尿肾损伤分子-1对药物肾毒性诊断性能的研究

目的 在庆大霉素诱导大鼠急性肾损伤模型中评价尿肾损伤分子-1(Kim-1)作为肾毒性生物标志物的诊断性能。方法 ip 60和120 mg/kg庆大霉素,每天给药1次,连续10 d,制备大鼠急性肾损伤模型。在给药第2、4、8、11天,进行肾脏组织病理分析,检测尿液Kim-1、血清尿素氮(BUN)和肌酐(Cr)水平。结果 病理学结果显示,庆大霉素组大鼠出现典型肾损伤变化,呈明显的剂量及时间相关性;与对照组比较,庆大霉素低、高剂量组尿液Kim-1浓度在给药第4天即开始出现显著升高(P<0.05),增幅程度明显高于传统指标BUN和Cr,并且呈显著剂量和时间相关性;受试者操作特性曲线(ROC)结果表明,尿Kim-1的曲线下面积(AUC)明显优于BUN和Cr。结论 尿Kim-1的肾毒性诊断性能优于传统肾功能评价指标,可作为一种药物肾毒性的候选生物标志物。     

抗HER2靶点抗体偶联药物大鼠重复给药毒性研究

目的：通过对大鼠尾静脉重复注射给药重组抗HER2人源化单克隆抗体偶联美登素衍生物DM1,对其进行临床前安全性评价。方法：大鼠随机分成5个试验组,包括空白对照组、受试物低（5 mg·kg^-1）、中（11 mg·kg^-1）、高（22 mg·kg^-1）剂量组和已知对照药品组（22 mg·kg^-1,Kadcyla?）,每组30只动物,雌性各半。尾静脉注射给药,每周给药1次,连续给药3次,末次给药后恢复3周。研究期间,在不同时间点对动物临床症状、体重、摄食量、体温、尿液、血液学、血清生化及组织病理学等指标进行检测。结果：给药后,动物出现一定程度的不良反应,且作用强度呈剂量依赖性递增。毒副反应症状包括摄食量减少、尿液pH值改变;血液学检查发现,动物Lymph、RBC、HGB、HCT、MCV、MCH、MCHC、APTT下降,WBC、Neut、Mono、Eos、Baso、Retic计数升高;血清生化检查发现,动物TG、A/G、Na⁺、K⁺下降,ALT、AST、ALP、GGT、CHO、LDH、BUN、TP升高;骨髓检查发现,受试物影响动物红系细胞成熟分化;受试物引起动物肝脏、脾脏、肺（含支气管）重量增加,睾丸、附睾重量减少;组织病理学检查发现,肝脏、肾脏、脾脏、垂体、肾上腺、舌、皮肤细胞有丝分裂项增加,睾丸生精细胞数目减少和变性坏死,附睾精子减少和纤维组织增生。对照品组动物,给药后出现上述同样的改变。试验结果表明,受试物和已知对照药品两种药物的大鼠毒性研究结果具有相似性。结论：大鼠尾静脉重复注射给予重组抗HER2人源化单克隆抗体偶联美登素衍生物DM1后,毒性靶器官为肝脏、肾脏、脾脏、胸腺、肺（含支气管）、肠系膜淋巴结、十二指肠、睾丸、附睾、眼球、垂体、肾上腺、皮肤、舌、胸骨（骨髓）。未见毒性反应剂量（NOAEL ≤ 5 mg·kg^-1）。上述研究结果支持该药物成功获得临床试验批准,为后续开展临床研究提供了参考依据。     

