Ammonia toxicity: Comparative protective effect of various arginine and ornithine derivatives,aspartate, benzoate,and carbamyl glutamate

Ornithine and arginine compounds were highly effective in preventing an increase in blood ammonia and in preventing or minimizing encephalopathy after acute subcoma, comainducing, or lethal doses of NH ₄ ⁺ . Similar protection was seen after subacute loading with glycine. Ornithine ketoacid derivatives were no more effective than ornithine alone or ornithine glutamate. Ornithine appeared to be a little more effective than arginine, but the differences were slight. Aspartate and glutamate alone were ineffective. Carbamyl glutamate was much less effective than either ornithine glutamate or arginine glutamate. Orotic acid excretion was markedly increased in the presence of excess NH ₄ ⁺ . This increment was eliminated with ornithine or arginine, although the reduction with arginine was unpredictably erratic. Aspartate increased the orotic acid excretion and the amount of urea formed. Sodium benzoate was borderline in its effect on the blood ammonia and on orotic acid excretion.     

门冬氨酸鸟氨酸治疗脂肪肝疗效Meta分析

目的 评价门冬氨酸鸟氨酸治疗脂肪肝患者的疗效。 方法 检索中国知网（CNKI）、万方、维普、PubMed、EMBASE、Medline和Cochrane library自建库至2017年7月20日发表的门冬氨酸鸟氨酸治疗脂肪肝患者的临床随机对照试验,应用Cochrane 手册进行风险偏倚评价,采用Jadad 7分量表进行文献质量评分。应用RevMan5.3进行Meta分析。 结果 纳入符合要求的9篇中文文献,共计727例脂肪肝患者。Meta分析结果显示,门冬氨酸鸟氨酸治疗脂肪肝患者临床总有效率显著高于常规对照组【OR=3.71,95%CI（1.85,7.46）,P=0.0002】; 降低总胆固醇合并效应值MD=-3.04,95%CI-3（.76,-2.31）,P<0.0000,降低甘油三酯（TG）合并效应值MD=-1.60,95%CI（-2.55,-0.65）,P=0.0009;降低血清ALT合并效应值MD=-34.04,95%CI（-61.73,-6.35）,P=0.02;降低AST合并效应值MD=-9.48,95%CI（-24.66,5.70）,P=0.22;相比异甘草酸镁治疗, 门冬氨酸鸟氨酸治疗脂肪肝患者的临床总有效率显著升高 【OR=4.06,95%CI（1.91,8.65）,P=0.0003】。 结论 门冬氨酸鸟氨酸治疗脂肪肝患者具有较好的治疗效果,可以改善肝功能指标,降低血脂水平。门冬氨酸鸟氨酸治疗脂肪肝患者的疗效尚需更多设计良好的临床试验证实。     

门冬氨酸鸟氨酸颗粒剂对慢性肝病患者血清谷氨酰转肽酶水平的影响

目的观察门冬氨酸鸟氨酸颗粒剂（瑞甘）对慢性肝病患者血清谷氨酰转肽酶（GGT）水平的影响。方法应用瑞甘治疗慢性肝病血清GGT持续升高的患者,以双环醇（百赛诺）为对照组,疗程30天。结果 50例治疗组患者治疗前GGT水平为196.98±190.80U/L,治疗后为96.10±89.84 U/L（P〈0.01）,30例对照组治疗前为168.06±87.10U/L,治疗后为117.30±52.63U/L（P〈0.05）;两组GGT水平,治疗前比较无明显差异,治疗后比较也无明显差异;GGT水平与ALT呈正相关（r=0.40,P〈0.001）。结论瑞甘与双环醇均能明显降低慢性肝病患者血清GGT水平,有减轻肝脏炎症损害,保护肝脏的作用,两药对GGT水平的作用相当。     

