The present paper describes the regulatory safety pharmacology studies that were carried out to support the clinical trial application for BIA 10-2474. Animal studies complied with worldwide regulatory guidelines (e.g. EEC Council Directive 75/318/EEC and subsequent amendments). Oral administration of BIA 10-2474 at doses of 30, 100 and 300 mg/kg to male Han Wistar rats did not cause any significant physiological or behavioral changes, affect the respiration rate or the tidal volume, the gastrointestinal transit, urinary output volume or pH, nor urinary sodium, potassium or chloride excretion. BIA 10-2474, at 30 μg/mL, slightly, but significantly, reduced the hERG outward tail currents by 10.62%, but had no effect at 1, 3 or 10 μg/mL. BIA 10-2474 (1.5, 4.5 and 15 μg/mL) had no substantial effects on resting membrane potential (RMP), maximal upstroke velocity (Vmax), action potential amplitude (APA), action potential duration at 30%, 60% and 90% or action potential triangulation over the 30-min superfusion period in the dog isolated Purkinje fiber. In conscious dogs monitored by telemetry, BIA 10-2474 (20, 50 and 100 mg/kg p.o.) did not significantly modify arterial blood pressure as compared with controls (inter-group comparison), although a tendency toward an increase in arterial blood pressure was observed at 100 mg/kg, with systolic blood pressure being the most affected parameter. In conclusion, BIA 10-2474 had no adverse effects on any of the major vital organ systems, and, unfortunately, the data shed no further light on the mechanism(s) responsible for the clinical trial accident with BIA 10-2474.
Keywords: BIA 10–2474; FAAH; HERG; safety pharmacology; telemetry.
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