The relationship between dissolution behaviour and plasma concentration after administration of a sustained-release preparation containing phenylpropanolamine hydrochloride was studied in 11 male volunteers. The testing for dissolution was carried out using the JP X rotating basket procedure, and human plasma samples were assayed for phenylpropanolamine hydrochloride by a specific high-performance liquid chromatography. Three hours after dosing, the mean peak plasma concentration was 104.1 ng/ml and the plasma concentration declined with a half-life of 4.85 h. The time course of plasma and dissolution data were analyzed by a non-linear least squares curve fitting method to compare in vivo and in vitro release behaviour. Plasma concentration changes of phenylpropanolamine hydrochloride were correlated with in vitro release behaviour of the sustained-release preparation.

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Seven kinds of suppositories were constructed with oleaginous base materials (Witepsol H-15 (H-15) and E-85 (E-85)) : a conventional type suppository containing valproic acid (VPA) mixed with E-85 (I), a conventional type suppository containing sodium salt of VPA (sodium valproate) (S-VPA) mixed with H-15 (II), hollow type suppositories containing VPA in the forms of oily liquid (free acid) (III), macrogol 1000 or 6000 mixture (IV or V), powder (S-VPA) (VI) and aqueous solution (S-VPA was dissolved in 0.9% NaCl solution) (VII) in each cavity. The content of VPA in type I was decreased considerably by volatility and type II was found to be hygroscopic. Therefore conventional type suppositories containing VPA or S-VPA were not of practical use, whereas III and VI prevented volatility of VPA and minimized the hygroscopic property of S-VPA. Plasma concentration of VPA was measured in rabbits after rectal administrations of III, IV, VI and VII. By using VI, the highest values of the mean of the peak plasma VPA concentration (C_max) (49.8±2.6 μg/ml) and the mean of the area under the plasma concentration-time curve (AUC) (90.0±3.7 h·μg/ml) were obtained. The C_max and the AUC estimated after administration of VII were not significantly different from those of VI. The C_max and the AUC were lower with III than with IV, VI or VII but the extent of bioavailability (EBA) of III was about 80%. These data on bioavailability suggested that VPA was efficiently absorbed into the rectum of rabbits after the administration of hollow type suppositories. Thus, it was concluded that hollow type suppositories containing VPA or S-VPA can be produced as practical preparations for use.

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In the presence of ribothymidine, the uptake of 5-fluorouracil (5-FU) was enhanced in Ehrlich ascites carcinoma cells in vitro, and was efficiently converted to FU-nucleotides. In these cells, almost all ribothymidine was found to be converted to thymine by, presumably, uridine phosphorylase. The enhanced uptake of 5-FU and its efficient conversion to FU-nucleotides were also observed in Ehrlich ascites carcinoma of ribothymidine-coadministered mice. The radioactivity of 5-FU-¹⁴C in the carcinoma cells, which was detected mainly in the acid-soluble fraction immediately after the administration and then shifted to the ribonucleic acid fraction, was approximately 2-fold higher in the ribothymidine-coadministered group than in the control group. On the other hand, ribothymidine-¹⁴C was also taken up by the carcinoma cells and an appreciable protion of its radioactivity appeared in the thymine fraction. Thymine produced from ribothymidine-¹⁴C was also detected in the extracellular ascitic fluid. The conversion of ribothymidine to thymine was assumed to be catalyzed by uridine phosphorylase, suggesting that ribose 1-phosphate was coproduced and served as a ribose donor for 5-FU. These results suggest that ribothymidine may act as a ribose donor for 5-FU to form FU-nucleotides via 5-fluorouridine in carcinoma cells, resulting in the potentiation of 5-FU activity.