酒石酸长春瑞滨胶束重复给药对Beagle犬肝、肾毒性研究

目的 研究长期重复给予注射用酒石酸长春瑞滨胶束（NVB-m）对Beagle犬肝、肾毒性的影响,同时设同类市售注射用酒石酸长春瑞滨（NVB）进行毒性比较研究。方法 Beagle犬48只,按体质量、性别随机分为对照组、空白胶束组、NVB组和NVB-m 6、12、24 mg/m²组,每组8只。NVB组给予24 mg/m²剂量的NVB,空白胶束组给予相同浓度的空白胶束,对照组给予生理盐水,静脉给药。进行一般状态观察,称取Beagle犬体质量,取血检测血清生化指标,采集尿液检测尿常规,大体解剖称量肝、肾质量,计算脏器系数并做组织病理学检查。结果 一般症状检查可见,NVB组、NVB-m 12、24 mg/m²组在给药期间有食欲不振、食量减少甚至拒食等症状,随给药次数增加而减轻。动物体质量在试验期间未见明显异常。血清生化检查可见,与对照组比较,给药期间NVB组及NVB-m 6、12、24 mg/m²组天冬氨酸转氨酶（AST）、天冬氨酸转氨酶（ALT）、总胆红素（TBIL）升高,总蛋白（TP）、白蛋白（ALB）降低,其中NVB-m 24 mg/m²组对动物TP影响较NVB组轻微;NVB组及NVB-m 24 mg/m²组动物ALT升高（部分组别部分时间差异显著P<0.05、0.01）,恢复期可恢复正常。尿生化检查、大体解剖及脏器质量检查、组织病理学检查未见明显异常。结论 NVB-m长期给药对Beagle犬有轻微肝毒性,主要表现为肝功指标异常;NVB-m对Beagle犬无肾毒性;NVB-m与NVB没有明显肝、肾毒性差异。     

比较万古霉素持续输注与间断输注引起肾毒性的荟萃分析

目的 比较万古霉素两种给药方式（持续输注与间断输注）引起的肾毒性。方法 计算机检索Embase、PubMed、The Cochrane Register of Controlled Trials和CBM、CNKI、万方数据库。采用Cochrane协作网提供的Revman5.2软件进行Meta分析。结果 共纳入2篇随机对照试验（RCT）和8篇观察性研究,共纳入患者1 764例,其中持续输注1 037例,间断输注727例。持续输注与间断输注引起的肾毒性发生率无显著性差异（P>0.05）。结论 万古霉素持续输注较间断输注不能有效降低肾毒性的发生率。     

补骨脂水提药渣大鼠三个月长期毒性试验研究

目的 研究补骨脂水提药渣大鼠ig给药的长期毒性。方法 SD大鼠70只,按体质量、性别随机分为5组：对照组、补骨脂生药粉高、低剂量组,补骨脂水提药渣高、低剂量组（各组高、低剂量均相当于生药6、3 g/kg,分别为临床等效剂量的11.11、5.56倍）,每组14只,雌雄各半,每日ig给药1次,连续给药12周。每周称大鼠体质量,药结束后,取心脏、肝脏、脾脏、肾脏、胸腺,称质量并计算脏器系数;血细胞分析仪检测血液学指标;全自动生化仪血清生化学指标;试剂盒法检测大鼠肝脏中氧化应激指标;做肝脏和肾脏组织病理学检查。结果 与对照组比较,生药粉和药渣高剂量组雄性大鼠体质量均显著下降（P<0.05）,而药渣组雌性大鼠体质量随给药时间延长无显著性变化;补骨脂生药粉和水提药渣雌性、雄性大鼠的肝系数均显著升高（P<0.01）;雄性大鼠生药粉和药渣高剂量组、雌性大鼠生药粉组和药渣高剂量组肾系数显著升高（P<0.05、0.01、0.001）;雄性大鼠生药粉高剂量组血小板（PLT）水平,药渣低剂量组红细胞（RBC）水平显著升高,生药粉低剂量组和药渣低剂量组白细胞（WBC）水平,药渣高剂量组PLT水平显著下降,雌性大鼠各给药组PLT均显著下降（P<0.05）;雄性大鼠生药粉组碱性磷酸酶（ALP）和三酰甘油（TG）水平均显著下降,总蛋白（TP）水平显著升高,生药粉低剂量组尿素氨（BUN）水平显著下降（P<0.05、0.01、0.001）;药渣高剂量组TP和白蛋白（ALB）、药渣低剂量组天冬氨酸转氨酶（AST）显著升高,丙氨酸转氨酶（ALT）和ALP显著下降（P<0.05、0.01、0.001）;雄性大鼠生药粉高剂量组和药渣组丙二醛（MDA）显著升高（P<0.05）,雌性大鼠生药粉组MDA和总抗氧化能力（T-AOC）、药渣组MDA均显著下降（P<0.05、0.01）。结论 长时间给予大剂量补骨脂水提药渣,对大鼠肝脏和肾脏功能均造成一定损害。     

