The effect of platelet-activating factor (PAF) on histamine release from the peritoneal mast cells of male guinea pigs at 4 weeks of age and one week of age (weaning) was investigated. PAF as well as compound 48/80 and concanavalin A were not found to release histamine from the mast cells of either age of guinea pigs. On the other hand, Ca²⁺ ionophore A23187 showed a significant, concentration-dependent histamine release from the mast cells obtained from guinea pigs of either age group. PAF (3×10^-7-3×10^-6 g/ml) significantly inhibited the histamine release induced by Ca²⁺ ionophore A23187 from the mast cells of guinea pigs at one week of age, but not from those of the older ones. Such an inhibition was not seen with lyso-PAF in either age group. CV-3988, a PAF antagonist, neutralized the inhibitory effect of PAF on the A23187-induced histamine release from the mast cells of guinea pigs at one week of age. These results indicate that PAF does not have a histamine-liberating action on guinea pig peritoneal mast cells, and that PAF inhibits the effect of A23187 on histamine release from mast cells through activation of PAF receptor in guinea pigs at one week of age.

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Intraperitoneally administered metoclopramide (MCP) markedly increased the serum concentration of imipramine (IPM) soon after oral administration. In contrast, intraperitoneally administered propantheline (PPT) slightly decreased the serum concentration. The administration of these two drugs had no significant effect on the serum concentration of IPM after intravenous bolus administration. It was concluded from pharmacokinetic analyses and gastric emptying experiments that the administration of MCP markedly increased the rate of IPM absorption by counteracting the gastric emptying delayed by IPM, but that the administration of PPT slightly decreased the rate of IPM absorption by strengthening the gastric emptying also delayed by IPM.

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Filmy local drug delivery systems (LDDSs) were administered to periodontal pockets in beagles with induced periodontitis, and the in vivo-in vitro correlation of drug release from the LDDS and changes in the clindamycin (CLDM) concentration in the periodontal pocket fluid were studied. The in vitro drug release rate from the LDDS was determined by the dissolution study, without agitation, using phosphate buffer as the dissolution medium at 37°C, and the in vivo drug release rate was determined according to the decrease in the drug load remaining in the LDDS after administration in periodontal pockets. The in vivo drug release rate from LDDSs was lower than the in vitro rate determined by the dissolution study, but the two rates showed a correlation in LDDSs that released drugs by diffusion. Therefore, the in vivo drug release rate was considered to be estimated from the results of the in vitro dissolution study. Changes in the drug concentration in the periodontal pocket fluid after administration of LDDS were dependent on the drug release properties of the LDDS. Also, when CLDM was administered as an aqueous solution in periodontal pockets, its concentration in the periodontal pocket fluid decreased according to a pseudo first-order equation. Therefore, the concentration in the periodontal pocket fluid after administration of a LDDS is considered to be simulated by the one compartment model based on a pseudo first-order elimination process.

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Intestinal absorption mechanism of fosfomycin (FOM), a water-soluble and small molecular antibiotic, at the clinical dose level was examined by both in situ single-pass perfusion technique of rat small intestine and oral administration in rat in vivo. Analyzing the luminal concentrationdependence of FOM absorption rates in situ by the equation composed of two terms of carrier transport of Michaelis-Menten type and simple-diffusion, apparent Michaelis constant (K₁), maximal transport velocity (J_max), and first-order diffusive absorption clearance (K_d) were 1.13 mM, 2.54 nmol/min/cm length, and 0.551μl/min/cm length, respectively. At the low FOM concentration in the lumen (0.1 mM), its absorption was reduced to about 60% of the control by inorganic phosphate ion at 1.0 mM in the same manner as the uptake in brush border membrane vesicles of rat small intestine (BBMVs) in vitro. Both the glycol form of FOM at 10 mM, the hydrolyzed metabolite of FOM in the stomach juice, and FOM itself at 10 mM reduced FOM absorption by about 50%, indicating the metabolite to be transported by the same carriers as those of FOM. At the higher FOM concentration (5 mM), its absorption was not reduced by any inhibitor described above. No inhibitory effect of 50 mM phosphate ion on FOM absorption following the oral dosing of 20 mg/kg FOM was found. It was concluded that FOM absorption at the clinical dose (10-20 mg/kg) is barely inhibited by the carrier-mediated system via phosphate transport system observed in the in vitro BBMVs.

