An overview of the safety pharmacology society strategic plan.

Safety Pharmacology studies are conducted to characterize the confidence by which biologically active new chemical entities (NCE) may be anticipated as safe. Non-clinical safety pharmacology studies aim to detect and characterize potentially undesirable pharmacodynamic activities using an array of in silico, in vitro and in vivo animal models. While a broad spectrum of methodological innovation and advancement of the science occurs within the Safety Pharmacology Society, the society also focuses on partnerships with health authorities and technology providers and facilitates interaction with organizations of common interest such as pharmacology, physiology, neuroscience, cardiology and toxicology. Education remains a primary emphasis for the society through content derived from regional and annual meetings, webinars and publication of its works it seeks to inform the general scientific and regulatory community. In considering the future of safety pharmacology the society has developed a strategy to successfully navigate forward and not be mired in stagnation of the discipline. Strategy can be defined in numerous ways but generally involves establishing and setting goals, determining what actions are needed to achieve those goals, and mobilizing resources within the society to accomplish the actions. The discipline remains in rapid evolution and its coverage is certain to expand to provide better guidance for more systems in the next few years. This overview from the Safety Pharmacology Society will outline the strategic plan from 2016 to 2018 and beyond and provide insight into the future of the discipline which builds upon a previous strategic plan established in 2009.

Protection against postischemic myocardial dysfunction in anesthetized rabbits with scavengers of oxygen-derived free radicals: superoxide dismutase plus catalase, N-2-mercaptopropionyl glycine and captopril.

Postischemic myocardial dysfunction in canine myocardium has been reported to be reduced by scavengers of oxygen-derived free radicals. One potential source of oxygen-derived free radicals in canine myocardium is xanthine oxidase, but human and rabbit myocardium either lack or possess very low levels of this enzyme. Therefore, the effects of scavengers of oxygen-derived free radicals on postischemic myocardial dysfunction produced by 15 min of ischemia and 3 h of reperfusion were evaluated in vivo in the rabbit. Superoxide dismutase (SOD) (45,000 U/kg) and catalase (55,000 U/kg) were given into the left atrium 10 min before ischemia, and followed by an additional 45,000 U/kg of SOD and 55,000 U/kg of catalase given over 85 min. This treatment reduced postischemic myocardial dysfunction, as did sulfhydryl-containing free radical scavengers N-2-mercaptopropionyl glycine (4 mg/kg, i.v.) and captopril (3 mg/kg, i.v.) given 5 min before and 60 min after reperfusion. SOD given alone at the same dose was ineffective, as was enalaprilat (0.3 mg/kg, i.v.), an angiotensin-converting enzyme inhibitor that does not scavenge oxygen-derived free radicals. Thus, postischemic myocardial dysfunction was reduced by scavengers of oxygen-derived free radicals in vivo in a species that is deficient in myocardial xanthine oxidase. This suggests that oxygen-derived free radicals derived from a source other than xanthine oxidase play a role in postischemic myocardial dysfunction.

Probucol reduces myocardial dysfunction during reperfusion after short-term ischemia in rabbit heart.

The effects of probucol, a lipophilic antioxidant, on the myocardial dysfunction (stunning) observed during reperfusion after 15-min ischemia in rabbit heart were studied. Rabbits received food with or without 1% probucol for 3 weeks. They were then anesthetized and prepared for recording of myocardial segment shortening, arterial blood pressure (BP), left ventricular pressure (LVP), rate of development of LVP (dP/dt), and a lead II ECG. Regional myocardial ischemia was produced by acute occlusion of the first marginal branch of the left coronary artery. Myocardial segment shortening was depressed after reperfusion in control rabbits. In comparison, myocardial segment shortening was significantly greater in probucol-treated rabbits than in control rabbits during reperfusion, indicating a beneficial effect. No hemodynamic or ECG changes measured could explain this difference. The number of premature ventricular contractions was reduced in the probucol-treated group, although the incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF) were not. Concentrations of probucol in serum and heart of five rabbits were 15.0 +/- 1.2 micrograms/ml and 17.5 +/- 2.5 micrograms/g (mean +/- SEM), respectively. Only probucol concentrations in the serum were positively correlated with the improvement in myocardial segment shortening (r = 0.91, p = 0.03). We conclude that a clinically relevant serum concentration of probucol reduces ischemia-induced myocardial stunning in the rabbit.

Antiarrhythmic and electrophysiologic effects of MDL 11,939, a novel class III antiarrhythmic agent in anesthetized dogs.

MDL 11,939 (alpha-phenyl-1-[2-phenylethyl]-4-piperidine-methanol) is a new class III antiarrhythmic agent that was evaluated for antiarrhythmic activity in anesthetized dogs. Intravenous (i.v.) administration of MDL 11,939 (1, 3, and 10 mg/kg) increased left ventricular effective refractory periods. Q-T interval, and Q-Tc in a dose-related way. The effects of MDL 11,939 on ventricular refractoriness were similar to those observed with administration of identical doses of d-sotalol, with the exception that those produced by MDL 11,939 lasted longer. Intraduodenal administration of 10 mg/kg MDL 11,939 also increased left ventricular effective refractory period (LV ERP). The increase in left ventricular refractoriness produced by MDL 11,939 occurred without a significant increase in QRS duration. MDL 11,939 (10 mg/kg i.v.) also protected against induction of ventricular tachycardia (VT) and ventricular fibrillation (VF) induced with programmed electrical stimulation (PES) in anesthetized dogs with chronic 4- to 7-day myocardial infarctions. In comparison, antiarrhythmic effects of bretylium (10 mg/kg i.v.) against PES-induced ventricular arrhythmias were dependent on additional administration of propranolol (0.1 mg/kg i.v.), whereas propranolol alone (0.1 mg/kg i.v.) was ineffective. The results observed with MDL 11,939 are consistent with its in vitro class III antiarrhythmic action and suggest utility for this agent in treatment of VT and VF.