朱砂及含朱砂制剂的肝肾毒性研究

目的 探讨朱砂、含朱砂制剂（柏子养心片）及甲基汞对大鼠的体内外毒性,为其临床安全用药提供科学依据。方法 ①对比甲基汞、朱砂及柏子养心片体外对人肝HL-7702细胞和人肾近曲小管上皮HK2细胞的毒性,计算半数抑制浓度（IC₅₀）。②SD大鼠随机分为对照组,朱砂组0.1 g/kg,柏子养心片0.2、0.4、0.8 g/kg组,甲基汞组0.001 g/kg,每天ig 1次,连续给药90 d后,取血及肝、肾组织;试剂盒法检测血清中丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、肌酐（CREA）、尿素氮（BUN）水平,测汞仪固体直接进样法检测肝、肾组织中汞蓄积量,并对大鼠肝脏和肾脏做组织病理学检查。结果 体外试验表明,朱砂、柏子养心片及甲基汞对HL-7702细胞的IC₅₀分别为7.852、6.035、0.009 5 g/L;对HK2细胞的IC₅₀分别为6.297、4.484、0.008 9 g/L。亚慢性毒性试验表明,甲基汞组大鼠肝、肾组织中汞蓄积量及血清中ALT、AST、CREA、BUN值均显著高于对照组,而朱砂及柏子养心片（高、中、低剂量）组与对照组比较均没有显著性差异;甲基汞组大鼠肝脏呈现肝细胞变性,肾脏可见明显肾小管损伤,而朱砂及柏子养心片（高、中、低剂量）组与对照比较没有明显差异。结论 朱砂及柏子养心片的体内外毒性均显著低于甲基汞,在目前药典规定的临床用量下使用安全性较好。     

双膦酸盐类药物致肾毒性的Meta-分析

目的 采用系统评价的方法研究双膦酸盐对患者肾毒性发生率、肌酐和尿素氮的影响。方法 计算机检索Pubmed,Embase,Cochrane Library,中国学术期刊全文数据库（CNKI）、中国生物医学文献数据库（CBM）、维普数据库（VIP）和万方数据库,从建库起到2018年1月25日,限定语言为英语和汉语的随机对照试验（RCT）和前瞻性非随机对照试验。筛选文献,提取数据,运用Stata 12.0进行系统评价。结果 最终纳入8个RCTs和8个前瞻性非随机对照临床试验,共11 240名患者。Meta-分析结果显示：与对照组相比,双膦酸盐显著增加患者发生肾毒性的风险[OR=1.58,95%CI（1.28,1.95）,P<0.000 1];而双膦酸盐治疗组与对照组比较,在血清肌酐和尿素氮方面,无显著性差异[MD=-1.06,95%CI（-5.43,3.30）,P=0.63;MD=-0.07,95%CI（-0.32,0.19）,P=0.61]。通过对患者使用的双膦酸盐种类、患者基础疾病、患者的平均年龄、不同试验类型以及给药途径进行亚组分析,双膦酸盐组肌酐值与对照组亦无统计学差异。结论 双膦酸盐明显增加了患者发生肾毒性的风险,但血清肌酐和尿素氮两种肾脏指标并无显著性差异。建议在今后双膦酸盐的应用中纳入更多肾毒性相关指标,以帮助临床更早的发现患者的肾损害。     

