Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Aminophenols/pharmacology , Aniline Compounds/pharmacology , Animals , Antimalarials/pharmacology , Chemical Phenomena , Chemistry , Haplorhini , Humans , Quinine/analogs & derivatives , Quinine/pharmacology , Quinolines/pharmacology , Salicylates/pharmacology , Species Specificity , Steroids/pharmacologyABSTRACT
The positive inotropic effect of anthopleurin-A (AP-A) was studied in vitro on isolated cat heart papillary muscles and in vivo in anesthetized and conscious dogs. In vitro, in low Ca2+ solution (1.27 mM), AP-A increased the force of contractions of isolated cat heart papillary muscles at concentrations from 0.2 x 10(-8) M and higher; on a molar basis, AP-A was more than 200 times as potent as digoxin and on a weight basis, 33 times as potent. In vivo in anesthetized dogs, AP-A at 0.2 microgram/kg/min i.v. increased myocardial contractile force; the geometric mean dose of AP-A required to increase the contractile force by 25% was 2.6 micrograms/kg; the corresponding dose of digoxin (infused at 2.8 micrograms/kg/min) was 107.4 micrograms/kg. The geometric mean lethal dose of AP-A for 8 dogs was 19.3 and that of digoxin 263.2 micrograms/kg i.v. The therapeutic index of AP-A was significantly higher than that of digoxin. All animals that received either AP-A or digoxin died in ventricular fibrillation. The reversal of t-wave was typical for AP-A. As measured by left ventricular pressure telemetry, AP-A, 2 micrograms/kg i.v. single dose, increased LV dp/dt max in conscious dogs for longer than 2 hr.
Subject(s)
Cardiotonic Agents , Animals , Blood Pressure/drug effects , Cats , Digoxin/pharmacology , In Vitro Techniques , Intercellular Signaling Peptides and Proteins , Myocardial Contraction/drug effects , Papillary Muscles/drug effects , Peptides , Sea Anemones , Stimulation, Chemical , Time FactorsABSTRACT
Some 2-(substituted phenyl)oxazolo[4,5-b]pyridines and 2-(substituted phenyl)oxazolo[5,4-b]pyridines have good antiinflammatory and analgesic activity. A few possess activity comparable to phenylbutazone or indomethacin without producing the irritation in the gastrointestinal tract that acidic antiinflammatory compounds cause.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Pyridines/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Arthritis, Experimental/physiopathology , Cyclooxygenase Inhibitors , Edema/physiopathology , Gastric Mucosa/drug effects , Lethal Dose 50 , Mice , Pyridines/pharmacology , Rats , Structure-Activity RelationshipSubject(s)
Indenes/metabolism , Sulindac/metabolism , Animals , Anti-Inflammatory Agents , Bile/metabolism , Biotransformation , Dogs , Guinea Pigs , Haplorhini , Kinetics , Male , Rabbits , Rats , Species Specificity , Sulindac/pharmacology , Sulindac/toxicityABSTRACT
The causal role assigned to the E and F prostaglandins in inflammatory processes, implied by the antiinflammatory action of prostaglandin synthetase inhibitors, is not consistent with the findings reported here that a compound (MK-447) capable of increasing levels of these prostaglandins is antiinflammatory in classical animal models of acute inflammation. That both MK-447 and prostaglandin synthetase inhibitors depress the enzymatic formation of PGG2 from arachidonic acid suggests that this endoperoxide plays a pivotal role in acute inflammation. However, in view of the intermediate nature of PGG2, it seems likely that such a pivotal role for this substance is a function of its ability to be converted to other inflammatory mediators. Possible candidates for a causal role are thromboxane A2 (TXA2) prostacyclin (PGI2), both of which derive from PGG2. However, direct evidence is presented to show that an oxygen equivalent released in the enzymatic conversion of PGG2 to PGH2 is a prime factor in inflammation.
