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INTRODUCTION: Azimilide dihydrochloride blocks both the rapid (I(Kr)) and slow (I(Ks)) components of the delayed rectified K+ current; dofetilide blocks only I(Kr). Their efficacies were assessed on atrial flutter reentrant circuits in dogs with surgically induced right atrial enlargement. METHODS AND RESULTS: Multiple biopsies of the tricuspid valve and banding of the pulmonary artery in male mongrel dogs made them susceptible, about 3 weeks postoperatively, to stimulation-induced sustained (5 min or longer) atrial flutter. Azimilide 3 mg/kg administered intravenously (i.v.) terminated flutter in 8 of 8 dogs, but a slower, nonsustained arrhythmia could be reinduced in 5. In these 5 dogs, azimilide 10 mg/kg terminated flutter and prevented reinduction. This dose increased effective refractory period significantly more in the slow conduction zone (25%) than in the normal zone (17%) and increased flutter cycle length (37%). Termination followed progressive conduction delay in the slow zone of the reentrant circuit. Dofetilide 1 microg/kg i.v. terminated flutter in 6 of 6 dogs, but the arrhythmia could be reinduced. At 3 microg/kg, flutter terminated in all dogs and could not be reinduced. Dofetilide also increased the effective refractory period significantly more in the slow zone (17%) than in the normal zone (12%) and increased cycle length (33%), leading to interruption of the arrhythmia circuit. CONCLUSION: In the canine right atrial enlargement model of circus movement atrial flutter, both azimilide 10 mg/kg i.v. and dofetilide 3 microg/kg i.v. were 100% effective in terminating flutter and preventing reinduction. Efficacy relied on a similar mechanism of differentially prolonged refractoriness in the slow conduction component of the reentrant circuit where drug-induced termination occurred.

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Binding of the class III antiarrhythmic agent azimilide to brain, heart, and other organ receptors was assessed by standard radioligand binding techniques. In a survey of 60 receptors, azimilide at 10 microM inhibited binding by more than 50% at serotonin uptake (K(i): 0.6 microM), muscarinic (K(i): 0.9 to -3.0 microM), Na(+) channel site 2 (K(i): 4.3 microM), and central sigma (K(i): 6.2 microM) sites. Lesser (20-40%) inhibition was seen at adrenergic, histamine, serotonin, purinergic, angiotensin II, dopamine uptake, and norepinephrine sites and at a voltage-sensitive K(+) channel. In rat ventricle, azimilide inhibited binding to alpha(1)- and beta-adrenergic and muscarinic receptors (K(i): < 5 microM) and to the L-type Ca(2+) channel (K(i): 37.3 microM). In rat brain, azimilide blocked ligand binding to these same receptors and to a serotonin receptor, and the breadth and potency of its interaction pattern differentiated it from ten other class III antiarrhythmics. Azimilide displayed agonist and antagonist action at five muscarinic receptor subtypes in transfected NIH 3T3 cells producing receptor-sensitive mitogenesis and beta-galactosidase activity. Agonist action predominated at M(2) and M(4) subtypes, and antagonist action predominated at M(1), M(3), and M(5) subtypes. The azimilide concentration for 50% maximum stimulation (EC(50)) in M(2)-expressing cells was 1.97 microM (vs 0.14 microM for carbachol). Azimilide's receptor interactions occur at concentrations from one to forty times those required to block cardiac delayed-rectifier channels but could contribute to the efficacy and safety of the drug.

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This article reports on the effect of income within race on African Americans' perception of the courts. Our findings are somewhat consistent with the previous research on black middle-class relative dissatisfaction with various American institutions. That is, unlike whites and Latirios in our study, we find that higher-income African Americans are more skeptical of the notion that blacks receive equal treatment in the courts. This same group also reported less confidence in the court's handling of specific types of cases (e.g., civil, criminal and juvenile delinquency cases.) However, better off blacks were more likely than poor blacks to have confidence in the U.S. Supreme Court and community courts. These findings point a more complex account of African American perceptions of the courts, an account that draws a distinction between diffused and specific support of the courts.

