硝硫氰胺在血吸虫病患者体内的清除和药物对大鼠肝胆系统毒性的研究

本文报告日本血吸虫病患者口服硝硫氰胺后,药物在体内的分布与清除及药物对大鼠肝胆系统的影响。 硝硫氰胺350 mg分3天口服的47例血吸虫病患者,首次给药后48小时的全血药浓度的平均值为1.56±0.18 μg/ml。末次给药后16天,血药浓度还维持在0.10 μg/ml。但药物主要存在于血浆中,血细胞与其它有形成分的含药量则较少。给药期原药经由尿的排泄量大于停药后的排泄量,药物的排出可持续到19天以上。在一例因其它疾病死亡的尸检脏器组织中,测得肝、肾、心、脾的药物含量均高于肌肉、脑、脂肪与血清中的含药量。 大鼠口服硝硫氰胺100 mg/kg/d×7,胆汁分泌量明显减少,与对照组比较胆汁量减少58.3％。药物能抑制肝脏分泌胆汁的能力,并使动物黄疸指数和胆红素升高。     

治疗血吸虫病新药硝硫氰胺的代谢研究

硝硫氰胺是一非锑类治疗血吸虫病的新药。在动物和人体研究了该药的代谢。家兔口服给药后4小时达到高峰血浓度。由二室模型对血浓度数据作药物动力学参数计算,得t_1/2ka、t_1/2)α和t_(1/2)β分别为0.815,0.924和105.8小时,Kel、K₂₁和K₁₂分别为0.0127、0.398和0.356小时^-1,V_f为0.934升。大鼠口服给药后4小时药物在各组织的浓度大小依次为:肝、肾、脾、肺、肌肉、心、脑和血。血吸虫浓度高于肝和血浓度,而且雌虫高于雄虫。该药由尿和胆汁排泄,大鼠一次口服的尿排泄持续3天以上,人连服三次排泄持续超过19天。尿代谢产物由层析、高速液相色谱、紫外光谱和化学方法检测,硝硫氰胺转化成氨基物再转化成N-葡萄糖醛酸甙,这种代转变化是其生物转化途径之一。     

硝硫氰胺抗日本血吸虫病的研究

硝硫氰胺是抗血吸虫病的一种新药物。本文进一步研究该药物对实验性日本血吸虫病的预防和治疗的作用。实验动物在感染血吸虫尾蚴前后,即使口服500mg/kg/天×2或4天的硝硫氰胺,血吸虫组比对照组仅减少32.3～59%。药物对童虫几乎无作用,而对成虫则有明显的疗效。病鼠一次口服硝硫氰胺40mg/kg,停药后1～8天的肝移率达93.6～100%。各实验治疗组的减虫率为74～100%,但此疗效的高低与剂量和疗程有关。     

艾普斯特在大鼠和犬的药代动力学

目的　研究艾普斯特(epristeride)在动物体内药代动力学,为临床试验提供依据。方法　采用HPLC方法测定生物样品中药物浓度。结果　大鼠po epristeride 10,20和40 mg.kg^-1后,3个剂量的血清药物浓度出现明显双峰。Beagle犬po 10　mg.kg^-1后血药浓度未出现明显双峰。 大鼠po 20　mg.kg^-1后3 h, 大部分组织中含量高于药后6 h含量; 药后24 h内尿和粪的排泄量分别占给药量的0.09%和42.9%, 12 h内胆汁排泄的主要为代谢产物, 原型药物仅为给药量的0.14%。本品蛋白结合率为92.3%。结论　Epristeride在10～40 mg.kg^-1范围内呈现一级动力学特征, C_max, AUC均与剂量呈正相关。药物在组织脏器中分布广泛, 主要经粪和胆汁排泄。     

芪嘧啶的药代动力学

本文报告芪嘧啶在大鼠(150 mg/kg)和家兔(100mg/kg)一次ig的药代动力学研究结果。采用分光光度法测定生物样品中的药物浓度,用3P87实用药代动力学程序处理药物浓度数据,并自动算出各项动力学参数和C-T曲线图。主要参数t_(1/2ke),t_(peak),C_(max),CL和V_d在大鼠分别为6.55 h,1.32 h,9.5μg/ml,1.46 L·kg~1·h~1和13.8 L/kg,家兔分别为1.98h,1.00h,7.1μg/ml,4.09L·kg~1·h~(-1)和11.7 L/kg。结果表明药物在大鼠肝中达峰时间短,峰浓度高,清除较慢,在肝、肾含量高于其它组织。由尿粪排泄量小,72 h累计量仅为给药量的11.5％,而且排泄速度慢,一次给药后72 h仍有一定量药物由粪尿排泄。     

