The effect of 7, 8-methylenedioxylycoctonine-type diterpenoid alkaloids on the toxicity of tall larkspur (Delphinium spp.) in cattle

Delphinium spp. contain numerous norditerpenoid alkaloids which are structurally delineated as 7, 8-methylenedioxylycoctonine (MDL) and N-(methylsuccinimido) anthranoyllycoctonine (MSAL)-type alkaloids. The toxicity of many tall larkspur species has been primarily attributed to their increased concentration of MSAL-type alkaloids, such as methyllycaconitine (MLA), which are typically 20 times more toxic than MDL-type alkaloids. However, the less toxic MDL-type alkaloids are often more abundant than MSAL-type alkaloids in most Delphinium barbeyi and Delphinium occidentale populations. Previous research demonstrated that MDL-type alkaloids increase the acute toxicity of MSAL-type alkaloids. In this study, we examined the role of MDL-type alkaloids on the overall toxicity of tall larkspur plants to cattle while controlling for the exact dose of MSAL-type alkaloids. Cattle were dosed with plant material from 2 different populations of tall larkspur containing either almost exclusively MDL- or MSAL-type alkaloids. These 2 plant populations were combined to create mixtures with ratios of 0.3:1, 1:1, 5:1, and 10:1 MDL- to MSAL-type alkaloids. The dose that elicited similar clinical signs of poisoning in mice and cattle was determined for each mixture on the basis of the MSAL-type alkaloid content. As the ratio of MDL- to MSAL-type alkaloids increased, the amount of MSAL-type alkaloids required to elicit clinical signs decreased. These results indicate that the less toxic MDL-type alkaloids in tall larkspur exacerbate the toxicity of the MSAL-type alkaloids. Consequently, both the amount of MSAL-type alkaloids and the amount of total alkaloids should be fully characterized to determine more accurately the relative toxicity of tall larkspur plant material.     

Evaluation of vaccination against methyllycaconitine toxicity in mice

The purpose of this study was to determine whether larkspur toxins conjugated to protein carriers would promote active immunity in mice. Mice were injected with several larkspur toxin-protein conjugates or adjuvant alone to determine whether the resulting immunological response altered animal susceptibility to methyllycaconitine, the major toxic larkspur alkaloid. Although vaccinations increased the calculated lethal dose 50% (LD50) for intravenous methyllycaconitine toxicity, overlapping confidence intervals did not provide evidence of differences between the vaccinated and control groups. In the lycoctonine conjugate (LYC)-vaccinated group, mouse survival was related (P = 0.001) to serum titers for methyllycaconitine doses up to 4.5 mg/kg of body weight. When mice withlow antibody titers were removed from the vaccinated groups in which titer was related to survival, the recalculated LD50 estimates were 20% greater than the LD50 of the control group. However, the 95% confidence intervals of the recalculated LD50 groups overlapped with the control groups. Overall, these results suggest that vaccination altered methyllycaconitine toxicity in mice and that vaccination may be useful in decreasing the effects of larkspur toxins in animals. Additional studies are warranted to continue development of potential larkspur vaccines for livestock.     

The toxicity and kinetics of larkspur alkaloid,methyllycaconitine, in mice

Larkspur poisoning sporadically kills from 5 to 15% of the cattle on North American mountain rangelands. Of the 40 different diterpenoid larkspur alkaloids, the one that is thought to be responsible for much of the toxicity has been identified as methyllycaconitine (MLA). Little is known of MLA toxicokinetics or excretion. The purpose of this study was to further characterize the clinical effects of MLA toxicity in mice and determine the toxicokinetics of MLA excretion. Eight groups of mice were dosed intravenously with 2.0 mg/kg of BW of MLA, killed, and necropsied at 0, 1, 2, 5,10,15, 30, and 60 min after injection. Treated animals were reluctant to move, trembled, and developed dyspnea, muscular twitches, and convulsions. Within several minutes, the clinical signs abated and behavior slowly returned to normal over approximately 20 min. At necropsy serum, brain, liver, kidney, and skeletal muscle were collected and frozen. Blood and tissues were extracted and analyzed for MLA with HPLC and electron spray mass spectrometry. Blood MLA elimination followed a normal biphasic redistribution and excretion pattern (r = 0.99) with a K of elimination of 0.0376 and half-life of 18.4 min. Other tissues had similar clearance rates. These data indicate the MLA is rapidly distributed and excreted. In mice, the clinical effects of poisoning seem to affect the central nervous system, causing dyspnea and "explosive" muscular twitches and convulsions. Because livestock commonly eat larkspur at subclinical doses, they are likely to have larkspur alkaloids in many tissues. These results suggest that animals exposed to larkspur should rapidly excrete MLA (within several hours) and that the residues in animal tissues are not likely to be a problem if animals are given several days to allow toxin clearance.     

