Smad2/3信号分子在小鼠胚胎腭发育和腭裂形成中的表达

背景：部分学者通过体外器官培养研究认为全反式维甲酸干扰了Smad2/3在腭部的表达,具体机制尚不明确。目的：观察腭突Smad2/3信号分子在胚鼠腭部发育及腭裂形成过程中的表达变化。方法：54只C57BL/6J近交系孕鼠随机分为3组,在妊娠10d,实验组一次性灌胃全反式维甲酸100mg/kg诱导胚鼠两侧腭突不能在中线融合,建立腭裂畸形动物模型;植物油对照组灌胃10mL/kg橄榄油,空白对照组不做处理。结果与结论：在植物油对照组中,从妊娠13d18时到妊娠14d18时腭间充质细胞中Smad2/3免疫阳性表达逐步增高,至妊娠15d8时表达开始出现下降,实验组也表现为这一变化趋势,且同一组间表达较植物油对照组明显;在腭中嵴上皮细胞中,植物油对照组随着腭突的融合,腭中嵴上皮带消失,Smad2/3表达也明显下降,实验组始终未融合,未见明显的Smad2/3阳性细胞。在整个胚腭正常发育和腭裂形成过程中,空白对照组与植物油对照组Smad2/3阳性细胞表达几乎无差异。提示过量全反式维甲酸可能通过干扰腭中嵴上皮细胞及间充质细胞中Smad2/3信号分子的表达,从而影响小鼠胚腭上皮间充质转化,与腭裂形成密切相关。     

腭裂小鼠牙胚发育中β-连环蛋白的表达

背景:牙齿发育生物学中信号传导是热点问题,β-连环蛋白是Wnt信号传导通路中的关键效应因子,其在发育的牙胚中有普遍表达,并且在内釉上皮、釉结、星网状层、中间层的表达有时空变化。目的:通过苏木精-伊红染色和免疫组化技术,观察牙胚在维甲酸诱导腭裂发生中的形态学变化及β-连环蛋白的表达变化。方法:选取C57BL/6J近交系小鼠,按雌雄比2:1于晚8时合笼,次日8时检查雌鼠,发现阴栓视为妊娠,定为E0d。18只孕鼠随机分为3组:在E10d,实验组以维甲酸100mg/kg对孕鼠行一次性灌胃,制备腭裂动物模型;植物油对照组给予10mL/kg橄榄油灌胃;空白对照组不做任何处理。结果与结论:β-连环蛋白在空白对照组E13d牙胚蕾状期、E14d帽状期、E16d钟状期上皮内均有表达,且空白对照组的表达随着牙胚发育的成熟而逐渐增加,实验组的变化趋势与空白对照组相同。3个时期的实验组β-连环蛋白在牙胚中的表达水平均高于空白对照组,植物油对照组和空白对照组表达无明显差异。提示维甲酸在诱导腭裂发生过程中,可能通过干扰上皮-间充质间的相互作用,上调β-连环蛋白在牙胚中的表达,使牙胚发育受阻。     

声诺维超声造影观察晚孕孕鼠胎盘超微结构改变的初步研究

目的探讨妊娠晚期Wister大鼠超声造影后胎盘组织超微结构的变化。方法将妊娠晚期Wister大鼠60只随机分为3组（每组20只）。对照组：经尾静脉注射生理盐水2．0ml／kg;高剂量组：注射声诺维剂量为23．6mg／kg（2．0ml／kg,11．8mg／m1）;低剂量组：注射声诺维剂量为0．236mg／kg（2．0ml／kg,0．118mg／m1）。采用Acuson Sequoia512型超声诊断仪,观察60只孕鼠注射造影剂后造影过程。于造影后即刻随机选取45只孕鼠（每组15只）剖检胎盘组织;并于造影后12h分别剖检其余15只孕鼠（每组5只）胎盘组织,电镜观察各组孕鼠胎盘超微结构变化。结果（1）60只孕鼠超声造影全程未见脐血管和胎鼠显影;电镜下见对照组及低剂量组孕鼠胎盘屏障结构完整清晰,而高剂量组胎盘合体滋养层细胞胞质内溶酶体数目增多,内质网扩张,基质内可见糖原沉积等超微结构改变;（2）注射声诺维12h后,对照组和低剂量组10只孕鼠（每组5只）胎盘组织超微结构与同组注射造影剂后即刻取检的45只孕鼠（每组15只）的胎盘组织超微形态结构比较无显著病理变化。高剂量组孕鼠胎盘组织电镜下见仅见基底膜层稍增厚。结论低剂量造影剂声诺维用于孕晚期大鼠胎盘造影是安全的,本研究为产科临床应用声诺维提供了对超微结构影响的依据。     

