2-(beta-Arylethylamino)- and 4-(beta-arylethylamino)quinazolines as phosphodiesterase inhibitors.

The existence of several forms of cAMP phosphodiesterase having differing kinetic characteristics suggests the feasibility of developing tissue-selective inhibitors of this enzyme. This observation is of particular importance in the development of therapeutic agents for the management of reversible obstructive airways disorders. The present report describes the design, synthesis and pharmacological characterization of a series of 6,7-dimethoxyquinazoline derivatives having beta-arylethylamine substituents at the 2- or 4-positions. The quinazoline nucleus is intended to confer a high degree of inhibitory activity for phosphodiesterase while the beta-aryethylamine moieties are designed to provide selectivity for adrenergically innervated tissue. The target compounds of this study, 6 and 7, were prepared via beta-arylethylamine displacement of chloride from an appropriate chloroquinazoline intermediate. The resulting products were evaluated for their ability to relax guinea pig tracheal smooth muscle and as inhibitors of phosphodiesterase.

Inhibition of acetaminophen hepatotoxicity by chlorpromazine in fed and fasted mice.

Acetaminophen hepatotoxicity has been shown previously to be potentiated by fasting, and the mechanism of hepatotoxicity has been correlated with depletion of reduced glutathione and the resulting elevation of cytosolic calcium. Chlorpromazine inhibited the hepatotoxicity of acetaminophen in a dose-dependent manner in fed and fasted mice. A 6 mg/kg dose of chlorpromazine prevented the acetaminophen-promoted increase in SGPT levels and prevented hepatic necrosis. Chlorpromazine did not prevent the depletion of reduced glutathione by acetaminophen in fed or fasted mice, although it did decrease the extent of reduced glutathione depletion caused by acetaminophen in fed mice from 80% depletion to 67% depletion. We propose that chlorpromazine causes a negative sensitivity modulation to calcium in hepatocytes, as evidenced by chlorpromazine preventing the acetaminophen-stimulated rise in phosphorylase a activity. We also propose that fasting potentiates acetaminophen hepatotoxicity by causing a positive sensitivity modulation to calcium in hepatocytes via the actions of glucagon.

Alteration of chemically induced hepatotoxicity by copper (II) (3,5-diisopropylsalicylate)2.

The effects of copper (II) (3,5-diisopropylsalicylate)2 (CuDIPS), which is a synthetic superoxide dismutase, on the hepatotoxicity of carbon tetrachloride and acetaminophen in fed and fasted animals were investigated. CuDIPS did not alter the covalent binding of metabolites of either of these chemicals to the hepatic endoplasmic reticulum. However, CuDIPS did inhibit the hepatotoxicity of carbon tetrachloride by inhibiting the induction of lipid peroxidation by carbon tetrachloride. CuDIPS had only a slight, and histologically insignificant, ability to decrease acetaminophen hepatotoxicity which is related to the inability of CuDIPS to prevent depletion of reduced glutathione by acetaminophen. The observation that fasting potentiates the hepatotoxicity of acetaminophen is emphasized, and the mechanism of this potentiation is suggested to be related to the depletion of reduced glutathione.

Rapid TLC determination of methadyl acetate and some in vitro metabolites.

Methadyl acetate was metabolized by microsomal preparations of rat liver to yield nor-methadyl acetate and 6-(dimethylamino)-4,4-diphenyl-3-heptanol. The identification and separation of these three compounds was established by TLC, using iodoplatinate spray as a visualizing agent.

Effect of a perfluorochemical emulsion on the rat hepatic mixed function oxidase system.

The perfluorochemical components of synthetic oxygen transporting emulsions may persist in hepatic tissue. After a single 30% blood exchange with the perfluorochemical emulsion, Fluosol-DA 20%, the effects on the microsomal metabolism of 7-methoxycoumarin and 7-ethoxycoumarin were studied over a 9-week period. Fluosol-DA treated animals were compared with controls (sham) and hetastarch-treated controls. Changes in dealkylase activities were compared with induction by phenobarbitone and 3-methylcholanthrene. The liver to body weight ratio increased by 49% in Fluosol-DA-treated rats over the controls at 1 week and the microsomal protein was increased in the Fluosol-DA-treated rats after 4 and 9 weeks. Fluosol-DA treatment induced 7-methoxycoumarin demethylase with peak differences occurring at 1 week and a Vmax 75% greater than controls. Fluosol-DA was a more potent inducer of demethylase than phenobarbitone. In addition, 7-ethoxycoumarin de-ethylase was induced by Fluosol-DA with a peak induction at 4 weeks. The Vmax at 4 weeks in Fluosol-DA-treated rats was 122% greater than control. In this case, Fluosol-DA produced less induction in de-ethylase than 3-methylcholanthrene. These studies show that Fluosol-DA induces more than one form of cytochrome P450 and the effects resemble those of phenobarbitone more than those of 3-methylcholanthrene. Hetastarch, a plasma expander, did not affect liver weights, microsomal protein content, or the cytochrome P450 system.