利用1H-NMR技术研究大黄素染毒后大鼠内源性代谢物的改变

目的 采用¹H NMR的代谢组学技术揭示大黄素的肾毒性机制,寻找肾脏损害的早期生物标志物.方法 雄性SD大鼠20只,随机分为溶剂对照,大黄素170、500、1 500 mg/(kg·d)3个剂量组,连续给药16 d,给药结束后收集24 h尿液,血浆及肾组织,测定¹H NMR谱,并进行血浆生化指标测定和肝脏组织病理学检查.结果 1 500 mg/(kg·d)大黄素服用16 d可引起大鼠血肌酐下降,大黄素可导致肾细胞胞浆中出现明显的空泡化改变.代谢成分的改变主要表现为血液中乳酸、糖、氨基酸和脂肪酸成分下降;尿液中乳酸、糖和氨基酸成分增加;肾脏组织中醋酸盐和肌酐/肌酸明显升高,乳酸和胆碱/磷酸卵磷脂水平下降,饱和与不饱和脂肪酸及磷脂的成分比例明显改变.结论 代谢组学分析在识别药物诱导代谢成分改变方面较传统技术更灵敏;脂肪和能量代谢紊乱参与了大黄素的肾毒性,尿液中氨基酸、葡萄糖氧化三甲胺(TMAO)及肌酐可作为大黄素诱导肾组织损害的潜在生物标志物.     

光泽汀体内遗传毒性风险评价

目的 评价光泽汀小鼠体内的遗传毒性。方法 C57BL/6J小鼠分为溶剂对照（0.5% CMC-Na）组、茜草素（200 mg·kg^-1，结构对照）组、乙酰基亚硝基脲（ENU，40 mg·kg^-1，阳性对照）组、甲基磺酸乙酯（EMS，200 mg·kg^-1，阳性对照）组和光泽汀低、中、高剂量（100、200、300 mg·kg^-1）组，溶剂、光泽汀和茜草素连续7 d ig给予，给药第1天记为D1，阳性对照ENU和EMS分别连续3 d给予，均每天给药1次。于D7、D56采集约0.5 mL外周血用于血清生化检测；于D14、D28、D42、D56采集外周血开展Pig-a基因突变试验；末次给药后采集肝、肾细胞开展彗星试验，分析每只动物至少100个细胞的尾DNA百分含量；末次给药后制备骨髓细胞样本，计算嗜多染红细胞的微核发生率。解剖后取心、肝、脾、肺以及肾脏进行组织病理学检查。结果 试验期间所有动物一般症状未见明显异常，各组动物体质量未见明显差异，未见与给予受试物有关的组织病理学改变。光泽汀低、中、高剂量组及EMS组肾脏尾DNA百分率均显著高于溶剂对照组（P<0.05、0.001），光泽汀高剂量组及EMS组肝脏尾DNA百分率与溶剂对照组比较显著增加（P<0.05、0.001）。光泽汀与茜草素的小鼠骨髓微核试验、Pig-a基因突变试验均为阴性。结论 100～300 mg·kg^-1光泽汀未见对小鼠整体产生明显毒性。光泽汀可导致小鼠肝、肾细胞DNA损伤，肾细胞DNA损伤程度更为严重。     

丹参注射液小鼠单次给药毒性试验研究

目的 观察单次静脉和腹腔注射给予丹参注射液后对小鼠产生的毒性。方法 采用经典半数致死量（LD₅₀）法进行小鼠单次给药毒性试验,动物分组后以不同的剂量静脉或腹腔注射给药1次,药后观察小鼠反应,检测体重和死亡率,连续观察14 d后剖检,观察主要脏器的病变。结果 丹参注射液小鼠单次静脉和腹腔注射给药半数致死量分别为：3.2 g·kg^-1和6.3 g·kg^-1。死亡小鼠毒性症状主要表现为俯卧不动、抽搐、呼吸困难,昏迷、尿失禁继而死亡。结论 丹参注射液大剂量腹腔和静脉注射可致小鼠全部死亡,但其半数致死量分别为临床用药剂量的65和129倍,安全范围较大。     

