Efficacy of ethane-1-hydroxy-1, 1-bisphosphonate (EHBP) for the decorporation of uranium after intramuscular contamination in rats

Purpose: To obtain compounds that will effectively reduce the fixation of uranium in its main target organs: bone and kidney. There is an urgent need for a chelating agent that is suitable and available for human use. Materials and methods: The efficacy of ethane-1-hydroxy-1, 1- bisphosphonate (EHBP), already in use as a therapeutic agent, was investigated in animal experiments. The effect of different treatment regimens was investigated on rats (EHBP: 50-100 mu mol kg-1; ligand/uranium ratio 2500 to 5000). Results: The present study shows that one prompt injection of EHBP reduced uranium deposition in kidneys by a factor of five after acute intramuscular contamination in rats. At the same time, the total body uranium in the treated animals was 70% of controls. When the treatment was delayed 30min after contamination, the kidney content was still reduced by a factor of two. Conclusions: EHBP has the advantage of clinical acceptance as a therapeutic agent for other purposes and its toxicity has been well studied. It therefore has a role in the treatment of human contamination with uranium.     

Aspects of 99mTechnetium binding from an ethane-1-hydroxy-1,1-diphosphonate-99mTc complex to bone

In vivo and in vitro experiments were under-taken to study factors influencing ^99mTc binding from an EHDP complex to bone. In vivo ^99mTc (IV) complexes of EHDP, ATP, citrate and ascorbate were injected into rats. The effects of pretreatment of rats with EHDP on EHDP- and ATP-Tc (IV) injection were examined. Citrate and ascorbate gave no bone scintigram, ATP gave a bone scintigram inferior to EHDP-Tc (IV). EHDP pretreatment deteriorated EHDP- and ATP-Tc (IV) scintigrams. Micro-autoradiography showed that Tc-activity is only found in the bone matrix of 15-day-old rats and that EHDP-pretreatment diminishes this labelling. In vitro experiments showed that EHDP also diminishes labelling of hydroxyapatite by EHDP-Tc (IV), but that an excess of Ca can augment this labelling. It is suggested that Tc (IV) binds to bone because EHDP binds to bone, permitting released Tc (IV) to bind to bone separately.     

Influence of pretreatment with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APB) on organ uptake of 211At and 125I-labeled amidobisphosphonates in mice

To minimize nontarget organ uptake in animals receiving radiolabeled amidobisphosphonates, the influence of pretreatment with cold 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APB, pamidronate) was studied. Three groups of animals were given pure 3-[125I]iodobenzamide-N-3-hydroxypropylidene-3,3-bisphosphonate (IBPB) and 3-[211At]astatobenzamide-N-3-hydroxypropylidene-3,3-bisphosphonate (ABPB) (control); co-injection of APB and IBPB/ABPB; and 1 h preinjection of APB followed by IBPB/ABPB, respectively. A significant reduction of uptake in normal tissue was observed, whereas the bone uptake remained constant at 35-50%ID/g tissue. This study suggests that co- or preinjection of pamidronate may reduce the normal organ radiation doses when using these radiohalogenated bisphosphonates for endoradiotherapeutic procedures.     

大鼠长期摄入贫铀后的病理形态学特点观察

目的 观察大鼠长期食入不同剂量的贫铀后,亲代(F0)和子代(F1)大鼠各组织器官的病理形态改变.方法 给F0和F1Wistar大鼠共64只喂食贫铀饲料,分为F0代低、中、高剂量组和F1代中、高剂量组,另取10只大鼠做对照.给低、中、高剂量组大鼠喂食的贫铀含量分别为0.4mg/(kg·d)、4mg/(kg·d)和40mg/(kg·d).F0代大鼠分别于7、14和20个月后处死,F1代大鼠分别于5、10和15个月后处死,分别取睾丸(卵巢)、脾脏、肾脏、肝脏、骨髓等脏器进行病理形态学观察.结果 F0代的中、高剂量组大鼠摄入贫铀14个月后可见雄性的精曲小管萎缩,管壁增厚呈空虚网状,生精细胞层次减少,间质细胞增生,但仍见有精子生成;高剂量组可见到精子呈异型性改变,细胞核浓缩深染,且随着摄入时间延长改变愈趋明显;F1代大鼠摄入贫铀5个月后就有上述改变且更为严重.F0代中、高剂量组大鼠摄入贫铀14个月后肾小球轻度萎缩,间质增生明显,20个月时肾小球萎缩纤维化;F1代大鼠摄入贫铀5个月后就有上述改变.F0代中、高剂量组摄入贫铀7个月时脾脏生发中心和淋巴鞘增生,淋巴母细胞增生活跃,20个月时脾小体减少,生发中心稀疏;F1代大鼠摄入贫铀早期和晚期有类似改变.F0和F1代高剂量组摄入贫铀早期肝脏有炎症细胞浸润,晚期骨髓有核细胞减少,脂肪细胞增加.其余脏器未见明显的病理形态学改变.结论 长期摄入贫铀对大鼠组织脏器的损伤具有一定的时间性和组织特异性,主要损伤集中在雄性生殖系统、免疫系统和造血系统,而对其他组织的损伤不明显.     

