Establishment And Application Of FOB And Implantable Telemetry System

During the drug development process, the undesired cardiac toxicity has been a major reason for compound failure. In clinical phaseⅠ, adverse event prevalence top five symptoms are headache/migraine, nausea, dizziness/vertigo, sommolence/sedation /yawning and fatigue. All five symptoms fall in the category of nervous system adverse effect's (AE's). Thus, in order to evaluate and assess the safety profile of a new chemical (or biological) entity, the new chemical entity (NCE) is tested in a hierarchy of physiological systems (central nervous, cardiovascular and respiratory) necessary for survival. These vital organ systems have been deemed the SafetyPharmacology Core Battery of studies. In this study, based on the current situation of safty pharmacology in our nation, we will establish the technical terrace according to the requests of ICH and GLP. We validate the nervous system and the cardiovascular system using reference compound, which will provide an important technique support for the safety pharmacology study of new drugs .According to ICH requests, we estabilished the Functional Observational Battery (FOB) firstly, and validated the system using Chlorpromazine, Diazepam and Baclofen. 40 rats were randomly divided into normal saline (SN) group, Chlorpromazine 20 mg/kg, Diazepam 20 mg/kg and Baclofen 18 mg/kg group. The SN animals had no obvious be havior change. All of the three reference compounds induced typical and expected transient effects on neurobehaviour and body temperature. In particular, chlorpromazine and diazepam induced depressive, anxiolytic or sedative effects associated with hypothermia. As expected, Chlorpromazine induced impairment of neurological,behavioral and autonomic functions, which lasted langer than Diazepam and Baclofen. Diazepam induced impairment of neurological function, and Baclofen induced more impairment of autonomic functions particularly in exophthalmia and lacrimation. The analysis of data collected in control animals allowed for the identification of 6 signs which scored differently from the assigned normality due to the characteristic fear reactions and the animal's habituation to experimental conditions and handling. The results showed no significance between two well trained operaters.7241-L was administrated to rats and nervous system function of rats was observed. The results showed that 7241-L 18.0 mg/kg induced twichs, abnormal posture, effective response depression, decreased heart rate. Most of the symtoms recovered after 30 min except the increased muscle tone and abnormal vocalization when handled. 2.0 mg/kg and 6.0 mg/kg induced increased muscle tone and abnormal vocalization when handled. The symtoms recovered after 2 hours. The symptoms were similar with the nicotinic signs and symptoms induced by cholinesterase inhibitor and the effects might be its enlarged efficacy of medicine function.The implanted telemetry system is the most primary system in safety pharmacology. By surgical intervention, we implanted the telemetry TL11M3-D70-PCTP transmitters to the dogs. The parameters of cardiovascular and respiratory systems in conscious telemetered animals were recorded and analyzed for 24h using Dataquest ART 4.8 system,and we used Terfenadine 30 mg/kg as the positive reference. The results showed that telemetry transmitters were implanted successfully,and the conscious animal parameters were obviously circadian. The highest of most parameters was at 09:00 AM. Terfenadine prolonged QTc interval of Beagle dogs. The conscious telemetered Beagle dogs could be used in the assessment of cardiovascular and respiratory changes during the course of safety pharmacology studies. We compared the effects of chemical A on conscious telemetered Beagle dogs and anesthetized Beagle dogs. Chemical A induced low heart rate and blood pressure on anesthetized Beagle dogs, while it induced only low heart rate on conscious telemetered Beagle dogs, which could be the combination effects of anesthetic agent. The conscious Beagle dogs could reflect animals'physiological functions more.we used the system to evaluate the effects of new chemical medicine H-004 on cardiovascular system. The results showed that H-004 (20-40mg/kg) induced transient Hypotension, and H-004 induced no adverse effects on ECG and respiration system. In summary, we have established the safety pharmacology terrace according to the requests of ICH and GLP, validated the nervous system and the cardiovascular system using reference chemicals, and provided an important technique support for the safety pharmacology study of new drugs, and applied them to the safety evaluation research.