4-硝基二苯胺-4'-硫代氨基甲酸(O)苯酯的抗血吸虫作用及毒性

本文证明硝硫氰胺(C 9333-(Go/CGP 4540)类的衍生物4-硝基二苯胺-4′-硫代氨基甲酸(O)苯酯(代号7720)有与硝硫氰胺同等强度的抗血吸虫作用。用粗粉混悬液灌胃治疗小白鼠实验性血吸虫病,7720和硝硫氰胺的CD₅₀分别为79.0μmol/kg/d(即28.8mg/kg/d)×5日和83.4μmol/kg/d(即22.6mg/kg/d)×5日。7720 16或32 mg/kg/d×5d已可使所试全部病免达寄生虫学治愈。未能测出小白鼠灌胃急性LD₅₀。通过对幼年大白鼠体重增长影响的观察,家犬亚急性毒性试验及内脏组织病理学检查等提示本药经口给药无严重毒性反应。本文还证明4-硝基-4′-异硫氰基二苯醚对家兔实验性血吸虫病亦有较佳疗效。     

硝硫氰胺水溶性衍生物的合成

目的 将脂溶性抗血吸虫病药物硝硫氟胺转化为水溶性衍生物，简化血吸虫患畜治疗的给药方式。方法 通过化学手段引入水溶性基团进行结构改造。结果 合成数全水溶性衍生物。结论 硝硫氰胺的氨基酸衍生物的钠盐水溶性良好。     

人组织型尿激酶型纤溶酶原激活剂单次静脉给药大鼠体内半衰期、组织分布及排泄

目的评价人组织型尿激酶型纤溶酶原激活剂(HTUPA)在SD大鼠体内的半衰期、组织分布及排泄。方法以125I为示踪剂标记药物HTUPA,SD大鼠单次静脉注射不同剂量的HTUPA,于给药后各时间点采集眼眶血样、尿粪样本和胆汁样本,以及不同时间点处死的大鼠脏器样本,以放射性同位素示踪结合三氯乙酸沉淀法定量检测血浆浓度,分析药物半衰期、组织分布及排泄率。结果大鼠静脉注射1、2和4 mg/kg的HTUPA,其药物浓度-时间曲线符合二室模型特征,平均分布半衰期(t1/2α)分别为(5.62±4.22)、(6.37±4.93)和(6.57±4.13)min;平均消除半衰期(t1/2β)分别为(49.21±19.36)、(41.17±18.50)和(43.68±28.67)min,且剂量与药时曲线下面积呈正相关(r=0.998 5);单次静脉给药2 mg/kgHTUPA,肝肾组织中含量最高,脑含量最低;96 h经尿液和粪便的累计排泄量占总给药量的79.08%和15.40%,24 h胆汁累计排泄量占总给药量的6.67%。结论 HTUPA作为新一代溶栓候选药,体内分布速度快,半衰期适合。     

应用薄层扫描研究大鼠一次口服硝硫苯酯的药代动力学

本文建立了血浆中硝硫苯酯TLC扫描定量法,并可同时测定血浆中代谢物硝硫氰胺浓度。该法专一、灵敏。大鼠单剂ig硝硫苯酯200mg/kg后,血浆硝硫苯酯C_(max)为0.510μg.ml~(-1),t_(max)为6 h,药—时曲线符合二室模型。t1/2ka,t1/2a、t1/2β分别为1.503,2.829和17.769 h;k_(10),k_(21)和k_(12)分别为0.068,0.141和0.075h~(-1),∫_0~∞cdt为12.367μg·h·ml~(-1)。本文还证明硝硫苯酯在吸收后,有部分转变为硝硫氰胺,其C_(max)为0.283μg·ml~(-1),t_(max)为6 h。硝硫苯酯和硝硫氰胺曲线下∫_0~(36)cdt分别为9.211和4.644μg·h·ml~(-1),后者约为前者的50%。     

