环磷酰胺诱导小鼠血小板减少症模型的建立(英文）

比较由环磷酰胺两种不同给药方式诱导小鼠血小板减少症模型的效果,并对效果较稳定的一种给药方式进行最佳造模剂量摸索,以期确定一个造模效果较好,毒副作用较低,利于观察治疗药物疗效的血小板减少症模型。模型A组,第1天尾静脉注射环磷酰胺200 mg/kg,然后连续6 d,每天1次以维持剂量30 mg/kg腹腔注射环磷酰胺。模型B组,按150 mg/kg皮下注射环磷酰胺,每天1次,连续3 d。结果显示模型B组造模效果较好,故以模型B组给药方法进行剂量摸索实验。由第7天的血小板计数可知环磷酰胺低（100 mg/kg）、中（120 mg/kg）、高（140 mg/kg）剂量均可引起血小板减少症,而低剂量组与其他组比较有高效低毒的特点,更有利于观察治疗药物的作用,可用于具有升血小板作用药物的药效学研究     

特种甘薯TSP-1提取物对环磷酰胺致血小板减少症小鼠的初步研究

ICR小鼠连续3d腹腔注射100mg/kg环磷酰胺,建立血小板减少症模型。将造模成功小鼠分别灌胃6g/kg和2g/kg剂量TSP 1水提取物、6g/kg和2g/kg剂量TSP 1石油醚提取物、2g/kg剂量TSP 1正丁醇提取物和1g/kg剂量TSP 1氯仿提取物,造模前、造模第3天和造模第6天尾部取血测定血小板和白细胞数量。结果表明：2g/kg TSP 1石油醚提取物、1g/kg TSP 1氯仿提取物可以显著升高环磷酰胺模型小鼠的血小板,但各提取物对环磷酰胺所致白细胞减少无治疗作用,提示特种甘薯氯仿与石油醚提取物具有进一步用于治疗血小板减少症的潜在价值。     

龙丹生血颗粒对骨髓抑制小鼠血象与巨核细胞影响的研究

目的:用环磷酰胺(CTX)复制小鼠骨髓抑制动物模型,观察龙丹生血颗粒对模型动物血液学检查和骨髓巨核细胞的影响。方法:70只昆明种小鼠标记后,除空白组外,其余动物首次尾静脉注射给予环磷酰胺200 mg/kg,第二天后改用每天腹腔注射30mg/kg,连续6天之后,断尾采血行血液学检查。挑选外周血血小板较正常组减少至30%以上的小鼠,随机分为模型、白介素-11、升血小板胶囊、龙丹生血颗粒大、中、小剂量6组,每组10只。龙丹生血颗粒大、中、小剂量组分别灌胃龙丹生血颗粒浸膏粉混悬液13.75 g生药/kg、6.88 g生药/kg、3.44 g生药/kg;升血小板胶囊组灌胃1.125 g内容物/kg;白介素-11组皮下注射白介素-11250μg/kg;正常组、模型组灌胃饮用水。各组每天给药1次,灌胃容积0.2 mL/10g,连续14天。分别于给药第7天、14天采血行外周血象检查,末次采血后处死动物,取股骨骨髓做骨髓涂片,光镜检查分类计数巨核细胞数量。结果:以给药后与给药前差值统计,龙丹生血颗粒大、中剂量组小鼠外周血PLT(给药14天)、WBC(给药7天)比模型组差值明显增大(P0.01或P0.05);龙丹生血颗粒各剂量组给药7天、14天的RBC、Hgb比模型组同期差值明显增大(P0.01或P0.05);龙丹生血颗粒中剂量组小鼠骨髓巨核细胞总数、颗粒巨核细胞比模型组显著增加(P0.05)。结论:龙丹生血颗粒对环磷酰胺导致小鼠外周血PLT、WBC、RBC、Hgb减少具有治疗作用,但对骨髓巨核细胞的恢复作用有待进一步证实。     

