氧代赖氨酸的抗癌及药理实验研究

氧代赖氨酸系我所抗菌素室从辽宁省大连地区土壤中分离得到的新种玫瑰录褐链霉菌(Streptomyces roseoviridofuscus n sp)所产生的抗菌素。经动物实验证明对多种实体瘤有效,本文继续报道以不同给药途径和给药方案对脑瘤-22小鼠的治疗作用。用氧代赖氨酸的总量为1～1.5g/kg,于按种后不同时间以腹腔、尾静脉、肌肉、口服给药,对脑瘤-22均有明显治疗作用,其抑制率为47～78％。氧代赖氨酸200～400 mg/kg静脉注射对狗的血象、肝、肾功能,心电图影响不明显,100 mg/kg剂量对猴也无毒性反应。以氚标记的氧代赖氨酸对实验小鼠进行研究,表明口服吸收良好。静脉注射或口服200mg/kg,均以肝放射性为高,瘤中放射性虽不高,但能维持48小时以上。放射性排出以肾脏为主,静脉注射后24小时从尿中排出约为63％。     

3H-莪术醇在正常大鼠及肿瘤小鼠体内的代谢研究

³H-莪术醇自大鼠胃肠道吸收迅速且完全。灌胃后5分钟血中即有放射性,15分钟达高峰,1小时仍保持较高浓度,放射性自血中消失的生物半衰期为11.5小时(t_(1/2)β)。静脉注射后血中放射性的消失分快、慢两相,生物半衰期分别为33分钟(t_(1/2)α)及12.5小时(t_(1/2)β)。放射性在正常大鼠体内分布情况与肿瘤小鼠者相似。肝及肾组织含量约为其它组织的2～2.5倍。肿瘤组织中的分布与其它组织无明显差别;组织中放射性的消失与血浆中者略呈平行关系。放射性与脂肪组织似有较强的亲和力,给药后4小时仍维持较高水平。放射性主要自尿排泄,口服或静脉注射后24小时分别自大鼠尿排出剂量的45.38%及51.91%。胆汁为另一排泄途径,大鼠口服或静脉注射后24小时,分别自胆汁排出36.47%及56.43%,而口服或静脉注射后72小时仅从粪回收6.77%及14.35%,可见,自胆汁排出的放射性大部分均又被重吸收入血。     

氧代赖氨酸对持瘤小鼠免疫功能影响的初步研究

用Winn试验观察氧代赖氨酸对持瘤小鼠免疫功能的影响,结果显示经药物治疗后持瘤小鼠的脾细胞与瘤细胞温育后再接种之平均瘤重明显低于未经处理的对照组,p<0.05,提示氧代赖氨酸能部分激活持瘤小鼠脾脏中的某些免疫活性细胞。用α-萘酚醋酸酯酶染色法观察小鼠外周血及脾脏中T淋巴细胞的含量。小鼠接种肿瘤后第3、6、9天ANAE~+ T淋巴细胞值与正常小鼠相比无明显变化(p>0.05)。经氧代赖氨酸(100、150、200mg/kg)治疗,所得结果相似,也无明显变化。     

~3H-莪术醇在正常大鼠及肿瘤小鼠体内的代谢研究

~8H-莪术醇自大鼠胃肠道吸收迅速且完全。灌胃后5分钟血中即有放射性,15分钟达高峰,1小时仍保持较高浓度,放射性自血中消失的生物半衰期为11.5小时(t_(1/2)β)。静脉注射后血中放射性的消失分快、慢两相,生物半衰期分别为33分钟(t_(1/2)α)及12.5小时(t_(1/2)β)。 放射性在正常大鼠体内分布情况与肿瘤小鼠者相似。肝及肾组织含量约为其它组织的2～2.5倍。肿瘤组织中的分布与其它组织无明显差别;组织中放射性的消失与血浆中者略呈平行关系。放射性与脂肪组织似有较强的亲和力,给药后4小时仍维持较高水平。 放射性主要自尿排泄,口服或静脉注射后24小时分别自大鼠尿排出剂量的45.38％及51.91％。胆汁为另一排泄途径,大鼠口服或静脉注射后24小时,分别自胆汁排出36.47％及56.43％,而口服或静脉注射后72小时仅从粪回收6.77％及14.35％,可见,自胆汁排出的放射性大部分均又被重吸收入血。     