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This study was designed to test whether phencyclidine (PCP)-induced turning behavior and locomotor stimulation result from the action of this drug on functionally different neuronal systems and different sites of the brain. PCP produced turning behavior towards the drug injection side with unilateral injection of PCP (50-100μg) into the globus pallidus, but not the nucleus accumbens and the caudate nucleus. This turning behavior was strongly attenuated by a gamma-aminobutylic acid (GABA) antagonist, bicuculline, and by pimozide which reduces dopaminergic transmission in non-injection sites. Turning behavior induced by intraperitoneal injection of PCP (7.5 mg/kg) was enhanced by a GABA agonist, baclofen, and attenuated by GABA antagonists (bicuculline, picrotoxin). On the other hand, PCP produced significant locomotor stimulation, sniffing, rearing and forward locomotion with unilateral injection of 25-100μg into the nucleus accumbens and the caudate nucleus. These behaviors were strongly antagonized by intraperitoneal injection of pimozide. The locomotor stimulation induced by intraperitoneal injection of PCP (5 mg/kg) was markedly enhanced by a small dose of methamphetamine and, by contrast, attenuated by reserpine, 6-hydroxydopamine, haloperidol, pimozide and a low dose of apomorphine which inhibits the release of dopamine by the stimulation of presynaptic receptors. These results suggest that PCP-induced turning behavior may be produced through stimulation of GABAergic transmission in the grobus pallidus, although PCP-induced locomotor stimulation, sniffing, rearing and forward locomotion may be produced by increasing dopaminergic transmission in the nucleus accumbens and the caudate nucleus.

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This study was designed to determine the action sites of phencyclidine (PCP) involved in the development of behaviors such as head-weaving, immobility, turning and backpedalling in relation to dopaminergic and serotonergic neuronal functions. Injection of PCP into the caudate nucleus or prefrontal cortex dose-dependently produced head-weaving, although the injection of PCP into the nucleus accumbens failed to produce head-weaving. The intensity of head-weaving induced by injection of PCP into the prefrontal cortex was relatively high when compared to that induced by injection of PCP into the caudate nucleus or lateral ventricle. Pretreatment with p-chlorophenylalanine (300 mg/kg), a serotonin (5-HT) synthesis inhibitor, attenuated head-weaving induced by injection of PCP into the prefrontal cortex. Injection of PCP (50-100μg) into the prefrontal cortex also produced immobility for 5 min post-injection. Rats pretreated with pimozide (1 mg/kg), a dopamine (DA) antagonist, also produced immobility after the injection of PCP into the prefrontal cortex and this effect was attenuated by pretreatment with ritanserin, a 5-HT₂ receptor antagonist. On the other hand, pretreatment with methamphetamine attenuated PCP (5 and 7.5 mg/kg)-induced turning and backpedalling but not head-weaving. Pretreatment with large doses of apomorphine, a DA agonist, also greatly attenuated PCP (7.5 mg/kg)-induced behaviors, i.e. head-weaving, turning and backpedalling. These effects of DA agonists were prevented by haloperidol (0.25 mg/kg), a DA antagonist. These results suggest that PCP-induced turning and backpedalling may be mediated by reducing dopaminergic transmission, although PCP-induced head-weaving and immobility may be produced by increasing serotonergic transmission in the prefrontal cortex.

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Using the basic equations for heat balance, a compartment model was constructed to simulate the physiological responses to heat and cold in rats. The model predicted steadystate situations of rectal temperature, skin temperature (pelt and tail), metabolic rate and evaporative heat loss.

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The binding property of some tertiary amines (chlorpromazine, promethazine and imipramine) and quaternary ammonium compounds (propantheline, mepenzolate and butylscopolamine) for gastric mucin was investigated. All tertiary amines tested bound gastric mucin to varying extents, and the binding of chlorpromazine was especially strong. Moreover, the absorption behaviors of chlorpromazine in rat intestinal loops was significantly inhibited in the presence of gastric mucin. On the contrary, all quaternary ammonium compounds tested did not bind gastric mucin and the absorption of propantheline was not affected in the presence of gastric mucin. These results suggested that gastrointestinal mucin produced a significant effect on the bioavailability of these tertiary amines after oral administration.

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Previous methods such as equilibrium dialysis to measure chinoform binding to human serum albumin are flawed with problems due to the drug's poor solubility in neutral aqueous solutions and its strong adsorption onto the surfaces of dialysis membrane and other apparatus. Accordingly, we adopted a previously reported improved partition equilibrium method to keep off such difficulties, and developed additionally a rapid method using oil-wells. Both of these methods were used in this study. The equilibration of both partition and binding was attained after 6 h by the standard method and after 2 h by the rapid method. Two binding sites were found on the albumin molecule. One had an extremely large affinity constant of 10⁸ M^-1 and the other had a moderate one of 10⁶ M^-1. These values obtained with both methods agreed well and were sufficiently reproducible. The bound percentage of chinoform in serum was estimated at 99.999% under the condition where chinoform reveals its nervous toxicity. The binding constant had a maximum at pH 7.6, the physiological pH of serum. The pH profile suggested the participation of a histidine residue in the binding site. The inhibition experiment with palmitic acid revealed that the first binding site of chinoform was not identical with that of palmitic acid. The present method is applicable to analyses of protein binding by other drugs showing similar physicochemical properties as chinoform.