门冬氨酸鸟氨酸联合醒脑静治疗肝性脑病患者疗效及其对血清炎症因子水平的影响

目的 探讨应用门冬氨酸鸟氨酸联合醒脑静治疗乙型肝炎肝硬化并发肝性脑病(HE)患者的疗效及其对认知功能和血清炎症因子水平的影响。方法 将62例乙型肝炎肝硬化并发HE患者随机分为观察组31例和对照组31例,在常规治疗的基础上分别给予醒脑静或醒脑静联合门冬氨酸鸟氨酸静脉滴注,两组均持续治疗2周。采用ELISA法检测血清白介素-6(IL-6)、C-反应蛋白(CRP)和肿瘤坏死因子-α(TNF-α)水平,应用数字连接试验(NCT)、数字符号试验(DS)、简易智力状态检查量表(MMSE)和长谷川痴呆量表(HDS)行认知功能评价。结果 在治疗2周末,观察组病死率为19.4%,显著低于对照组的35.5%(P<0.05);治疗后,观察组MMSE评分为(28.1±3.2)分,显著高于对照组【(22.1±2.8)分,P<0.05】,HDS评分为(27.7±2.6)分,显著高于对照组【(19.0±2.1)分,P<0.05】,DS评分为(60.7±1.9)分,显著高于对照组【(43.1±4.0)分,P<0.05】,而NCT用时为(51.6±5.9)s,显著短于对照组【(62.4±6.5)s,P<0.05】;观察组血清IL-6水平为(11.8±0.9)ng/L,显著低于对照组【(14.9±1.0)ng/L,P<0.05】,血清CRP水平为(13.6±1.7)ng/L,显著低于对照组【(15.5±1.9)ng/L,P<0.05】,血清TNF-α水平为(12.0±1.0)ng/L,显著低于对照组【(15.9±1.2)ng/L,P<0.05】;观察组血氨(NH₃)水平为(54.9±5.6)μmol/L,显著低于对照组【(85.3±8.7)μmol/L,P<0.05】,而两组血清胆红素和白蛋白水平差异无统计学意义(P>0.05)。结论 应用门冬氨酸鸟氨酸联合醒脑静治疗乙型肝炎肝硬化并发HE患者有一定的效果,在综合治疗的基础上可降低近期病死率,可能与有效地抑制了机体的炎症反应,降低血NH₃水平有关,其远期疗效仍有待于进一步观察。     

Pathophysiology of alcoholic brain damage: synergistic effects of ethanol,thiamine deficiency and alcoholic liver disease

Chronic alcoholism results in brain damage and dysfunction leading to a constellation of neuropsychiatric symptoms including cognitive dysfunction, the Wernicke-Korsakoff Syndrome, alcoholic cerebellar degeneration and alcoholic dementia. That these clinically-defined entities result from independent pathophysiologic mechanisms is unlikely. Alcohol and its metabolite acetaldehyde are directly neurotoxic. Alcoholics are thiamine deficient as a result of poor diet, gatrointestinal disorders and liver disease. In addition, both alcohol and acetaldehyde have direct toxic effects on thiamine-related enzymes in liver and brain. Alcoholics frequently develope severe liver disease and liver diseaseper se results in altered thiamine homeostasis, in cognitive dysfunction and in neuropathologic damage to astrocytes. The latter may result in the loss of neuron-astrocytic trafficking of neuroactive amino acids and thiamine esters, essential to CNS function. The present review article proposes mechanisms whereby the effects of alcohol, thiamine deficiency and liver disease combine synergistically to contribute to the phenomena of cognitive dysfunction and alcoholic brain damage.     

不同载体和不同导入途径对外源基因肝脏靶向导入效果的比较

目的 比较脂质体和糖化多聚赖氨酸对所携带的导入基因肝脏靶向定位效果的影响。同时观察静脉途径和腹腔对导入基因肝脏靶向定位效果的影响。方法 将真核细胞表达质粒分别与脂质体和糖化多聚赖氨酸偶联,分别经尾静脉注射和腹腔注射导入大鼠体内,运用原位杂交和免疫组织化学的方法观察目的基因在肝脏和其他肘器中的分布表达,结果 经 质体或糖化多聚赖氨酸包埋的质粒ＤＮＡ导入体内２４ｈ后均见明显表达,一周后逐渐下降,三周时     

Effects of liver failure on inter-organ trafficking of ammonia: implications for the treatment of hepatic encephalopathy