桂皮醛对抗血小板聚集和血栓形成的特点

目的：观察桂皮醛对血小板聚集和血栓形成的影响。方法：实验于2005—07／11在第四军医大学药学系药物研究所实验室完成。④体外血小板聚集实验：制备大鼠洗涤血小板，观察0．15，0．30和0．60mmol／L桂皮醛对胶原蛋白（100mg／L）和凝血酶（3U／mL）诱导的大鼠体外血小板聚集的抑制作用。桂皮醛购自中国医药集团上海化学试剂公司，纯度〉98％。②出、凝血时间测定及胶原蛋白-肾上腺素诱发体内血栓形成实验：取BALB／c小鼠60只，随机分成6组（n=10），生理盐水组灌胃生理盐水；阿司匹林组灌胃阿司匹林100mg／kg为阳性对照；还设置桂皮醛灌胃（250，500mg／kg）和腹腔注射（50，100mg／kg）4个剂量组。所有动物每天给药1次，10μL/g，连续11d。第10天给药后1h采用断尾法和玻片法测定小鼠出血、凝血时间；第11天给药后1h观察小鼠尾静脉注射胶原蛋白（3．57mg／kg）-肾上腺素（0．143mg／kg）混合血栓诱导剂后5min内的存活率。⑧动-静脉旁路血栓形成实验：SD大鼠48只，随机分为6组（n=8）。生理盐水组灌胃生理盐水；阿司匹林组灌胃阿司匹林80mg／kg为阳性对照；桂皮醛分为灌胃200，400mg／kg组和腹腔注射40，80mg/kg4个剂量组。所有动物每天给药1次，10μL／g，连续10d。末次给药后1h测定动-静脉旁路丝线上的血栓湿质量。结果外鼠60只和大鼠48只全部进入结果分析。①桂皮醛能够明显抑制胶原蛋白和凝血酶诱导的大鼠体外血小板聚集，并呈剂量依赖性，与对照组比较差异显著（P〈0．05，0．01）。②桂皮醛显著延长小鼠出、凝血时间，与对照组比较差异非常显著（P〈0．01）。⑧胶原蛋白-肾上腺素诱发性小鼠肺动脉栓塞存活率：生理盐水组为10％，阿司匹林组为80％，桂皮醛各剂量组为70％～100％。④动-静脉旁路丝线上的血栓湿质量：阿司匹林组和桂皮醛各剂量组均低于生理盐水组（P〈0．01）；桂皮醛各剂量组对大鼠血栓的抑制率范围为30％～43．4％。结论：桂皮醛体外能够明显抑制胶原蛋白和凝血酶诱导的大鼠血浆中血小板的聚集；体内能够显著延长小鼠断尾后的出、凝血时间，减轻大鼠动-静脉旁路丝线上血栓的质量。提示桂皮醛具有明显抗血小板聚集和体内抗血栓作用。     