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The class III antiarrhythmic azimilide (E-1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]-amino]-3-[4-(4-methyl-1- piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride; WHO No. 7299, CAS 149888-94-8), by slow infusion or stepwise bolus doses, was evaluated for effects on heart rate, blood pressure, and cardiac pump function, excitability, and refractoriness in anesthetized dogs. Infusion (0.6 mg/kg/min) in male beagles (n = 5) to a maximum dose of 54 mg/kg increased QTc more than 20 ms at 2.0 mg/kg. At a dose of 8.9 mg/kg i.v., QTc increased 34% above baseline and remained elevated throughout the subsequent infusion and for at least 60 min postinfusion. At this maximum class III dose, azimilide increased heart contractile force (HCF) 10% and +dP/dt 34% and decreased heart rate (HR) 12%, without significantly changing mean blood pressure (MBP), left ventricular end diastolic pressure, -dP/dt, stroke volume (SV), or cardiac output (CO). At the mean maximum 47 mg/kg i.v. dose, QTc remained elevated, but decreases were observed in HCF (-27%), +dP/dt (-24%), -dP/dt (-35%), SV (-16%), and CO (-52%). Cumulative intravenous bolus injections of azimilide (0.3, 1, 3, 10, and 30 mg/kg) in male mongrels (n = 5) increased effective refractory period (ERP) and +dP/dt (18% and 16%, respectively, at 10 mg/kg) as a function of dose and significantly decreased HR (-22% at 10 mg/kg). MBP decreased significantly (-23%) only at the highest dose. Ventricular fibrillation threshold (VFT) was unchanged at 30 mg/kg. Effects of dl- (n = 3) and d-sotalol (n = 4) on ERP and HR were similar to azimilide's, but both compounds caused a greater MBP depression and VFT elevation. These results suggest that azimilide is well tolerated by the cardiovascular system, providing an increase in contractility and a slight decrease in HR at intravenous doses that produced a large or maximum increase in cardiac refractoriness.

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The ventricular proarrhythmic actions of five class III antiarrhythmic agents were compared in the Carlsson rabbit model. In adrenergically stimulated anesthetized rabbits, azimilide, clofilium, dofetilide, sematilide, and d,l-sotalol caused premature ventricular contractions and nonsustained and sustained ventricular tachyarrhythmias (NSVT and SVT) at pharmacologically equivalent intravenous doses that increased QTc intervals 20% (ED20). There were no significant differences between agents in the percentage of rabbits with serious arrhyhthmias at the ED20 doses of 5.2, 0.033, 0.015, 0.66, and 2.8 mg/kg i.v., respectively. Proarrhythmia was dose-dependent. Linear regression analysis of arrhythmia score versus log dose estimated the NSVT doses as 6.2, 0.055, 0.0089, 1.5, and 5.7, respectively. Analysis of arrhythmia states during a 10-min window after infusion when QTc prolongation was 20% showed that the compounds differed significantly in the proportion of time treated rabbits spent in SVT and combined NSVT and SVT. Rabbits treated with azimilide spent significantly less time in SVT and combined NSVT and SVT, followed in order of increasing time by d,l-sotalol, sematilide, clofilium, and dofetilide.

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The class III antiarrhythmic agent, azimilide, has been shown to inhibit dihydroalprenolol binding to the beta-adrenergic receptor of rat brain and heart in an in-vitro ligand-binding assay. Azimilide, was assessed for beta-adrenergic activity, either agonist or antagonist, in the isolated perfused guinea pig heart in comparison with class III reference agents and the class II agent, propranolol. Varying concentrations of compound (0.03-100 microM) were retrogradely perfused and the effects on corrected QT interval, baseline heart rate, and isoproterenol-stimulated heart rate were measured. Propranolol, dl-sotalol, azimilide, and d-sotalol inhibited isoproterenol-induced tachycardia with IC50 values (the concentration giving 50% inhibition of isoproterenol-stimulated heart rate) of 0.12, 1.4, 14.6, and 38.0 microM, respectively. Clofilium, dofetilide, and sematilide did not affect the action of isoproterenol. Dofetilide, clofilium, azimilide, sematilide, dl-sotalol, and d-sotalol increased the QTc interval approximately 20 ms at concentrations of 0.1, 0.3, 1.0, 3.0, 30.0, and 100.0 microM, respectively. The class III antiarrhythmic agents also slowed baseline heart rate and exhibited linear R-R and QT-interval relationships of similar slope. Azimilide's antagonism of isoproterenol in this isolated heart model may reflect a direct receptor interaction or a contribution from the bradycardic action of the compound, which distinguishes it from several other pure IKr-blocking class III antiarrhythmic agents.