INDIRECT PARASYMPATHOMIMETIC ACTIVITY OF THE CLASS III ANTIARRHYTHMIC SUBSTANCE / -SOTALOLIN VITRO: REVERSIBLE INHIBITION OF CHOLINESTERASE ISOENZYMES FROM BLOOD AND THE HUMAN CENTRAL NERVOUS SYSTEM

Inhibitory effects of the class III antiarrhythmic compound / -sotalol on acetylcholinesterase (AChE; EC 3.1.1.7) isoenzymes of both erythrocytes and the human caudate nucleus and on serum cholinesterase (ChE; EC 3.1.1.8) were studiedin vitrousing a spectrophotometric kinetic assay with acetylthiocholine (ASCh) as substrate. Sotalol concentrations in the assays varied from 0.32 to 3.2m . All isoenzymes studied were inhibited by / -sotalol in a reversible and concentration-dependent manner. Double reciprocal plots of the reaction velocity against varying ASCh concentrations revealed that / -sotalol reduced substrate affinity (apparent Michaelis constant, KM, increased) of serum ChE, but did not change the enzyme's maximal rate of ASCh hydrolysis (V_max). Thus, / -sotalol inhibition of serum ChE was of the competitive type (rate constant for reversible competitive inhibition: K_i=0.51m ). In contrast, / sotalol reduced the maximal reaction velocity of the AChE isoenzyme from the central nervous system (caudate nucleus), but had no influence on substrate affinity of the enzyme (K_Mwith ASCh unchanged) indicating purely non-competitive inhibition kinetics (rate constant of reversible non-competitive inhibition: K_i′=0.44m ). / -sotalol inhibition of erythrocyte AChE was of mixed competitive/non-competitive type (K_i=0.31m , K_i′=0.49m ). Non-competitive / -sotalol inhibition of caudate nucleus AChE and the non-competitive component of erythrocyte AChE inhibition cannot be overcome by increased concentrations of the cholinergic transmitter acetylcholine (ACh). Peak / -sotalol plasma levels as described in the literature for both humans (15μ ) and experimental animals (dogs: 18μ ; rats: 260μ ) as well as maximal myocardial concentrations of the substance (dogs: 46μ ; rats: 478μ ) are in the range of about 2% to 100% of the sotalol inhibition rate constants determined in the present paper for cholinesterase isoenzymesin vitro. Thus, / -sotalol inhibition of ACh hydrolysisin vivomay contribute to both the well known antiarrhythmic potential and proarrhythmic side effects of the compound.     

Synthesis and evaluation of 2,6-piperidinedione derivatives as potentially novel compounds with analgesic and other CNS activities

New 2,6-piperidinediones 2_a–g and 4_a–d were prepared by initial condensation of aromatic aldehydes or cycloalkanones with cyanoacetamide to give α-cyanocinnamides l_a–g or cycloalkylidenes 3_a,b which underwent Michae1 addition with ethyl cyanoacetate or diethylmalonate. Compounds 4_a–d were alkylated by various alkyl halides to produce the N-alkylated 2,6-piperidinedione derivatives 5_a–m. Some new selected compounds 2_a–c,f, 4_a–d & 5_e,h,j were pharmacologically evaluated for potential anticonvulsant, sedative and analgesic activities. These compounds exhibited significant anticonvulsant and analgesic effects after a single I.P. administration 100 mg/kg b.wt. . On the other hand all the investigated compounds induced hypnotic activity and prolonged the phenobarbital sodium- induced sleep as compared with the control group and the most potent compound was found to be 2_f.     