核与辐射应急医学救援中放射性核素内污染阻吸收与促排药物使用时机探讨

放射性核素内污染是核与辐射事故应急医学救援中的常见问题,其医学处理是救援的重点内容。阻吸收和促排是放射性核素内污染治疗的主要手段,往往涉及药物使用,通常使用越早治疗效果越好。我国发布的多个标准、规范对于阻吸收药物的使用认识一致,认为在明确或高度疑似有放射性核素过量摄入时即可尽快使用阻吸收药物及措施。但对促排药物的使用时机表述存在差异性,容易在应用中造成困惑。通过梳理分析相关标准、规范的适用范围和适用条件,并结合国外的研究进展,就核与辐射应急医学救援中内污染促排药物的使用时机提出建议。认为,国内核事故场内应急的内污染阻吸收与促排药物使用策略与国外新近提出的"紧急处理方案"的思想值得借鉴、提倡,即对于高风险群体怀疑有放射性核素摄入就立即开始药物治疗的方法是谨慎可取的,后续如果内照射剂量评估达不到相关干预水平,停止治疗即可。同时,探讨了前述内污染处理药物使用策略在应用中需要注意的问题,以供相关人员参考。     

贫铀长期接触后在大鼠体内的吸收分布特点

目的：检测贫铀长期接触后在大鼠体内各重要脏器的吸收分布特点。方法：通过手术在大鼠体内植入贫铀片或给予含贫铀50μg／L和70μg／kg饮水及饲料，建立植入／摄入贫铀动物模型。采用铀萤光发光法检测大鼠在接触贫铀1、6、12和18个月后体内各脏器的贫铀含量。结果：从1到18月，各个脏器中的贫铀含量均随接触时间的延长而增加。以肾脏和骨组织贫铀含量最高，第18个月摄入组肾脏及骨组织分别达到（3305.61±1234．30）ng／g及（2804．57±1518．01）ng／g，植入组分别达到（3927．53±1742．90）ng／g，（3760．85±1822.30）ng／g。结论：无论是植入途径还是摄入途径，肾脏和骨组织均为贫铀的主要蓄积靶器官。     

Efficacy of 3,4,3-LIHOPO for reducing neptunium retention in the rat after simulated wound contamination

Purpose: The ligand 3,4,3-Li(1,2-HOPO) was tested for Np removal after intramuscular injection of 237 Np nitrate in rats. Materials and methods: Two experiments were performed, one with simultaneous injection of neptunium and LIHOPO at dosages ranging from 3 to 200mumolkg -1 and the other with delayed administration of LIHOPO 30mumolkg -1 from 5min to 30min after Np injection. Results: The data obtained after simultaneous injections showed that the ligand dosage effectiveness was not linear and depended on the tissues being considered. For bones, the best results were obtained with 200 mumolkg -1 LIHOPO, where retention was reduced to 11% of controls. Maximum efficacies for removal in liver and kidney were obtained with 30mumol kg -1 LIHOPO, where retention was reduced to 39% and 1.6% of controls, respectively. At higher dosages, LIHOPO seemed to have a reverse effect on these tissues, demonstrated by a significant accumulation of the radionuclide. The delayed administration of LIHOPO dramatically decreased its efficacy. When administered 5min after Np, LIHOPO was still efficient (60%, 37%, 7% of controls in bone, liver, kidneys, respectively) but not when treatment was delayed to 30min. Conclusions: These results demonstrated that LIHOPO was able to complex Np at the wound site but not after translocation to blood.     

