Portal vein embolization by fine needle ethanol injection: experimental and clinical studies

ＩＮＴＲＯＤＵＣＴＩＯＮＨｅｐａｔｏｃｅｌｌｕｌａｒｃａｒｃｉｎｏｍａ（ＨＣＣ）ｉｓｏｎｅｏｆｔｈｅｍｏｓｔｃｏｍｍｏｎｍａｌｉｇｎａｎｃｉｅｓｉｎＣｈｉｎａ．Ｔｈｅｒｅｓｅｃｔｉｏｎｒａｔｅｉｓｌｅｓｓｔｈａｎ３０％ｓｉｎｃｅｍｏｓｔｐａｔｉｅｎｔｓａｒｅａｓｓｏｃｉａｔｅｄｗｉｔｈｃｉｒｒｈｏｓｉｓａｎｄｐｏｏｒｌｉｖｅｒｆｕｎｃｔｉｏｎ．Ｆｕｒｔｈｅｒｍｏｒｅ,ｔｈｅｒｅａｒｅｔｕｍｏｒｅｍｂｏｌｉｉｎｔｈｅｐｏｒｔａｌｖｅｉｎｗｈｉｃｈｌｉｍｉｔｓｓｕｒｇｉｃａｌｒｅｓｅｃｔｉｏｎ．Ｐｏ…     

Tumor remission in Yoshida sarcoma-bearing rts by selective targeting of magnetic albumin microspheres containing doxorubicin.

Magnetically responsive albumin microspheres containing doxorubicin and magnetite (Fe3O4) were selectively targeted to Yoshida sarcoma tumors in rats by utilizing an extracorporeal magnet. Tumor cells were inoculated subcutaneously in the tail of rats, and the tumors were allowed to grow to an average size of 9 X 45 mm prior to initiating treatment. Drug-bearing microspheres (0.5 mg of doxorubicin per kg of body weight) were infused proximal to the tumor through the ventral caudal artery while the tumor was exposed to an external magnetic field of 5500 Oe for 30 min. Control animals received free doxorubicin administered either intravenously (5 mg/kg) or infused intraarterially (5 and 0.5 mg/kg), drug-bearing microspheres infused intraarterially (0.5mg/kg), without the external magnet, or placebo microspheres with magnetic localization. Of the 12 animals treated with a single dose in the experimental group, 9 exhibited total remission of the tumor, representing a disappearance of tumors as large as 60 mm in length. Marked tumor regression was observed in the remaining three rats, and no deaths or metastases occurred in the experimental group. In contrast, significant increases in tumor size with widespread metastases occurred in all control groups and most rats died. These experiments indicate that targeting of oncolytic agents to solid neoplasms by magnetic microspheres may be a means of increasing the efficacy and decreasing the toxicity of antitumor agents.     

乙酸灌注兔肝门静脉分支的实验研究

目的观察乙酸灌注兔肝门静脉分支后兔肝组织的大体及显微镜下病理变化,探讨乙酸栓塞门静脉分支引起兔肝组织坏死的机制.方法19只兔分为5组,0.250 ml/kg组2只,0.188 ml/kg组3只,0.125 ml/kg组3只,0.050ml/kg组3只,0.025 ml/kg组8只,剖腹后经门静脉右外支按每公斤体重注入50%乙酸.观察肝组织改变,并作病理检查.结果乙酸灌注兔肝门静脉分支后,可造成门静脉分支管腔内膜炎症,管腔狭窄,甚至血栓形成,伴行的肝动脉分支亦因乙酸作用形成内膜炎及血栓,导致相应区域肝组织变性坏死,肝、肾功能指标随之变化.结论经门静脉分支灌注乙酸同时,在门静脉、肝动脉内造成程度不等的栓塞,降低或阻断了相应肝组织的血供,其结果等同于门静脉、肝动脉双栓塞,为临床超选肝癌门静脉供血支灌注乙酸治疗肝癌提供了理论依据.     

