Core battery studies

• Central nervous system (mice, rats, canines and cynomolgus monkeys)
  • Functional observational battery (FOB) in rats, canines and non-human primates, or modified Irwin's method in mice (both tests including body temperature measurements) are used to assess effects on the central nervous system.

• Cardiovascular system (canines and cynomolgus monkeys)
  • ECG, heart rate and blood pressure are measured in unanesthetized animals using a telemetry system. ECG and heart rate measurements are also possible using an ambulatory Holter ECG monitor. Further more, measurements are also possible during the infusion of a test article into catheterized animals. Animals can be restrained or unrestrained.
  • ECG, heart rate, blood pressure, left ventricular pressure and blood flow are measured in anesthetized animals.
  • Assessment of the effects of a test article on hERG currents. (Both HEK293 and CHO cells are available.)

• Respiratory system (rats, canines and cynomolgus monkeys)
  • Respiratory rate, tidal volume and minute ventilation are measured in unrestrained, conscious rats.
  • Blood gases are measured in conscious canines or non-human primates.

Follow-up and supplemental studies

• Central nervous system
  • Gross behavioral observations (canines and cynomolgus monkeys)
    Gross behavioral observations include cage-side observations, response to external stimuli, and observations of secretions and excreta. Non-human primates can be most beneficial, depending on the specific properties of a test article, due to their different metabolic pathways to mice and rats.
  • Motor coordination (mice and rats)
  • Motor activity (mice and rats)
  • Synergistic/antagonistic effects on anesthesia (mice and rats)
  • Algesic effects (mice and rats )
    Details available upon request.
  • Observation for catalepsy (mice and rats)
    Catalepsy-inducing effects are evaluated by scoring the duration of time animals spend standing on their hind legs.
  • Observation for catalepsy (canines and rhesus monkeys)
    Catalepsy-inducing effects are evaluated by scoring the respective durations of standing and resting positions.
  • Aversion (rhesus monkeys)
    Aversion effects are assessed in rhesus monkeys that are trained to press a lever to obtain feed. These monkeys are observed for decreasing lever-pressing rates when injection and feeding occur simultaneously.

• Cardiovascular and respiratory systems (rats, guinea pigs, cynomolgus monkeys)
  • The chronic atrioventricular block (AVB) monkey model allows highly sensitive detection of the onset of drug-induced QT prolongation and deadly proarrhythmia such as Torsades de Pointes (TdP). The necessity to predict TdP with the accuracy that this model allows is discussed in the ICH-S7B Guideline (2005) for the US, EU and Japan.
  • Action potential duration (APD) is determined using the ventricular or papillary muscles of guinea pigs.
  • Cardiac effects are investigated using isolated guinea pig atrium.
  • Airway resistance is assessed by measuring the Enhanced pause (Penh) in unrestrained, unanesthetized rats.

• Gastrointestinal system
  • Gastrointestinal transit (mice and rats )
    Effects on gastrointestinal transit are investigated using charcoal powder or barium.
  • Gastrointestinal mucosa (rats)
    Effects on the gastrointestinal mucosa are investigated based on gross and histopathological examinations in necropsied rats.
  • Gastric secretions (rats, canines and cynomolgus monkeys)
    Effects on gastric secretions are investigated by pylorus ligation method in rats, or gastric lavage method in rats, canines and cynomolgus monkeys.
  • Intestinal secretions (rats)
    Effects on intestinal secretions are investigated by measuring water content in the intestinal tract of rats, which is ligated and isolated after a certain period of time from dosing.
  • Bile secretions (rats)
    Effects on bile secretions are investigated in conscious rats.
  • Emesis response (canines and cynomolgus monkeys)
    Frequency of treatment-related vomiting and vomitus are observed.

• Autonomic nervous system (rats, rabbits and guinea pigs)
  • Effects on the autonomic system are evaluated using isolated ileum from rats or guinea pigs, or isolated blood vessels or other extracted organs from rabbits.

• Skeletal muscle (mice and rats)
  • Effects on the neuromuscular junction are assessed using sciatic nerve-gastrocnemius specimens obtained from rats.

• Renal/urinary system (rats, canines and cynomolgus monkeys)
  • Effects on water and electrolyte metabolism are assessed by measuring urinary volume and Na, K, and Cl levels.

• Blood (rats, rabbits and canines)
  • Effects on hemolysis and blood coagulation are assessed.