Efficacy of 3,4,3-LIHOPO for reducing neptunium retention in the rat after simulated wound contamination

PURPOSE: The ligand 3,4,3-Li(1,2-HOPO) was tested for Np removal after intramuscular injection of 237Np nitrate in rats. MATERIALS AND METHODS: Two experiments were performed, one with simultaneous injection of neptunium and LIHOPO at dosages ranging from 3 to 200 micromol kg(-1) and the other with delayed administration of LIHOPO 30 micromol kg(-1) from 5 min to 30 min after Np injection. RESULTS: The data obtained after simultaneous injections showed that the ligand dosage effectiveness was not linear and depended on the tissues being considered. For bones, the best results were obtained with 200 micromol kg(-1) LIHOPO, where retention was reduced to 11% of controls. Maximum efficacies for removal in liver and kidney were obtained with 30 micromol kg(-1) LIHOPO, where retention was reduced to 39% and 1.6% of controls, respectively. At higher dosages, LIHOPO seemed to have a reverse effect on these tissues, demonstrated by a significant accumulation of the radionuclide. The delayed administration of LIHOPO dramatically decreased its efficacy. When administered 5 min after Np, LIHOPO was still efficient (60%, 37%, 7% of controls in bone, liver, kidneys, respectively) but not when treatment was delayed to 30 min. CONCLUSIONS: These results demonstrated that LIHOPO was able to complex Np at the wound site but not after translocation to blood.     

喹胺酸和LICAM(C)对大鼠体内238Pu和241Am的促排效果比较

喹胺酸(Quinamic acid, QAA, 811)是一种异哇啉类络合剂, 对钍有较好的促排效果。本文主要研究大鼠静脉注入(iv)²³⁸Pu和²⁴¹Am各26kBq/kg后1小时, 经皮下注入(so)不同剂量.(1～30μmol/kg)QAA, 或静脉注入核素后立即灌胃(po)QAA(30μmol/kg)对²³⁸Pu、²⁴¹Am的促排疗效, 并与LICAM(C)相比较。实验观察到QAA对降低骨肝中²³⁸Pu、²⁴¹Am的蓄积量有较好的作用, QAA对²³⁸Pu的促排效果高于对²⁴¹Am.在剂量(1～30μgmol/kg)对肝、肾中²³⁸Pu和骨、肾中²⁴¹Am蓄积量的降低, QAA优于LICAM(C)；灌胃QAA(30μttmol/kg)伍用NaHCO₃(5mmol/kg的)疗效, 对骨、肝中²³⁸Pu蓄积量的降低, QAA和LICAM(C)二间无差异(P>0.05), 但对²³⁸Pu在肾中蓄积量和对²⁴¹Am在骨, 肾中蓄积量的降低, QAA明显优于LICAM(C)。     

Efficacy and toxicity of N,N',N",N"'-tetra(2,3,4-trihydroxybenzoyl)-spermine for decorporation of 239Pu from mice

Male SAS/4 mice were injected i.v. with 6.6 kBq 239Pu-citrate. After 1 or 24 h a single i.p. injection of 15 or 30 mumol kg-1 or repeated (three or four) daily injections of 30 mumol kg-1 of tetra-THB-spermine were given, and at 4 or 7 days Pu retention was measured in liver, kidneys and femur. Besides tetra-THB-spermine, equimolar doses of tetra-DHB-spermine were injected for comparison, or equimolar doses of diethylene triamine-pentaacetic acid (DTPA) as a reference compound. Histological changes in kidneys and liver were examined after i.p. injections of 30 mumol kg-1 or at 2-13 times higher doses of tetra-THB-spermine. The results show that: (1) Introduction of an additional hydroxy group into the aromatic moieties of tetra-DHB-spermine results in increased hydrophilicity, lower toxicity and a lower renal retention of Pu. (2) Tetra-THB-spermine and tetra-DHB-spermine are similarly effective in removing plutonium from liver and bone. Their efficacies in removing Pu from bone are approximately similar to those of DTPA but for whole-body removal they are generally inferior. (3) Multiple (30 mumol kg-1) of tetra-THB-spermine were no more effective than a single injection at mobilizing Pu from the liver. (4) Four injections of tetra-THB-spermine induced cloudy swelling and fatty degeneration in epithelial cells of the proximal convoluted tubules. At levels of 400 mumol kg-1 tetra-THB-spermine produced severe degenerative glomerular lesions, foci of liver necrosis and thromboses of the portal vein branch.     

Testing of methyleneiminodiacetic-catechol and other aromatic chelating agents for decorporation of 238Pu and 241Am in rats

The removal of 238Pu and 241Am by five chelating agents prepared in China was compared in pilot experiments with removal by Ca-DTPA and LICAM(C). The most promising substance is quinamic acid (a methyliminodiacetic polyquinoline derivative, code name 811 or 703-73), especially in combination with Ca-DTPA. However, the best over-all reduction of both 238Pu and 241Am in all the organs studied was achieved by Ca-DTPA-administered at a ten-fold human equivalent dosage.     