多索茶碱在大鼠体内的药代动力学

为全面了解多索茶碱在大鼠体内代谢情况,用高效薄层色谱法和光密度扫描法,给大鼠ig多索茶碱后,测定在不同时间各组织和体液中多索茶碱的含量。结果表明,多索茶碱在大鼠体内药代动力学为一室模型并能在体内迅速转化为其它代谢产物。T_1/2(Ke)为1.17～3.75h,达峰时间T(peak)为0.72～1.46h,Cmax,AUC及CL/F呈剂量依赖关系。给药1h,以胃壁浓度最高,8h除胃肠组织浓度降低较慢外,其它组织中药物浓度明显降低。尿、粪及胆汁中原形药总排出量占给药量的5.2%。血浆蛋白结合率约25%。提示多索茶碱在体内可能转化为其它代谢产物。     

国产湿痛喜康的毒性研究

给小鼠iv和ig国产湿痛喜康,LD_(50)分别为135±10.27和320±96mg/kg。给佐剂性关节炎大鼠ig湿痛喜康28d,体重增加,血清AKP、SGPT和BUH无明显改变。病解无明显形态学变化。给3条狗ig湿痛喜康16mg/kg, 每天1次,连用5d,两条中毒死亡,1条存活。另3条狗ig湿痛喜康16mg/kg,隔日1次,自首剂给药后10～20d达到稳态中毒血药浓度(分别为73.9,44.9,72.5μg/ml)。于给药后17～25d死亡。出凝血时间延长约2～3倍,血浆BUN值升高。病检除1条狗可见间质性肾炎和肝细胞局灶性坏死外,其余未见明显特征性改变,给大鼠ig湿痛喜康(5、10、20和40mg/kg),对消化道有损伤作用。UD_(50)为14.75mg/kg(95％可信区间为19.4～19.93mg/kg),与血药浓度呈平行关系。     

用生物鉴定法观察抗血吸虫新药吡喹酮在家兔体内的吸收、分布和排泄

用以血吸虫为标本的生物鉴定法,观察了抗血吸虫新药吡喹酮在家兔体内的代谢。自家免胃肠道的不同部位注入吡喹酮时,以小肠的吸收最好,直肠次之,而结肠和胃则较差。药物自小肠吸收后,周围静脉血浆的药浓度较门静脉的低10倍以上。家兔口服吡喹酮100mg/kg的血浆药浓度与皮下注射20mg/kg的相仿;肌肉注射吡喹酮20mg/kg的血浆药浓度较皮下注射的为高;若静脉注射相同剂量,则于注射完毕时虽有甚高的血药浓度值,但药物可迅速自血浆中消除。吡喹酮多次给药时无积蓄作用;若每4小时给药一次,连给3次,则可依次增加血浆的药浓度。家兔一次口服吡喹酮30分钟～4小时,以胃、小肠组织的含药量较高,肝、肾和脑等次之。给药后24小时,除胃和小肠外,其余脏器组织中的药物均已消除。此外,自服药兔的粪、尿中检获有生物活性的物质。     

硝硫氰胺对日本血吸虫作用的电子显微镜观察

本文通过透射电子显微镜观察感染日本血吸虫病的小白鼠经硝硫氰胺治疗后,其体内虫体体壁的超微结构的变化。结果表明,硝硫氰胺对血吸虫虫体壁包括表皮,肌层和皮层细胞的超微结构都有程度不等的影响。并且发现表皮内的二种主要包含物,多膜层小泡(M、L、V、)及盘状颗粒(D、G)的减少与消失对表皮的超微病理改变有密切的关系。同时,对血吸虫虫体标本超薄切片的制备方法也进行了探索。     

抗肿瘤药物的研究ⅩⅤ.AT-16对动物肿瘤的疗效

AT-16是由氯霉素基团与氮芥結合而成的新的化合物。根据其原有基团的性貭,推想到二者結合后的可能效用,我們研究了它对动物的实驗性抗癌作用及毒性表現。結果发現:(1)AT-16对大白鼠肉瘤M-57、Jensen瘤及小白鼠肉瘤180、脑瘤53、淋巴白血病固体型均有显著的抑制作用;其中以对肉瘤M-57及Jensen瘤的疗效最好,抑制率可达到94—99%以上,并可使长大的肉瘤M-57消退。(2)能使吉田腹水瘤大白鼠的生存时間比对照組延长6倍以上。(3)将AT-16給家兔連續灌胃10日,在接近中毒剂量组,可見到有白血球下降、食量減退、体重減輕等現象。(4)用不同剂量的AT-16給猴子連續灌胃14日,观察呼吸、心率、血压、心电图、血象、体重及粪便常規,結果只是50毫克/公斤/日剂量組有輕度白血球下降現象,停药后随即恢复。其他均未見异常。     