阿苯达唑微球肝动脉灌注对大鼠肝泡状棘球蚴病的治疗作用

目的观察阿苯达唑-PEG6000固体分散体壳聚糖微球经肝动脉灌注治疗大鼠肝泡状棘球蚴病的效果。方法将肝泡状棘球蚴病模型大鼠30只,随机均分为3组,即生理盐水对照组(A)、空白微球组(B)和阿苯达唑微球组(C),A、B和C组分别经肝动脉灌注0.3 ml生理盐水、空白微球2.7 mg/kg(溶于0.3 ml生理盐水)、阿苯达唑-PEG6000固体分散体壳聚糖微球2.7 mg/kg(溶于0.3 ml生理盐水)。于灌注后第1、3、7、14和42天采集大鼠外周静脉血,检测白细胞(WBC)、门冬氨酸氨基转移酶(AST)和丙氨酸氨基转移酶(ALT)的值。第42天处死全部大鼠,取肝泡状棘球蚴组织,观察各组病理变化。结果各组大鼠白细胞第1天出现暂时性升高[A组(86.11±19.14)×109/L、B组(117.11±21.76)×109/L和C组(118.11±24.52)×109/L],第7天恢复正常[A组(7.85±6.57)×109/L、B组(11.73±4.85)×109/L和C组(8.49±1.36)×109/L]。B、C组在第3天AST、ALT达到最高值[B组AST(193.15±21.57)U/L、ALT(78...     

Transarterial embolization and low-dose continuous hepatic arterial infusion chemotherapy with oxaliplatin and raltitrexed for hepatocellular carcinoma with major portal vein tumor thrombus

AIM To determine the efficacy and safety of transarterial embolization and low-dose continuous hepatic arterial infusion chemotherapy with oxaliplatin and raltitrexed in hepatocellular carcinoma(HCC) with major portal vein tumor thrombus(MPVTT).METHODS eighty-six patients with MPVTT accepted routine embolization. The catheter was kept in the hepatic artery and oxaliplatin(50 mg in 250 m L of glucose) was infused by pump for 4 h,followed by raltitrexed(2 mg in 100 m L of 0.9% saline) infusion by pump for the next 1 h. The efficacy and safety were evaluated afterthe transarterial chemoembolization(TACe).RESULTS Full or partial embolization was achieved in 86 cases,where all the cases received low dose continuous hepatic arterial infusion chemotherapy. Complete responses(CRs),partial responses(PRs),stable disease(SD),and disease progression(PD) for intrahepatic disease were observed in 0,45,20,and 21 patients,respectively. The 1-,2-and 3-year overall survival rates of the 86 patients were 40.7%,22.1%,and 8.1% respectively,and the median survival time was 8.7 mo. Complication was limited. CONCLUSION TACE with low dose continuous hepatic arterial infusion of oxaliplatin and raltitrexed could be an option in MPVTT patient; it was shown to be effective in patients with advanced HCC with MPVTT with less toxicity.     

Enhanced antitumor efficacy on hepatoma-bearing rats with adriamycin-loaded nanoparticles administered into hepatic artery

AIM: To investigate the antitumor activity of adriamycin (ADR) encapsulated in nanoparticles (NADR) and injected into the hepatic artery of hepatoma-bearing rats. METHODS: NADR was prepared by the interfacial polymerization method. Walker-256 carcinosarcomas were surgically implanted into the left liver lobes of 60 male Wistar rats, which were divided into 4 groups at random (15 rats per group). On the 7th day after implantation, normal saline (NS), free ADR (FADR), NADR, or ADR mixed with unloaded nanoparticles (ADR+NP) was respectively injected via the hepatic artery (i.a.) of rats in different groups. The dose of ADR in each formulation was 2.0 mg/kg body weight and the concentration was 1.0 mg/mL. Survival time, tumor enlargement ratio, and tumor necrosis degree were compared between each group. RESULTS: Compared with the rats that received NS i.a., the rats that received FADR or ADR+NP acquired apparent inhibition on tumor growth, as well as prolonged their life span. Further significant anticancer efficacy was observed in rats that received i.a. administration of NADR. Statistics indicated that NADR brought on a more significant tumor inhibition and more extensive tumor necrosis, as compared to FADR or ADR+NP. The mean tumor enlargement ratio on the 7th day after NADR i.a. was 1.106. The mean tumor-bearing survival time was 39.50 days. Prolonged life span ratio was 109.22% as compared with rats that accepted NS. CONCLUSION: Therapeutic effect of ADR on liver malignancy can be significantly enhanced by its nanopaticle formulation and administration via hepatic artery.     