基于数据挖掘及动物实验探讨维持洛哌丁胺诱导便秘小鼠模型稳定性的研究

目的 通过文献数据挖掘与实验研究相结合的方法,挖掘洛哌丁胺诱导便秘小鼠模型造模特点及影响因素,为建立稳定的实验便秘模型提供一定参考。方法 文献研究部分以便秘及动物模型为主题词,检索中英文数据库,筛选使用洛哌丁胺诱导便秘小鼠模型的实验研究,提取资料并进行分析;动物实验部分,采用雄性C57BL/6小鼠,给予5 mg/kg及10 mg/kg的洛哌丁胺灌胃,每日给药1次。从含水率、首次黑便时间、小肠推进率等评价造模效果,观察洛哌丁胺不同剂量及给药时间对便秘小鼠的影响。结果 纳入符合标准的文献69篇,洛哌丁胺给药剂量多为5、10 mg/kg,多用灌胃给药,频率为给药1次,给药时间多为30 min。根据文献研究结果,实验部分从造模第1天开始,5 mg/kg及10 mg/kg组与空白组相比含水率显著降低,差异具有统计学意义(P<0.05),而造模第7～14天,5 mg/kg组与10 mg/kg相比含水率明显升高(P<0.05),对比造模3、7、14 d后含水率变化情况,各模型组均在停药1 d后升高,至停药后14 d含水率均保持在较高水平;对比造模3、7、14 d的首次黑便时间,造模7、1...     

人参多糖对环磷酰胺的增效减毒作用

目的探讨人参多糖（ginseng polysaccharide,GPS）对化疗药物环磷酰胺（cyclophosphamide,CTX）抗肿瘤的增效减毒作用。方法建立小鼠肝癌H22实体瘤模型,随机分组,设模型对照组（生理盐水）、环磷酰胺组（30 mg/kg）、人参多糖给药组（7.5、15、30 mg/kg剂量组）和联合给药组（GPS 7.5、15、30 mg/kg,CTX 30 mg/kg）;人参多糖尾静脉注射,CTX腹腔给药,连续给药10 d;测定抑瘤率、血液学指标、脾脏系数和胸腺系数,评价人参多糖对环磷酰胺的增效减毒作用。结果 GPS、GPS＋CTX各组肿瘤生长明显低于模型对照组（P〈0.01）,GPS中、高剂量＋CTX联合给药组肿瘤生长明显低于CTX组（P〈0.05,P〈0.01）。GPS高剂量＋CTX组与CTX组相比,体重、脾脏指数和胸腺指数明显升高（P〈0.05）。结论人参多糖对化疗药物环磷酰胺抗小鼠肝癌H22肿瘤具有增效减毒作用。     

大鼠再生障碍性贫血模型制备

目的诱导稳定而可逆的大鼠再生障碍性贫血模型。方法模型A组造模第1天以直线加速器剂量率为240 cGy/min,SSD=100 cm,全身照射1.2 min,分别于第4、6、8天腹腔注射环磷酰胺35 mg/kg和氯霉素43.75 mg/kg,共3次;模型B组造模第1天以直线加速器剂量率300 cGy/min,SSD=100 cm,全身照射1.2 min。分别于第4、5、6天腹腔注射环磷酰胺35 mg/kg和氯霉素43.75 mg/kg,共3次。对照组造模第1天以假照射。于造模9、12、15 d后进行网织红细胞计数、外周血象检查、骨髓活检。结果造模第9天与对照组比较,A组、B组的白细胞（WBC）、红细胞（RBC）、血小板（PLT）、血红蛋白（HGB）、网织红细胞计数（RET）均明显降低,差异有显著性（P〈0.05）。于造模第15天,A组RBC、HGB值继续下降,WBC、PLT、RET值回升,与对照组比较降低,差异有显著性（P〈0.05）;B组WBC、RBC、HGB、PLT值有显著回升,与对照组比较降低,差异有显著性（P〈0.05）;RET值与对照组比较升高,差异有显著性（P〈0.05）。结论模型A组具有复制周期短,成功率高、重复性好,死亡率低等优点。适合用于治疗药物研究的实验。     

小麦α-淀粉酶抑制剂减肥作用的实验研究

研究小麦中α-淀粉酶抑制剂对肥胖症大鼠的影响。将肥胖大鼠随机分为以下5组:模型对照组、阳性药对照组(曲美3 mg/kg),α-淀粉酶抑制剂45,15,5 mg/kg 3个剂量组。其中阳性药对照组和AI组从造模当天起每天ig给药一次,模型空白组则ig同体积的生理盐水,连续灌胃4周,动态检测质量、体长。在实验结束时,各给药组与模型组相比较,Lee指数和脂肪湿重都有不同程度的降低,其中高剂量组变化明显,与曲美组比较效果相当。高、中剂量的α-淀粉酶抑制剂能有效地减少营养性肥胖大鼠的质量和体内脂肪,且AI的减肥效应与其剂量呈正相关性。     

