients with renal dysfunction, respectively. The serum DMO/TMO ratio at 4 h after oral dosing in patients of PTBD and renal dysfunction was not significantly changed in comparison with the ratio reported previously in healthy volunteers. The elimination half-life of TMO was also not altered in patients with PTBD in comparison with that reported previously in volunteers. These results suggests that metabolism and urinary and biliary excretion of TMO are not changed in patients with PTBD and renal dysfunction.

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7-Ethenyloxycoumarin (7-vinyloxycoumarin, VOC) was metabolized by rat liver microsomes in the presence of a reduced nicotinamide adenine dinucleotide phosphate-generating system to 7-hydroxycoumarin (HOC) and glycolaldehyde via the unstable epoxide, 7-(epoxyethoxy) coumarin, as an obligatory intermediate which had a half life of 5.4 min in 0.1 M phosphate buffer, pH 7.4, at 37°C. The epoxide of VOC accumulated in the microsomal incubation mixture in the presence of the epoxide hydrolase inhibitor, 3, 3, 3-trichloropropene 1, 2-oxide, was isolated and identified. HOC and glycolaldehyde were auto-decomposition products of the putative highly unstable intermediate, 7-(1', 2'-dihydroxyethoxy) coumarin, mostly formed by microsomal epoxide hydrolase from the epoxide. Direct fluorophotometry of HOC made it possible to determine epoxidizing activities of very small quantities of the microsomes from untreated rat liver (&ge;5μg protein). VOC was epoxidizied by rat liver microsomal cytochrome P-450, inducible by 3-methylcholanthrene (3-MC) and phenobarbital (PB), and the microsomal epoxidation reactions were inhibited by IgG preparations raised against the major cytochrome P-450 components isolated from 3-MC and PB-pretreated rat liver microsomes. In the untreated, 3-MC- and PB-pretreated rat liver microsomes, at least two monooxygenase components with different affinity were strongly suggested by a kinetic study, carried out using the antibodies, to be involved in the epoxidation of VOC.

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Human serum immunoglobulin G light chain (Fr. I-L), which was reduced and carboxamidemethylated, showed no effect on formyl-methionyl-leucyl-phenylalanine (FMLP)-induced chemotaxis nor on phagocytosis of yeasts when directly added to guinea pig polymorphonuclear leukocytes (PMNs). However, intravenously administered Fr. I-L inhibited emigration of leukocytes into the peritoneal cavity and promoted phagocytosis of yeasts in a yeast-induced peritonitis model in mice. Moreover, Fr. I-L reduced FMLP-induced chemiluminescence (CL) from PMNs. These facts indicated that the anti-inflammatory action of Fr. I-L was caused by inhibiting emigration of leukocytes into the injured site and scavenging superoxide radicals from the cells.

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The effects of ten 1-substituted 2-n-butyl-5, 6-methylenedioxyindenes on mice and guinea pigs were investigated for their allergic reactions in the development of a new anti-allergic drug. Antiallergic effects were determined by testing the effect of agents on passive cutaneous anaphylaxis (PCA) in mice and Schultz-Dale reaction in guinea pig tracheal muscle. 2-Butyl-1-[N-methyl-N-[2-(N', N'-dimethylamino) ethyl] amino]-5, 6-methylenedioxyindene (1) indicated the most potent anti-allergic activity. Since our previous experiments indicated that 2-n-butyl 3-dimethyl amino-5, 6-methylenedioxyindene (MDI-A) and its derivatives showed a potent anti-allergic effect by interfering with the calcium (Ca) movement in the allergic reaction in guinea pigs, the effect of 1 and MDI-A on allergic reaction and Ca-induced contraction of tracheal muscle in these animals were compared. The present data indicate the superiority of 1 in both reactions.

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The comparative effects of antihypertensive agents, quinazoline or quinazolinedione residues (prazosin, bunazosin, terazosin, SGB-1534, and ketanserin), on the binding of [³H] prazosin, [³H] p-aminoclonidine and [³H] dihydroalprenolol ([³H] DHA) to α₁, α₂-, and β-adrenoceptors in the rat orain were examined using radioligand binding assay methods. pA₂ values were also obtained in the isolated rat aorta (α₁-adrenoceptor) using phenylephrine as an agonist. A strong inhibition by these drugs of [³H] prazosin binding to α₁-adrenoceptors was observed, while the inhibition of [³H] DHA binding to β-adrenoceptors and [³H] p-aminoclonidine binding to α₂-adrenoceptor was found to be very weak. The rank order of antagonistic potencies of these drugs against the α₁-adrenergic receptors was determined by inhibition constants (K_i) with SGB-1534=prazosin=bunazosin > terazosin > ketanserin. The pA₂ value of these drugs, in contrast, had prazosin with higher pA₂ value than that of SGB-1534. From these two different types of experiments, it was clear that these drugs antagonized α₁-adrenoceptors even in the central nervous system, and the side chains bound to quinazoline and quinazolinedione residues may play an important role in the antagonistic potencies for α₁-adrenoceptors in the central nervous system as in the peripheral tissues.

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The pharmacological properties of 8-hexyloxy-3-(1H-tetrazol-5-yl)-2H-chromen-2-one, KP-136 were compared with those of an antiallergic medicament, disodium cromoglycate (DSCG) in experimental asthma models. KP-136 (0.125-1 mg/kg i.v., 0.5-2 mg/kg p.o.) produced a dosedependent inhibition to allergic asthma of rats and was more potent than DSCG (1-5 mg/kg i.v.). KP-136 (1 mg/kg, i.v.) was also effective on allergic asthma of guinea pigs, although DSCG was ineffective even at a high dose of 50 mg/kg (i.v.). In rats, both KP-136 and DSCG significantly blocked the reduction of histamine content of the trachea after allergic asthma and inhibited the antigeninduced histamine release from lung fragments (KP-136 0.5μg/ml, DSCG 50μg/ml) and peritoneal exudate cells (KP-136 0.1μg/ml, DSCG 10μg/ml). KP-136 also showed relaxation activity for isolated guinea pig trachea at high doses of 2 and 5μg/ml. The major mechanism of the potent antiasthmatic activity of KP-136 is postulated to be the blocking of bronchoactive mediator release. The relaxation of smooth muscle is also suggested to be an additive mechanism.

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The unidirectional influx of benzylpenicillin through the bloodbrain barrier was examined with an in situ rat brain perfusion technique using purified [³H] benzylpenicillin. The major transport system of benzylpenicillin through the blood-brain barrier was via a saturable process with a one-half saturation concentration of approximately 8-30μM. This transport system was significantly inhibited by probenecid (100μM) and ceftriaxone (2 mM), indicating that the transport system may be shared by some organic anions including third generation cephalosporin antibiotics. These findings suggest that concomitant administration of β-lactam antibiotics could produce a drug interaction to alter the drug penetration into the central nervous system.

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