雌激素诱导C57BL/6妊娠小鼠肝损伤的比较研究

目的比较雌激素对C57BL/6同种系和异种系妊娠小鼠肝脏的影响,探讨妊娠期肝损伤小鼠模型选择C57BL/6异种系妊娠小鼠的可能性。方法选择健康C57BL/6雄鼠、BALB/c雄鼠分别和C57BL/6雌鼠交配,得到C57BL/6同/异种系妊娠小鼠,并分为对照组、溶剂组和不同剂量给药组。给药组从怀孕10 d起连续4 d分别每天皮下注射不同剂量17-α-乙炔雌二醇。结果给药的异种系孕鼠血清中除碱性磷酸酶(ALP)指标外丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、总胆红素(TBIL)和甘胆酸(CG)升高水平与同种系孕鼠比较差异有统计学意义(P<0.05),其肝脏组织病理学结果也不同,且剂量为1.0μg/g体重的异种系孕鼠肝脏NK细胞出现集聚和活化现象。结论雌激素对C57BL/6同种系和异种系妊娠小鼠肝脏作用不同,选择雌激素诱导C57BL/6异种系妊娠小鼠建立妊娠期肝损伤模型能够反映该病的肝脏免疫学变化。     

AMG-1对小鼠慢性戊四唑点燃癫痫的抑制作用

探讨AMG-1对小鼠戊四唑（PTZ）腹腔注射诱导的癫痫点燃模型的保护作用。方法：健康小鼠60只,制备PTZ诱导小鼠慢性癫痫点燃模型,随机分为6组各10只,分别给予生理盐水、DMSD、地西泮及1、5、10mg／kg AMG-1干预,记录小鼠痫性发作潜伏期和强直性惊厥率的变化。结果：1、5、10mg／kg的AMG-1对小鼠PTZ慢性点燃癫痫均有剂量依赖性的抑制作用,对小鼠癫痫的发作级别、潜伏期、大发作持续时间等均有显著抑制作用,显著减少小鼠发作后的死亡率。结论：AMG-1对小鼠PTZ慢性癫痫形成过程有剂量依赖性的抑制作用。     

脂多糖联合D-氨基半乳糖诱导急性重症肝炎小鼠模型的建立

目的：建立存活时间较长的急性重症肝炎小鼠模型。方法：将50只BALB／c小鼠平均分成5组,其中A、B、C、D4组为实验组,E组为对照组;实验组分别给予D氨基半乳糖（D-GaIN）和脂多糖（LPS）,剂量分别为800mg／kg和10μg／kg、500mg／kg和10μg／kg、500mg／kg和5μg／kg、300mg／kg和5,ug／kg,用生理盐水稀释至1mL,行腹腔注射;对照组E腹腔注射生理盐水2mL。以12h死亡率、24h死亡率及肝组织学改变为观察指标。结果：A、B、C、D及E组小鼠12h死亡率分别为80％％、30％、10％、0和0;24h死亡率分别为909,6、60％、30％、0和0;A和B组小鼠肝组织学均呈急性重症肝炎表现,C组中有5只小鼠肝组织学符合重症肝炎的表现,而该组其余小鼠及D组所有肝组织学虽有炎症改变,但达不到重症肝炎的程度,E组肝组织学表现正常。结论：LPS10ug／kg联合D～GaIN500mg／kg可成功建立12h存活率较高的急性重症肝炎小鼠模型。     

