| Objective:Based on experiments,the effect of Semen Ziziphi Spinosae to diazepam was investigated,which can improve the hypnotic effect of diazepam and reduce its side effect on treating insomnia.Methods:Part 1.The effect on improving sleep quality of Semen Ziziphi Spinosae.1.The minimum effective dose of fried Semen Ziziphi Spinosae on improving sleep quality.The experimental animals were divided into blank control group,positive control group,and fried Semen Ziziphi Spinosae administration group on different doses with 16 mice in each group.In the fried Semen Ziziphi Spinosae administation group,the mice were given orally fried Semen Ziziphi Spinosae in the doses of 5g/kg?10g/kg?20g/kg(equivalent to the crude herb)for 7 days respectively.In the positive control group,the mice were given orally the matching distilled water for 6 days respectively and diazepam in the doses of 2.5mg/kg for the 7th day.In the blank control group,the mice were given orally the matching distilled water for 7 days respectively.After 30 min of administration of the 7th day,the mice in each group received an injection of pentobarbital sodium at the subthreshold dose(34 mg/kg).The number of mice which were fall asleep within 30 min in each group was recorded.2.Dose-response of raw and fried Semen Ziziphi Spinosae on improving sleep qualityThe experimental animals were divided into blank control group,positive control group,and raw and fried Semen Ziziphi Spinosae administration group on different doses with 20 mice in each group.In the raw and fried Semen Ziziphi Spinosae administration group,the mice were given orally fried Semen Ziziphi Spinosae in the doses of lOg/kg,20g/kg,40g/kg,80g/kg,160g/kg(equivalent to the crude herb)for 7 days respectively.In the positive control group,the mice were given orally the matching distilled water for 6 days respectively and diazepam in the doses of 2.5mg/kg for the 7th day.In the blank control group,the mice were given orally the matching distilled water for 7 days respectively.After 30 min of the last administration,the mice in each group received an ip injection of pentobarbital sodium(52 mg/kg,superthreshold dose).The sleep latency and sleep time were recorded.Dose-response of raw and fried Semen Ziziphi Spinosae on improving sleep quality was investigated.3.Time-effect of raw and fried Semen Ziziphi Spinosae on improving sleep qualityThe experimental animals were divided into blank control group,positive control group,and raw and fried Semen Ziziphi Spinosae administration group of different time of pouring medicine with 20 mice in each group.In the raw and fried Semen Ziziphi Spinosae administration group,the mice were given orally fried Semen Ziziphi Spinosae in the doses of 80g/kg(equivalent to the crude herb)for 3,7,14,21 days respectively.In the positive control group,the mice were given orally the matching distilled water except for the third,7th,14th,21st day and were given orally diazepam in the doses of 2.5mg/kg for the third,7th,14th,21st day.In the blank control group,the mice were given orally the matching distilled water for 21 days respectively.After 30 min of the administration on the third,7th,14th,21st day,the mice in each group received an ip injection of pentobarbital sodium(52 mg/kg,superthreshold dose).The sleep latency and sleep time were recorded.4.Comparison of raw and fried Semen Ziziphi Spinosae on improving sleep qualityThe experimental animals were divided into blank control group,positive control group,and Semen Ziziphi Spinosae administration group on same doses and different concocting methods with 20 mice in each group.In the Semen Ziziphi Spinosae administration group,the mice were given orally raw,fried,and raw+fried(l:1)Semen Ziziphi Spinosae in the doses of 80g/kg(equivalent to the crude herb)for 7 days respectively.In the positive control group,the mice were given orally the matching distilled water for 6 days respectively and diazepam in the doses of 2.5mg/kg for the 7th day.In the blank control group,the mice were given orally the matching distilled water for 7 days respectively.After 30 min of the last administration,the mice in each group received an ip injection of pentobarbital sodium(52 mg/kg,superthreshold