麦迪霉素的药理研究

本文概要的报告了麦迪霉素的药理研究。在急性毒性实验中,小鼠口服麦迪霉素的半数致死量(LD_(50))为5900±400mg/kg,腹腔注射的半数致死量为275±7mg/kg。在用狗所做的亚急性毒性实验中证明麦迪霉素的毒性较小。给家兔一次口服200mg/Kg,血浓度在30分钟达到高峰,约为7.54微克/毫升。24小时由尿中排出率为1.99％。给大鼠一次口服 200mg/kg,组织中的浓度以肝组织最高,其次为脾、肾、肺和胰,在脑组织中未能测出。     

唑来膦酸急性毒性试验研究

按新药审批“急性毒性试验”的要求与方法 ,用昆明小鼠以灌胃、静脉注射两种给药途径进行了唑来膦酸急性毒性试验。结果显示 ,昆明小鼠口服给药受试物 LD50 为 713 .5 ( 667.8～ 763 .2 ) mg/kg;静脉给药 LD50 为 13 .8± 0 .8( 12 .6～ 14 .3 ) mg/kg。     

云芝多糖在小鼠体内的抗病毒和免疫促进作用

云芝多糖是从担子菌杂色云芝培养物中提出的多糖。胞内多糖(IPPV)是从云芝深层培养菌丝体细胞内提出的一种匍聚糖,小鼠口服或腹腔注射,可显著保护流感病毒静脉感染所致死亡和肝脏病理损伤,口服最小有效量500mg/kg一次或每日一次 3日都有效;腹腔注射50～200mg/kg一次有效,多次给药无效。腹腔注射100mg/kg一次,对小鼠疤疹病毒静脉注射所致死亡和肝病变有23.8～28.6％的保护作用,但无统计学意义。胞内多糖腹腔注射50mg/kg一次,可促进小鼠肝Kupfer细胞吞噬功能,防止静脉注射流感和疱疹病毒所引起的Kupfer细胞吞噬功能抑制。胞内多糖和自云芝深层培养液提出的胞外多糖(EPPV)腹腔注射小鼠,可诱生血清干扰素,胞外多糖诱生干扰素滴度高于胞内多糖。进一步工作有可能提高云芝多糖的疗效。     

碘化二甲基木防己的降压作用

本文报告碘化二甲基木防己碱(DTI)降压作用的研究。DTI给麻醉动物静脉注射,对狗0.05～0.1 mg/kg使血压下降42.3～61.5%,持续1小时左右恢复至原血压水平;对猫0.00625～0.0125 mg/kg使血压下降26.5～43.5%,持续2～4小时恢复至原血压水平;对兔0.005～0.01 mg/kg使血压下降24.3～61.0%,5小时不能恢复至原血压水平;0.5～1.0 mg/kg使大鼠血压下降27.2～41.1%。DTI的降压作用机制主要与其对神经节的阻断作用有关。本药对小鼠口服和静注的LD₅₀分别为522.0 mg/kg及2.23 mg/kg。     

毛萼乙素纳米混悬剂.Ⅱ.对小鼠肝癌H22移植瘤的生长抑制作用

采用小鼠肝癌H22移植性肿瘤模型,考察不同给药途径和剂量下,毛萼乙素纳米混悬剂的抗肿瘤作用及毒性.在适宜的给药剂量下,毛萼乙素纳米混悬剂经静脉注射、腹腔注射和灌胃3种途径给药均可抑制小鼠肝癌H22移植瘤的生长,并呈现明确的量效关系,但其毒性也随着剂量的增加而明显增大.在10 mg/kg的剂量下,腹腔注射的抑瘤作用优于静脉注射;但该途径给药产生的毒性也比静脉注射大.灌胃给药的抑瘤作用最弱,且高剂量时会产生严重的胃肠道不良反应.     