5-氟尿嘧啶诱导小鼠化疗性肠黏膜炎模型的建立

目的研究5-氟尿嘧啶(5-fluorouracil,5-FU)诱导小鼠化疗性肠黏膜炎动物模型。方法采用不同剂量的5-FU单次或连续5 d腹腔注射给予小鼠,每日观察小鼠体重、腹泻情况,并分别于末次给药后72 h或24 h,观察小鼠外周血象及小肠组织病理形态学改变。结果与正常组比较,单次或连续5 d给予5-FU后,各剂量组小鼠出现不同程度的腹泻及体重降低,外周血象白细胞和血小板水平明显降低(P0.05或P0.01),其中单次给药400 mg/kg组、连续给药50,100 mg/kg组出现明显的肠黏膜炎病理特征,100 mg/kg组剂量过高,死亡率达100%。结论单次或连续5 d给予5-FU诱导小鼠肠黏膜炎的作用呈剂量相关性,其中单次给药以400 mg/kg为合适剂量,连续5 d给药以50 mg/kg为合适剂量。     

DS-1226对慢性限制活动大鼠的抗抑郁作用

目的研究人参皂苷水解脱糖产物DS-1226对慢性限制活动大鼠的抗抑郁作用,为抗抑郁药物的研发提供实验数据。方法将90只雄性Sprague-Dawley大鼠随机分为6组,每组15只,分别为对照组（control）、模型组（model）、西酞普兰组（citalopram,100 mg/kg）、低剂量组（DS-1226,18.75 mg/kg）、中剂量组（DS-1226,37.5mg/kg）、高剂量组（DS-1226,75 mg/kg）。预防7 d给药后进行每天14 h连续28 d的限制活动造模并连续给药。造模过程中每周监测体重并在造模完成后进行糖水偏爱、新奇事物、自主活动实验,测试完成后处死动物取血清检测皮质酮含量。结果经过慢性限制活动应激后,模型组大鼠的体重和糖水偏爱指数降低,对新奇事物的探索行为以及自主活动尤其是中央区的活动减少,血中的皮质酮含量升高。但中剂量、高剂量的DS-1226和西酞普兰能不同程度的提高慢性限制活动大鼠的体重和糖水偏爱指数,增加对新奇事物的探索次数、探索时间、降低潜伏期时间,增加自主活动尤其是中央区的活动,降低血中皮质酮的含量。结论 DS-1226具有改善慢性限制活动大鼠抑郁行为的作用。     

不同剂量白介素-11治疗化疗后血小板减少的临床对比研究

目的:研究不同剂量重组人白介素-11(rhIL-11)对恶性肿瘤患者化疗所致血小板减少的疗效及不良反应.方法:采用随机对照的方法,对46例因化疗引起血小板Ⅱ度以上减少的恶性肿瘤患者给予rhIL-11治疗.A组22例,rhIL-11用量为1.5mg/d,B组24例,3mg/d,皮下注射,血小板升高至正常时停止给药.结果:rhIL-11治疗后,血小板严重减少(20× 109/L)的持续天数,B组少于A组(p=0.031);血小板恢复至正常的时间,A、B组的中位数分别为11天和8天,有统计学意义.B组血小板最低值高于A组,PLT＜50 × 109/L持续天数,出血并发症以及减少血小板榆注的例数,B组亦少于A组,但两组比较没有显著性差异(p＞0.05).主要不良反应:四肢、腰背肌肉酸痛伴骨骼及关节疼痛、乏力、发热、头痛及头晕,均为Ⅰ-Ⅱ度,两组比较没有显著性差异(p＞0.05),停药后或口服"百服宁"均恢复.结论:rhIL-11是一种有效且安全的治疗恶性肿瘤患者化疗所致血小板减少药物,可以在临床常规应用.对比1.5mg,每天皮下注射3.0mg的剂量疗效可能更好些,不良反应可以耐受.     

Experimental infection of mice by Salmonella typhi inoculated orally: influence of immunosuppressive therapy

Various immunosuppressive treatments were used in order to induce a Salmonella typhi infection in mouse by oral route. Neither low protein diets nor administration of mucin, iron, streptomycin or silica could modify animal's sensitiveness, but, cyclophosphamide injections enhanced lethal effect of bacteria, while silica increased the number of bacteria in the blood and the spleen.     

