The hypolipidemic drug RMI 14,514 (5-tetradecyloxy-2-furoic acid) has an oral LD50 of over 5000 mg/kg in rats. In a chronic toxicity study (6 months drug diet) doses of 30, 100, or 300 mg/kg/day produced no obvious signs of toxicity or abnormal clinical pathology parameters, other than prominent growth retardation at 300 mg/kg, which was somewhat alleviated when the dose was reduced to 200 mg/kg after 6 weeks. Hepatic change in the form of mild lipid accumulation was noted histopathologically after 6 months of treatment at 100 or 300 mg/kg/day, but was not present at 3 months or after 4 weeks off drug. The administration of RMI 14,514 in the diet to pregnant rats at 30, 100, or 150 mg/kg/day on Days 7 thru 21 of pregnancy (day 1 = day sperm detected) did not induce any teratogenic effects. When rats were exposed to the drug from implantation thru sexual maturity (126 days of age) at the same dosage, it produced no adverse developmental or behavioral effects, except for slight reduction in weight gain from birth to sexual maturity at 150 mg/kg/day. The drug caused reductions in plasma cholesterol and total fatty acids, but no distinct changes in various tissue lipids, except in the erythrocyte where fatty acids and phospholipids were reduced. These differences did not affect membrane integrity of the erythrocyte as far as osmotic or mechanical fragility tests could determine. The drug, which bears a structural resemblance to long-chain fatty acids, was incorporated into tissue lipids in detectable amounts, but tended to disappear from tissues at a rate similar to that of expected lipid turnover after treatment was stopped.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

Biochemical studies on the mechanism of cardiotonic activity of MDL 17,043.

MDL 17,043 (1,3-dihydro-4-methyl-5-[4-(methylthio)-benzoyl]-2H-imidazol-2-one) is a new drug with cardiotonic properties. Its effects on several biochemical systems considered to be important in myocardial contraction were investigated and compared with those produced by amrinone and theophylline. Dog cardiac phosphodiesterases (PDEs) were separated into three major forms and labeled PDE I, II, and III according to the order of elution during isolation by column chromatography. PDE I and II, considered to be "high-Km" enzymes for cyclic AMP, were not inhibited by MDL 17,043, amrinone, or theophylline in concentrations of 50 microM. PDE III, a "low-Km" enzyme, was strongly inhibited by MDL 17,043. Kinetic studies showed the inhibition to be characteristic of partial competitive inhibition. At 0.25 microM cyclic AMP, 1.3 microM MDL 17,043 caused 50% inhibition of PDE III (I50), while the I50 for amrinone and theophylline were estimated to be 19.5 microM and 119 microM, respectively. Dog kidney Na+, K+-ATPase was inhibited 54% by 100 microM MDL 17,043 while amrinone caused an 18% inhibition at the same concentration. Ca2+-ATPase and Ca2+ uptake by dog sarcoplasmic reticulum vesicles were unchanged by MDL 17,043 concentrations up to 300 microM and 100 microM, respectively. It is suggested that the inhibition of PDE III is related to the cardiotonic effects produced by MDL 17,043 and amrinone, although inhibition of Na+, K+-ATPase may also play a role at high concentrations of these drugs.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMedDate not supplied

Studies on the mechanism of the positive inotropic effect of piroximone in cat papillary muscle.

The mechanism of the inotropic effect of piroximone HCl [MDL 19205A, 4-ethyl-1,3-dihydro-5-(4-pyridinylcarbonyl)-2H-imidozol-2-on e HCl] was studied in the cat papillary muscle paced electrically in vitro. Piroximone produced a concentration-dependent positive inotropic effect accompanied by an increase in rate of contraction and rate of relaxation, but abbreviated time to peak tension and relaxation time. The positive inotropic effect produced by piroximone was antagonized by carbachol, 3 X 10(-6) M, whereas that produced by increasing calcium concentration was not affected by carbachol. In potassium chloride (22 mM) depolarized muscle, piroximone restored contractility, which was not affected by propranolol (10(-6) M) or by tetrodotoxin (2 X 10(-5) M), but was inhibited by nifedipine (10(-7) M). Piroximine also elevated tissue cyclic AMP (cAMP) content in the papillary muscle. Although nifedipine inhibited the restoration of contractility, it did so without altering the increase of cAMP produced by piroximone. These results suggest that piroximone causes an increase in calcium influx that is mediated by an increase in cAMP, and the results are consistent with the hypothesis that specific inhibition of the high affinity cAMP phosphodiesterase (PDE III) plays a role in the positive inotropic effect of piroximone.

1-Methyl-3-isobutylxanthine↗

PubMedDate not supplied

Studies on the mechanism of the cardiotonic activity of MDL 19205: effects on several biochemical systems.

MDL 19205, 4-ethyl-1,3-dihydro-5-(4-pyridinyl-carbonyl)-2H-imidazol-2-one, is a new drug with cardiotonic properties. Its effects on several biochemical systems considered to be important in myocardial contraction were investigated. Cyclic nucleotide phosphodiesterases (PDEs) from dog hearts were separated into three isoenzymes, F I, F II, and F III, and effect of the drug on these enzymes was tested. MDL 19205 inhibited F III PDE specifically and produced little or no inhibition of F I and F II PDEs. The IC50 for inhibition of F III PDE was 8.6 microM when 0.5 microM cyclic AMP (cAMP) was used, whereas no more than 10% inhibition of F I and 18% of F II PDEs occurred at drug concentrations up to 200 microM when 1 microM cAMP was used. Concentrations of MDL 19205 up to 100 microM had no effect on Ca2+-adenosine triphosphatase (ATPase) or Ca2+ uptake by dog cardiac sarcoplasmic reticulum. At 100 microM, the drug produced a weak (18%) inhibition of Na+,K+-ATPase. It is suggested that inhibition of F III PDE may be the primary mechanism by which MDL 19205 produces its cardiotonic effect. Inhibition of Na+,K+-ATPase may also be involved at very high concentrations of this drug.

Adenosine Triphosphatases↗