Abstract   Hepatic encephalopathy due to acute or chronic liver failure is invariably associated with hyperammonemia. High ammonia concentrations have deleterious effects on brain function by both direct and indirect mechanisms. There is increasing evidence to suggest that hyperammonemia in liver failure results from altered inter-organ ammonia trafficking. Under normal conditions the gut produces ammonia from glutamine and urea. During liver failure, the contribution of the gut to hyperammonemia is predominantly the consequence of a diminished hepatic elimination rather than increased intestinal production. Normally, the liver removes ammonia by two distinct pathways, namely urea and glutamine synthesis catalyzed by enzymes that are, respectively, localized in the periportal and perivenous hepatocytes. The skeletal muscle relies solely on glutamine synthesis to remove ammonia. During liver failure, muscle glutamine production increases and the muscle becomes the major route for ammonia detoxification. The kidney is capable of both producing and removing ammonia. Under normal conditions, the kidney produces ammonia from glutamine which is mainly excreted into the renal vein, the remainder being excreted into the urine. However, in liver failure the excretion of the ammonia produced by the kidney is increased. Like skeletal muscle the brain relies solely on glutamine synthesis to remove ammonia. But unlike muscle, glutamine synthetase in the brain operates at nearly maximal capacity in normal conditions, and its activity is reduced during chronic liver failure. A better understanding of the alterations of inter-organ ammonia trafficking could give rise to combined therapies aimed at reducing ammonia production and increasing ammonia removal by target organs.     

Comparative effects of thyroid hormone analogs on the activities of brain and liver mitochondria and nuclei in thyroidectomized rats

Several thyroid hormone analogs have been tested for thyromimetic activity on rat brain and liver subcellular organelles. The compounds were administered immediately after thyroidectomy to 90 g male S-D rats for 10 days, by daily s.c. injection. In cerebral cortex and liver we measured the activities of mitochondrial succinate cytochrome c reductase and a-GPD, and nuclear RNA polymerase I. Brain mitochondrial enzymes were unchanged in thyroidectomized (Tx) and in Tx-treated rats, whereas the activities of these enzymes in liver mitochondria were partially restored by the treatments. RNA polymerase I activity in brain and liver dropped significantly 10 days after thyroidectomy and daily injection of thyroid hormones or analogs maintained the nuclear activity at a normal level. Correlation between the structure of thyroid hormone analogs and their subcellular effects is in good agreement with previous binding and in vivo studies. Enzyme activities stimulated by T₃ were lowered by replacing the T₃ side-chain by an acetic acid group or by substituting the bridged oxygen atom by atom by CO. In contrast, the activity was enhanced by substituting iodine with a 3' isopropyl group. Although less active than iodine, the 3,5-dimethyl substituents may be introduced without a complete loss of nuclear activity.     

Effect of treatment willingness on specialist assessment and treatment uptake for hepatitis C virus infection among people who use drugs: the ETHOS study

Among people who inject drugs (PWID) with chronic HCV, the association between HCV treatment willingness and intent, and HCV specialist assessment and treatment were evaluated. The Enhancing Treatment for Hepatitis C in Opioid Substitution Settings (ETHOS) is a prospective observational cohort. Recruitment was through six opioid substitution treatment clinics, two community health centres and one Aboriginal community controlled health organisation in Australia. Analyses were performed using logistic regression. Among 415 participants (mean age 41 years, 71% male), 67% were ‘definitely willing’ to receive HCV treatment and 70% reported plans to initiate therapy 12 months postenrolment. Those definitely willing to receive HCV treatment were more likely to undergo specialist assessment (64% vs 32%, P < 0.001) and initiate therapy (36% vs 9%, P < 0.001), compared to those with lower treatment willingness. Those with early HCV treatment plans were more likely to undergo specialist assessment (65% vs 27%, P < 0.001) and initiate therapy (36% vs 5%, P < 0.001), compared to those without early plans. In adjusted analyses, HCV treatment willingness independently predicted specialist assessment (aOR 3.06, 95% CI 1.90, 4.94) and treatment uptake (aOR 4.33, 95% CI 2.14, 8.76). In adjusted analysis, having early HCV treatment plans independently predicted specialist assessment (aOR 4.38, 95% CI 2.63, 7.29) and treatment uptake (aOR 9.79, 95% CI 3.70, 25.93). HCV treatment willingness was high and predicted specialist assessment and treatment. Strategies for enhanced HCV care should be developed with an initial focus on people willing to receive treatment and to increase treatment willingness among those less willing.     

