Safety Pharmacology

Cardiovascular System

The S7A guideline requires the effects of all drug candidates on blood pressure, heart rate, and the electrocardiogram to be evaluated.  Additionally, if warranted, further evaluation of the following endpoints may need to be studied including cardiac output, ventricular contractility, vascular resistance, the effects of endogenous and/or exogenous substances on the cardiovascular responses.

When conducting in vivo studies, the guidelines prefer use of unanesthetized animals. “Data from unrestrained animals that may be chronically instrumented for telemetry, other suitable instrumentation methods for conscious animals, or animals conditioned to the laboratory environment are preferable to data from restrained or unconditioned animals.”¹

Safety pharmacology studies require the use of non-rodent species, most often primates or canines, as rats do not possess the hERG (IKr) channel.  Therefore, researchers are unable to study the potential effects of a drug which may cause QT-I prolongation.

DSI solutions allow for continuous measurement of cardiovascular endpoints such as blood pressure, ECG, heart rate and more.  Analysis of these endpoints can provide common biomarker information including, but not limited to, contractility, heart rate variability, and arrhythmia.

Respiratory System

The S7A guideline also requires measurements of pulmonary function.  Follow up studies may be required if adverse effects raise concern for human safety.

Respiratory toxicology studies are performed on pharmaceuticals or chemicals when inhalation is the primary route of exposure or when the airways are the focus of interest.

Most studies are performed in rodents; rats being the primary choice. When warranted, other species are considered. Although respiratory rate and tidal volume are the typical endpoints desired, many additional derived parameters and supplemental pulmonary function measurements are available.

DSI solutions help assess the impact of compound and their potential side effects on major organ systems.

Central Nervous System

Finally, the S7A guideline requires evaluation of the drug’s effect on the central nervous system including effects on motor activity, behavioral changes, coordination, sensory/motor reflex responses and body temperature. These are typically evaluated in rodents using the Irwin Test (or modified Irwin Test) and/or Functional Observational Battery (FOB).

The Irwin Test asses parameters including, but not limited to, death, convulsions, changes in coordination and balance, aggression, fear, analgesia, and reflexes.  Within the Harvard Bioscience family, several products are available to assist with these assessments including analgesia meters, paw volume tests, spontaneous pain tests, thermal tests, mechanical tests, automatic and manual foot misplacement tests, and rota rod.

In addition, Harvard Bioscience offers products to assist in FOB assessments such as the Grip Strength Meter which is used to screen for neurobehavioral toxicity.

Although not part of the core battery requirements, follow up studies may be considered to evaluate sleep and seizure liability.  These studies may utilize video-EEG on rodents or large animals to identify spontaneous seizure events or assess the burden of sleep and sleep disruptions resulting from the test compound.  These studies may use implantable telemetry or hardwired systems to measure EEG.

DSI solutions allow researchers to measure biopotentials of interest such as EEG, EMG, and EOG as well as body temperature, and locomotor activity.  Video monitoring can also be integrated to monitor animals throughout a study.