二苯乙烯(芪)的一些药理作用

芪(二苯乙烯)通常用于化学工业,对其药理活性的研究很少。通过动物实验我们发现芪能明显保护CCl₄引起的小鼠肝损害,表现在使高的SGPT及SGOT降低、BSP潴留减少、肝组织病变减轻等。芪明显促进肝糖元生成,此作用强度与可的松相近,但芪没有可的松那样的抗炎作用。在去肾上腺小鼠,芪仍能明显促进肝糖元生成,故此作用似乎不通过体内的垂体-肾上腺系统。芪对小鼠戊巴比妥睡眠时间影响不明显。根据实验资料分析,芪对CCl₄肝损害的保护机制大概不是通过酶诱导,也不象某些抗氧化剂那样直接对抗CCl₄的作用,但有可能与其促进肝糖元生成有某种关系。芪有微弱的雌激素作用(约为己烯雌酚的数万分之一)。芪的毒性很低,小鼠一次腹腔注射LD₅₀为6.5 g/kg,灌胃LD₅₀大于8 g/kg,但油溶液毒性较大(灌胃LD₅₀为0.92g/kg)。长期大量给予芪,对雄小鼠的生长及睾丸发育有抑制作用,给狗服芪50 mg/kg/天连续一个月以上未见明显异常反应。     

广地龙的降压作用和降压机制的探讨

本文对广地龙毒性、降压作用和降压机制作了初步探討。广地龙热浸剂给小鼠靜脉注射时,LD₅₀=38.5克/公斤。热浸剂(0.1克/公斤)連續給大鼠灌胃45天,未发現毒性反应。給麻醉狗按0.1克/公斤靜脉注射热浸剂或乙醇浸出液,在給药30—45分钟出現血压下降,一般可維持2—3小时。正常大鼠一次用大剂量(10克/公斤)灌胃或腎型高血压大鼠用个剂量(50毫克/公斤)长时間(2周)灌胃,均有明显的降血压作用。在后一种情况下,多数大鼠血压下降出現于給药的第3—7天,并于停药后第2周回升到用药前水平。广地龙降压机制可能是由于它直接作用于脊髓以上的中枢神經系統或通过某些內感受器反射地影响中枢神經系統,引起部分內脏血管的扩张而使血压下降。     

异汉防已甲素在大鼠体内的药代动力学及其组织分布

本文报道用反相高效液相色谱法测定生物样品中异汉防己甲素的含量,其最低检出极限可达10 ng/ml。大鼠ⅳ异汉防已甲素的时量曲线属二室开放模型。给大鼠ⅳ本品12.5及25mg/kg后,药物自血浆的消除符合线性动力学,但ⅳ50mg/kg后为非线性动力学。组织分布以肺脏含量最高,血浆最低。大鼠ig异汉防己甲素100及250 mg/kg后,其血浆的时量曲线呈明显的双峰现象。其组织分布以肝脏含量最高,血浆最低。     

Disposition of amiodarone and its proximate metabolite, desethylamiodarone, in the dog for oral administration of single-dose and short-term drug regimens