The acute toxicity of the death camas (Zigadenus species) alkaloid zygacine in mice, including the effect of methyllycaconitine coadministration on zygacine toxicity

Death camas (Zigadenus spp.) is a common poisonous plant on foothill rangelands in western North America. The steroidal alkaloid zygacine is believed to be the primary toxic component in death camas. Poisonings on rangelands generally occur in the spring when death camas is abundant, whereas other more desirable forage species are limited in availability. In most cases where livestock are poisoned by plants in a range setting, there is more than one potential poisonous plant in that area. One common poisonous plant that is often found growing simultaneously in the same area as death camas is low larkspur (Delphinium nuttallianum). Consequently, the objectives of this study were to conduct acute toxicity studies in mice and to determine if coadministration of low larkspur will exacerbate the toxicity of death camas. We first characterized the acute toxicity of zygacine in mice. The LD(50) of zygacine administered intravenously (i.v.) and orally was 2.0 ± 0.2 and 132 ± 21 mg/kg, respectively. The rate of elimination of zygacine from whole blood was determined to be 0.06 ± 0.01/min, which corresponds to an elimination half-life of 13.0 ± 2.7 min. The i.v. LD(50) of total alkaloid extracts from a Utah and a Nevada collection were 2.8 ± 0.8 and 2.2 ± 0.3 mg/kg, respectively. The i.v. LD(50) of methyllycaconitine (MLA), a major toxic alkaloid in low larkspur, was 4.6 ± 0.5 mg/kg, whereas the i.v. LD(50) of a 1:1 mixture of MLA and zygacine was 2.9 ± 0.7 mg/kg. The clinical signs in mice treated with this mixture were very similar to those of mice treated with zygacine alone, including the time of onset and death. These results suggest that there is an additive effect of coadministering these 2 alkaloids i.v. in mice. The results from this study increase knowledge and understanding regarding the acute toxicity of death camas. As combined intoxications are most likely common, this information will be useful in further developing management recommendations for ranchers and in designing additional experiments to study the toxicity of death camas to livestock.     

苦豆子总碱对小鼠急性毒性试验研究

采用改良寇氏法测定苦豆子总碱提取物对小鼠腹腔注射的急性毒性,评价其安全性,为临床安全用药提供依据。给试验组小鼠灌服不同浓度的苦豆子总碱提取物,观察给药后小鼠的临床表现与死亡情况,采用改良寇氏公式计算LD50及LD50的95%可信限,结果表明,苦豆子总碱经腹腔注射的LD50为559.24 mg/kg,95%可信限为471.95-663.59 mg/kg。试验结果提示,苦豆子总碱的毒性较低,临床用药安全可靠。     

硫代甜菜碱的一般毒性研究

为提供硫代甜菜碱的安全性评价资料,本试验进行了硫代甜菜碱对小鼠的一般毒性研究。采用改良Karber法测得DMSP对小白鼠的口服急性毒性LD50为3739.4mg/kg,属低毒;用剂量递增连续20d染毒法测得DMSP对小白鼠的累积系数K>5.3,属基本无蓄积;耐受性试验结果表明,连续用药,小白鼠能对硫代甜菜碱产生耐受现象;小鼠亚急性毒性试验的结果表明,DMSP在使用剂量范围内对小鼠的行为、体重、饮食状况、生理和生化指标均无不良影响。提示硫代甜菜碱毒性极低,在临床使用剂量下,作为饲料添加剂长期使用不会引起毒性反应。     

三聚氰胺对小白鼠亚慢性毒性

将80只昆明小白鼠随机分为4组（每组20只）：空白对照组（Ⅰ组）、三聚氰胺高剂量组（300mg／kg）（Ⅱ组）、三聚氰胺中剂量组（150mg／kg）（Ⅲ组）和三聚氰胺低刺量组（37．5mg／kg）（Ⅳ组）,试验周期为30d。试验期内观察小白鼠一般情况、体质量变化及食物利用率。结果显示：三聚氰胺染毒组小鼠体增重缓慢,食物利用率极显著降低（P〈0．01）;Ⅱ、11组小鼠血清ALT、AST、BUN、Cr和UA值显著高于Ⅰ组（P〈O．05）,Ca和P显著低于Ⅰ组（P〈0．05）;Ⅱ组小鼠肝、肾指数显著高于I组（P〈0．05）,Ⅱ、Ⅲ组脾指数显著低于Ⅰ组（P〈o．05）;Ⅱ、Ⅲ组小鼠肺、肝、脾、肾及膀胱有病理变化。结果表明,三聚氰胺亚慢性毒性会影响动物生长,造成肺、肝、肾及脾损害。     