Exercise and uric Acid: implication in cardiovascular disease.

The association of elevated serum uric acid (SUA) concentration (hyperuricemia) with gout has been known for many years, but more recently hyperuricemia has been observed to be associated with many of the known major risk factors for coronary heart disease (hypertension, stress, hypercholesterolemia) with much greater frequency than in the general population. Several epidemiological studies have indicated a beneficial relationship between physical activity, risk factor modification, and susceptibility to coronary heart disease. Physical activity has been shown to modify not only the major identified risk factors but SUA levels as well. Whereas acute exercise lasting between one-half and three hours elevates SUA in proportion to intensity of exercise, chronic exercise lowers SUA levels. Mechanisms for these changes are discussed as well as implications in relation to coronary disease.J Orthop Sports Phys Ther 1984;6(1):34-39.

Dantrolene inhibition of the hepatic mixed function oxidase system.

The effect of dantrolene sodium, a skeletal muscle relaxant, on the hepatic MFO system has been investigated. The dantrolene produces a dose related inhibition of the system. Single doses of 100 mg/kg and accumulative doses up to 125 mg/kg prolong pentobarbital sleeping time and decrease the rate of aminopyrine N-demethylation without altering cytochrome P450 content. However, single doses of 400 mg/kg and accumulative doses of 500 mg/kg do cause a decrease in cytochrome P450 content as part of the dantrolene induced inhibition of the hepatic MFO system.

Antagonism of acetaminophen hepatotoxicity by phospholipase A2 inhibitors.

A 250 mg/kg subcutaneous injection of acetaminophen (APAP) given to fasted mice was hepatotoxic as indicated by elevated serum alanine aminotransferase activity and electron microscopic studies. When extramitochondrial Ca2+ levels were 200 nM or greater, the APAP caused loss of mitochondrial Ca2+ homeostasis in a two step process that represents a sequence of events. The first step occurs 0 to 3 hours after APAP administration and the second step occurs 6 to 12 hours after APAP administration. Loss of mitochondrial Ca2+ homeostasis 6 to 12 hours after APAP correlates chronologically with nuclear damage as indicated by loss of nuclear Ca2+ sequestration between 6 and 12 hours after APAP administration. Pretreatment of mice with the phospholipase A2 (PLA2) inhibitors chlorpromazine or diltiazem one hour prior to APAP administration inhibits loss of mitochondrial Ca2+ homeostasis, prevents nuclear damage, and inhibits APAP hepatotoxicity as indicated by serum alanine aminotransferase activity and electron microscopic studies. This protective effect of chlorpromazine and diltiazem does not interfer with initial actions of APAP that influence mitochondrial function, but interfers with the sequence of events initiated by APAP that leads to loss of mitochondrial Ca2+ homeostasis and hepatotoxicity.

Alteration of digoxin toxicity by 6-hydroxydopamine and soironolactone.

The possibility that the Na+-K+ ATPase of cardiac adrenergic neurons is the toxic receptor site of cardiac glycosides was investigated by performing a chemical sympathectomy in dogs using 6-hydroxydopamine to destroy the adrenergic neurons. No alteration was seen in the therapeutic, toxic, or lethal dose of digoxin after the administration of 6-hydroxydopamine, indicating that the toxic receptor of digoxin is not located on the adrenergic nerve endings. Pretreatment of control dogs with spironolactone increased the toxic and lethal dose of digoxin without changing the therapeutic dose of digoxin. However, spironolactone pretreatment of chemically sympathectomized dogs produced an increase pretreatment of chemically sympathectomized dogs produced an increase in the therapeutic, toxic, and lethal doses of digoxin. Therefore, the destruction of this neuronal tissue decreases the therapeutic effectiveness of digoxin in the presence of spironolactone, and abolishes the ability of spironolactone to alter the therapeutic ratio of digoxin.

Ferric ions located in hippocampal subfields of the mouse: effects on behavior.