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Azimilide, a novel class III antiarrhythmic agent, blocks both the slowly activating (IKs) and rapidly activating (IKr) components of the delayed rectifier potassium current, which distinguishes it from conventional potassium channel blockers such as sotalol and dofetilide, which block only IKr. Azimilide is being developed to prolong the time to recurrence of atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia in patients with and without structural heart disease. Azimilide is also being studied for its role in prevention of sudden cardiac death in high-risk patients after myocardial infarction (MI). Preclinical and clinical studies indicate that azimilide prolongs cardiac refractory period in a dose-dependent manner, as manifested by increases in action potential duration, QTc interval, and effective refractory period. Azimilide does not affect PR or QRS interval and minimally affects hemodynamic properties such as blood pressure and heart rate. Its in vivo effects appear to be rate-independent and are maintained under ischemic or hypoxic conditions, properties of potential clinical significance. Azimilide has shown excellent efficacy (>85%) in suppressing supraventricular arrhythmias in a variety of dog models. It also suppressed complex ventricular arrhythmias in infarcted dogs and, in a sudden death cardiac model, decreased mortality. Azimilide pharmacokinetics are very predictable. The drug is completely absorbed, and the extent of absorption is not affected by food. It can be administered once daily. Clinical data suggest that dose adjustments of azimilide are not required for age, gender, hepatic or renal function, or concomitant use of digoxin or warfarin. Azimilide has a good safety profile in open-label safety studies in >800 supraventricular arrhythmia patients, most with structural heart disease. The incidence of serious adverse events, including torsade de pointes, is low. The rate of patient withdrawal from long-term studies is also encouragingly low. Unlike amiodarone, azimilide has shown no evidence of pulmonary or ocular toxicity. Azimilide is expected to provide a unique new therapy for the prevention of supraventricular arrhythmias and sudden cardiac death when Phase III clinical trials are complete and safety and efficacy are confirmed.

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The class III antiarrhythmics azimilide dihydrochloride and dl-sotalol were evaluated for ability to suppress induction of ventricular tachyarrhythmias (VT) in anesthetized, male mongrel dogs 4-6 days after surgical infarction of the left ventricle (LV) produced by ligation/reperfusion of the left anterior descending coronary artery. Postmortem infarcts averaged 28.2 +/- 3.3% and 27.5 +/- 3.9% of the LV for azimilide- and sotalol-treated dogs, respectively. Both agents (0.3-30 mg/kg i.v.) increased ventricular effective refractory period as a function of dose in LV normal and infarcted zones without increasing conduction time. Azimilide was well tolerated hemodynamically up to 30 mg/kg i.v., whereas sotalol produced a significant and dose-related decrease in both blood pressure and heart rate. Azimilide was effective in five (56%) of nine dogs in preventing induction of ventricular arrhythmias by programmed electrical stimulation (PES) at doses from 1 to 30 mg/kg. Efficacy was seen for nonsustained and sustained VT and for ventricular fibrillation. Although sotalol (0.3-10 mg/kg) was effective in all five VT dogs tested, one of two nonsustained ventricular tachyarrhythmia (NSVT) dogs and two of three sustained ventricular tachyarrhythmia (SVT) dogs were reinducible with the baseline arrhythmia at doses higher than the effective dose, and one dog died after 30 mg/kg of sotalol. Both agents increased the cycle length of VT. Thus azimilide simultaneously increased refractoriness and provided antiarrhythmic efficacy as suppression of PES-induced ventricular arrhythmias in infarcted dogs without the hemodynamic depression seen with sotalol.