霉酚酸酯对小鼠异基因骨髓移植后急性移植物抗宿主病的预防作用

目的：探讨新型免疫抑制剂霉酚酸酯（MMF）对小鼠异基因骨髓移植（allo-BMT)后急性移植物抗宿主病（aGVHD)的预防作用。方法：用主要组织相容性抗原（MHC）完全不合的纯种近交系小鼠[供鼠：雌性C57BL／6J（H－2^b)鼠；受鼠：雄性BALB／c(H-2^d)鼠]建立allo-BMT/aGVHD动物模型，随机分6组，给予MMF、环孢菌素A（CsA) 甲氨喋呤（MTX）或联合不同剂量MMF作为aGVHD预防方案。观察其aGVHD的预防作用。结果：移植小鼠出现典型的aGVHD症状，未用aGVHD预防方案的移植小鼠（第6组）死亡高峰在移植后第5－第7天，死亡率达100％。用不同aGVHD预防方案的1－5组小鼠aGVHD症状明显减轻，平均生存时间（MST）较第6组显著延长（分别延长3．4，8．4，9．0，6．1，8．8d（P＜0．05）。不同aGVHD预防方案的移植小鼠之间，移植后外周血常规变化差异无显著性。经用各预防方案后，移植小鼠cGVHD病理表现减轻，且MMF、CsA、MTX三药联合组的病理分级轻于MMF单药组或CsA MTX标准方案组。结论：MMF单药及与CsA MTX联合均能有效预防小鼠allo-BMT后的aGVHD，减轻其症状和病理损害程度，显著延长平均生存时间。小剂量MMF（≤30mg/kg）与CsA TMX的联用效果优于大剂量MMF（60mg/kg）与CsA MTX的联用效果。适当剂量的MMF（10－60mg/kg）对骨髓植入和造血恢复没有显著影响。     

龙虾壳聚糖干预后糖尿病小鼠血糖和糖耐量的变化

目的：观察龙虾壳聚糖对四氧嘧啶致糖尿病小鼠的降血糖作用。方法：实验于2005-04／12在江苏大学医学技术学院生化研究室和江苏大学医学部实验动物中心完成。实验动物选用45d的健康雄性ICR清洁级小鼠100只。①龙虾壳聚糖对正常小鼠空腹血糖的影响：取正常小鼠20只，禁食3h后测定空腹血糖，按血糖水平的高低随机抽签法分成龙虾壳聚糖组和正常对照组，每组10只。龙虾壳聚糖用10g/L醋酸配制，龙虾壳聚糖组小鼠按剂量200mg／（kg&;#183;d）连续灌胃；正常对照组以10g/／L醋酸20mL／kg灌胃，连续30d。30d后禁食3h测定其空腹血糖值。②制备糖尿病模型：取正常小鼠80只，用四氧嘧啶生理盐水溶液尾静脉注射制备糖尿病小鼠模型，剂量100mg／kg，容积10mL／kg，6d后测定禁食3h后各小鼠的空腹血糖，以血糖值≥25mmol／L者确定为高血糖模型成功动物。③龙虾壳聚糖对尿病小鼠空腹血糖的影响：取高血糖模型成功大鼠40只，随机分成龙虾壳聚糖50，100和200mg／kg 3个剂量组和高血糖模型对照组，每组10只。模型对照组给予10g／L醋酸灌胃，剂量20mL／kg，连续30d；龙虾壳聚糖50。100和200mg／ks剂量组分别给予龙虾壳聚糖50，100和200mg／（kg&;#183;d）（用10g/L醋酸配制），连续30d。第31天禁食3h后测定各组小鼠的空腹血糖值，比较各组动物血糖值及血糖下降百分率。血糖下降百分率=[（实验前血糖值-实验后血糖值）／实验前血糖值]&;#215;100％。②龙虾壳聚糖对糖尿病小鼠糖耐量的影响：在各组小鼠测定空腹血糖值后，龙虾壳聚糖50，100和200mg／kg剂量组分别继续给予龙虾壳聚糖50，100和200mg／（kg&;#183;d）；模型对照组给予10g／L醋酸灌胃，剂量20mL／kg。15-20min后经口给予葡萄糖溶液2．0g/kg,于0，0．5，2h分别测定各组小鼠的血糖值。观察模型对照组与龙虾壳聚糖50，100和200mg／kg剂量组在给予葡萄糖后各时间点血糖曲线下面积的变化。血糖曲线下面积=0．25&;#215;（0h血糖值＋4&;#215;0．5h血糖值＋3x2h血糖值）。结果：实验小鼠100只均进入结果分析，无脱失值。①龙虾壳聚糖在50，100和200mg／kg的剂量下，糖尿病小鼠的空腹血糖值明显低于模型对照组（P〈0．01，P〈0．001），血糖降低百分率分别达16．08％、19．05和25．00％，模型对照组小鼠的血糖值仅降低9．92％。②龙虾壳聚糖100和200mg／kg剂量组均具有不同程度地增强糖尿病小鼠的糖耐量作用，血糖曲线下面积：模型对照组为（57．6&;#177;3．69）mmz，龙虾壳聚糖100和200mg／kg剂量组分别为[（52．1&;#177;3．06），（49．2&;#177;2．52）mml，明显低于模型对照组（P〈0．05和P〈0．001）。③龙虾壳聚糖对正常小鼠的血糖水平无明显影响（P〉0．05）。④模型制备和行为学结果：糖尿病小鼠模型制备6d测定禁食3h后各小鼠的空腹血糖值为25～28mmol/L。并出现了明显的多饮多尿消瘦等糖尿病症状。结论：龙虾壳聚糖对糖尿病小鼠具有降血糖和增强糖耐量的作用，且不     

