Cardiotonic activity of a new, non-catecholamine and non-glycoside positive inotropic agent, 5-methyl-6-(4-pyridyl)-2H-1, 4-thiazin-3 (4H)-one hydrochloride (ZSY-27), was investigated in isolated guinea pig left atria, cat right ventricular papillary muscle and cross-circulated excised dog papillary muscle preparations, and in anesthetized open-chest dogs. In electrically driven guinea pig left atria and cat papillary muscle preparations, ZSY-27 (3×10^-6-10^-4M) increased the developed tension in a concentration-related manner. The positive inotropic effect of ZSY-27 was not blocked by propranolol (3×10^-8M) in the guinea pig atria, but was significantly inhibited by carbachol (5×10^-6M) in cat papillary muscle preparations. The positive inotropic effect of ZSY-27 was comparable to that of milrinone in guinea pig atria. ZSY-27 (0.01-3mg) increased dose-dependently the developed tension in cross-circulated excised dog papillary muscle preparations as well. In anesthetized dogs, ZSY-27 (0.03-1 mg/kg, i.v.) produced a dose-dependent increase in left ventricular contractile force and a decrease in blood pressure, while the increase in heart rate was relatively small. The pharmacological profile of ZSY-27 in anesthetized dogs was similar to that of milrinone. These results suggest that ZSY-27 is potent cardiotonic agent with vasodilator activity and its effect may be partially due to an increase in the intracellular adenosine 3', 5'-cyclic monophosphate level.

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The effect of KW-3049, (±)-(R^*)-2, 6-dimethyl-4-(m-nitrophenyl)-1, 4-dihydropyridine-3, 5-dicarboxylic acid (R^*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride on myocardial infarction in rats was examined, in comparison with some other drugs. Extension of myocardial infarction was assessed by separately determining the tissue creatine kinase (CK) activity of left ventricular free wall (LVFW) and that of interventricular septum. Loss of CK activity was limited to LVFW until 6 h after the ligation of the left main coronary artery, while 24 h after the ligation, it extended to the septum. Therefore, the effects of drugs were examined mainly in rats following 6 h of coronary artery ligation. Pretreatments with KW-3049 at 1 and 3 mg/kg (p.o.), given 1 h before coronary artery ligation, significantly reduced the loss of CK activity of LVFW by 45.3 and 39.7%, respectively. Also, posttreatment with KW-3049 at 30 μg/kg (i.p.), given 10 min after the ligation, significantly reduced the loss of CK activity by 30.6%. On the other hand, nifedipine (3, 10 mg/kg, p.o.), propranolol (100 mg/kg, p.o.), OKY-1581 (100 mg/kg, p.o.) and BM 13.177 (100 mg/kg, p.o.), each of which was given 1 h before coronary ligation, did not significantly reduced the loss of CK activity. Coronary artery ligation for 6 h significantly decreased the myocardial contents of adenosine triphosphate (ATP) and creatine phosphate (CP). Pretreatments with KW-3049 at 1 and 3 mg/kg (p.o.) reduced the decrease in ATP and CP. These results suggest that KW-3049 possesses a superior cardioprotective effect in comparison with the other drugs examined. The possible implications for the protection by KW-3049 are discussed.

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Metabolic pathways of cyanate in rats were studied by means of measurements of cyanate, carbamyl phosphate and S-carbamyl group. Approximately 30-50% of cyanate administered to rats (0.5 mmol/kg body weight) was found in buffered gastric contents, and was also detected as ammonia liberated by acid hydrolysis. However, the gastric excretion of cyanate was a temporary phenomenon just after cyanate administration. Biliary and urinary excretion of cyanate and acid-soluble S-carbamyl group are minor metabolic pathways.

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Phenytoin (PHT) dosage adjustment in a clinical situation is difficult because of the nonlinear metabolism of the drug. Therefore, many techniques have been advocated to aid in dosage adjustments based on single-point PHT concentration determined at steady-state (SS). We retrospectively investigated seven methods in a population of 90 outpatients treated with PHT. The dose needed to achieve a desired PHT concentration at SS was calculated based on an observed SS dose-concentration pair using the Richens and Dunlop nomogram (RD), the Rambeck nomogram, the Martin nomogram, the Chiba nomogram, a population clearance method, the Wagner dosing equation and the Bayesian feedback method (B). Mean prediction error, mean absolute error (MAE), and root mean squared error (RMSE) were separately calculated for each method, and served as a measure of prediction bias and precision. The MAE and RMSE were lowest for method B (MAE=28.7 mg/d, RMSE=36.8 mg/d), followed by method RD (MAE=30.3 mg/d, RMSE=40.8 mg/d). Therefore, we recommend the use of method B to make routine PHT dosage adjustments in pediatric patients when only one dose and one concentration are available.

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Studies on the effect of ginseng saponins on the development of tolerance to morphine have been carried out using isolated preparations of guinea-pig ileum (GPI) and mouse vas deferens (MVD). Incubation of GPI preparation with morphine resulted in the development of tolerance to the inhibitory effect of morphine on the electrically evoked contractions. Ginseng total saponins and one of the constituents, protopanaxatriol saponin, suppressed the development of morphine tolerance in a concentration dependent manner in GPI preparation, though another constituent, protopanaxadiol saponin, did not affect the tolerance development substantially. In the MVD preparation, the development of tolerance to the morphine effect was observed as well, but none of the ginseng saponins affected it. It has been well established that electrically evoked contractions of GPI and MVD are mediated by acetylcholine and norepinephrine, respectively, and presumably their release is regulated presynaptically by opioid receptors. The fact that ginseng saponins suppressed the development of morphine tolerance only in the GPI preparation suggest that the inhibitory effect is mediated through an effect on the cholinergic system, without the involvement of direct action on opioid receptors.

