Hx0507 Of General Pharmacology Studies

Part OneThe Safety Study in CNS with HX0507 in MiceObjective: To explore the CNS safety of HX0507 in mice in comparisonwith DIPRIVAN^TM by observing the changes of tail response, spontaneouslocomotor activity, motor coordination and learning-memory. Methods: 200Kunming mice were divided into 4 arrays, each array of 50 mice wererandomly allocated to normal saline group, DIPRIVAN^TM group (25mg/kg),and three treatment groups of low (50mg/kg), mid (75mg/kg) and high(100mg/kg) dose level of HX0507 to monitor one of the four followingparameters:①tail-flick latency,②spontaneous locomotor activity,③numbers of mice dropping from Mouse Rota-Rod,④escape latency. Afterintravenous injection, if the mouse lost its righting reflex, we began recordingthe data when the mouse regained the righting reflex; if the mouse did notlose its righting reflex, we began recording the data immediately after theinjection. All data were recorded every 5 min for 30 rain. Numerical datawere presented as means±SD, which were analyzed within group byStutent's Paired t-test and across group by ANOVA. Categorical data wereanalyzed by Fisher's Exact Test. P values＜0.05 was considered statisticallysignificant. Result: Tail-flick latency in mid-dose HX05075 group andhigh-dose HX05075 group were significantly longer than that in normalsaline group at 20 min (P＜0.05). There were no significant differences intail-flick latency among low-dose HX05075 group, mid-dose HX05075group, high-dose HX05075 group, and DIPRIVAN^TM group (P＞0.05) at all time points. The counting numbers of spontaneous locomotor activity in threetreatment groups as well as DIPRIVAN^TM group were significantly largerthan normal saline group (P＜0.05), and while the the numbers in mid, highdosage groups of HX0507 were significantly less DIPRIVAN^TM group(P＜0.05) at 5 min. The number of mice dropping from Mouse Rota-Rod wassignificantly larger in HX0507 high-dose groups than in normal saline groupand DIPRIVAN^TM group at 5 min (P＜0.05). No differences in escapelatency were found between the five groups (P＞0.05).. Conclusion: Thelow and mid dosage of HX0507 are safe to the central nervous system ofmice. Only at the 5min that number of mice dropping from Mouse Rota-Rodin the high dosage group was more than that of DIPRIVAN^TM and vehiclecontrol group (P＞0.05), indicating high dosage of HX0507 is also safe tothe central nervous system in mice. Part TwoThe Safety Study in Respiratory and CardiovascularSystems with HX0507 in Beagle DogsObjective: To examine the respiratory and cardiovascular systems safety ofHX0507 in Beagle dogs in comparison with DIPRIVAN^TM by observing thechanges of respiratory rate and amplitude, blood pressure, electrocardiogram,heart rate and body temperature, and discuss the possible mechanisms ofadverse effects. Method: 30 Beagle dogs were randomly divided into blankgroup, DIPRIVAN^TM group (5.4mg/kg), and three treatment groups of low(30mg/kg), mid (45mg/kg) and high (60mg/kg) dose level of HX0507,with each group of 6 dogs. Vital signs were monitored (invasive/noninvasive)in each dog followed by administrating midazolam(0.2mg/kg) andfentanyl(10μg/kg). 10min after the injection of midazolam and fentanyl theBeagle dogs received a bolus injection of drug according to which group theywere in, and their respiratory rate and amplitude, pulse oxygensaturation(S_PO₂), systolic and diastolic blood pressure, mean arterial pressure,heart rate,Ⅱlead electrocardiogram and body temperature were recorded at0min,0.5min,1-20min(recorded every minute),25min,30min. Oxygendelivery/assisted ventilation or ephedrine were applied when there was adecrease of S_PO₂ or blood pressure. Numerical data were presented as means±SD, which were analyzed before/after bolus injection by Stutent's Pairedt-test and across group by ANOVA. Categorical data were analyzed by Fisher's Exact Test. P values＜0.05 was considered statistically significant.Result: A single bolus injection of HX0507 at the low (30mg/kg), mid(45mg/kg) and high (60mg/kg) dosage level did suppress Beagle dogs'respiratory system, and the depression was dose-dependent, but the degree ofdepression in all the there treatment groups were smaller than DIPRIVAN^TMgroup with statistical difference; this respiratory depression could beretrieved by oxygen delivery or assisted ventilation. Three dosages ofHX0507 caused hypotension in Beagle dogs and the effect was alsodose-dependent; the effect of hypotension between low, mid dosage groups ofHX0507 and DIPRIVAN^TM group showed no statistically difference andcould be retrieved by ephedrine. No obvious influences on electrocardiogram,heart rate and body temperature of Beagle dogs were shown in threetreatment groups and DiPRIVAN^TM group. Conclusion: HX0507'scardiovascular depression at low (30mg/kg) and mid (5.4mg/kg) dosage isthe same as DIPRIVAN^TM (5.4mg/kg), but their respiratory depression is lessthan DIPRIVAN^TM (5.4mg/kg) (with statistically difference), high dosage ofHX0507 shows an evident respiratory and cardiovascular depression. Theefficacy of measures dealing with adverse effects is a safeguard to the clinicaluse of HX0507.