dose).The sleep latency and sleep time were recorded.Part 2.Effect of fried Semen Ziziphi Spinosae to diazepam on hypnotic synergism and hangover attenuated.1.The minimum effective dose of diazepam on hypnotic effect in mice.The experimental animals were divided into blank control group and diazepam injection administration group on different doses with 20 mice in each group.In the diazepam injection administration group,the mice were given diazepam injection in the doses of 5.2mg/kg,10.4mg/kg,15.6mg/kg,20.8mg/kg,41.6mg/kg by intraperitoneal injection in single administration.In the blank control group,the mice were given the matching distilled water for 7 days by intraperitoneal injection respectively.The number of mice which were fall asleep,sleep latency,and sleep time were recorded.2.Effect of fried Semen Ziziphi Spinosae to diazepam on hypnotic synergismThe experimental animals were divided into blank control group,diazepam control group,and Semen Ziziphi Spinosae synergism administration group with 12 mice in each group.In the Semen Ziziphi Spinosae synergism administration group,the mice given orally fried Semen Ziziphi Spinosae in the doses of 80g/kg(equivalent to the crude herb)for 7 days respectively.In the diazepam control group,the mice were given the matching distilled water for 7 days by intraperitoneal injection respectively.After 30 min of the last administration,the mice in each group received an i.p.injection of diazepam injection in the doses of 20.8mg/kg.The sleep latency,and sleep time were recorded.3.Effect of fried Semen Ziziphi Spinosae to diazepam on hangover attenuated.The experimental animals were put into Mouse active device after 30min from righting reflex recovery in the experiment" Effect of fried Semen Ziziphi Spinosae to diazepam on hypnotic synergism".Activity times and standing times in 5 min were recorded.After 5 min accommodated in the open-field then,experimental animals were put into the elevated plus maze.Open arm enteries,close arm enteries,open arm stay time and Number of fall down from the maze were recorded.4.Effect of fried Semen Ziziphi Spinosae to concentration of diazepam in plasma.The experimental animals were divided into diazepam control group,and Semen.Ziziphi Spinosae synergism administration group with 8 rats in each group.In the Semen Ziziphi Spinosae synergism administration group,the mice given orally fried Semen Ziziphi Spinosae in the doses of 56g/kg(equivalent to the crude herb)for 7 days respectively.In the diazepam control group,the mice were given the matching distilled water for 7 days by intraperitoneal injection respectively.After 30 min of the last administration,the rats in each group received an i.p.injection of diazepam injection in the doses of 30mg/kg.0.5 ml blood sample was drawn from the medial canthus of each group at 5min?15min?30min?45min,1h?1.5h?2.5h?4h?6h?10h after injection,and the plasma concentrations of diazepam were determined by HPLC.Results:Part 1.The effect on improving sleep quality of Semen Ziziphi Spinosae.1.The minimum effective dose of fried Semen Ziziphi Spinosae on improving sleep quality.Compared to the blank control group,the fried Semen Ziziphi Spinosae in the doses of 20g/kg(equivalent to the crude herb)could significantly increase the sleep rate within 30 min(p<0.01),with no significant difference in the doses of 5g/kg and 10 g/kg.2.Dose-response of raw and fried Semen Ziziphi Spinosae on improving sleep qualityCompared to the blank control group,the raw Semen Ziziphi Spinosae in the doses of 10g/kg,20g/kg,40g/kg,80g/kg,160g/kg could significantly increase the sleep duration of mice(p<0.05),with no significant difference in sleep latency(p>0.05).The fried Semen Ziziphi Spinosae in the doses of 20g/kg,40g/kg,80g/kg,160g/kg could significantly increase the sleep duration of mice(p<0.05),with no significant difference in sleep latency(p>0.05).The effect of raw and fried Semen Ziziphi Spinosae was dose dependent,and the effects reaches a maximum in the doses of 80g/kg.3.Time-effect of raw and fried Semen Ziziphi Spinosae on improving sleep qualityCompared with the blank control group,raw and fried Semen Ziziphi Spinosae could significantly increase the sleep