Norfloxacin和其他喹诺酮类药物的药物动力学比较

喹诺酮类药物口服吸收良好。口服Norfloxacin1～2小时后即出现峰浓度。血药和尿药浓度随给药剂量的增加而增高。单次口服200和400 mg后峰血药浓度各为0.8±0.2和1.6±0.6mg/L。如果本品和食物一起口服,峰浓度稍见推迟,血药浓度曲线下的总面积则无变化。本品多次给药无蓄积作用。每8小时口服200mg,连服7日,血药浓度在2天内达到稳态。无论剂量如何,给药后48小时内约有25～40％的药物以原形通过肾小管主动分泌经尿排出。单次给药     

抗肿瘤药物的研究 ⅩⅦ.Sb-71对Zn65渗入Ehrlich腹水瘤细胞的影响

文献报导恶性肿瘤的发生和生长与某些微量金属有密切的关系。鉴于絡合剂可影响机体微量元素的代謝,所以作者在研究Sb-71的作用机制时,着重探討它及其类似物对Zn⁶⁵渗入瘤細胞的影响,結果如下: (1)Sb-71及其类似物(ATA以及Hg,Bi,Pb,Sn和Ba的EDTA螫合物)以不同浓度加入Ehrlich瘤細胞腹水液,在体外37℃溫孵,在3小时內均对Zn⁶⁵渗入瘤細胞有一定的抑制作用,其抑制率为22—60%不等。其中以ATA和Sb-71的抑制作用較强。但吐酒石则无明显的抑制作用。(2)Sb-71剂量30毫克/公斤腹腔注射,对Zn⁶⁵渗入小鼠Ehrlich腹水瘤細胞有非常明显的抑制作用,以給药后5—7小时作用最显著,主要是使核蛋白中的脉冲数減少,12小时后逐渐接近于对照組水平。渗入肝組織蛋白的放射强度并不受药物的影响,表示其作用有明显的組織选择性。ATA同样剂量腹腔注射則无明显的抑制效能,相反的可以促进腹水清液中Zn⁶⁵的減少。(3)EDTA-Hg、EDTA-Bi和EDTA-Pb剂量分别为4,10和200毫克/公斤腹腔注射时,对Zn⁶⁵渗入小鼠Ehrlich腹水瘤細胞的影响均不如Sb-71明显,除EDTA-Hg組总氮脉冲数較对照組明显減少外,其他与对照組比較均无显著的差异。     

低效价肝素对兔主动脉壁摄取125Ⅰ-胆固醇的影响

低效价肝素(38 U/mg)50 mg/kg,给家兔iv,可抑制兔主动脉壁摄取¹²⁵I—CH,在第12h,抑制率为53%,对已被去甲肾上腺素损伤的动脉内皮,肝素仍可降低主动脉壁¹²⁵I-CH的摄取量,抑制率为34.6%。iv¹²⁵I-CH 50μCi/kg 12 h后,备组血中¹²⁵I-CH的cpm无显著差异。但动脉壁与血中cpm的比值差异非常显著,一次iv后,肝素降低动脉内皮通透性的作用可持续24h以上。     

高三尖杉酯碱在大鼠及小鼠的代谢

本文报告³H-高三尖杉酯碱在正常大鼠、小鼠和荷瘤小鼠体内的吸收、分布和排泄。给大鼠静注后,t_1/2(α)和(β)分别为2.1和53.7分钟。静注后15分钟,以骨髓、肾和肝的放射性最高。荷瘤小鼠体内的放射性分布情况与正常大鼠的趋势相仿。静注后24小时,自大鼠尿排泄剂量的42.2%,在粪中排出6.3%,其中原形药放射性占剂量的15.9%。静注后48小时,自胆汁排泄剂量的57.7%,其中原形药放射性占剂量的20.2%。该碱经肌注也可被迅速吸收入血。     