中西医结合治疗慢性肝衰竭多地域、多中心、随机、对照研究

目的观察中西医结合治疗方案对慢性肝衰竭患者病死率、并发症发生率以及中医症状改善率的影响。方法采用随机对照设计,将纳入对象随机分配入试验组和对照组,分别给予中西医结合和内科综合治疗。结果经χ2检验,在治疗第8周、第12周、第24周和第48周,2组病死率差异无统计学意义,生存分析表明试验组的生存率略低于对照组,但经Log-rank检验,2组生存曲线差异无统计学意义;治疗第5周、第6周、第7周及第24周4个时间点试验组腹水发生率低于对照组(P<0.05),在治疗第48周试验组的肝性脑病发生率低于对照组(P<0.05);在改善乏力、腹胀、水肿等中医临床症状方面试验组优于对照组。结论个体化复杂干预的中西医结合治疗方案与单纯西医治疗比较,在降低慢性肝衰竭病死率方面未显示出优势,但在控制腹水、肝性脑病等并发症方面有一定作用,特别是在改善中医症状方面具有明显优势。     

从慢加急性肝衰竭共识讨论到肝衰竭定义和分型诊断

2008年3月23-26日,第18届亚太肝脏研究学会(APASL)年会在韩国首尔召开.此次大会的主题为"肝脏病学新视野".     

重组人脑利钠肽和硝酸甘油治疗急性失代偿性心力衰竭疗效和安全性的随机、开放、平行对照的多中心临床研究

目的比较重组人脑利钠肽和硝酸甘油治疗急性失代偿性心力衰竭(心衰)的治疗效果和安全性。方法试验对入选的209例急性失代偿性心衰患者的临床资料采用随机、开放、平行对照、多中心方法进行采集和统计分析。入选患者随机分配为导管组和非导管组,导管组应用Swan-Ganz导管进行血流动力学监测,分别在给药的0、15、30min和1、2、4、8、12、24h结束时测量记录治疗前后的肺毛细血管楔压(PCWP)、肺动脉压(PAP),分别于给药的1、4、8、24h测量右房压(RAP)、心排量(CO)和心排指数(CI)。导管组与非导管组均记录治疗前后的呼吸困难程度、出入量以及全身临床情况评估。分组后患者再随机分入试验组(重组人脑利钠肽)和对照组(硝酸甘油),试验组使用重组人脑利钠肽首先以0·15μg/kg静脉冲击后,以0·0075μg·kg-1·min-1连续静脉滴注;对照组静脉持续滴注硝酸甘油。安全性评估采用用药过程中及用药后定期测量血压、心率,并对过程中所有不良事件进行记录。结果试验资料显示,两组治疗期间的液体出量均显著增加;试验组的呼吸困难和临床状况好转率显著优于对照组;试验组的PCWP、PAP比对照组有显著下降,而两组RAP和CI差异无统计学意义。在与药物相关的不良事件方面,两组差异无统计学意义。结论重组人脑利钠肽能明显改善急性失代偿性心衰患者的血流动力学、呼吸困难程度及全身临床状况,在有效降低PCWP方面优于硝酸甘油,其安全性与硝酸甘油类似。     

Protective effect of melatonin on ascorbate-Fe2+ lipid peroxidation of polyunsaturated fatty acids in rat liver, kidney and brain microsomes: a chemiluminescence study

Melatonin (N-acetyl-5-methoxytryptamine), the main secretory product of the pineal gland, is a free radical scavenger that has been found to protect against lipid peroxidation in many experimental models. In the present study the effect of melatonin on lipid peroxidation of long chain polyunsaturated fatty acids located in rat liver, kidney and brain microsomes was determined using gas chromatography and a chemiluminescence assay. In vitro assays showed that after incubation of rat liver, kidney or brain microsomes in an ascorbate-Fe++ system, at 37 degrees C for 180 min, the total cpm originated from light emission (chemiluminescence) was found to be lower in those membranes incubated in the presence of melatonin. The incubation of rat liver, kidney or brain microsomes in the presence of ascorbate-Fe2+ resulted in lipid-peroxidation of membranes as evidenced by light emission and decrease of docosahexaenoic acid 22:6 n-3 and arachidonic acid 20:4 n-6. In the presence of melatonin (0.5, 1.0, 1.5 mm), light emission percent inhibition of microsomes was: (liver - 3.33, 9.98, 39.40) (kidney - 46.79, 61.88, 68.36) and (brain - 33.36, 28.89, 43.32). Not all fatty acids were equally protected after the addition of melatonin to the incubation medium. Our results indicate a selective protection of C20:4 n6 and C22:6 n3 by melatonin during non-enzymatic lipid peroxidation of rat liver, kidney and brain microsomes.     