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INTRODUCTION: The effects of a Class III agent, azimilide dihydrochloride, on atrial flutter circuits were studies in a functional model of single loop reentrant atrial flutter using dogs, 3 to 5 days after production of sterile pericarditis. METHODS AND RESULTS: A computerized mapping system was used to construct activation maps from 138 to 222 epicardial sites in the right atrium. Doses of 3, 10, and 30 mg/kg i.v. azimilide dihydrochloride were analyzed in 8 dogs in which sustained atrial flutter lasting more than 30 minutes was induced by burst pacing. Atrial flutter was always due to single loop circus movement reentry in the lower right atrium. At 3 mg/kg, azimilide dihydrochloride terminated atrial flutter in 2 dogs; however, atrial flutter was reinduced. At 10 mg/kg, atrial flutter was terminated in all 8 dogs but was reinduced in 4 dogs with slower rate. At 30 mg/kg, atrial flutter was terminated in the remaining 4 dogs and could not be reinduced. Atrial flutter cycle length always increased prior to termination. Isochronal activation maps showed that the increase in cycle length was due to additional conduction delays in the slow zone of the reentrant circuit. The site of termination was always located within the slow conduction zone situated in the lower right atrium between the line of functional conduction block and the AV ring. Effective refractory periods (ERPs) were measured at selected sites in the slow zone and normal zone at twice diastolic threshold for the 10 mg/kg dose. Azimilide preferentially prolonged ERP in the slow zone (42.4 +/- 20.1 msec, mean +/- SD) compared with the normal zone (23.3 +/- 15.4 msec, P < 0.0001). The increase in cycle length corresponded with the increase in ERP in the slow zone. CONCLUSIONS: In a functional model of circus movement atrial flutter, azimilide dihydrochloride terminates and prevents reinduction of atrial flutter by a preferential increase in refractoriness leading to further conduction delay and conduction block in the slow zone of the functional reentrant circuit.

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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.

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High-pressure liquid chromatography with ultraviolet-visible spectral analysis of toluene extracts of samples from two Cretaceous-Tertiary (K-T) boundary sites in New Zealand has revealed the presence of C(60) at concentrations of 0.1 to 0.2 parts per million of the associated soot. This technique verified also that fullerenes are produced in similar amounts in the soots of common flames under ambient atmospheric conditions. Therefore, the C(60) in the K-T boundary layer may have originated in the extensive wildfires that were associated with the cataclysmic impact event that terminated the Mezozoic era about 65 million years ago.

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Two chemically similar nonsteroidal anti-inflammatory drugs, orpanoxin and F-1067, had almost identical potencies and efficacies as anti-inflammatory (rat paw edema) and analgesic (mouse writhing) agents, but differed markedly in gastrotoxicity. Orpanoxin alone aggravated stomach lesions in rats subjected to pylorus ligation and failed to protect stomachs of rats challenged with indomethacin. The compounds did not differ in their in vitro enzyme inhibition effects, both failing to inhibit 5- and 15-lipoxygenase and both inhibiting prostaglandin synthetase. Extraction of prostaglandins from the gastric mucosa of pylorus-ligated rats revealed, however, that the safer F-1067 depleted prostaglandin 6-keto-F1 alpha less and increased prostaglandin E2 much more than did orpanoxin. A possible causality is suggested.

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A quantitative method for testing antiinflammatory agents in beagles has been developed, based on measurement of paw inflammation induced by a local injection of carrageenin. Carrageenin [0.5 mL of 2% (wt/vol) in saline] was injected into the plantar region of the hindpaws of pentobarbital-anesthetized beagles. Paw pressure changes registered from a water-filled balloon held on the top of the paw by a light adhesive tape wrapping were monitored for 240 min. In control dogs given 0.5% (wt/vol) methylcellulose (10 mL/kg orally) just before carrageenin, paw pressure increased significantly (p less than 0.05) over eightfold, from 2.9 +/- 0.8 mm Hg (mean +/- SEM, n = 29 paws) at 75 min to 26.0 +/- 3.5 mmHg at 240 min. The increase in paw pressure was significantly inhibited by the cyclooxygenase inhibitors, ibuprofen, indomethacin, and orpanoxin, and partially inhibited by the lipoxygenase inhibitor, phenidone, administered orally before carrageenin injection. Thus this model, with further characterization, could provide a convenient, quantitative way of assessing the efficacy of nonsteroidal antiinflammatory agents in dogs.

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Platelets from normal and malignant hyperthermia (MH)-susceptible pigs were evaluated for differences in 45calcium uptake in the absence or presence of caffeine (2-16 mM), halothane (0.05-0.5%), or halothane and caffeine together. There were no statistically significant differences in basal or halothane-inhibited calcium uptake by platelets from either source. There was a small statistically significant difference in calcium uptake between platelets from normal and MH-susceptible pigs in the presence of 16 mM caffeine and 0.5% halothane. Calcium uptake by platelets from one pedigree of MH-susceptible pigs were stimulated in a concentration-dependent manner by caffeine. These data suggest that exposure of platelets to caffeine may have potential for identifying MH-susceptibility.