Protective effect of the yeast glucomannan against cyclophosphamide-induced mutagenicity.

Glucomannan (GM) isolated from Candida utilis with molecular weight 30 kDa was administered either intraperitoneally or orally prior to cyclophosphamide (CP) injection and its effect on the frequency of micronuclei was evaluated in polychromatic erythrocytes of mouse bone marrow. GM administration by either route decreased significantly (p<0.002) the clastogenic effect of CP. The protective effect was concentration-dependent, with a higher decrease achieved by 200 mg/kg than by 100 mg/kg b. wt. (body weight). The fact that GM was effective also at oral administration is indicative of the passage of GM molecules through the wall of the gastrointestinal tract. The important characteristics of GM isolated from C. utilis, such as good water solubility, relatively small molecular weight (30 kDa), and antimutagenic effect exerted also at oral administration, appear to be promising features for its prospective use as a natural protective agent.     

Heparin-associated thrombocytopenia: low frequency in 104 patients treated with heparin of intestinal mucosal origin.

A prospective study of 104 patients receiving heparin obtained from porcine intestinal mucosa for 4 or more days was conducted to determine the frequency of associated significant thrombocytopenia (platelet count less than 100 x 10(9)/I on 2 consecutive days). No episodes of significant thrombocytopenia were identified in the 13 patients receiving heparin by continuous intravenous infusion for a mean of 8.0 days or in the 38 patients receiving heparin subcutaneously for a mean of 9.9 days. In 1 of the 26 patients receiving heparin as intermittent intravenous boluses for a mean of 8.2 days significant thrombocytopenia developed; this patient had laboratory evidence of disseminated intravascular coagulation. In none of the 17 patients receiving uninterrupted heparin therapy for 4 or more days by more than one route of administration but for less than 4 days by any single route did significant heparin-associated thrombocytopenia develop. Of the 104 patients 13 had one or more platelet counts of less than 150 x 10(9)/I, but in most it was not possible to definitely relate the thrombocytopenia to the heparin therapy. Platelets in normal platelet-rich plasma did not aggregate when heparin and serum from patients with thrombocytopenia were added. The frequency of heparin-associated thrombocytopenia noted in this study was considerably lower than that reported previously.     

双歧杆菌对免疫抑制小鼠白色念珠菌感染的保护作用

为探讨双歧杆菌对白色念珠菌感染的保护作用,作者采用环磷酰胺腹腔注射方法复制了免疫抑制小鼠模型,研究白色念珠菌感染前后两歧双歧杆菌灌饲的保护作用。结果表明：白色念珠菌感染前灌饲两歧双歧杆菌能有效地抑制白色念珠菌在小鼠肠道中的定植,并且保护肠粘膜的完整性。对其机理的研究认为,两歧双歧杆菌可能是通过调整肠道菌群平衡、增加肠道中生理菌群的数量、降低肠道ｐＨ值、以及产生抗菌物质等途径发挥保护作用     

Resolution of bronchial hyperresponsiveness and pulmonary inflammation is associated with IL-3 and tissue leukocyte apoptosis

We have used two models of murine pulmonary inflammation to investigate the signals responsible for the resolution of bronchial hyperresponsiveness (BHR). Both protocols involved two sensitizations with OVA followed by serial aerosolized challenge with OVA. We determined that administration of the second sensitization by aerosol (model A) was associated with a transient response, whereas administration by the i.p. route (model B) induced a sustained response, in the form of BHR and eosinophilia. This difference in kinetics was due solely to the route of the second Ag administration and was not associated with Ag dose or adjuvant. Differences in kinetics of lung eosinophilia/BHR were shown to be independent of IgE levels and IL-4 or IL-5. However, IL-3 levels in model A closely correlated with the rate of leukocyte clearance by apoptosis and were observed concomitant with a decline in BHR. Blockage of IL-3 in model B increased leukocyte apoptosis but reduced tissue eosinophilia and BHR. The use of mouse models in which a single different administration of allergen is associated with a failure/success to resolve inflammation and BHR by 72 h postchallenge indicates a link between IL-3 production, leukocyte apoptosis, and BHR responses.     