景蜂胶囊调节小鼠免疫功能的量效分析

目的：观察不同剂量的景蜂胶囊对小鼠免疫功能的影响。 方法：①对小鼠免疫器官质量的影响：选择BALB／c小鼠50只。按随机数字表法分成5组，即空白对照组。贞芪扶正胶囊组（0．8s／kg）和景蜂胶囊（由红景天、枸杞、高原油菜蜂花粉、党参、女贞子多糖和黄芹多糖组成）0．4，0．8，1．2g／kg组，每组10只，连续给药7d，测量各组小鼠胸腺和脾脏质量。②对小鼠网状内皮系统吞噬功能的影响：取BALB／c小鼠50只，分组及给药方法同上。连续给药7d，尾静脉注射墨汁10mL／kg，分别称取肝，脾质量。计算廓清指数k和校正指数。③对体液免疫功能的影响：取BALB／c小鼠50只、分组及给药方法同上。连续给药3d后，给予绵羊红细胞悬液0．2mL进行免疫，免疫4d后，麻醉摘取小鼠眼球取血，分离血清，计算每个样品的半数溶血值。④对细胞免疫功能的影响：取BALB／c小鼠50只，分组及给药方法同上。连续给药7d。第8天麻醉剪去小鼠尾梢0．2cm，取血推片，计数100个淋巴细胞，计算T淋巴细胞百分率。⑤对小鼠迟发型变态反应的影响：取BALB／c小鼠50只，分组及给药方法同上。连续给药3d后，尾静脉注射绵羊红细胞悬液0．1mL进行致敏。5d后。在小鼠左侧脚掌注射绵羊红细胞悬液0．1mL，在小鼠右侧脚掌注射生理盐水0．1mL，24h后测量两侧脚掌厚度的差值。 结果：250只小鼠全部进入结果分析，无脱失。①各组小鼠的胸腺、脾脏质量相比差异无显著性意义（P〉0．05）。②景蜂胶囊0．8，1．2g／kg组小鼠的廓清指数、校正指数均显著高于空白对照组（P〈0.05～0．01）。③景蜂胶囊0．4，0．8，1．2g／kg组小鼠的溶血素抗体生成水平均显著高于空白对照组（P〈0．05--0．01）。④景蜂胶囊0．8，1．2g／kg组小鼠外周血T淋巴细胞百分率均显著高于空白对照组（P〈0．05-0．01）。⑤景蜂胶囊1．2g／kg组小鼠左、右侧脚掌厚度的差值显著大于空白对照组（P〈0．05）。 结论：景蜂胶囊具有提高小鼠免疫功能的作用，其中0．8，1．2g/kg剂量组表现更为显著。     