Delay of occurrence of reperfusion-induced ventricular fibrillation in the isolated rat heart with superoxide dismutase.

The effects of superoxide dismutase (SOD) on reperfusion-induced ventricular fibrillation (R-VF) were determined in isolated, perfused rat hearts with reperfusion after durations of regional myocardial ischemia ranging from 5 to 37.5 min. SOD (100 U/ml) was perfused during both ischemia and reperfusion periods. Regional myocardial ischemia was produced by acute occlusion of the left anterior descending coronary artery (LAD). Reperfusion after a brief period of ischemia (8 min) resulted in R-VF in 33% of SOD-perfused hearts as compared with 100% of control hearts that exhibited this arrhythmia (p less than 0.05). The incidence of R-VF was not affected by SOD with intermediate duration of ischemia of 10, 15, and 22.5 min. Reperfusion after a relatively long 30-min period of ischemia did not result in R-VF in control hearts, but 87% of SOD-treated hearts still exhibited this arrhythmia (p less than 0.05). No hearts exhibited R-VF with reperfusion after 37.5 min of ischemia. Thus, SOD shifted the occurrence of R-VF to longer durations of ischemia without affecting the peak incidence of this arrhythmia. In contrast to effects of SOD on incidence of R-VF, SOD had no effect on onset times of this arrhythmia. Nor did SOD affect reperfusion-induced ventricular tachycardia (VT), heart rate (HR), or coronary flow. These results suggest that SOD may have delayed onset of electrophysiologic derangements that were specifically responsible for R-VF. SOD may be classified as a modulator of R-VF.

Effect of physical training on coronary collateral circulation of the rat.

The influence of physical training on coronary collateral circulation following acute ligation of the left coronary artery was determined in pentobarbital-anesthetized rats. Coronary blood flows were determined with 15-microns microspheres during a wide range of perfusion pressures and during adenosine infusion. The demarcation between normal and ischemic tissue was achieved using nitroblue tetrazolium strain and thioflavin S fluorescence. Contractile performance was not altered by training, with the exception of a lower left ventricular end-diastolic pressure when afterload was elevated. Blood flow to and the size of the central ischemic zone were not influenced by training. However, in border zones, where collateral dependent flow is expected to be most pronounced, blood flow as a percent of normal was increased (16%, P less than 0.02) in trained animals. This increased was abolished by coronary vasodilation with adenosine. These results indicate that training caused a limited increase in collateral blood flow to the border zone. Further, tissue reactivity to adenosine following short periods of ischemia is normal in trained rats but decreased in border (11%) and ischemic (21%, P less than 0.05) zones in sedentary rats. Whether his small increase in blood flow to the border tissue, along with a retained capacity for dilatation, could lead to an improved salvage of tissue remains to be evaluated.

Coronary blood flow in physically trained rats.

Coronary blood flow was measured using labelled microspheres (15 micrometer diameter) in sedentary and endurance trained rats during hypoxaemic conditions designed to develop coronary dilatation (Pa,O2 6.0 to 6.7 kPa [45 to 60 mmHg]). Rats that were trained for 12 to 18 weeks (26.8 m per minute, 15% gradient, 1 hour per day) had a significantly greater coronary blood flow conductance (15.3 +/- 1.0 mm3.min-1.kPa-1 aortic diastolic pressure, n = 20) than sedentary animals (10.8 +/- 0.9, n = 19). Even though cardiac hypertrophy (17%) was found in the trained animals, this increase in perfused mass accounted for only one-third of the increase in total coronary blood flow. Thus, there was a greater coronary blood flow per unit mass of the myocardium in the trained rats.

Biochemical adaptations in skeletal muscle of trained thyroidectomized rats.

The cytochrome c concentrations of the different types of skeletal muscle of trained and nontrained normal and thyroidectomized rats were measured. Animals were trained by treadmill running 1 mph, at a 15% incline, 1 h/day, 5 days/wk for at least 12 wk. This training program induced an expected 50% increase in cytochrome c in the high-oxidative fast-twitch red (FTR) and slow-twitch red (STR) fibers and only a 25% increase in the low-oxidative fast-twitch white (FTW) fibers of the normal rats. This same training program caused a greater increase (100%) in the FTR and STR fibers of the thyroidectomized runners and a dramatic 243% increase in the FTW fiber. Even though the thyroidectomy procedure caused a reduction in oxidative capacity of all types of skeletal muscle fibers to about one-half normal, the absolute increase in cytochrome c in the muscles of the trained thyroidectomized animals was essentially the same or greater than that of the normal trained animals. These results indicate that the adaptive response to training of an increased oxidative capacity in skeletal muscle occurs in the absence of normal thyroid function. They also suggest that the exercise bouts of the thyroidectomized animals were performed with a relatively greater involvement of the FTW muscle fibers.