Acute and Sub-chronic Toxicity of Indole Alkaloids Extract from Leaves of Alstonia scholaris (L.) R. Br. in Beagle Dogs

Alstonia scholaris(L.)R.Br.,an evergreen tropical plant rich in indole alkaloids with significant physiological activity,is traditionally used to treat respiratory diseases in China.This study was conducted to establish the toxicity profile of the alkaloid extract(TA)of A.scholaris leaves in non-rodents.After oral administration of a single dose(4 g/kg.bw),a num-ber of transient symptoms,such as unsteady gait,drooling,emesis,and reddening of peri-oral mucosa,were observed,but no treatment-related mortality.A sub-chronic toxicity study with a range of doses of TA(20,60 and 120 mg/kg.bw)was conducted for a 13-week treatment period,followed by 4-week recovery observation.Except for emesis and drooling in majority of animals in 120 mg/kg.bw treatment group,no clinical changes were observed in TA-treated animals.Data from electrocardiography,bone marrow,urine,fecal,hematology and clinical chemistry analyses were comparable between TA-treated and control animals.No significant differences in the relative organ weights and histopathological characteristics were evident between the TA-treated and control groups.Accordingly,the non-observed-adverse-effect-level(NOAEL)of TA was established as 120 mg/kg.bw.Our results add further knowledge to the safety database for indole alkaloid extracts from A.scholaris with potential utility as novel drug candidates.

Acute and Chronic Toxicity of Indole Alkaloids from Leaves of Alstonia scholaris (L.) R. Br. in Mice and Rats

Alstonia scholaris(L.)R.Br.(Apocynaceae)is an evergreen tree that has been used to treat lung diseases.In this study,the toxicity profile of indole alkaloids from leaves of A.scholaris was investigated.In acute toxicity tests,mice were adminis-tered total alkaloids(TA)and five indole alkaloids.In a chronic toxicity test,rats were continuously administered TA(50,100,and 300 mg/kg bw)for 13 weeks,followed by a 4-week recovery.A single administration of TA affected the behavior of mice,and at 12.8 g/kg bw,prone position,shortness of breath,wheezing,and convulsion were observed.The half-lethal dose(LD50)in mice was 5.48 g/kg bw,almost 2740 times the clinical dose in humans.Among the five indole alkaloids,the maximum tolerance dose in mice ranged from 0.75 to 4 g/kg bw.The TA-treated rats did not die and showed no adverse effects or dose-dependent changes in weight or food and water consumption,despite fluctuations in hematological and bio-chemical parameters compared with historical data.Furthermore,both gross and histopathological observations revealed no abnormalities in any organ.With daily oral administration to rats,the non-observed-adverse-effect-level of TA was 100 mg/kg bw.The results indicate that TA is safe for clinical use.