Distribution and metabolism of 14C-sulfoquinovosylacylpropanediol (14C-SQAP) after a single intravenous administration in tumor-bearing mice

1. Sulfoquinovosylacylpropanediol (SQAP) is a novel potent radiosensitizer that inhibits angiogenesis in vivo and results in increased oxigenation and reduced tumor volume. We investigated the distribution, metabolism, and excretion of SQAP in male KSN-nude mice transplanted with a human pulmonary carcinoma, Lu65.

2. For the metabolism analysis, a 2?mg (2.98?MBq)/kg of [glucose-U-¹⁴C]-SQAP (CP-3839) was intravenously injected. The injected SQAP was decomposed into a stearic acid and a sulfoquinovosylpropanediol (SQP) in the body.

3. The degradation was relatively slow in the carcinoma tissue.1,3-propanediol[1-¹⁴C]-SQAP (CP-3635) was administered through intravenous injection of a 1?mg (3.48?MBq)/kg dose followed by whole body autoradiography of the mice.

4. The autoradiography analysis demonstrated that SQAP rapidly distributed throughout the whole body and then quickly decreased within 4 hours except the tumor and excretion organs such as liver, kidney.

5. Retention of SQAP was longer in tumor parts than in other tissues, as indicated by higher levels of radioactivity at 4 hours. The radioactivity around the tumor had also completely disappeared within 72 hours.

     

Dopamine and interscapular fat hemorrhage in the rat pup

Female Sprague-Dawley rats were given dopamine during gestation. Several hours after birth, interscapular adipose tissue hemorrhages appeared in some of the offspring of dopamine-treated rats. Dopamine (10 mg/kg/day ip) administered during Days 1–7, 8–14, and 15–21 of gestation caused hemorrhages in 14.8, 6.2, and 0.0% of the offspring, respectively. Only 1.9 and 1.6% of 21-day fetuses from rats given either dopamine (10 mg/kg/day ip) or saline, respectively, during Days 1–7 of gestation had hemorrhages in the interscapular fat. During Days 1–7 of gestation, dopamine (10 mg/kg/day) given intramuscularly produced hemorrhages in only 3.0% of the offspring; intraperitoneal administration led to 14.8% hemorrhage. Female rats were given a single dose of 2.0 μCi of [¹⁴C]dopamine (10 mg/kg ip) on Day 7 of gestation and sacrificed after birth. No radioactivity was detected in the interscapular fat, liver, kidney, or brain of the newborn pups. Only the maternal adrenal gland and kidney contained measurable radioactivity (0.011 and 0.006% of the dose per gram of tissue). Moreover, rats given 0.5 μCi of [¹⁴C]dopamine (10 mg/kg im) on Day 3 of gestation excreted 99.9% of the radioactivity in their urine within 4 days. Neither vaginal norepinephrine content nor adrenal tyrosine hydroxylase activity in 21-day pregnant rats was altered by dopamine treatment during Days 1–7 of gestation. Thus, neither exogenous dopamine nor endogenous catecholamines appear to be the final mediator of the hemorrhagic mechanism.     

Effects of salicylate on the incorporation of orotic acid into nucleic acids of mouse tissues in vivo

In mice, given intraperitoneal injections of orotic acid-5-³H, two peaks of incorporation of radioactivity at 30 min and 6 h occurred in the RNA of kidney and of liver and its subcellular components. The concurrent administration of salicylate, in doses of 200 mg/kg body weight and above, significantly inhibited the incorporation of the labelled orotic acid at 30 min but not at 6 h.     