Treatment of hepatoma with liposome-encapsulated adriamycin administered into hepatic artery of rats

AIM: To observe the therapeutic effects of liposome-encapsulated adriamycin (LADM) on hepatoma in comparison with adriamycin solution (FADM) and adriamycin plus blank liposome (ADM BL) administered into the hepatic artery of rats. METHODS: LADM was prepared by pH gradient-driven method. Normal saline, FADM (2 mg/kg), ADM BL (2 mg/kg), and LADM (2 mg/kg) were injected via the hepatic artery in rats bearing liver W256 carcinosarcoma, which were divided into four groups randomly. The therapeutic effects were evaluated in terms of survival time, tumor enlargement ratio, and tumor necrosis degree. The difference was determined with ANOVA and Dunnett test and log rank test. RESULTS: Compared to FADM or ADM BL, LADM produced a more significant tumor inhibition (tumor volume ratio: 1.243±0.523 vs 1.883±0.708, 1.847±0.661, P < 0.01), and more extensive tumor necrosis. The increased life span was prolonged significantly in rats receiving LADM compared with FADM or ADM BL (231.48 vs 74.66, 94.70) (P < 0.05). CONCLUSION: The anticancer efficacies of adriamycin on hepatoma can be strongly improved by liposomal encapsulation through hepatic arterial administration.     

Myocardial micronecrosis produced by microsphere embolization. Role of an alpha-adrenergic tonic influence on the coronary microcirculation

Microspheres approximately 25 or 50 micrometers in diameter were systemically embolized from the left ventricular cavity. The number of microspheres given was empirically chosen to minimize the possibility of more than one microsphere lodging in an arteriole (3 mg/kg), yet was sufficient to allow for adequate histological assessment. The dogs were sacrificed after 24 hours, and focal areas of myocytolytic necrosis were noted in the myocardium. Groups of dogs were given pretreatment with drugs 10 minutes before embolization. Dogs pretreated with phentolamine (n = 8) and prazosin (n = 2) did not reveal any areas of myocardial necrosis after embolization with 25-micrometers microspheres. Cardiac lesions were also prevented in four of five dogs pretreated with verapamil. In contrast, cardiac lesions were not prevented by pretreatment with yohimbine (n = 2), dipyridamole (n = 3), propranolol (n = 2), or atropine (n = 2). Drug pretreatment with phentolamine or verapamil was not able to prevent cardiac lesions after embolization with 50-micrometers microspheres. Furthermore, despite a greater number of microspheres physically present in the subendocardial layer, the necrotic lesions were more frequent in the mid-wall and epicardial layers. Lesions produced by 25- or 50-micrometers emboli were also significantly smaller in the endocardium. Systemic embolization with microspheres excluding the coronary circulation did not produce cardiac lesions. We conclude that mechanical interruption of the coronary circulation with a 25-micrometers microsphere may be a necessary but not sufficient condition to produce cardiac necrosis. An alpha 1-adrenergic mechanism is also involved in the production of these lesions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Temporary blood flow stasis with degradable starch microspheres (DSM) for liver metastases in a rat model.