短程全脑放疗在非小细胞肺癌脑转移病人中的疗效观察

目的探讨非小细胞肺癌脑转移病人的全脑放疗的疗程以及影响其预后的因素。方法分析101例非小细胞肺癌脑转移全脑放疗病人,其中35例接受5天5×4GY的放疗,另外66例接受2周10×3GY或4周20×2GY的放疗,同时观察6个可能影响预后的因素：包括年龄、性别、KPS、脑转移灶数、是否有颅外转移灶、肺癌确诊到全脑放疗时间、递归分割分析级别。结果全脑放疗的疗程与生存率没有相关性,通过单变量分析：（年龄〈60岁：年龄≥60岁,P=0．020）、（KPS≥70：KPS〈70P〈0．001）、肿瘤确诊到接受全脑放疗时间（〉12月：≤12月P=0．007）、有无颅外转移（P〈0．001）,提高生存率与这些因素有显著相关性。结论短程的5×4GY更容易被大部分非小细胞肺癌脑转移病人所接受,因为它与长程放疗生存率相似,短程放疗节约治疗时间、节省治疗费用。     

慢加急性乙型肝炎肝衰竭临床特征及血浆置换治疗对其预后的影响

目的探讨乙型肝炎相关的慢加急性肝衰竭患者的临床特征,以及血浆置换（PE）对慢加急性肝衰竭治疗的疗效。方法按肝衰竭诊疗指南的诊断标准,收集2012年5月至2014年2月我科诊治的52例乙型肝炎相关慢加急性肝衰竭患者的住院临床资料。使用德国BE公司血液凝固分析仪检测凝血功能指标;使用美国 Beckman LH750 血球分析仪检测血细胞计数;使用日立7600全自动生化分析仪检测血清生化指标。结果16例死亡患者入院时凝血酶原时间（PT）为（48.8±11.7）s、活化部分凝血酶时间（APTT）为（65.8±19.0）s、凝血酶原时间国际标准化比率（INR）为（2.4±1.0）、血氨为（100.1±74.7）μmol/L,均显著高于36例生存患者[分别为（42.7±14.0）s、（48.0±11.4）s、（1.7±0.4）和（47.9±21.5）μmol/L,P<0.05];死亡组入院时凝血酶原活动度（PTA）为（31.8±12.9）%、血小板计数为（85.6±61.3）×10⁹/L、白蛋白为（29.2±4.1）g/L、血钾为（3.8±0.5）mmol/L,均显著低于生存组[分别为（47.9±21.2）%、（133.4±50.7）×10⁹/L、（32.8±4.7）g/L、（4.1±0.6）mmol/L,P<0.05];死亡组发生肝性脑病、腹水、自发性腹膜炎、电解质紊乱和发生2个以上并发症所占比例（分别为37.5%、68.75%、25%、62.5%、62.5%）显著高于生存组（分别为2.8%、30.35%、2.8%、11.11%、11.11%,P<0.05）;患者在接受PE治疗后PTA[（44.8±23.5）%]、白细胞计数[（8.0±3.6×10⁹）/L]、白蛋白[（36.4±3.6）g/L]、血尿素氮[（7.1±4.6）mmol/L]较治疗前显著升高[分别为（36.6±14.6）%、（5.9±2.8×10⁹）/L、（33.7±4.1）g/L、（5.4±3.8）mmol/L,P<0.05],红细胞计数[（3.9±0.7×10⁹）/L]、血红蛋白[（119.5±18.2）g/L]、ALT为[（100.6±67.9）U/L]、AST[（120.0±62.8）U/L]、总胆红素[（335.7±121.3）μmol/L]、间接胆红素[（226.3±77.9）μmol/L]较治疗前显著降低[分别为（4.2±0.8×10⁹）/L、（130.6±23.8）g/L、（300.0±302.3）U/L、（227.2±174.6）U/L,（410.8±129.8）μmol/L,（290.4±100.5）μmol/L,P<0.05]。结论凝血酶原时间、血小板和白蛋白是判断乙型肝炎相关的慢加急性肝衰竭患者预后的敏感的实验室指标,发生并发症的患者预后差,PE治疗可暂时改善患者的凝血功能及肝功能指标,却对其生存无影响。