血根碱的急性毒性研究

为评价血根碱的安全性,采用改良寇氏法进行了血根碱的急性毒性试验。分别采用腹腔注射与灌胃两种给药方式,一次性对小鼠给予不同剂量血根碱,连续观察7 d。结果表明,小鼠腹腔注射血根碱的最大耐受量为15.0 mg/kg,其LD50为9.4 mg/kg,LD50的95%可信限为8.6-10.3 mg/kg;灌胃给药的最大耐受量为2 000 mg/kg,其LD50为1 029.7 mg/kg,LD50的95%可信限为903.7-1 173.2 mg/kg。该结果为血根碱临床剂量的选择奠定了基础。     

复方茜草灌注液对小鼠蓄积毒性试验

为评价复方茜草灌注液的安全性,采用20 d剂量递增连续染毒法对小鼠进行蓄积毒性试验,观察给药期间小鼠的体重变化和死亡情况,以蓄积系数评价其蓄积毒性。结果显示,各试验组小鼠未发现有明显毒性反应,无小鼠死亡,但对小鼠的体重增长有一定影响。表明复方茜草灌注液在小鼠体内无明显的蓄积毒性作用。     

乳杆菌FGM9菌株对小鼠毒性作用研究

评价乳杆菌FGM9菌株对昆明种小鼠的一般毒性作用。将80只小鼠随机分为8组,设两个阴性对照,分别灌胃和腹腔注射实验菌株,灌胃剂量分别为4.5×109、4.5×107和4.5×105CFU/mL,注射剂量分别为5.2×109、5.2×107和5.2×105CFU/mL,连续7 d记录小鼠的一般体征、中毒及死亡情况。结果各组小鼠均无死亡,未见任何毒性反应,健康体征均为Ⅰ级,各实验组体重变化与对照组相比无显著差异;各组小鼠未见任何异常病变,脏器系数与对照组相比亦无显著差异(P0.05),血液学指标正常。表明乳杆菌FGM9菌株对小鼠无不良影响。     

The effects of selected bulky substituents on the pulmonary toxicity of 3-furyl ketones in mice

Preliminary studies examined the toxicity of a series of simple alkyl 3-furyl ketone congeners of perilla ketone, 1-(3-furyl)-4-methylpentan-1-one (1), in mice, but little was known about how aromatic or bulky side chains might affect toxicity. Therefore, 3-furylphenyl ketone (2) 3-furylphenethyl ketone (3) and 1-3-furyl-4, 4-dimethylpentan-1-one (4) were synthesized to examine this problem. The 48-h LD50 (i.p.) in Notre Dame Swiss mice for each analog was greater than that of the parent toxicant, perilla ketone (1, 30 +/- 5; 2, 173 +/- 4; 3, 150 +/- 11; 4, 79 +/- 5 mumol/kg). Absorption and distribution of these compounds should be similar based on their lipophilicities. Preliminary evidence suggested that the reduced toxicities of 2, 3 and 4 compared with 1 cannot be explained on the basis of 13C-NMR (electron density) characteristics. Instead, the reduced potency likely is the result of steric hindrance of bioactivation by the bulky side chain substituents and(or) alternative metabolism on the phenyl ring rather than the furan ring of 2 and 3.     

壳聚糖对饲料镉致罗非鱼急性毒性的影响

通过两个试验研究了壳聚糖对饲料中镉致罗非鱼急性毒性的影响。试验1将360尾罗非鱼随机分为两个处理(对照组和试验组),每个处理3个重复,比较壳聚糖添加后饲料镉致罗非鱼96 h半致死剂量的变化情况。对照组一次性投喂镉水平分别为0.00%、0.10%、0.25%、0.50%、1.00%和2.00%的6种对照饲料;试验组饲料镉含量与对照组相同,并加入10%壳聚糖,同法进行饲料镉对罗非鱼的急性毒性试验。试验2将160尾罗非鱼随机分为两个处理,每个处理4个重复,分别投喂镉含量为0.50%的对照组和试验组饲料,研究饲料中添加壳聚糖对镉致罗非鱼半致死时间的影响。试验结果为:两个试验中试验组鱼的死亡率均低于对照组;对照组96 h半致死剂量(LD50)和半致死时间(LT50)分别为(49.67±6.11)mg/kg.BW和(47.76±3.03)h,试验组96 h LD50和LT50分别为(86.05±6.11)mg/kg.BW和(65.20±6.09)h,试验组96 h LD50和LT50与对照组相比差异极显著(P<0.01),表明壳聚糖能够缓解饲料中镉对罗非鱼的急性毒性。     

The effect of cadmium chloride on the immune response in mice.