Intermittent cyclophosphamide treatment of autoimmune thrombocytopenia

Cyclophosphamide was given intermittently rather than daily to 14 patients with autoimmune thrombocytopenic purpura. Eight patients responded and six did not. In those who responded the rise in platelet count was rapid, and in all patients the lack of toxicity was striking. Intermittent cyclophosphamide seems effective in some cases of autoimmune thrombocytopenia and is safe, at least in the short term. Controlled trials would be required to prove that intermittent is better than daily administration.     

Immunocytochemical analysis of apoptotic bone marrow cells after treatment of mice with WR-2721 and chemotherapeutic drugs

The effects of the aminothiol WR-2721 (Amifostine) and the chemotherapeutic drugs, cyclophosphamide (CP) and cisplatin (CDDP) on induction of apoptosis in bone marrow cells of adult male Swiss mice were studied. The mice received intraperitoneal injections of WR-2721 (400 mg/kg), cyclophosphamide (200 mg/kg), and cisplatin (10 mg/kg). WR-2721 was administered alone, or 30 min before treatment of mice with CP or CDDP. The number of apoptotic bone marrow cells was determined at 7 h and 24 h after the agent(s) administration. The In Situ Cell Death Detection Kit, AP based on TUNEL technique, and Fast Red Substrate System were used for microscopic analysis of immunocytochemically stained apoptotic cells. Application of cyclophosphamide and cisplatin resulted in a distinct increase of the number of apoptotic cells in the mouse bone marrow. After treatment of mice with WR-2721 prior to administration of CP or CDDP, as compared to the chemotherapeutic treatment only, the tendency to a decrease--albeit statistically insignificant--in the number of apoptotic cells was observed. Application of WR-2721 alone, without subsequent administration of the chemotherapeutic agents caused an inconsiderable increase in the number of apoptotic cells. The degree of apoptotic DNA cleavage in cells of the mouse bone marrow varied depending on the agent(s) given and the time interval after the drug administration.     

A putative role for platelet-derived PPARγ in vascular homeostasis demonstrated by anti-PPARγ induction of bleeding, thrombocytopenia and compensatory megakaryocytopoiesis

Widely known for its role in adipogenesis and energy metabolism, PPARγ also plays a role in platelet function. To further understand functions of platelet-derived PPARγ, we produced rabbit polyclonal (PoAbs) and mouse monoclonal (MoAbs) antibodies against PPARγ 14mer/19mer peptide-immunogens. Unexpectedly, our work produced two key findings. First, MoAbs but not PoAbs produced against PPARγ peptide-immunogens displayed antigenic crossreactivity with highly conserved PPARα and PPARβ/δ. Similarly, Santa Cruz PoAb sc-7196 was monospecific for PPARγ while MoAb sc-7273 crossreacted with PPARα and PPARβ/δ. Second, immunized rabbits and mice exhibited unusual pathology including cachexia, excessive bleeding, and low platelet counts leading to thrombocytopenia. Spleens from immunized mice were fatty, hemorrhagic and friable. Although passive administration of anti-PPARγ PoAbs failed to induce experimental thrombocytopenia, megakaryocytopoiesis was induced 4-8-fold in mouse spleens. Similarly, marrow megakaryocytopoiesis was enhanced 1.8-4-fold in immunized rabbits. These peptide-immunogens are 100% conserved in human, rabbit and mouse; thus, immune-mediated platelet destruction via crossreactivity with platelet-derived PPARγ likely caused bleeding, thrombocytopenia, and compensatory megakaryocytopoiesis. Such overt pathology would cause significant problems for large-scale production of anti-PPARγ PoAbs. Furthermore, a major pitfall associated with MoAb production against closely related molecules is that monoclonicity does not guarantee monospecificity, an issue worth further scientific scrutiny.     

Stem cell-conditioned medium does not protect against kidney failure

Paracrine secretion of mediators may be the main route by which stem cells protect against injuries. Stem cells commonly secrete different bioactive molecules. In this study, we examined the hypothesis that administration of conditioned media of stem cells can diminish the burden of kidney injury. A mouse model of cisplatin-induced nephropathy was developed to test the putative renoprotective effects of conditioned media of human umbilical cord blood USSCs (unrestricted somatic stem cells) as well as mouse bone marrow MSCs (mesenchymal stem cells). None of these two types of conditioned medium could protect against kidney failure in terms of serum urea and creatinine, histopathologic examinations and physical activity score. Neither MSC- nor USSC-conditioned media were effective in protecting against kidney injury in our study. Possible explanations for our observations are offered, and related literature is reviewed.