可益能与 肝病.

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1 可益能与 肝病

2 治疗脂肪肝的合理性 抗病毒药物引起脂肪肝导致纤维化进而硬化 这个观察是从采用干扰素和病毒唑治疗丙型肝炎患者中获得
卡尼汀抗高血脂的作用是众所周知的 Romano 研究显示对丙型肝炎患者采用12个月卡尼汀和干扰素病毒唑联合使用，比单独使用干扰素和病毒唑有更好的抗高脂血的作用，肝的纤维化和硬化都被卡尼汀所降低 It is well described that in patients affected by Hepatitis C, the progressive deterioration of hepatic detoxifying functions and the persistent fatty degeneration lead to cirrhosis and to hyperammonemia, the leading cause hepatic encephalopathy. Whit regard to this often fatal event, interesting results have been obtained by Malaguarnera with L-Carnitine treatment on one hundred and fifty cirrhotic patients (10 with alcoholism, 41 HBV, 78 HCV, 21 cryptogenetic cirrhosis). Results showed that in all classes of Hepatic Encephalopathy graded patients, blood ammonia is significantly reduced by 3-months oral L-Carnitine treatment (4 g/d), and neuro-psychometric performance was significantly improved by L-Carnitine treatment. 在丙型肝炎病人中已经有了很好的描述，进行性肝解毒功能衰退和持久的脂肪变性导致肝硬化和血氨过多,导致肝性脑病。关于这个经常的致命事件, Malaguarnera给出了有趣的结果，可益能治疗150位肝硬化患者 (10个酒精肝、41 HBV,78 HCV,21 细胞生成的肝硬化)。结果表明,在所有类型的肝性脑病患者、血氨是显著减少通过3个月口服可益能治疗(4 g/d)，神经心理测量的表现是由可益能治疗而显著提高。

3 治疗脂肪肝的合理性 Malaguarnera研究显示，没有酒精脂肪肝的患者显示，24周可益能的治疗降低了肝酶，使得血浆脂质变的正常，降低了血糖和胰岛素抵抗，降低了肝炎症和纤维化 Malaguarnera研究显示，可益能治疗显著降低了高血氨症，显著改善神经心理测量性能 It is well described that in patients affected by Hepatitis C, the progressive deterioration of hepatic detoxifying functions and the persistent fatty degeneration lead to cirrhosis and to hyperammonemia, the leading cause hepatic encephalopathy. Whit regard to this often fatal event, interesting results have been obtained by Malaguarnera with L-Carnitine treatment on one hundred and fifty cirrhotic patients (10 with alcoholism, 41 HBV, 78 HCV, 21 cryptogenetic cirrhosis). Results showed that in all classes of Hepatic Encephalopathy graded patients, blood ammonia is significantly reduced by 3-months oral L-Carnitine treatment (4 g/d), and neuro-psychometric performance was significantly improved by L-Carnitine treatment. 在丙型肝炎病人中已经有了很好的描述，进行性肝解毒功能衰退和持久的脂肪变性导致肝硬化和血氨过多,导致肝性脑病。关于这个经常的致命事件, Malaguarnera给出了有趣的结果，可益能治疗150位肝硬化患者 (10个酒精肝、41 HBV,78 HCV,21 细胞生成的肝硬化)。结果表明,在所有类型的肝性脑病患者、血氨是显著减少通过3个月口服可益能治疗(4 g/d)，神经心理测量的表现是由可益能治疗而显著提高。

4 可益能在丙型肝炎中作用 结论： 慢性HCV患者，疲劳的严重程度和低的卡尼汀水平有关，建议口服卡尼汀会对 缓解HCV患者疲劳有效果
Anty R. et al. 发现血浆卡尼汀浓度与HCV的疲劳有关，但是与肠道易激综合症无关 结果： 慢性HCV和IBS患者的疲劳指数显著高于健康对比 与健康人相比，HCV患者有较低的调节脂肪量的血浆总卡尼汀和自由卡尼汀 慢性HCV患者的疲劳指数与血浆卡尼汀水平呈负相关 irritable bowel syndrome (IBS)，肠道易激综合症 Patients with chronic hepatitis C had significant lower plasma levels of total and free carnitine adjusted for fat mass compared with healthy subjects. 与健康人相比，HCV患者有较低的调节脂肪量的血浆总卡尼汀和自由卡尼汀 In patients with chronic hepatitis C fatigue scores negatively correlated with carnitine plasma levels. 慢性HCV患者的疲劳指数与血浆卡尼汀水平呈负相关 Conclusions：In patients with chronic hepatitis C, the severity of fatigue is associated with a low level of carnitine, suggesting that an oral supplementation of L-carnitine may be effective to relieve fatigue in chronic hepatitis C. 结论：慢性HCV患者，疲劳的严重程度和低的卡尼汀水平有关，表明口服卡尼汀会对缓解HCV患者疲劳有效果 结论： 慢性HCV患者，疲劳的严重程度和低的卡尼汀水平有关，建议口服卡尼汀会对 缓解HCV患者疲劳有效果

