ABSTRACT
Objective To observe the changes of circadian characteristics and stress-response-related physiological parameters including respiration, blood pressure, electrocardiography and body temperature of conscious rhesus monkeys by implantable telemetry technique. Methods Surgery was performed on 8 rhesus monkeys (half male and half female, 3-5 years old) for implantation of a telemetry transmitter. After 3 weeks of recovery, the physiological parameters of respiration, blood pressure, electrocardiography and body temperature of the conscious rhesus monkeys without binding were automatically recorded by a DSI telemetry system and the data were analyzed by the Ponemah software. Results Some electrocardiographic indexes showed significant differences at daytime and nighttime (P＜ 0. 05 or P＜ 0. 01) including mean heart rate (HR) ( 155. 0-122. 4 times/min), respiratory rate interval (RR-I) (410. 8-535. 7 ms), T-wave amplitude (T-A) (0. 181-0. 157 mV), PR interval (PR-I) (80. 4-87. 4 ms), QT interval (QT-I) (224. 8-263. 9 ms), and corrected QTcb interval (QTcb) (352. 3-366. 7 ms). The indexes of blood pressure and respiration at daytime were significantly higher than those at nighttime (P＜ 0. 01), including the mean systolic pressure (SYS) at daytime and nighttime (144. 6-131. 6 mmHg), diastolic pressure (DIA) (99. 8- 89. 9 mmHg), mean arterial pressure (MAP) (121. 5-110. 2 mmHg), tidal volume (TV) (64. 5-36. 6 mL), minute ventilation (MV) (1931. 9-920. 1 mL/min), and respiratory rate (RR) (32. 3-25. 4 times/min). Cleaning and feeding activities of the laboratory staff at 9: 00 a.m. and 2: 00 p.m. had a certain effect on the stress-responses in the monkeys. Conclusions The parameters of respiration, blood pressure, electrocardiography and body temperature of the conscious rhesus macaques observed by implanted telemetry system show obvious circadian changes, which can truly reflect the changes of physiological indexes at daytime and nighttime, and avoid the stress in hungry monkeys caused by the feeding and cleaning activities of laboratory staff. This technique can improve the efficiency of drug safety pharmacology studies, reduce the number of animals used and meet the requirements of 3R principles.
ABSTRACT
Aim To explore the toxicity and safety of five kinds of known positive drugs, cyclophosphamide, acetyl salicylic acid, tetracycline hydrochloride, dexa-methasone acetate and azacitidine, using zebrafish em-bryos. Methods We selected normally developed 4 hpf zygote, and used water bath infecting method to add the drug to the artificial seawater. Each drug had five concentrating groups, a separate control group and solvent control group. We observed the dead zebrafish embryos after 120 hpf drugs, counted the number of deaths and deformities of zebrafish embryos, and cal-culated mortality abnormal rate, the median lethal con-centration (LC50 ), concentration for 50% of maximal effect (EC50 ), therapeutic index (TI) under 120 hpf condition. We also used the formula TI = LC50 / EC50 to calculate positive drug therapeutic index. Based on measured LC50 we calculated most nonlethal concentra-tion (MNLC) of each drug setting, namely 1 / 10 MN-LC, 1 / 3 MNLC, MNLC,LC10 four concentration, tha-lidomide as a positive control, vitamin C as a negative control, artificial seawater as control, 0. 5% DMSO as solvent control. Put in 28. 5 ℃ environment for 120 hours,embryo development was observed daily for de-velopmental state,mortality,deforming rate and abnor-mal condition. Results The result of five drugs LC50 in descending order: cyclophosphamide > azacitidine> tetracycline hydrochloride > acetylsalicylic acid >dexamethasone acetate. EC50 in descending order: cy-clophosphamide > tetracycline hydrochloride > azaciti-dine > acetylsalicylic acid > dexamethasone acetate. The TI values of cyclophosphamide, acetyl salicylic acid, tetracycline hydrochloride, dexamethasone ace-tate, azacitidine were 1. 92, 1. 11, 1. 05, 1. 44, 2. 99, respectively. Conclusion Zebrafish embryo model can be used in the preliminary evaluation of drugs, and the study of early developmental toxicity and safety.