Hydroxypropylcellulose (HPC)-ethylcellulose (EC) microcapsules containing piretanide prepared by a solvent evaporation technique, were evaluated on pharmacokinetic, pharmacodynamic and pharmacological parameters in spontaneously hypertensive rats (SHR). HPC-EC₁₀ (5 : 3) microcapsules showed sustained plasma piretanide levels and almost the same AUC (area under the curve) as compared with piretanide solution. Effect of treatment with the microcapsules (single oral administration per day in doses of 10 and 30 mg/kg) and the solution (double oral administration per day in doses of 5 and 15 mg/kg) was examined for 4 weeks on urine volume and urinary electrolytes excretion and blood pressure. The microcapsules and solution induced dosedependent diuresis throughout the experimental period and a reduction in blood pressure from 2 weeks of the treatment. HPC-EC₁₀ (5 : 3) microcapsules containing piretanide were satisfactory as a sustained-release preparation in the light of the anti hypertensive effect even at a half frequency of daily dosing of the solution.

View full abstract

The blood-brain barrier (BBB) transport of choline was compared between stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar KY rats (WKY). The permeability surface area product (PS) of [³H] choline through the BBB in SHRSP (3.03×10^-3±1.09×10^-3ml/min/g brain) was significantly lower than that in WKY (7.23×10^-3±0.97×10^-3ml/min/g brain) in the presence of respective rat sera. No significant difference in the brain vascular space was indicated from the apparent uptake of [³H] sucrose between SHRSP and WKY. There was no significant difference for the Michaelis constant of choline transport between SHRSP (262±97μM) and WKY (180±32μM). However, the maximum velocity in SHRSP (3.41±1.19 nmol/min/g brain) was 37% lower than in WKY (5.40±0.38 nmol/min/g brain). Brain microdialysis technique was employed to collect the brain interstitial fluid in the rat hippocampus. The concentration of free choline in the brain dialysate in SHRSP was about half of that in WKY, while no significant difference was observed for the plasma concentration of free choline between SHRSP and WKY. In contrast, no significant difference was observed for the transport of D-[³H] glucose, 3-methyl-[³H] D-glucose and [³H]-phenylalanine through the BBB between SHRSP and WKY. Accordingly, the decreased choline concentration in the brain interstitial fluid ascribed to the specific dysfunction of the BBB choline transport has been demonstrated in SHRSP.

View full abstract

A mathematical model to account for the blood-to-plasma distribution of cyclosporin A (CyA) in human blood was derived, and alterations in the blood-to-plasma distribution of CyA under several influencing conditions were examined using this model. The model was derived on the assumption that there are two CyA binding sites in human blood, which exist in plasma and cellular fractions. In the plasma fraction, the CyA binding sites are mainly lipoproteins (LPs), in which CyA exhibits nonsaturable, low affinity binding with LPs independent of drug concentration. In the cellular fraction, the binding site of CyA is the CyA binding protein (CBP), in which CyA shows a specific binding in a temperature dependent, saturable process. The results obtained from simulative studies agreed with previous reports on the blood-to-plasma distribution of CyA, indicating the usefulness of this approach. And also, this model may be used to predetermine individual variations in the blood-to-plasma distribution of the drug in renal transplant patients.

View full abstract

The effects of clonidine on the vagal reflex-induced tracheal constriction have been investigated in anesthetized, paralyzed, and artificially ventilated mongrel dogs. The cervical trachea was transected in situ into two parts. Responses of the tracheal musculature were measured as changes in the intratracheal pressure on an air-filled balloon introduced into the rostral side of the transected trachea. Reflex tracheal constriction was induced by afferent electrical stimulation at the central cut end of the vagus nerve. Drugs were injected or infused close intraarterially (i.a.) into the bilateral cranial thyroid arteries in such a way that each drug was applied just to the rostral trachea. The reflex tracheal constriction was abolished by a close i.a. infusion of 3 μM atropine. The magnitude of the reflex tracheal constriction was slightly reduced by a close i.a. infusion of 10μM clonidine and was significantly reduced by the infusion of clonidine at a concentration of 100 and 300μM. The response to 100μM clonidine was antagonized by a close i.a. infusion of 1μM yohimbine. The tracheal constriction induced by i.a. injection of 5.5 nmol acetylcholine was unaffected by infusion of 10, 100 and 300μM clonidine. The vagal reflex-induced tracheal constriction seems to be inhibited by stimulation of prejunctional α₂-adrenoceptors.

View full abstract

The combination of phenytoin (DPH) and allopurinol is used for the treatment of a neurological disease. However, interactions between DHP and allopurinol and the mechanism are little known. The repeated dosing of allopurinol at higher doses (20 and 50 mg/kg) significantly retarded the elimination of DPH from the circulation and dramatically decreased the urinary excretion of p-hydroxyphenytoin (HPPH), a major metabolite of DPH. However, a single administration of allopurinol (10 or 50 mg/kg) did not give rise to these effects. Allopurinol did not affect the hepatic extraction of DPH and renal plasma flow rate. Allopurinol (50 mg/kg/d) dosed repeatedly could not inhibit the hepatic drug metabolizing enzyme activities. The in vitro hydroxylation of DPH was inhibited only slightly and the kinetic plots gave apparently non-competitive inhibition. The less inhibitory effect of allopurinol on the in vitro hydroxylation did not agree with the in vivo data. These results indicate that the inhibitory effect of allopurinol is not mediated by cytochrome P-450 dependent monooxygenase reactions.