褪黑素抑制H22荷瘤小鼠肿瘤生长效果的研究

目的观察褪黑素对H22荷瘤小鼠模型肿瘤生长的抑制效果。方法复苏并培养H22细胞,将H22细胞以皮下注射方式接种到小鼠右侧腋部,建立H22荷瘤小鼠肿瘤模型,随机分为生理盐水组（对照组）、10mg／kg褪黑素组、20mg／kg褪黑素组,腹腔注射,1次／d,共注射14d,接种肿瘤15d后处死小鼠,观察肿瘤质量体积及肿瘤转移情况。结果成功构建H22荷瘤小鼠模型,褪黑素治疗组中,小鼠肿瘤的质量、体积较对照组明显降低（P〈0.05）,且具有一定的量效关系。结论褪黑素对H22荷瘤小鼠肿瘤生长有明显抑制效果。     

Enhancement of cytocidal and antitumor effect of cisplatin by caffeine in human osteosarcoma

A nontoxic dose of caffeine enhanced the cytotoxicity of cisplatin in human osteosarcoma cells (OST strain). Synergistic cytotoxicity was seen in vitro in OST cells when 2 mmol caffeine was added to a nontoxic dose of cisplatin (2 micrograms/ml). Caffeine reduced S-phase, G2/M-phase, and S-and-G2/M-phase accumulation by cisplatin on the DNA histogram, and nuclear fragmentation of tumor cells was frequently observed. Flow cytometric analysis appeared to be useful in assessing the efficacy of the combination of cisplatin and caffeine. The antitumor effect of the combination of cisplatin and caffeine was examined in OST transplanted to BALB/C athymic mice. Regression of the tumor was observed when cisplatin was given at a dose of 10 mg/kg. When 4 mg of caffeine was given once a day for three days after the administration of cisplatin, marked regression of the tumor was observed in groups treated with 5 or 10 mg/kg of cisplatin, without significant weight loss. These results indicate that caffeine enhances the antitumor effect of cisplatin on transplanted osteosarcoma in BALB/C athymic mice.     

Comparative activities of amoxycillin, amoxycillin/clavulanic acid and tetracycline against Chlamydia trachomatis in cell culture and in an experimental mouse pneumonitis

The activity of amoxycillin, amoxycillin/clavulanic acid and two tetracycline antibiotics was investigated against three strains of Chlamydia trachomatis in vitro. McCoy cells were infected and single doses of antibiotic administered 24 h after infection. The percentage of infected cells was calculated at intervals up to 72 h after infection. Amoxycillin and clavulanic acid, alone and in combination, reduced the incidence of inclusion formation of all three strains. Particularly good activity was observed against the laboratory-adapted strain C. trachomatis Sa2f and a clinical isolate C. trachomatis LB1, where a progressive reduction in numbers of inclusions was observed with time. Minocycline and oxytetracycline were the most active agents tested. In an experimental animal model, mice were inoculated intranasally with C. trachomatis MoPn (ATCC VR123) which caused a fatal pneumonia within 16 days, and treated orally for four days commencing at 24 h after infection. At doses producing clinically achievable serum concentrations, amoxycillin (10 mg/kg), amoxycillin/clavulanic acid (10 + 5 mg/kg) and minocycline (5 mg/kg) all protected the mice over a 21-day period. The majority of the animals treated with clavulanic acid alone (20 mg/kg) survived the infection. Treatment with oxytetracycline was less effective, a dose of 160 mg/kg being required to protect 70% of the mice. The results indicate that amoxycillin and amoxycillin/clavulanic acid were more effective against C. trachomatis MoPn in vivo than might be predicted from in-vitro data, suggesting that amoxycillin/clavulanic acid may have potential for the treatment of polymicrobial infections involving C. trachomatis.     