Using stereotaxic techniques mice were chronically implanted with either stainless steel or platinum-iridium wire probes aimed at the dentate gyrus of the hippocampus. Following a recovery period these mice were trained in a single-trial inhibitor avoidance task. Significant performance deficits were found in those animals subsequently shown to have ferric ions (Fe+3) bilaterally located in the dentate gyrus. The presence of Fe+3 in other hippocampal subfields did not result in behavioral deficits. We hypothesize that the Fe+3 are of vascular origin. Two hypotheses are suggested to account for the observed correlation between the presence of Fe+3 bilaterally in the dentate gyrus and the observed behavioral deficit.

Calcium antagonism in isolated rat uterus by methylmethacrylate.

Methylmethacrylate (MMA) was evaluated for the ability to block actions of calcium in the isolated rat uterine preparation. MMA blocked receptor-mediated contraction and the phasic and tonic portions of the KCl induced contraction of the uterus. The effects of MMA could be antagonized by increasing the concentration of calcium. In the Ca++-free, K-depolarized preparation, MMA produced dose related depression of contraction.

Interaction of dantrolene with the hepatic mixed function oxidase system.

Dantrolene pretreatment of rats (100 mg/kg/day for five days) causes a fifty percent decrease in hepatic mixed function oxidase (MFO) system activity and a fifty percent decrease in cytochrome P450 content. Recovery of hepatic MFO system activity after discontinuing dantrolene therapy is slow (only sixty-three percent recovery in ten days) and greatly exceeds the half-life of dantrolene in rats (thirty-one minutes). The inactivation of the hepatic MFO system and the slow-recovery of its activity is apparently caused by dantrolene binding and forming a stable complex with hepatic proteins. 14C-dantrolene (1.0 mg/kg) administered i.v. eighteen hours before sacrificing the rats forms a stable complex with hepatic microsomal and soluble proteins. The dantrolene binding to hepatic proteins is decreased by phenobarbital pretreatment and is enhanced by diethylmaleate pretreatment.

Dantrolene sodium: urinary metabolites and hepatotoxicity.

Dantrolene is metabolized by the hepatic MFO system to hydroxydantrolene which is conjugated with glucuronic acid or with sulfate. Dantrolene is also metabolized by nitroreductase to aminodantrolene. The aminodantrolene inhibits the hepatic MFO system. Acetylation of aminodantrolene blocks the inhibitory effects of aminodantrolene on the hepatic MFO system. Intermediates in the nitroreductase pathway form glucuronide and mercapturic acid conjugates. The mercapturic acid conjugation reaction is a detoxification mechanism for an electrophilic metabolite of dantrolene.

Inhibition of the positive atrial chronotropic effect of isoproterenol by exposure to an acrylate floor finish.

Application of a commercial acrylate sealer/finish to the floor of our animal quarters resulted in almost complete elimination of the positive chronotropic response of the hypoxic rat atria to isoproterenol. Forty-eight hours exposure to this sealer/finish decreased sensitivity to isoproterenol by approximately 1000-fold and decreased maximal response by 70%. The elimination of the response to isoproterenol was associated with the resin portion of the sealer/finish and was reversible on removal of the rats from exposure to the product.

Inhibition of carbon tetrachloride induced hepatotoxicity by dantrolene sodium.

A 50 mg/kg dose of dantrolene sodium decreased the hepatotoxicity of carbon tetrachloride in fed and fasted rats, as indicated by lower levels of SGPT following a toxic dose of carbon tetrachloride; however, the dantrolene sodium pretreatment did not inhibit the induction of lipid peroxidation by carbon tetrachloride. The dantrolene sodium did inhibit superoxide production by the hepatic endoplasmic reticulum in fasted rats. Also, the dantrolene sodium inhibited covalent binding of [14C] carbon tetrachloride to the hepatic endoplasmic reticulum in fasted rats, but not in fed rats.

Inhibition of isoproterenol positive atrial chronotropic effect by methylmethacrylate polymer and monomer.

Atria from rats exposed in vivo to methylmethacrylate polymer or monomer were superfused and chronotropic responses to isoproterenol determined. Control and polymer-exposed atria superfused with oxygen-saturated buffer yielded dose-response curves which were essentially identical with regard to maximal increase and potency of isoproterenol. Control atria superfused with buffer containing 70% of possible oxygen saturation showed a 10-fold decrease in isoproterenol potency and a maximal effect approximately 75-80% that of fully oxygenated atria. Atria exposed to methylmethacrylate polymer and superfused with 70% oxygen saturated buffer showed a 100-fold decrease in isoproterenol potency and a maximal effect approximately 25% that of fully oxygenated control atria. Exposure of rats to methylmethacrylate monomer in vivo resulted in complete abolition of the chronotropic response to isoproterenol in atria superfused with 70% oxygen saturated media.