A reliable liver metastasis model using intraportal injections of sarcoma cells was established in syngeneic hooded Lister rats to study the blood supply of the tumours and to evaluate the role of degradable starch microspheres (DSM) in conjunction with selective hepatic arterial and portal venous chemotherapy. The tumour/normal liver (T/L) ratio after intra-arterial and intraportal injection of 113Sn microspheres was 1.04 (range: 0.38-1.15) and 0.03 (range: 0.006-0.22), respectively. After intravenous 14C-iodoantipyrine quantitative autoradiography of tumour and normal regions demonstrated a mean T/L ratio of 0.74 +/- 0.05. After hepatic artery ligation (HAL) and portal vein ligation (PVL) the values were 0.32 +/- 0.05 and 0.42 +/- 0.05, respectively. These results confirm that the vascularity of the tumours in this model is similar to human colorectal cancer metastases. Radiolabelled 14C 5-Fluorouracil (5-FU) was given intravenously, via the hepatic artery and via the portal vein (the latter two routes with and without DSM). Quantitative autoradiography of tumour regions showed that selective hepatic arterial administration with DSM resulted in a significantly increased concentration of 14C-5-FU within the tumours. These results suggest that DSM may enhance the therapeutic benefit of hepatic arterial 5-FU by increasing its uptake into tumours.     

Evaluating the safety of forsythin from Forsythia suspensa leaves by acute and sub-chronic oral administration in rodent models

Objective: To access the toxicity of forsythin from Forsythia suspensa leaves and evaluate its safety,Methods: Acute toxicity was determined by oral administration of a single dose of 18 100 mg/kg forsythin in NIH mice,Sub-chronic toxicity was evaluated by oral administration of several doses of forsythin for 30 days at does of 0,540,1 620,and 6 480 mg/kg in SD rats.Results: In the acute toxicity study,mortality was not observed after 14 days,In addition,clinically relevant adverse effects,or variations in body weight or food consumption were not observed,Similarly,after 30 days in the sub-chronic toxicity study,no mortality or significant toxicological effects such as decreased food consumption,body weight,biochemical parameters and vital organs etc,were noticed,Conclusion: The results revealed that the forsythin from Forsythia suspensa leaves has low or no toxicity via oral administration,and therefore is suitable for further development and applications.     

Synergistic action of hepatocyte membrane defect and activated complement system in liver cell death--an experimental approach to fulminant hepatic failure

The hypothesis was tested whether under the presence of a membrane defect of hepatocytes an activation of the complement system leads to massive liver cell necrosis. Low doses of galactosamine (50, 100, and 200 mg/kg) were administered to rats with and without an additional i.v. injection of sublethal doses of endotoxin (1.5 mg/kg). The latter was done in order to activate the complement system via the C3-bypath. Neither after doses of 50 mg/kg and 100 mg/kg nor after an additional administration endotoxin liver cell necrosis were observed. A dose of 200 mg/kg led to moderate liver cell necrosis, and when administered with endotoxin fulminant hepatic necrosis developed. The explanation was given that only after 200 mg/kg alterations of hepatocytes membranes were present, which prepare liver cells for complement mediated hepatocytolysis. In rats to which 1 g/kg galactosamine was given in addition to endotoxin it was demonstrated by immunohistology that the third component of complement was already fixed on hepatocyte plasma membranes at hour 3 and was accumulated within areas of necrotic liver parenchymal cells at hour 12. Thus, liver cell death is suggested as complement mediated if the membranes are altered. Clinical implications are given in concern of fulminant hepatic failure and an approach to effective treatment regims.     

葡聚糖微球肝栓塞治疗肝癌疗效的病理学评估

病理组织学评估葡聚糖微球栓塞治疗肝癌的疗效。11例原发性肝癌行葡聚糖微球肝栓塞治疗，栓塞后择期作有切除术。切除后的肝瘤标本作组织病理研究以观察肿瘤的坏死程度及葡聚糖微球在人体内的状况。7例肝癌病灶为完全坏死，未见存活癌细胞；另4例为不完全坏死。两者相比，完全坏死组肿瘤较为远离膈面、肝裂、及胆囊窝等动脉侧支吻合丰富的区域。葡聚糖微球能产生均一的末梢性动脉栓塞。微球在体内191天仍未被吸收。门脉系统内未见栓子微球。部分远离肝侧支循环的肝癌可通过葡聚糖微球肝栓塞得到临床治愈。     

Effect of phentolamine on the somatostatin-induced inhibition of glucagon and insulin secretion.