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The effects of sodium-(E)-3-(4-(3-pyridylmethyl) phenyl)-2-methyl propenoate (OKY-1581) and (E)-3-(4-(imidazolylmethyl)phenyl)-2-propenoic acid (OKY-046), potent inhibitors to thromboxane A₂ synthetase, on peroxisomal β-oxidation and on lipid levels of liver and serum in the rat were studied. When the animals were administered with OKY-1581 at the dose levels of 100 and 500 mg/kg body weight for 2 weeks, the activity of peroxisomal β-oxidation increased 2.2-and 6.3-fold respectively. Catalase activity increased 1.3-fold, whereas D-amino acid oxidase (DAAO) and urate oxidase activities did not change. Carnitine acetyltransferase and carnitine palmitoyltransferase activities also increased 2.2- - 4.1-fold and 2.7- - 4.2-fold respectively. These changes of the enzymes related to lipid metabolism were also confirmed by the results of a cell fractionation study. Moreover, the induction of peroxisome proliferation-associated polypeptide having a molecular weight of 80000, which is a bifunctional enzyme in the peroxisomal β-oxidation system was also observed electrophoretically in the light mitochondrial fraction of the liver of OKY-1581-treated rat. The contents of triglyceride and cholesterol in the serum decreased. These results indicated that the action of OKY-1581 in enhancing hepatic peroxisomaloxidation is similar to that of a potent hypolipidemic peroxisome proliferator such as clofibrate. On the other hand, differing from OKY-1581, OKY-046 at the dose level of 500 mg/kg for 2 weeks showed no effect on serum and liver lipid levels and on the activities of the peroxisomal enzymes, including a cyanide-insensitive fatty acyl-CoA oxidizing system and carnitine acetyl transferase.

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In order to clarify the central mechanism of clonidine (CL)-induced sexual dysfunction such as erectile and ejaculatory disturbances, we examined the effects of intracerebroventricularly (i.c.v.) administered CL on erection and ejaculation in male dogs. CL (0.5-5μg/kg) produced a dose-related inhibition of ejaculation but not significant inhibition of erection by the manual stimulation of the penis. Sperm was not found in the urine drawn from the urinary bladder, suggesting that the inhibitory effect of CL on ejaculation was not due to retrograde ejaculation. The ejaculatory disturbance elicited by CL (5μg/kg) was antagonized by an α₂-adrenoceptor antagonist, yohimbine (1-10μg/kg, i.c.v.) in a dose-related manner. In contrast to the effect of yohimbine, it was unaffected by an α₁-adrenoceptor antagonist, prazosin (3 and 10μg/kg, i.c.v.). These results indicate that i.c.v. administered CL may selectively inhibit the ejaculatory response, which is presumably mediated through the stimulation of α₂-adrenoceptors.

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The mutagenicity of 2-hydroxylamino-4-nitrotoluene (2HA4NT), 4-hydroxylamino-2-nitrotoluene (4HA2NT), 2-hydroxylamino-6-nitrotoluene (2HA6NT) or 4-acetylamino-2-hydroxylaminotoluene (4AA2HAT) towards Salmonella typhimurium strains TA98 and TA100 was investigated in the absence and presence of uridine-5'-diphosphoglucuronic acid (UDPGA), acetyl CoA or 3'-phosphoadenosine-5'-phosphosulfate (PAPS) systems, or S9 mix. None of the hydroxylaminonitrotoluenes (2HA4NT, 4HA2NT or 2HA6NT) were mutagenic in both strains while 4AA2HAT was a base-pair substitution mutagen in the UDPGA and PAPS systems. The indirect mutagenic activity was markedly decreased by omission of microsomal fraction (MCF) or UDPGA from the UDPGA system and by addition of β-glucuronidase to the system. Similarly, the mutagenic activity was markedly decreased either when 105000×g supernatant fluid (S105), adenosine triphosphate (ATP) or Na₂SO₄ was omitted from the PAPS system or when pentachlorophenol (PCP) or aryl sulphatase was added to the system. Moreover, the mutagenic activity in either system was markedly decreased by the addition of glutathione (GSH). These results suggested that two esterifications with glucuronic acid and sulfuric acid may play an important role in the appearance of mutagenic activity of 4AA2HAT.

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