Single-dose AmBisome (Liposomal amphotericin B) as prophylaxis for murine systemic candidiasis and histoplasmosis

AmBisome is a liposomal formulation of amphotericin B that has broad-spectrum antifungal activity and greatly reduced toxicity compared to the parent drug. In this study, amphotericin B deoxycholate (Fungizone) (1 mg/kg) and AmBisome (1 to 20 mg/kg) were tested as single-dose prophylactic agents in both immunocompetent and immunosuppressed C57BL/6 mice challenged with either Candida albicans or Histoplasma capsulatum. Prophylactic efficacy was based on survival and fungal burden in the target organ (kidneys or spleen). At 9 to 10 days after histoplasma challenge, 80 to 90% of both immunocompetent and immunosuppressed mice in the control and Fungizone groups had died. All AmBisome-treated mice survived, although in the AmBisome groups given 1 mg/kg, the mice became moribund by day 10 to 12. No spleen CFU were detected in the histoplasma-challenged mice given 10 or 20 mg of AmBisome per kg. By 23 to 24 days after histoplasma challenge, fungal growth and/or death had occurred in all immunosuppressed mice except for four mice receiving 20 mg of AmBisome per kg. There were still no detectable fungi in the spleens of immunocompetent mice given 10 or 20 mg of AmBisome per kg. In the C. albicans experiment at 7 days postchallenge, all animals in both untreated and treated groups were alive with culture-positive kidneys. The kidney fungal burdens in AmBisome groups given 5 to 20 mg/kg were at least 1 log unit lower than those in the Fungizone group and significantly lower than those in the untreated control group (P < 0.05). There was a trend toward decreasing fungal growth in the kidneys as the dose of AmBisome was increased. In conclusion, these results show that a single high dose of AmBisome (5 to 20 mg/kg) had prophylactic efficacy in immunocompetent and immunosuppressed murine H. capsulatum and C. albicans models.     

Plasma and pulmonary pharmacokinetics of bleomycin in murine strains that are sensitive and resistant to bleomycin-induced pulmonary fibrosis

Previous studies have shown that C57Bl/6N mice are sensitive and BALB/c mice are resistant to the pulmonary fibrotic effects of bleomycin (BLM). We assessed the plasma elimination and pulmonary content of BLM in C57Bl/6N and BALB/c mice treated with a single dose of [3H]BLM (80 mg/kg i.v.) to determine whether these murine strains show corresponding differences in BLM pharmacokinetics and pulmonary disposition after systemic administration of the drug. Serial blood samples were obtained from each animal and lungs were collected after pulmonary lavage or vascular perfusion with saline. Administration of BLM (80 mg/kg i.v.) produced significant elevations in lung hydroxyproline (35%) in C57Bl/6N but not in BALB/c mice. In contrast, BALB/c mice were more sensitive to pulmonary fibrosis induced with cyclophosphamide (200 mg/kg i.p.) compared to C57Bl/6N mice, indicating that strain sensitivity to pulmonary fibrosis is drug specific in these mice. BLM showed first order plasma elimination kinetics over 30 min in both strains with a shorter half-life in the sensitive strain (9.6 +/- 0.3 min in C57Bl/6N vs. 12.7 +/- 1.9 min in BALB/c). Plasma elimination deviated from first order kinetics after 30 min in both strains and plasma levels of BLM were up to 2-fold higher in the resistant strain over a 3-hr time course. Radioactivity in saline-perfused lungs was also significantly higher (1.5-2-fold) in BALB/c mice for least 1 hr after BLM injection. A similar fraction of the total lung radioactivity (approximately 80%) was recovered from both strains by pulmonary lavage, suggesting that BLM enters the alveolar spaces relatively freely in each strain.(ABSTRACT TRUNCATED AT 250 WORDS)     

Treatment of Histoplasmosis with MK-991 (L-743,872)

BALB/c nu/+ immunocompetent and athymic (nu/nu) mice were infected intravenously with yeast cells of Histoplasma capsulatum. Mice were either given water (controls) intraperitoneally (i.p.) or given MK-991 i.p. once daily or twice daily. Protection was measured as prolonged survival or reduction in tissue counts. MK-991 was protective in immunocompetent mice, prolonging survival and reducing counts in spleen and livers at a dose as low as 0.05 mg/kg of body weight/day. MK-991 was modestly effective in athymic mice at a higher dose, 5 mg/kg/day. These studies suggest that MK-991 may be appropriate for clinical development in histoplasmosis.     