A comparative study of the plasma disposition and tissue distribution of amiodarone and its proximate metabolite, desethylamiodarone, for a single oral dose and short-term oral dosage regimens was conducted in the dog. Four groups of male mongrel dogs (six per group) received one of the following oral dosage regimens: single dose of 40 mg amiodarone/kg; 40 mg amiodarone/kg/day for 10 days and then 30 mg/kg/day for 4 days; 40 mg amiodarone/kg/day for 10 days, 30 mg/kg/day for 4 days, and then no treatment for 14 days; and 40 mg amiodarone/kg/day for 10 days, 30 mg/kg/day for 4 days, and then 20 mg/kg/day for 5 days/week for 2 weeks. The plasma and tissue amiodarone and desethylamiodarone concentrations were determined by HPLC. The plasma concentration of amiodarone was greater than that of desethylamiodarone for the four dosage regimens. The apparent plasma elimination half-life of amiodarone was prolonged following repeated drug administration (3.2 days) compared with a single drug dose (7.5 hr). There was extensive extravascular distribution of amiodarone and desethylamiodarone resulting in progressive tissue accumulation of drug and metabolite for the short-term regimens. For most of the dosage regimens, the concentration of amiodarone was greater than that of desethylamiodarone in left and right ventricles, thyroid gland, adipose tissue, and kidney, whereas the parent drug and metabolite concentrations were similar in lung, liver, and brain. There was predominant accumulation of amiodarone in adipose tissue and desethylamiodarone in lung. After cessation of amiodarone administration, there was rapid elimination of parent drug and metabolite from all tissues, except for amiodarone from adipose tissue.(ABSTRACT TRUNCATED AT 250 WORDS)     

大子蒿对下丘脑—垂体—肾上腺皮质系统的影响

Pharmacological effects of Tibetan medical plant Artemisia sieversiana on the hypothalamo-pituitary-adrenocortical axis are reported in present paper.The alcoholic (60%) extract of A. sieversiana (AEAS) injected intraperitoneally at 460 mg/kg in rats enhanced significantly the levels of corticosterone of the peripheral and adrenal venous plasma from 41±1.8 to 78±2.1 μg/100ml and from 1220±64 to 2020±56μg/ml (mean+SE) respectively. Administrations of AEAS at 3 g/kg orally or 460 mg/kg/day ip (for 6 days) also produced a marked increase. However, the increase was not detected in hypophysectomized rats. The effect of AEAS could be blocked completely by morphine in combination with pentobarbital, but not by pentobarbital alone, nor by prior injection of dexamethasone, chlorpromazine or cortisone acetate in rats under pentobarbital sodium anesthesia.We also demonstrated that in the same doses AEAS (ip) markedly increased the 5-HT content in the diencephalon of rats but not the 5-HIAA and NE contents. The action of AEAS which had been shown to result in the activation of the pituitary-adrenocortical system, was not abolished by prior treatment with reserpine at 4 mg/kg, but was completly blocked by the injection of atropine (250 μg) into the lateral ventricle of the brain. In intact rats AEAS produced a decrease of the amount of GABA in the diencephalon and significant increase of glutamine levels, while in adrenolectomized rats the effects were reversed.It is considered that the antiphlogistic effects of AEAS are due to its activation of ACh and 5-HT system and inhibition of GABA in the hypothalamus. Through the regulative action of the neurotransmitters, CRF is further activated, and, finally, it leads to the serial response of the pituitary-adrenocortical system.     

Augmentation of sulfate ion absorption from the rat lung by heavy metals.

In rats injected ip with 500 mg of cyclotrimethylenetrinitramine (RDX)/kg, the respective mean times to first seizure and to death were 23.8 and 171.0 min, and the mean plasma concentrations of RDX at seizure and death were 5.2 and 13.8 μg/ml. Following 100 mg/kg po, the plasma concentration was 2.1 μg/ml at 4 hr and 3.0 μg/ml at 24 hr, while the urine concentration was 5.5 μg/ml at 4 hr and 6.9 μg/ml at 24 hr. In the 6 days following 50 mg/kg po, 0.7% was excreted as RDX in the feces and 2.4% in the urine. Irrespective of dosage or route of administration, the concentration of RDX was greatest in kidney, most variable in liver, and did not accumulate in the brain. Twenty-four hours after po dosing with 50 mg of [¹⁴C]RDX/kg, the liver and urine contained large amounts of RDX metabolites, and, after the first 4 days, 90% of the total radioactivity was recovered: 34% in the urine, 43% as ¹⁴CO₂, 3% in the feces, and 10% in the carcass. In miniature swine dosed with 100 mg/kg po, the plasma concentration was 1.6 μg/ml at 2 hr and 4.7 μg/ml at 24 hr, while the urinary concentration was 2.0 μg/ml at 2 hr and 3.6 μg/ml at 24 hr. At 24 hr, the concentrations of RDX in brain, heart, liver, kidney cortex, kidney medulla, and fat were between 4.4 and 9.1 μg/g. Convulsions in pigs occurred 12–24 hr after dosing with RDX.