Synthetic cyclic somatostatin was infused into either the cranial pancreaticoduodenal artery or the femoral vein of anesthetized dogs with or without previous administration of phentolamine. Somatostatin infused into the pancreatic artery at a dose of 50 ng/kg/min for 10 min caused significant decreases in blood flow and plasma basal concentrations of both glucagon and insulin in the cranial pancreaticoduodenal vein, resulting in a profound decline of bihormonal output during the infusion. Arterial plasma glucose was not reduced during the administration of somatostatin in the pancreatic artery. These somatostatin-induced decreases failed to be eliminated by a 0.2 mg/kg injection of phentolamine into the femoral vein followed by a 9-min infusion of this alpha-adrenergic blocker (0.02 mg/kg/min) into the pancreatic artery immediately prior to the somatostatin administration. An inhibition of glucagon and insulin output and a fall of plasma glucose caused by somatostatin (1.7 microgram/min) infused into the femoral vein for 30 min also were not abolished by a prolonged and simultaneous infusion of phentolamine (0.2 mg/min) into the femoral vein over a period of 2 hr. These results indicate that alpha-adrenergic receptor mechanisms do not play a major role in the inhibition of islet glucagon and insulin secretion by somatostatin.     

肝多发血管瘤肝动脉介入栓塞治疗及疗效分析

目的 评价肝动脉介入栓塞术在治疗肝多发血管瘤的疗效,探讨术前、术中、术后正确的处理对提高患者治愈率及预防和减少并发症方面的作用。方法以我院2010年1月～2013年3月收治的25例肝多发血管瘤进行肝动脉介入栓塞治疗的患者为研究对象,观察其并发症及疗效。结果25例患者,其中1例2个血管瘤融合为直径共12cm的病灶分2次栓塞,第1次栓塞,1个月后瘤体体积缩小50％以上,给予第2次栓塞,6个月后复查,瘤体完全消失;其余24例病灶均1次栓塞成功,3个月后复查,病灶完全消失。全组病例均随访3个月到48个月,现全部治愈,无一例复发。结论肝动脉介入栓塞治疗肝多发血管瘤安全、有效,建议首选;介入栓塞治疗前注意适应证的选择,术中技术人员娴熟的操作,术后注意并发症的处理,才能取得满意的治疗效果。     

Ranitidine-acetaminophen interaction: effects on acetaminophen-induced hepatotoxicity in Fischer 344 rats

Cimetidine has been shown to protect against acetaminophen-mediated hepatotoxicity in both rats and mice. In contrast to cimetidine, ranitidine recently has been determined to potentiate the hepatotoxic action of acetaminophen in Fischer 344 rats. The present studies were designed to characterize this ranitidine-acetaminophen interaction. Acetaminophen administration (750 mg per kg, p.o.) to F344 rats produced maximal hepatic necrosis, 24 hr after treatment, as assessed by SGPT activity and histopathology. Ranitidine pretreatment 30 min prior to acetaminophen treatment increased the toxicity but did not alter its course. Ranitidine administration (50 mg per kg) enhanced acetaminophen hepatotoxicity throughout the toxic dose range of acetaminophen (600 to 1,000 mg per kg) and potentiation of acetaminophen hepatotoxicity by ranitidine was dose-dependent. Maximal increases were observed at 50 mg per kg ranitidine whereas, doses of ranitidine greater than 100 mg per kg inhibited acetaminophen toxicity. SGPT data were corroborated by histopathologic evaluation. Ranitidine was not hepatotoxic when administered alone (500 mg per kg), or following glutathione depletion, or after induction of hepatic mixed-function oxidase activity. The results obtained in these studies support the suggestion that, at high doses (greater than 100 mg per kg), ranitidine reduces acetaminophen hepatotoxicity by reducing metabolic activation, while at lower doses ranitidine potentiates acetaminophen hepatotoxicity. Inhibition by ranitidine of acetaminophen conjugation is proposed as a possible mechanism of this potentiation.     

