Azimilide exhibited antiarrhythmic activity in several rodent models of ventricular arrhythmias. In the mouse chloroform model, azimilide provided limited efficacy by the i.p. route (50% at 100 mg/kg versus 20% by vehicle), and no efficacy by the oral route (300 mg/kg). In a rat model in which arrhythmias are induced by ligation and reperfusion of the left descending coronary artery (CALR model), azimilide provided dose-dependent (1-18 mg/kg) efficacy by the intravenous route. The estimated dose that suppressed ventricular fibrillation (VF) was 5.0 mg/kg i.v. At 18 mg/kg i.v. azimilide also partially suppressed ventricular tachyarrhythmia (VT) and extrasystoles (VES). Rats dosed orally (100 mg/kg) were fully protected from VF. In isolated guinea pig hearts exposed to 1 microM ouabain, azimilide at 10 microM prevented the VT and VF seen in 69% and 23%, respectively, of control hearts. In anesthetized guinea pigs, azimilide at 10 and 30 mg/kg i.v. increased the dose of ouabain required to induce VES. While sematilide, dofetilide, and E-4031 significantly increased sensitivity to the arrhythmogenic actions of ouabain (by lowering the dose that caused VF), azimilide did not. Azimilide's antiarrhythmic profile in these rodent models differs from that of other class III agents, since azimilide had less efficacy in the mouse chloroform model, could suppress VT and VES as well as VF in the CALR rat model, and protected from or did not aggravate cardiac glycoside-induced arrhythmias in guinea pigs. These results demonstrating the antiarrhythmic efficacy of azimilide in the intact animal suggest that the compound has a different profile than other class III agents.

Orpanoxin, a nonsteroidal anti-inflammatory drug (NSAID) lacking gastric ulcerogenic effects in the therapeutic dose range in rats, was compared with six reference NSAIDs for oral activity in the rat paw carrageenin-induced edema assay. Tested NSAIDs were ranked on the basis of oral mg/kg ED50 values: piroxicam, 0.55; orpanoxin, 35.6; diflunisal, 59.6; benoxaprofen, greater than 300; tolmetin sodium, greater than 300; and sulindac, greater than 300. Zomepirac sodium was inactive. Only the three most potent compounds produced greater than 60% inhibition of edema. Inhibition was generally greater at 4 h than at 6 h post carrageenin for all compounds. Oral activity of orpanoxin was also demonstrated in the guinea-pig u.v.-induced erythema model (ED50 = 24.2 mg/kg p.o. when given 1 h before irradiation) and in the mouse ear croton oil induced edema test (ED50 value = 131 mg/kg p.o.). Topical activity of orpanoxin was assessed in both the guinea-pig and mouse models. In the guinea-pig u.v.-induced erythema model, application (1 h after u.v.) of 1, 5, and 10% (w/v) orpanoxin creams (containing 10% urea) significantly inhibited erythema at 2, 3, and 4 h post-irradiation. Orpanoxin, mefenamic acid, and indomethacin as 1% creams inhibited total erythema scores 70, 92 and 74%, respectively. Evidence for topical activity in the mouse ear assay was also obtained for orpanoxin in diethyl ether or 10% urea cream, but not in dimethylsulfoxide. It was concluded that orpanoxin has anti-inflammatory activity comparable to reference NSAIDs in the rat paw edema test, is active orally in rat, mouse, and guinea-pig models, and shows topical activity in the guinea-pig and the mouse.

To determine specificity of rodent models of arrhythmia for different Vaughan Williams classes of antiarrhythmic drugs, we tested 17 drugs from the four classes in one in vitro and four in vivo models. In the mouse chloroform-induced ventricular fibrillation model and in the guinea pig ouabain-induced arrhythmia model, drugs of classes I (amefalone, aprindine, lidocaine, mexiletine, phenytoin, procainamide, or quinidine), II (metoprolol or propranolol), and IV (bepridil) were active. Class 111 drugs (bretylium, clofilium, or melperone did not suppress ouabain arrhythmias, but were active in the mouse chloroform model. In the rat coronary artery ligation model, disopyramide (class I), amefalone and melperone significantly (P c 0.05) reduced the number of extrasystoles. Propranolol, sotalol, and verapamil (class IV) were less effective. In the rat coronary artery ligationlreperfusion model, all four classes of antiarrhythmic agents were active in vitro (isolated heart) and in vivo (anesthetized rat). Thus, one model of automaticity, the guinea pig ouabain model, detected class I, II, and IV drugs, whereas another automaticity model, the mouse chloroform model, also detected class 111 agents. The model of reentry induced by ischemia plus reperfusion (rat coronary artery ligation reperfusion) can be recommended as a screen for new antiarrhythmic agents based on its sensitivity to all four classes of antiarrhythmic drugs. The Vaughan Williams class of an antiarrhythmic agent must be determined, however, by additional mechanism studies. [P S E B M 1989, Vol1911 umerous authors have pointed to the need for small animal models of cardiac arrhythmia N that may be of use in screening for new antiarrhythmic agents. Problems with large animal models, particularly dogs, were cited by Clark et al. (1) as "time, money, and the amount of compound needed" and prompted their development of the coronary arteryligated rat model. Curtis et al. (2) in their excellentreview of rat ischemia-reperfusion models noted that the rat could be recommended for its lack of effective coronary collaterals, low cost, quantitative assessment of arrhythmias, availability of clinically relevant concomitant diseases, extensive biochemical data, and similarities to larger animals in drug responses. Although there have been many studies of small animal models of cardiac arrhythmias (see references in (3)), most reports deal with model methodology and