EFFECT OF POLICOSANOL SUCCESSIVE DOSE INCREASES ON PLATELET AGGREGATION IN HEALTHY VOLUNTEERS

Policosanol is a cholesterol-lowering drug with hypocholesterolemic effects demonstrated in experimental models, healthy volunteers and type II hypercholesterolemic patients. In addition, antiplatelet effects of policosanol have been shown in experimental models and healthy volunteers. The effect of successively increasing doses of policosanol on platelet aggregation was investigated in a randomized, placebo-controlled, double-blind study conducted in 37 healthy volunteers. The volunteers were on a placebo-baseline period (two tablets per day) for 7 days and thereafter they received randomly, under double-blind conditions, placebo or policosanol (10mgday⁻¹) for 7 days. After this period dosage was doubled to 20mgday⁻¹for the next 7 days and then again doubled to 40mgday⁻¹, while the control group received placebo tablets all the time. Platelet aggregation as well as coagulation time was measured at baseline and after each dosing step. Results showed that antiplatelet effects of policosanol were successfully enhanced throughout the study, thus suggesting a dose-dependent relationship. No significant effect was reached during the first dosing period, but significant reductions of epinephrine and ADP-induced platelet aggregation were observed after the second one. Finally, a significant inhibition of platelet aggregation induced by all the agonists was observed at the last dosing step. Coagulation time remained unchanged during the trial.     

NEURAMIDE STIMULATES ADRENOCORTICOTROPIN BUT NOT PROLACTIN RELEASE FROM RAT PITUITARY

Neuramide (NMD), a substance found in crude preparations of porcine stomach extract, is a viral inhibitor that also has putative immunostimulatory effects. The effects of NMD on stress-hormone (ACTH and prolactin—PRL) release were assessed inin vivoandin vitrostudies. In the former, blood levels of corticosterone and PRL were measured in NMD-treated male rats.In vitroexperiments were performed to evaluate the effects of NMD and three of its fractions (obtained with high performance liquid chromatography) on ACTH and PRL release from perfused rat pituitary slices. NMD increased plasma corticosterone levelsin vivoand produced dose-dependent increases inin vitropituitary release of ACTH. No effects on PRL secretion were observedin vivoorin vitro. The stimulatory effects on ACTH release were caused by the NMD fraction with a molecular weight of >5000<10000Da.     

Investigation of the prevalence of tetQ, tetX and tetX1 genes in Bacteroides strains with elevated tigecycline minimum inhibitory concentrations

In this study, the antibiotic susceptibilities to tigecycline and tetracycline of 35 selected Bacteroides fragilis group strains were determined by Etest, and the presence of tetQ, tetX, tetX1 and ermF genes was investigated by polymerase chain reaction (PCR). tetQ was detected in all 12 B. fragilis group isolates (100%) exhibiting elevated tigecycline minimum inhibitory concentrations (MICs) (≥8 μg/mL) as well as the 8 strains (100%) with a tigecycline MIC of 4 μg/mL, whilst tetX and tetX1 were present in 15% and 75% of these strains, respectively. All of these strains were fully resistant to tetracycline (MIC ≥ 16 μg/mL). On the other hand, amongst the group of strains with tigecycline MICs < 4 μg/mL (15 isolates), tetQ, tetX and tetX1 were found less frequently (73.3%, 13.3% and 46.7%, respectively). All but two strains harbouring the tetQ gene in this group were non-susceptible to tetracycline, with a MIC > 4 μg/mL. These data suggest that in most cases tigecycline overcomes the tetracycline resistance mechanisms frequently observed in Bacteroides strains. However, the presence of tetX and tetX1 genes in some of the strains exhibiting elevated MICs for tigecycline draws attention to the possible development and spread of resistance to this antibiotic agent amongst Bacteroides strains. The common occurrence of ermF, tetX, tetX1 and tetQ genes together predicted the presence of the CTnDOT-like Bacteroides conjugative transposon in this collection of Bacteroides strains.     

鼻渊净胶囊的HPLC指纹图谱研究

目的 建立鼻渊净胶囊的高效液相色谱(HPLC)指纹图谱.方法 采用Agilent SB-C18(4.6 mm×250 mm,5μm)色谱柱,乙腈-水为流动相、以1.0 ml/min流速行梯度洗脱,检测波长210 nm,柱温30℃,洗脱时间为80 min.采用中药色谱指纹图谱相似度评价系统(2004A版)对检测出色谱进行...     