Effects of lipopolysaccharide on TNF-alpha production, hepatic NOS2 activity, and hepatic toxicity in rats with cirrhosis

BACKGROUND/AIMS: Septic shock results in high mortality in patients with cirrhosis. Nitric oxide synthase 2 (NOS2) is induced by bacterial lipopolysaccharides (LPS) and plays a major role in the inflammatory response to bacterial infections. Little is known about the regulation of NOS2 in cirrhosis under septic conditions. Thus, the aim of this study was to determine tissue NOS2 activity, serum nitrate and tumor necrosis factor (TNF-alpha) levels and hepatic toxicity in cirrhotic rats after LPS administration. METHODS: Serum nitrates, TNF-alpha and transaminases were determined after LPS-administration in rats with secondary biliary cirrhosis and in sham-operated rats. Liver, lung, aortic and peritoneal macrophage NOS2 activities were determined by converting L[14C] arginine into L[14C] citrulline in a calcium free medium. Nitrate and TNF-alpha production were determined in a culture medium of peritoneal macrophages after in vivo LPS administration. RESULTS: LPS (1.5 mg/kg) induced 50% mortality in cirrhotic rats and no mortality in sham-operated rats. After LPS, TNF-alpha, nitrate and transaminase levels were significantly higher in cirrhotic rats compared to sham-operated rats. After LPS administration, there were no differences in NOS2 activity in the aorta, lungs, or peritoneal macrophages of the two groups, whereas NOS2 activity was significantly higher in the cirrhotic liver compared to the normal liver. CONCLUSIONS: In rats with cirrhosis, LPS administration induces higher mortality, hepatic toxicity, hepatic NOS2 activation and TNF-alpha release than in sham-operated rats. These results confirm the harmful role of septic shock in liver disease.     

Superiority of combined chemo-embolization and portal infusion with 5-fluorouracil over locoregional infusion concepts in Novikoff hepatoma-bearing rats

The aim of this study was to investigate experimentally whether there is a superior effect of the combination of hepatic artery chemo-embolization with portal vein infusion over either of the two treatment modalities alone. Novikoff hepatoma cells transplanted under the liver capsule of Sprague Dawley rats were used as a model. Tumor growth was assessed at 7 and 21 days after tumor inoculation. The prolamine solution Ethibloc was employed for embolization, and 5-fluorouracil was used as a chemotherapeutic agent for both infusion and chemo-embolization. All arterial treatment modalities were administered in a super-selective manner. There was no intolerable toxicity after dosages of 55 to 125 mg 5-fluorouracil/kg body weight. With regard to therapeutic efficacy the results show that embolization is an effective therapeutic means for inducing tumor necrosis in selected liver areas. As a consequence, the ranking of all treatment modalities was based on the combined evaluation of tumor size and extent of tumor necrosis. According to this evaluation, hepatic artery chemo-embolization was superior to the respective type of infusion (P<0.01). In addition, the combination of both modalities in the form of hepatic artery chemo-embolization and portal vein infusion was effective in destroying more than 97% of vital tumor tissue (P<0.01). These results suggest the need for a comparative clinical study.     

The hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea protect rats against thioacetamide-induced fulminant hepatic failure.