Efficacy of alcoholates and clay in percutaneous contamination of rats with highly toxic organophosphorus compounds]

Efficacy of decontamination by alcoholate and clay has been examined in animals percutaneously poisoned by nerve war gases (VX, soman) and organophosphorous insecticides (parathion, dichlorvos, terbufos) at exposure of 2, 5 and 60 minutes. High efficacy was achieved after two minutes using alcoholates which, except for VX, was lower for 50% after 5 minutes. The similar results were also achieved with clay in nerve war gas poisoning, however, the efficacy of this material was somewhat lower. By delayed decontamination (after 60 minutes) in animals poisoned by parathion and terbufos somewhat lower but still satisfying efficacy was achieved (ZI = 3.3, that is, 11.5). The results obtained have shown that efficacy of decontamination, except for the used materials, depends also on duration of the procedure.     

长期食入低剂量贫铀对大鼠的生殖毒性研究

目的 研究长期食入低剂量贫铀对大鼠的生殖毒性。方法给予初断乳大鼠含贫铀饲料，食入贫铀的剂量分别为0、0．4、4和40mg·k^-1·d^-1，4个月后，采用两代-窝法观察整体生殖毒性效应；放射免疫法检测睾酮（T）、黄体生成素（LH）、卵泡刺激素（FSH）等血清性激素水平；比色法测定睾丸中乳酸脱氢酶同工酶（LDH—X）、琥珀酸脱氢酶（SDH）及Na^＋-K^＋’ATPase、ca2’-ATPase等精子生成和代谢有关酶的比活性。结果亲代（F0代）大鼠各项指标未见显著改变。子代（F1代）高剂量组的受孕率、正常分娩存活率、幼仔出生存活率、幼仔哺育存活率均下降，与对照组相比，差异有统计学意义。食入贫铀的F0代大鼠血清性激素含量较正常组增加，但F1代除T升高外，其余性激素均下降。Fn代高剂量组睾丸中LDH含量降低；F1代大鼠中、高剂量组SDH、LDH和Na^＋-K^＋-ATPaSe含量降低。结论长期食入低剂量的贫铀对F0代大鼠未见明显生殖毒性，但F1代大鼠的生殖毒性效应显著增加。     

罗格列酮对脓毒症大鼠空肠短肽载体的调控机制研究

目的 探讨罗格列酮对脓毒症大鼠空肠短肽载体(PepT1)表达的调控作用及其机制.方法 健康成年SD大鼠48只,随机分为盲肠结扎穿刺(CLP)组(C组)、假手术组(S组)、罗格列酮组(R组)、罗格列酮+胰岛素组(RI组)、CLP+胰岛素组(CI组)和正常对照组(N组),每组8只.C、CI、S组大鼠术前30min给予等量生理盐水灌胃;R、RI组CLP前30min给予罗格列酮(20mg/kg)灌胃;RI、CI组在CLP后150min经股静脉注射胰岛素(10U/kg);N组大鼠未做任何处理.6组大鼠分别于术前30min及术后30、60、90、120、150min测空腹血糖,并在150min时取动脉血和近端空肠待检.采用紫外分光光度法测定血清D-乳酸水平,ELISA法检测血清IL-6、TNF-α、IL-10水平变化,Western blotting检测空肠PepT1表达.结果 术前给予罗格列酮可降低脓毒症大鼠呼吸频率、外周血中性粒细胞水平及CLP术后血糖,降低血清炎性因子TNF-ot、IL-6、IL-10水平以及D-乳酸水平,增加基础状态下和胰岛素刺激下的PepT1表达.结论 罗格列酮可通过降低炎性因子水平而提高脓毒症时空肠肠黏膜PepT1的表达.     

Comparison of the effects of enriched uranium and 137-cesium on the behaviour of rats after chronic exposure

PURPOSE: A radionuclide that accumulates in the central nervous system is likely to exert both a chemical and a radiological effect. The present study aimed at assessing the behavioral effect of two radionuclides previously shown to accumulate in the central nervous system after chronic exposure--uranium and cesium. MATERIALS AND METHODS: Rats were exposed for 9 months to drinking water contaminated with either enriched uranium at a dosage of 40 mg U x l(-1) or 137-cesium at a dosage of 6500 Bq x l(-1), which correspond to the highest concentrations measured in some wells in the south of Finland (uranium) or in the milk in Belarus in the year following the Chernobyl accident (137-cesium). RESULTS: At this level of exposure, 137-cesium had no effect on the locomotor activity measured in an open-field, on immobility time in a forced swimming test, on spontaneous alternation in a Y-maze and on novel object exploration in an object recognition test. Enriched uranium exposure specifically reduced the spontaneous alternation measured in the Y-maze after 3 and 9 months exposure although it did not affect the other parameters. CONCLUSION: Enriched uranium exposure altered the spatial working memory capacities and this effect was correlated with previously described accumulation of uranium in the hippocampus which is one of the cerebral areas involved in this memory system.