Activity of aminocandin (IP960) compared with amphotericin B and fluconazole in a neutropenic murine model of disseminated infection caused by a fluconazole-resistant strain of Candida tropicalis

OBJECTIVES: To compare the activity of aminocandin (IP960), a new echinocandin with broad-spectrum in vitro activity against Aspergillus and Candida spp., with that of amphotericin B and fluconazole in a temporarily immunocompromised murine model of disseminated candidiasis. METHODS: Mice were rendered neutropenic with cyclophosphamide and infected intravenously 3 days later with a fluconazole-resistant Candida tropicalis strain. Mice were treated with intraperitoneal amphotericin B (5 mg/kg/dose), oral fluconazole (50 mg/kg/dose), intravenous aminocandin (0.1--5 mg/kg/dose) or solvent control for 9 days. Mice were observed for survival and survivors were sacrificed 11 days post-infection. Kidneys, liver, brain and lungs were removed for semi-quantitative culture. RESULTS: Control mice had 90--100% mortality. After infection with C. tropicalis, aminocandin 2.5 and 5 mg/kg/day and amphotericin B yielded 80% survival; aminocandin 1 mg/kg/day yielded 70% survival; aminocandin 0.25 and 0.1 mg/kg/day yielded 30% and 20% survival, respectively; and fluconazole 50 mg/kg/day and control regimens yielded 10% and 0--10% survival, respectively. Aminocandin 2.5 and 5.0 mg/kg/day and amphotericin B were superior in reducing mortality compared with aminocandin 0.25 and 0.1 mg/kg/day, fluconazole and controls (P<0.047). The only regimen to reduce organ burdens below detectable levels was amphotericin B, which cleared 40% of mice. All organ burdens in the aminocandin 1.0, 2.5 and 5.0 mg/kg/day and amphotericin B regimens were significantly lower than other groups (P<0.02). CONCLUSIONS: The data demonstrate that aminocandin at doses of >or=1.0 mg/kg/day is as effective as amphotericin B at improving survival and reducing organ burdens in this murine model of disseminated C. tropicalis.     

巨细胞病毒对小鼠心脏移植术后急性排斥反应的影响

目的观察巨细胞病毒（cytomegalovirus,CMV）感染对同种异基因小鼠腹腔异位移植心脏急性排斥反应的影响。方法 BALB/c小鼠80只,C57BL/6小鼠40只,按供、受鼠基因不同分为3组（每组20对）：同质移植组（A组,BALB/c→BALB/c）、环胞素A组（B组,C57BL/6→BALB/c）和小鼠巨细胞病毒联合环胞素A组（C组,C57BL/6→BALB/c）,施行小鼠腹腔异位心脏移植术。A组无药物干预,B组术后腹腔注射CsA 20mg/kg.d,C组除腹腔注射CsA 20mg/kg.d外,术后第1d腹腔接种104PFU小鼠巨细胞病毒（MCMV）0.2ml。术后观察移植鼠心脏跳动情况、移植心脏存活时间、移植心脏的病理组织学以及MCMV病毒滴度测定。结果术后10d,A组移植心脏几乎无排斥反应;B组移植心脏搏动有力,显微镜下观察移植心脏心肌间质内有局灶性炎症细胞浸润,心肌有变性;C组移植心脏搏动微弱,体积增大,重量增加,显微镜下见心内、外膜下及心肌间质有弥漫性淋巴细胞及单核细胞浸润;心肌细胞可发生变性、坏死。C组（12.4±1.3d）移植心脏存活时间明显低于B组（16.7±1.9d）（P〈0.01）,而A组移植心脏长期存活（观察60d）。结论巨细胞病毒感染加速小鼠腹腔异位移植心脏急性排斥反应。