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Selectivity of captopril, enalapril (MK-421), enalaprilat (MK-422), ketoace, and SA-300 for inhibiting kininase II when angiotensin (ANG) I versus bradykinin (BK) is the substrate has been studied in vitro. Potency for inhibiting purified rabbit lung ANG I-converting enzyme (ACE) using a tripeptide substrate with an ANG I-like (hippurylhistidylleucine, HHL) or a BK-like (hippurylphenylalanylarginine, HPA) cleavable dipeptide was determined. Inhibition of ANG I-induced and potentiation of BK-induced contractions of isolated guinea pig ileum strips was measured. For the enzyme assay, the inhibitor concentration which reduced the rate of HHL and HPA hydrolysis 50% (IC50) from the control value was estimated. All tested compounds more potently inhibited hydrolysis of the ANG I-related tripeptide by the purified enzyme. Ketoace, with a selectivity ratio (HPA IC50:HHL IC50) of 23, was the most substrate-dependent inhibitor. For the isolated ileum assay, the inhibitor concentration which augmented the contractile response to BK by 50% (AC50) or inhibited the contractile response to ANG I by 50% (IC50) was calculated. Only enalaprilat retained a selectivity ratio (BK AC50:ANG I IC50) in the guinea pig ileum system greater than one. Ketoace, with a ratio of 0.038, was the least ANG I-selective by this criterion. In vivo selectivity data on captopril seem more in accord with the ileum, rather than the enzyme, results. It was concluded that converting enzyme inhibitors differ in their relative selectivity for inhibiting kininase II reactions using different substrates.

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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 III 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 less than 0.05) reduced the number of extrasystoles. Propranolol, sotalol, and verapamil (class IV) were less effective. In the rat coronary artery ligation/reperfusion 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 III 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.

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Dantrolene sodium has been compared with reference antiarrhythmic agents in rodent models of cardiac arrhythmia. In a coronary-artery-ligation model in rats, dantrolene sodium (3, 10 and 20 mg/kg i.v.) significantly decreased extrasystoles, episodes of ventricular tachyarrhythmia, and frequency, duration, and total episodes of ventricular fibrillation in a dose-dependent manner. In an electrically induced fibrillation model in rats, dantrolene sodium (10 and 20 mg/kg i.v.) significantly raised ventricular fibrillation threshold in a dose- and time-dependent manner. In contrast to its activity in these models, dantrolene sodium was not active in two chemically induced models involving automaticity. Aconitine-induced arrhythmias in rats and mice and ouabain-induced arrhythmias in guinea pigs were not suppressed by i.v. (10 or 20 mg/kg) or i.p. (100-3000 mg/kg) doses of the drug. These results show that the antiarrhythmic potential of dantrolene sodium, predicted by in vitro Class III and Class IV electrophysiological effects, is expressed in whole animal models.

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A manager works with people, time, and things to meet the goals of the organization. To meet those goals, the manager must motivate people to perform the jobs the manager has decided need to be done. The manager must manage his or her time as well as the time of the staff. Management in the OR is not limited to the director and the head nurse. It includes all the staff. If the staff is involved and willing to participate, everybody functions better.

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1. The effect of orpanoxin, a nonsteroidal anti-inflammatory drug, on cyclo-oxygenase and lipoxygenase activity in human polymorphonuclear leucocytes (PMNL) and platelets was studied ex vivo to see if lipoxygenase inhibition contributed to orpanoxin's mechanism of action. 2. In PMNL, orpanoxin (50, 100, and 200 mumols/l), like indomethacin (100 mumols/l), had little effect on synthesis of leukotriene B4 or 5S-hydroxy-6-trans,8,11,14-cis-eicosatetraenoic acid. BW755c at 100 mumols/l inhibited synthesis of both. 3. In PLT, orpanoxin (100 mumols/l) inhibited formation of cyclo-oxygenase products (thromboxanes, prostaglandins, and 12-L-hydroxy-5,8,10-heptadecatrienoic acid) and increased synthesis of the lipoxygenase product, 12S-hydroxy-5,8-cis,10-trans,14-cis-eicosatetraenoic acid. Effects of indomethacin (100 mumols/l) and benoxaprofen (100 mumols/l) in platelets were qualitatively similar to those of orpanoxin. 4. These results indicate that the discrepancy between the low potency of orpanoxin in inhibiting bovine seminal vesicle cyclo-oxygenase in vitro and its high potency as an anti-inflammatory agent in vivo is not explained by its having an additional lipoxygenase inhibitory mechanism.

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