duration of mice(p<0.01)only for 7-day-administration,with no significant difference in sleep latency among all the groups(p>0.05).Compared with raw Semen Ziziphi Spinosae,fried Semen Ziziphi Spinosae could significantly increase the sleep duration(p<0.05),with no significant difference for 3,14,21-day-administration.4.Comparison of raw and fried Semen Ziziphi Spinosae on improving sleep qualityCompared to the blank control group,3 Semen Ziziphi Spinosae administration groups could all significantly increase the sleep duration of mice(p<0.05),with no significant difference among the 3 Semen Ziziphi Spinosae administration groups(p>0.05).Part 2.Effect of fried Semen Ziziphi Spinosae to diazepam on hypnotic synergism and hangover attenuated.1.The minimum effective dose of diazepam on hypnotic effect in mice.According to the experimental results,the dose of diazepam injection that caused the mice to fall asleep was established as 15.6 mg/kg,while the dose at which all mice in the group were asleep was 20.8 mg/kg.2.Effect of fried Semen Ziziphi Spinosae to diazepam on hypnotic synergismCompared to the diazepam control group,the fried Semen Ziziphi Spinosae could significantly lengthen the sleep duration of mice(p<0.01),with no significant difference in sleep latency(p>0.05).3.Effect of fried Semen Ziziphi Spinosae to diazepam on hangover attenuated.In the locomotion test,compared with the blank control group,the standing times and the activity times significantly reduced in diazepam control group(p<0.01);Compared with the diazepam control group,the fried Semen Ziziphi Spinosae could significantly increase the standing times and the activity times(p<0.01).In the EPM test,compared with the blank control group,diazepam could significantly reduce total arm enteries(p<0.01),with percentages of open arm entries increased.Compared with the diazepam control group,the fried Semen Ziziphi Spinosae could significantly reduce total arm enteries(p<0.01),with percentages of open arm entries increased.Compared with the blank control group,diazepam could significantly reduce total arm stay time(p<0.05),with percentages of open arm stay increased.Compared with the diazepam control group,percentages of open arm stay reduced.Compared with the blank group,diazepam could significant increase the number of experimental animals fallen down from the maze(p<0.01).Compared with diazepam control group,there was no significant difference in the number of the fried Semen Ziziphi Spinosae administration group(p>0.05).4.Effect of fried Semen Ziziphi Spinosae to concentration of diazepam in plasma.The test results showed that,the plasma drug concentration of rats in the diazepam control group reach the peak at 1h after administration and metabolism completely at 10h.The plasma drug concentration of rats in the fried Semen Ziziphi Spinosae + diazepam administration group reach the peak at 1h after administration and metabolism completely at 6h after administration.Fried Semen Ziziphi Spinosae could significantly reduced the plasma concentrations of diazepam at every time point,with difference at 1h after administration(p<0.05)and significant difference at the other time points(p<0.01).Compared to the diazepam control group,the plasma DZP concentration increased faster by 13.47%of 5min-15min,7.10%of 15min-30min,0.31%of 30min-45min,0.41%of 45min-lh after administration,and decrease faster by 20.91%of lh-1.5h,24.31%of 1.5h-2.5h,41.56%of 2.5h-4h,36.83%of 4h-6h after administration.Conclusion:1.The minimum effective dose of fried Semen Ziziphi Spinosae on improving sleep quality is 20g/kg.2.Raw and fried Semen Ziziphi Spinosae can improving sleep quality,and it has a dose-response relationship.The optimal dose is 80g/kg.3.The best time for the medicine application of raw and fried Semen Ziziphi Spinosae on improving sleep quality is 7 day.4.The effect of raw and fried Semen Ziziphi Spinosae has no significant difference.5.Fried Semen Ziziphi Spinosae can enhance the hypnotic effects of diazepam.6.Fried Semen Ziziphi Spinosae can attenuate the hangover of diazepam.7.Fried Semen Ziziphi Spinosae can accelerate the metabolism of diazepam in rats. |
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