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.

Genotoxicity and Safety Pharmacology Studies of Indole Alkaloids Extract from Leaves of Alstonia scholaris (L.) R. Br.

Indole alkaloids extract(IAAS)was prepared from leaves of Alstonia scholaris(L.)R.Br.,an evergreen tropical plant widely distributed throughout the world.This plant has been used historically by the Dai ethnic people of China to treat respiratory diseases.This study evaluated the genotoxicity and safety pharmacology of IAAS to support clinical use.The bacterial reverse mutation(Ames)test,in vitro mammalian chromosomal aberration test,and in vivo mammalian erythrocyte micronucleus(MN)test were performed to evaluate genotoxicity.Mice were administered IAAS(240,480,or 960 mg/kg bw)once orally to observe adverse central nervous system effects.Furthermore,beagle dogs were administered IAAS(10,30,60 mg/kg bw)once via the duodenum to evaluate its effects on the cardiovascular and respiratory systems.IAAS with or without S9-induced metabolic activation showed no genotoxicity in the Ames test up to 500μg/plate,in the mammalian chromosomal aberration test up to 710μg/mL,or in the MN test up to 800 mg/kg bw.No abnormal neurobehavioral effects were observed in mice following treatment with up to 960 mg/kg bw of IAAS.Moreover,blood pressure,heart rate,electrocardiogram parameters,and depth and rate of breathing in anesthetized beagle dogs did not differ among the IAAS doses or from the vehicle group.These data indicated that IAAS did not induce mutagenicity,clastogenicity,or genotoxicity,and no pharmaco-toxicological effects were observed in the respiratory,cardiovascular,or central nervous systems.Our results increased understanding of safety considerations associated with IAAS,and may indicate that IAAS is a possible drug candidate.

Gait analysis combined with the expression of TGF-β1,TGF-β3 and CREB during Achilles tendon healing in rat

Purpose:To observe the changes of gait behavior and the expression of wound healing factors of transforming growth factor-β1(TGF-β1),TGF-β3 and cAMP response element binding protein-1(CREB-1)during the healing of Achilles tendon in a rat model,and to investigate whether gait analysis can be used to evaluate the tendon healing.Methods:Achilles tendon of 40 healthy male Sprague-Dawley rats were transected and sutured to establish the Achilles tendon injury(ATI)model.They were randomly divided into 4 groups based on the observational time point at 1,2,4 and 6 weeks after injury(n=10 for each group).Before modeling,9 rats were randomly selected for CatWalk gait analysis,which contained step cycle,single stance time and average speed.Data were recorded as the normal controls.After then,ATI models were established in the left hind limbs of the all 40 rats(ATI group),while the right hind limbs were only cut and sutured without injury of the Achilles tendon(sham operation group).At 1,2,4 and 6 weeks after injury,the gait behavior of the corresponding group of rats(n=9)as observed and recorded by CatWalk platform.After then,the rats were sacrificed and Achilles tendon of both limbs was harvested.The tendon healing was observed by gross anatomy and histological examination,and the protein and mRNA expression of TGF-β1,TGF-β3,CREB-1 were observed by immunohistochemistry and qPCR.The results of tendon gross grading were analyzed by Wilcoxon rank sum test,and other data were analyzed by one-way analysis of variance among multiple groups.Results:Compared with normal controls,all gait indexes(step cycle,single stance time and average speed)were greatly affected following ATI,which however improved with time.The step cycle was significantly lower at 1,2 and 4 weeks after ATI(compared with normal controls,allp<0.05),but almost returned to the normal level at 6 weeks((0.694±0.102)vs.(0.503±0.094)s,p>0.05).The single stance time of the ATI group was significantly shorter at 1 and 2 weeks after operation((0.078±0.010)s at 1 week,(0.078±0.020)s at 2 weeks,allp<0.001)and revealed no significant difference at 4 weeks(p=0.120).The average speed of ATI group at 1,2,4,6 weeks was significantly lower than that in the normal control group(allp<0.001).Conclusion:Gait behavior indexes are associated with Achilles tendon healing.The study gives an insight of TGF-β1,TGF-β3,CREB-1 changes in the coursing of Achilles tendon healing and these cytokines may be able to be used to regulate the Achilles tendon healing.

Two-body physics in quasi-low-dimensional atomic gases under spin-orbit coupling

One of the most dynamic directions in ultracold atomic gas research is the study of low-dimensional physics in quasi-low-dimensional geometries, where atoms are confined in strongly anisotropic traps. Recently, interest has significantly intensified with the realization of synthetic spin-orbit coupling （SOC）. As a first step toward understanding the SOC effect in quasi-low-dimensionM systems, the solution of two-body problem; in different trapping geometries and different types of SOC has attracted great attention in the past few years. In this review, we discuss both the scattering-state and the bound-state solutions of two-body problems in quasi-one and quasi-two dimensions. We show that the degrees of freedom in tightly confined dimensions, in particular with the presence of SOC, may significantly affect system properties. Specifically, in a quasi-one-dimensional atomic gas, a one-dimensional SOC can shift the positions of confinement-induced resonances whereas, in quasi- two-dimensional gases, a Rashba-type SOC tends to increase the two-body binding energy, such that more excited states in the tightly confined direction are occupied and the system is driven further away from a purely two-dimensional gas. The effects of the excited states can be incorporated by adopting an effective low-dimensional Hamiltonian having the form of a two-channel model. With the bare parameters fixed by two-body solutions, this effective Hamiltonian leads to qualitatively different many-body properties compared to a purely low-dimensional model.