BACKGROUND/AIMS: Reactive oxygen species, proinflammatory cytokines, glutathione depletion and nitric oxide have all been implicated in the pathogenesis of fulminant hepatic failure. The aim of the present study was to examine the respective roles of these factors in the pathogenesis of thioacetamide-induced fulminant hepatic failure in rats. METHODS: Fulminant hepatic failure was induced by 3 consecutive intraperitoneal injections of thioacetamide (400 mg/kg) at 24-h intervals. Rats were pretreated with one of the following agents: the free radical scavengers dimethylsulfoxide (4 g/kg every 6 h) or dimethylthiourea (200 mg/kg every 12 h), the glutathione donor, N-acetylcysteine (130 or 200 mg/kg every 6 h), or the anti-tumor necrosis factor-alpha agents pentoxifylline (100 and 200 mg/kg) and soluble tumor necrosis factor receptor (100 or 1000 microg/rat). The nitric oxide synthase inhibitor N-mono-methyl arginine ester (L-NAME, 0.1 mg/ml) was administered in the drinking water, starting 7 days prior to thioacetamide administration. RESULTS: Serum levels of liver enzymes, blood ammonia and prothrombin time and the stage of hepatic encephalopathy were significantly improved in rats treated with dimethylsulfoxide or dimethylthiourea compared to the other treatment groups (p<0.001). Liver histology and the survival rate in these rats were not adversely affected by thioacetamide administration (p<0.001), while in all the other treatment groups those parameters were similar to control rats with fulminant hepatic failure. Furthermore, dimethylsulfoxide ameliorated liver damage and improved survival even when its administration was initiated 8 and 16 h after the first thioacetamide injection. The hepatic concentration of methanesulfinic acid, which is produced after direct interaction of dimethylsulfoxide with hydroxyl radicals, was increased five-fold in rats treated with thioacetamide+dimethylsulfoxide (p<0.001), suggesting a role for hydroxyl radical scavenging in the protection from fulminant hepatic failure in this model. In the group of thioacetamide-treated rats that were pretreated with L-NAME, liver enzymes, blood ammonia levels and the mortality rate were higher than in the control group, treated with thioacetamide only. CONCLUSIONS: In thioacetamide-induced fulminant hepatic failure, the hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea prevent liver injury. Neither N-acetylcysteine nor antagonists of tumor necrosis factor-alpha are protective in this rat model. Inhibition of nitric oxide formation aggravates liver damage and reduces the survival of rats with thioacetamide-induced liver damage.     

Effects of idebenone on memory impairment induced in ischemic and embolization models of cerebrovascular disturbance in rats

Two rat models of memory impairment in passive avoidance learning induced by cerebrovascular disturbance, were established to estimate the effects of a cerebral metabolic enhancer, idebenone. Transient and global cerebral ischemia in rats, produced by 4-vessel occlusion for 200 s immediately after the acquisition trial of passive avoidance learning, shortened the latencies in the retention test trial performed 24 h later. This retrograde amnesia was reversed significantly by idebenone administered orally or intraperitoneally at the doses of 10 and 30 mg/kg before the retention test trial. Idebenone at a dose of 10 mg/kg, given intraperitoneally before or immediately after the ischemia, also markedly inhibited the appearance of amnesia. In the second model, permanent and cerebral hemisphere embolization produced by injecting 2,000 microspheres into the internal carotid artery, significantly impaired passive avoidance learning performed 7 days later. The repeated administration of idebenone (30 mg/kg, i.p.). once a day after the embolization, significantly improved the impairment of passive avoidance learning in the embolized rats. Furthermore, physostigmine and arginine-vasopressin as reference compounds improved the impairment of passive avoidance learning in these models. These findings suggest that idebenone ameliorates memory impairment induced by cerebral vascular disturbance in rats.     

Effect of low-molecular-weight heparin on recombinant tissue plasminogen activator-induced thrombolysis in canine pulmonary embolism.

We employed a canine model of pulmonary embolism induced by radioactive blood clots to determine if low-molecular-weight heparin augments recombinant tissue plasminogen activator (rtPA)-induced thrombolysis. Following embolization, dogs were randomized: group 1 dogs received heparin; group 2 dogs received low-molecular-weight heparin; group 3 dogs received 1.5 mg/kg of rtPA over 45 minutes; group 4 dogs received rtPA 3 mg/kg over 45 minutes; and group 5 dogs received 1.5 mg/kg of rtPA plus low-molecular-weight heparin. Over three hours, little thrombolysis occurred in groups 1 and 2. In contrast, significant thrombolysis occurred in groups 3 to 5, 46 percent, 49 percent, and 46 percent, respectively (all p less than 0.01 compared with groups 1 and 2). We conclude that there is an upper limit to the dose-thrombolytic rate relationship with rtPA, and that low-molecular-weight heparin does not augment rtPA-induced thrombolysis.