View full abstract

The effects of alminoprofen and other non-steroidal antiinflammatory drugs (NSAIDs) on the writhing reaction caused by kaolin, acetylcholine, phenylquinone and zymosan were studied. Aspirin, indomethacin, ibuprofen and diclofenac-Na, as cyclooxygenase inhibitors, showed similar potency ratios on four writhing tests, although, alminoprofen exhibited a somewhat rather higher potency ratio on kaolin- and zymosan-induced writhing models than on acetylcholine- and phenylquinone-induced writhing models. All NSAIDs, cyclooxygenase inhibitors except alminoprofen showed similar shapes in illustrations of potency ratio when the potency of aspirin was expressed as 1.0. The potency of alminoprofen produced a figure unlike those of other cyclooxygenase inhibitors. These results suggest that alminoprofen has a different pharmacological profile from other general NSAIDs in terms of analgesic action. This combination method with potency ratios for writhing reactions caused by the above four inducers could be a simple method for classification of pharmacological profiles of the analgesic actions of NSAIDs.

View full abstract

Antinociceptive effects of peroral administration of an oriental medicine Kei-Kyoh-Zoh-Soh-Oh-Shin-Bu-toh (TJ-8023) were examined using rats and mice. TJ-8023 (100mg·kg^-1·d^-1) inhibited the induction of adjuvant-induced hyperalgesia of rats in the paw-pressure test following prophylactic administration, and normalized the nociceptive threshold at a dose of 600 mg·kg^-1·d^-1, without effects on adjuvant-induced inflammation. Mice suffering from repeated cold stress showed a decrease in nociceptive threshold for tail-pressure stimulation. Such a hyperalgesia was reversed by a single (30 and 100mg/kg) or repeated administration (100 and 300 mg·kg^-1·d^-1) of TJ-8023. The nociceptive threshold of non-stressed mice was not affected by TJ-8023 (100mg/kg). Nociceptive responses of mice to cold-plate stimulation were also not affected by repeated administration of TJ-8023 (300, 600 and 1200 mg·kg^-1·d^-1). The present results demonstrate the antinociceptive action of TJ-8023, and suggest that it is more effective in easing a hyperalgesia in morbid state than in suppressing a nociception in the normal one.

View full abstract

To clarify the influence of medium-chain glycerides (MCG) on a biological membrane, we investigated the membrane transport of D-glucose and sulfanilic acid in the brush-border membrane (BBM) vesicles pretreated with MCG. The size distribution of the BBM vesicles determined by electron microscopic observation was not significantly different between the vesicles incorporated with MCG and those of the control. However, the amount of D-glucose taken up by the vesicles at an equilibrated stage (30 min) was significantly decreased in the MCG-treated ones based on unit content of protein. Based on these results we estimated the membrane transport of D-glucose and sulfanilic acid in consideration of vesiculation or filter-capturing efficiency in MCG-treated vesicles. The rates of Na⁺ gradient-independent D-glucose transport and sulfanilic acid transport were significantly greater in MCG-treated vesicles than in the control. On the other hand, the magnitude of overshooting effect in Na⁺ gradient-dependent uptake of D-glucose in MCG-treated vesicles was maintained similar to the control. Comparison of kinetic parameters for active D-glucose transport at different concentrations indicated that K_m and V_max were not significantly different between MCG-treated and the control vesicles. These results indicated that passive diffusion of D-glucose and sulfanilic acid was significantly increased but Na⁺ -glucose cotransporter was not significantly changed by the incorporation of MCG in the intestinal BBM vesicles.

View full abstract

The preventive effects of carteolol, a β-adrenoceptor antagonist, on secondary lesions were pathophysiologically examined in stroke-prone spontaneously hypertensive rats (SHRSP) from 8 to 30 weeks of age. Carteolol was added to the drinking water in doses of 0.005% (8 to 18 weeks of age) to 0.01% (19 to 30 weeks of age) (3.8 and 6.0 mg/kg/d, respectively). These animals gained significantly more weight than the untreated control SHRSP, and their heart rate was reduced from 14 weeks of age. Suppression of blood pressure rise was not definite, however, histology revealed prevention of the development or aggravation of secondary hypertension-related lesions, such as myocardial fibrosis, proliferative arteriolitis, necrotic arteriolitis and renal glomerular lesions. A decrease in nonesterified fatty acids in the serum was evident. Thus, carteolol has cardiac as well as renal protective effects, in the SHRSP.

View full abstract

A new pyrrolidinone derivative, valproyl-2-pyrrolidinone (VP), was synthesized, followed by evaluation as a cognitive drug. VP gave rise to a significant protective effect against cerebral anoxia together with a potent prolongation of latency time for the reversal of scopolamine induced transient disruption of the memory of a passive avoidance response in rats. The quantitative experiment using HPLC demonstrated a significant reduction of hippocampal aspartate (Asp) and glutamate (Glu) following the intraperitoneal administration of VP at a dose of 300 mg/kg.

View full abstract

The effects of straight chain fatty acids on seizures induced by picrotoxin and pentylenetetrazole were studied in mice. After i.p. injection capric, lauric, myristic, palmitic and stearic acid delayed the onset of picrotoxin-induced clonic convulsion in a dose-dependent manner. The survival time was also prolonged by the pretreatment with lauric, myristic, palmitic and stearic acid. However, the onset of the clonic convulsion induced by pentylenetetrazole was delayed only by lauric acid. The prolongation of the survival time was also observed only in the animals pretreated with capric and lauric acid. These results suggest that the straight chain fatty acids examined in the present study possess anticonvulsant activity in mice.

View full abstract