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The mechanism whereby Azone^[○!R] (AZ, 1-dodecylazacycloheptan-2-one) enhances drug penetration through the hairless rat abdominal skin was investigated thermodynamically. Three kinds of drugs, indomethacin, ibuprofen and sulfanilamide which have similar solubilities in a mixed organic solvent (ethanol-diethylcarbitol, 40 : 60, v/v), were selected to evaluate the drug penetration with or without 5% AZ. Transdermal delivery rates were determined at 27 and 37°C by using an in vitro diffusion cell procedure and the abdominal full-thickness skin of hairless rat. The solubility of each of the three drugs in the solvent with AZ was similar to that without AZ. Ethanol in the vehicle penetrated through the skin prior to the drugs. Activation energies for the skin penetration of the three drugs in the presence of AZ were decreased compared to those in its absence. For all drugs the partition coefficients between the skin and vehicle with AZ were 2-80 times higher than those without it. The activity coefficients of drugs in the presence of AZ in the skin were 2-90 times lower than those without the enhancer. These results suggested that the enhancing effect of AZ was not due to changing the solubility of the drugs in solvents but to increasing the thermodynamic activities and the affinities of the drugs to skin.

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The effects of m-and o-dichlorobenzenes (DCBs), 1, 2, 4-trichlorobenzene (TCB) and their methylsulfonyl metabolites on the activities of hepatic microsomal reduced nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome c reductase, reduced nicotinamide adenine dinucleotide (NADH)-cytochrome b_δ reductase and uridine diphosphate (UDP)-glucuronyltransferase (UDPGT) were studied. The treatment of rats with m-DCB, 1, 2, 4-TCB, 2, 4-, 3, 5-or 3, 4-dichlorophenyl methyl sulfone (DCPSO₂Me) or 2, 4, 5-trichlorophenyl methyl sulfone (TCPSO₂Me) significantly increased NADPH-cytochrome c reductase activity, but o-DCB had no effect on this enzyme activity. All three chlorinated benzenes slightly reduced NADH-cytochrome b_δ reductase activity, whereas the methylsulfonyl compounds elicited no change in the enzyme activity. Treatments with m-and o-DCBs, 1, 2, 4-TCB and 2, 4, 5-TCPSO₂Me enhanced UDPGT activities toward both chloramphenicol (CP) and p-nitrophenol (NP). 2, 4-, 3, 5-and 3, 4-DCPSO₂Mes increased the activity of UDPGT toward CP but not toward p-NP. These findings concerning the effects of 2, 4-, 3, 5-and 3, 4-DCPSO₂Mes on the activities of NADPH-cytochrome c reductase and UDPGT support our hypothesis that the methylsulfonyl metabolites derived from m-and o-DCBs are phenobarbital-type inducers of the hepatic microsomal drug-metabolizing enzymes. It is concluded that the methyl sulfone derivatives of m-and o-DCBs and 1, 2, 4-TCB are inducers of phase I reactions in hepatic microsomal drug metabolism, and they have increasing effects on the phase II enzyme activities, such as UDPGT. Thus, the methyl sulfones seem to play an important role in the inducing effects of their parent compounds, m-and o-DCBs and 1, 2, 4-TCB, on the drugmetabolizing enzyme systems.

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Bone resorbing activity was determined in organ culture by following the change of biological half life of ⁴⁵Ca (T_1/2) incorporated into bone salts of chick embryonic femur. The elevation of calcium or phosphate ion in the medium brought about an increase of T_1/2, indicating that the bone resorption was inhibited. Conversely, the decrease of calcium or phosphate content in the medium resulted in the decrease of T_1/2. A change of the magnesium ion concentration in the medium had no discernible effect on T_1/2. These results suggest that a direct regulating system exists between bone resorption of chick embryonic femur and calcium or phosphate content in the medium and this phenomenon is specific for calcium or phosphate ion.

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The purpose of the present investigation was to study if the stimulating effect of nizatidine on the intestinal smooth muscle is related to the acetylcholinesterase activity. Isolated segments of guinea pig ileum were used in Tyrode solution at 37°C. Nizatidine (from 3.2×10^-6 to 3.2×10^-4M) exerted a concentration-dependent contractile effect on the guinea pig ileum. The average maximum activity (mean±S.E.M.) of nizatidine (3.2×10^-4M) was 96.21±6.19% of the average maximum activity of neostigmine (3.2×10^-6M). The acetylcholine-induced contractions (from 10^-8 to 3.2×10^-6M) were augmented by nizatidine (from 10^-5 to 10^-4M) in a similar way to that by neostigmine (from 10^-8 to 10^-7M). The acetylcholine-induced contractions were prevented by acetylcholinesterase (0.1 unit/ml). This acetylcholinesterase activity was inhibited by nizatidine (from 10^-5 to 10^-4M) and this inhibition was similar to that of neostigmine (from 10^-8 to 10^-7M). These findings suggest that the stimulating effect of nizatidine on the intestinal smooth muscle of the guinea pig ileum could be explained by the inhibition of acetylcholinesterase activity.

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