Six week old BDF1 female mice were exposed to cadmium chloride in the drinking water at concentrations ranging from 0 to 50 micrograms/mL cadmium for three weeks. The humoral immune response against sheep red blood cells which is T-lymphocyte and macrophage dependent, was suppressed in a dose dependent fashion with the maximum suppression of 28.2% observed in the highest exposure group (P less than 0.0001). Mitogen studies demonstrated that cadmium was a weak mitogen, producing a dose-dependent enhancement of blastogenesis (P = 0.026). T-lymphocyte responses which were induced by concanavalin A were not affected by cadmium exposure (P = 0.284). A dose-dependent enhancement of the B-lymphocyte activity was produced in the presence of cadmium when the lymphocytes were induced with Escherichia coli, lipopolysaccharide, a B-lymphocyte mitogen (P = 0.007). These results suggest that the immunosuppressive effects of cadmium associated with the humoral immune response are not due to an impairment of lymphocyte proliferation, an intermediate step involved in the generation of an immune response. The immunosuppressive effects were produced at relatively low cadmium exposures as indicated by the renal cadmium concentrations suggesting that the immune systems is very vulnerable to the toxic effects of cadmium.     

乳酸恩诺沙星对小鼠的急性毒性试

采用新药乳酸恩诺沙星测定了其对实验小鼠的半数致死量（LD50）, 为其可溶性粉开展药效试验提供依据。按照农业部关于一般毒性试验及临床试验规范进行试验。结果表明, 乳酸恩诺沙星对小白鼠灌胃染毒及腹腔注射染毒的 LD50分别为3579 mg/kg,和571.3 mg/kg,其95％可信限分别为3011~4255 mg/kg和498.3~655.1 mg/kg。研究提示, 乳酸恩诺沙星属低毒物质,其可溶性粉能用于开展药效试验。     

硫代甜菜碱对小鼠的急性和亚急性毒性试验

为硫代甜菜碱的安全性评价提供资料,试验进行硫代甜菜碱对小鼠的急性毒性和亚急性毒性研究。采用改良寇氏法测得硫代甜菜碱对小鼠的口服急性毒性LD50为3739.4mg/kg体质量,LD50的95%可信限为3449.1～4054.2mg/kg体质量,属低毒;采用经口灌胃法对小鼠连续给药1个月,30d后各项指标的测定结果表明,硫代甜菜碱在使用剂量范围内对小鼠的行为、体质量、饮食状况及生理生化指标均无不良影响。硫代甜菜碱毒性极低,在临床使用剂量下,作为饲料添加剂长期使用不会引起毒性反应。     

交感神经对小鼠脾脏中淋巴细胞转化率的影响

神经、内分泌、免疫诸系统间存在着相互作用,这是近30年来新兴的神经免疫学中主要的研究成果。交感神经及其递质去甲肾上腺素(NE)在体内和体外条件下对免疫细胞功能的调节作用是神经免疫学中研究最早、报道最多的内容之一。脾脏中T淋巴细胞和B淋巴细胞转化率分别代表了机体的细胞免疫和体液免疫,但是,对于外周交感神经损毁后,脾脏中淋巴细胞转化率的影响还未见报道。因此,本研究利用6-OHDA损毁小鼠交感神经模型,检测了脾脏中不同浓度ConA诱导的T淋巴细胞转化率,不同浓度LPS诱导的B淋巴细胞转化率,以探讨交感神经对机体免疫状态的影响…     

克洛素隆对小鼠的急性毒性试验

一次性口服或皮下给予小鼠不同剂量的克洛素隆,观察其急性毒性.结果:小鼠分别口服克洛素隆5251.9、6827.5、8875.7、11538.5、15000 mg/kg体重,肉眼未见毒副反应亦无死亡,属于实际无毒;分别皮下注射克洛素隆655.4、819.2、1024、1280、1600、2000、2500、3125mg/kg体重,其半数致死量为1 224.05 mg/kg体重.     

The effect of enrofloxacin on sperm quality in male mice

Current study was designed to evaluate toxic effects of enrofloxacin on male mice reproductive system. In the treatment group enrofloxacin was administered subcutaneously to male mice at a fixed dose of 150 mg/kg once daily for 15 days, whereas saline solution was given in the same regimen in the control group for the same period. Mice were sacrificed on day 15 and analyzed for sperm quality. In addition to routine examination of sperm material, spermatogenetic activity and organization of each animal were graded according to Johnsen's scoring to assess the spermatogenesis relying on seminiferous tubule cross-section scores. A significant decrease in both epididymal sperm count and sperm motility besides abnormal spermatozoa rate were observed in enrofloxacin group compared to controls (P < 0.01, for all). Johnsen's score in control mice were better than those in treatment group (P < 0.01). These results suggested that a fixed 150 mg/kg dose of enrofloxacin would lead disruption of spermatogenesis in the testes causing deterioration of motility and content of sperms as well as morphological abnormalities.