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Inhibitory effects of various histamine receptor-blocking agents including antiallergic agents on metabolic activations of neutrophils were examined by measuring leukotrienes (C₄, D₄ and E₄) formation, arachidonic acid release and superoxide generation. The stimulation of neutrophils by calcium ionophore (A23187) causes the production of leukotrienes concomitantly with the release of arachidonic acid from the cells and these were effectively diminished with a variety of antihistaminic agents. Almost all the histamine H₁ receptor-blocking drugs studied here showed as inhibitors of the metabolic activations of neutrophils, although the degree was dependent on the drug concentrations. The order of potency of the inhibitory effects on the arachidonic acid release were : homochlorcyclizine, clemastine, and azelastine (IC₅₀<20μM) > oxatomide (IC₅₀<60μM) and diphenylpyraline >triprolidine, meclizine, diphenhydramine (IC₅₀>100μM). The superoxide generation from neutrophils activated by phorbol 12-myristate 13-acetate was also effectively inhibited by these agents, but generally lower concentrations were required to obtain the same degrees of effects. These results indicated that some of the histamine H₁ receptor-blocking drugs, such as clemastine and homochlorcyclizine, may act as inhibitors of formation of leukotrienes at the locus of inflammation.

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The present study was designed to determine the regional hemodynamic effects of prolonged β-adrenergic receptor inhibition in conscious stroke-prone spontaneously hypertensive rats (SHRSP) using a radioactive microsphere method. When the regional blood flow was compared between 10 and 30 weeks of age, the age-related changes in organ blood flow were observed in several organs, i.e., the reduction of flow rate in kidney, adrenal gland and intestines. The reduction of flow rate in these organs contributes strongly to the age-related rise of total peripheral resistance. Carteolol, a β-adrenoceptor antagonist, was given at a dose of 10 mg/kg/d from 10 to 30 weeks of age. These animals gained more weight than the untreated control SHRSPs, and heart rate was reduced significantly. Blood pressure was not affected. However, the prolonged treatment with carteolol prevented the age-related reduction of the blood flow rate in the kidney, adrenal gland and intestines. Thus, our findings indicate that carteolol had appreciable and beneficial effects on the maintenance of flow rates in the above organs of SHRSP without any change in blood pressure.

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The opioid activity and the selectivity for opioid receptor (subtypes) of newly synthesized fluorinated enkephalin (Enk) analogues, [2R, 4R], [2R, 4S], [2S, 4S] and [2S, 4R] trifluoro-Leu⁵-Enk (KKF-31, 32, 33 and 34) were investigated. The inhibitory effect of KKF-compounds on the electrically induced contractions of guinea-pig ileum (GPI) and mouse vas deferens (MVD) were dosedependent but relatively lower than that of L-Leu⁵-Enk, except that KKF-34 was rather slightly more potent than L-Leu⁵-Enk in MVD preparations. In GPI preparations, the pA₂ values of naloxone for these compounds were higher than those of naltrindole while the values of naltrindole for KKF-compound were higher than those of naloxone in MVD preparations. Intracerebroventricular KKF-31 and KKF-32 at doses of 20 and 10 nmol/mouse, respectively, produced analgesia comparable to 0.1 nmol Tyr-D-Arg-Phe-Lys-NH₂ and 100 nmol Tyr-D-Thr-Gly-Phe-Leu-Thr; however, neither KKF-33 nor 34 produced analgesia up to the doses of 100 nmol/mouse. Both naloxone, 1 mg/kg, i.p., and naltrindole, 10 mg/kg, i.p., antagonized KKF-31- and KKF-32-induced analgesia. The results suggest that the introduction of trifluoromethyl group in Leu⁵ results in the alternation of the opioid activity and receptor selectivity. Although KKF-33 and KKF-34 possessed a more potent in vitro inhibitory effect than KKF-31 and KKF-32, mediated through μ- and δ-opioid receptors in both preparations, they did not show any appreciable analgesic effect. KKF-31 and KKF-32 produce naloxone-and naltrindole-reversible analgesia irrespective of in vitro μ- and δ-opioid activity.

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An in vitro screening test for drugs that decrease blood viscosity was carried out on many pharmacologically active compounds such as Ca-antagonists, α-antagonists, β-antagonists, α, β-antagonists, α-agonists, β-agonists, α, β-agonists, autacoids and others. The results revealed that various types of microcirculatory-improving drugs, vasodilators, and antagonists decreased blood viscosity, while the agonists and autacoids had no significant effect. These findings suggest that this assay is useful for screening compounds related to hemorheology.

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