栝楼不同药用部位质量控制的研究进展

瓜蒌子、瓜蒌皮、瓜蒌、天花粉来源于栝楼的不同药用部位,4味药材均为常用的大宗药材,现行版《中国药典》对其制定的质量标准过于简单,无法科学合理地控制其质量。本文对瓜蒌子、瓜蒌皮、瓜蒌、天花粉安全性和有效组分的研究进行综述,明确了相关研究存在的问题并针对问题提出建议,为科学全面的药材及饮片标准的制定提供参考依据。     

生川乌配伍白蔹、白及反药组合在大鼠血中移行成分的研究

目的鉴定生川乌配伍白蔹、白及的入血成分,比较配伍前后血中移行成分的变化特征。方法大鼠ig给予生川乌配伍白蔹、白及提取物,收集血浆样品并采用UPLC-QTOF/MS法鉴定入血成分,由半定量分析比较配伍前后血中移行成分的变化。结果检测配伍组20个成分,均为来自于生川乌的原形成分,配伍组中双酯型生物碱的相对质量分数均显著降低,单酯型生物碱中苯甲酰乌头原碱的相对质量分数显著降低,醇胺型生物碱中宋果灵的相对质量分数显著降低,其他没有显著性变化。结论生川乌配伍白蔹、白及能够改变其血中移行成分的体内过程。     

AMELIORIATION OF CHEMICALLY-INDUCED HEPATOCYTE INJURY BY CYCLOSPORINE A

Cyclosporine A, beside its current applications, possesses potential hepatoprotective effects. This study was directed to investigate the effect of Cyclosporine A pretreatment on hepatic injury due to carbon tetrachloride (CCl₄) and -galactosamine. Rats were injected by two successive doses of Cyclosporine A (5mgkg⁻¹day⁻¹). Six hours after the second dose, 1mlkg⁻¹of CCl₄was administered i.p. Effects associated with Cyclosporine A pretreatment were examined by using isolated hepatocytes and hepatocytes that were immobilized and continuously perfused. -Galactosamine (5m ) was added directly to the perfusion medium. After isolation, hepatocytes were examined histologically by light and electron microscopy, immobilized and perfused for further metabolic functional activity evaluation. Cyclosporine A pretreatmentin vivoproduced hepatoameliorative effects of various degrees which were statistically significant as manifested by: (1) an increased trypan blue exclusion after CCl₄; (2) an improved ureagenesis after CCl₄; (3) a reduction in the lipid droplets accumulation in the cytoplasm produced by CCl₄administration; (4) well preserved cytoplasmic organelles as mitochondria, endoplasmic reticulum ER, nuclear chromatin structures that were altered by CCl₄; and (5) an increased hepatocytes survival in the agarose gel matrix, reduction of LD leakage and improvement of ureagenesis after -galactosamine addition to the perfusion medium. The beneficial effect of Cyclosporine A pretreatment in modifying hepatotoxicity of chemical insults merits further studies.     

EFFECTS OF 2-GUANIDINE-4-METHYLQUINAZOLINE ON GASTRIC ACID SECRETION IN RATS

In this study 2-guanidine-4-methylquinazoline (2-GMQ) appeared to decrease basal and stimulated gastric acid secretion, while structurally related compounds as dimethyl- biguanide, cyanoguanidine and 2-cyanoamino-4-methylpyrymidine did not. Thus, there is an antisecretory effect when the biguanide group is associated with a lipophilic structure. The antisecretive effects exerted by 2-GMQ are associated with anti H₂-histamine activity.The anti H₂-histamine nature of the effects of 2-GMQ was confirmed by the capacity of this compound of depressing the chronotropic activity of the isolated guinea pig auricle increased by histamine, as well as relaxant activity in rat uterus contracted by histamine, since both preparations are rich in H₂-histamine receptors.