Pharmacokinetics and Biodistribution of a Nucleotide-Based Thrombin Inhibitor in Rats

Purpose. To characterize the pharmacokinetic and tissue distribution profiles of a nucleotide-based thrombin inhibitor (GS522, phosphodiester oligonucleotide, GGTTGGTGTGGTTGG) following intravenous administration to rats. Methods. Pharmacokinetic study: 10 mg/kg, 20 mg/kg, 30 mg/kg (6 animals/dose) were administered to rats by rapid injection into the femoral vein. Blood samples were collected over a 45 minute period. Plasma concentrations of GS522 were determined using capillary gel electrophoresis with laser-induced fluorescence detection. Biodistribution Study: l0mg/kg (400l, 31.46 Ci/ml) of ³H-GS522 was administered to rats by rapid injection into the femoral vein. The animals were sacrificed by decapitation at 1, 5, 10, 30, 60, 360 minutes post-dose (3 rats/point). Brain, blood, duodenum, eyes, heart, kidney, liver, lungs, muscle, pancreas, skin, spleen and vein samples were collected, processed and quantitated using liquid scintillation counting. Results. The pharmacokinetic profile declines in multiexponential manner, exhibiting extremely fast distribution and elimination (t_1/2 = 7.6–9.0 min, Cl = 22.0–28.0 ml/min, V = 83.9–132.4 ml/kg). GS522 follows linear pharmacokinetics, with the area under the curve being proportional to the dose (Rsq = 0.9744). Highest radioactivity levels were detected in kidney, liver and blood (39.7, 15.7 and 15.3% dose/ respective organ). Less than 1% of the dose was detected in the heart, spleen and lungs, and >0.3% of the dose was found in the brain and eyes. The oligonucleotide associated radioactivity was uniformly distributed between the brain regions (left and right lobe and cerebellum). Six hours following the dose administration a statistically significant increase (p < 0.05) in radioactivity levels was observed in the brain, eyes, skin, liver, pancreas and vein. Conclusions. The pharmacokinetic and biodistribution profiles of GS522 following intravenous administration to rats at three doses were characterized. The oligonucleotide associated radioactivity was widely distributed in tissues. The amount of radioactivity sharply decreased with time in most tissues. Kidney, liver and muscle were the main sites of accumulation. The oligonucleotide associated radioactivity did not cross the blood brain barrier to an appreciable extent. In addition, a statistically significant increase (p < 0.05) in the radioactivity levels observed in select tissues suggested a re-uptake mechanism for intact oligonucleotide or its degradation products.     

黄花夹竹桃次甙乙的药代动力学研究

本文研究[³H]标记的黄花夹竹桃次甙乙(Neriifolin简称次甙乙)在大鼠体内的药代动力学。静脉注射后[³H]-次甙乙在血浆中的消除半衰期(T_1/2β)为5天,分布容积(Vd)为15.3L/kg。药物的主要分布在肝脏、胆汁和胃肠道内。灌胃给药吸收迅速完全,30 min血药浓度即达高峰。无论静脉注射或灌胃后,放射性主要从粪中排出,尿中较少,排出形式主要是代谢产物。[³H]-次甙乙与血浆蛋白的结合为91.7%。结果表明:次甙乙在大鼠体内的药代动力学特点与一般亲脂性强心甙相似。     

当归(Angelica sinesis)及其成分阿魏酸钠对小鼠吞噬功能的影响

当归为中医常用的补血活血药之一。设想当归的补血活血可能和增强机体免疫功能有关,故进行本项研究。实验分两部分:(1)给小鼠静脉注射当归16g/kg或阿魏酸钠100～200mg/kg均能显著地促进单核吞噬细胞系统对刚果红的廓清率。(2)给小鼠灌胃阿魏酸钠0.3g/kg或皮下给0.2g/kg能增强腹腔巨噬细胞吞噬鸡红细胞的能力。皮下给当归20g/kg也有增强作用。