5 可益能在丙型肝炎中作用 结果： 12个月可益能治疗显著降低了干扰素加病毒唑的高脂血症
可益能治疗降低了使用干扰素a和病毒唑治疗的慢性HCV患者的脂肪肝（肝细胞的脂肪变性/细胞中脂肪堆积产生脂肪滴） 研究评价了可益能治疗采用干扰素a和病毒唑治疗脂肪肝的患者的作用 采用剂量：12个月 剂量 2g/d 口服 患者： A组（35人）：干扰素加病毒唑 B组（35人）：干扰素加病毒唑加可益能 结果： 12个月可益能治疗显著降低了干扰素加病毒唑的高脂血症 接下来的6个月随访，组织学显示肝脏的纤维化和硬化显著降低 结论： 可益能能够预防使用干扰素和病毒唑治疗的HCV患者的脂肪肝 Romano et al - L-Carnitine Treatment Reduces Steatosis in Patients with Chronic Hepatitis C Treated with α-Interferon and Ribavirin 可益能治疗降低了使用干扰素a和病毒唑治疗的慢性HCV患者的脂肪肝（肝细胞的脂肪变性/细胞中脂肪堆积产生脂肪滴） Study evaluated the effect of L-Carnitine administration on steatosis in patients treated with Interferon- α and Ribavirin. 研究评价了可益能治疗采用干扰素a和病毒唑治疗脂肪肝的患者的作用 Dose used: 2 g/d os, 12-months 剂量 2g/d 口服 Results: After 12-months treatment with L-Carnitine significantly reduced the hyper-lipidemic effect of interferon plus Ribavirin 12个月可益能治疗显著降低了干扰素加病毒唑的高脂血症 After 6-months follow-up, hepatic fibrosis and steatosis, as histologically evidenced, is significantly reduced in patients treated with L-Carnitine. 接下来的6个月随访，组织学显示肝脏的纤维化和硬化显著降低 Conclusions: L-Carnitine treatment prevents liver steatosis in patients with hepatitis C treated with Interferon-α and Ribavirin. 可益能能够预防使用干扰素和病毒唑治疗的HCV患者的脂肪肝

6 可益能在非酒精脂肪肝中的作用 可益能补充到饮食中：一个新的治疗非酒精性脂肪肝的手段-一个随机对照研究 患者：
A组 (n=36) ：可益能2g/d，口服，24周，外加饮食 B组 (n=36) ：安慰剂加饮食 结果：24周可益能治疗 • 降低了肝酶（转氨酶） • 使血脂正常 • 降低血糖水平和胰岛素抵抗 • 降低肝脏炎症和纤维化 所有的病人对可益能都耐受 结论：可益能治疗在治疗非酒精性脂肪肝中可成为一种有效的治疗选择 转氨酶是人体代谢过程中必不可少的“催化剂”，主要存在于肝细胞内。当肝细胞发生炎症、坏死、中毒等，造成肝细胞受损时，转氨酶便会释放到血液里，使血清转氨酶升高。 通常，体检中主要检查的转氨酶是谷丙转氨酶(ALT)。1%的肝脏细胞损害，可以使血中ALT的浓度增加1倍。因此，ALT水平可以比较敏感地监测到肝脏是否受到损害。 Malaguarnera et al L -Carnitine Supplementation to Diet: A New Tool in Treatment of Nonalcoholic Steatohepatitis – A Randomized and Controlled Clinical Trial. 可益能补充到饮食中：一个新的治疗非酒精性脂肪肝的手段- 一个随机对照研究 结果：24-weeks L-carnitine treatment: 24周可益能治疗 • reduced liver enzymes; 降低了肝酶（转氨酶） • normalized plasma lipid profile; 使血脂正常 • decreased plasma glucose level and insulin resistance; 降低血糖水平和胰岛素抵抗 • decreased hepatic inflammation and fibrosis. 降低肝脏炎症和纤维化 L-carnitine treatment was well tolerated in 100 % of patients. 所有的病人对可益能都耐受 Conclusions L-carnitine treatment can represent a useful therapeutic options in NASH. 可益能治疗在治疗非酒精性脂肪肝中可成为一种有用的治疗选择

7 L-Carnitine in Hepatitis C
可益能在丙型肝炎中作用 Malaguarnera et al - 可益能在肝性脑病患者中的效果 研究评价了可益能对肝性脑病患者的精神状况和氨的作用的影响 使用剂量: 4 g/d 口服, 3个月 患者: 150 人 结果: 一个月可益能治疗（ 4 g/d 口服）后，轻微肝性脑病和1级、2级肝性脑病患者的血清氨水平显著下降 2-3个月的治疗，可观察到持久的血清氨水平的降低趋势 可益能在精神功能评价的心理计量测试中也有显著治疗效果 结论： 可益能治疗对肝硬化病人的氨沉积引起的脑病具有保护作用 肝性脑病（hepatic encephalopathy, HE）是由于急、慢性肝病或各种原因的门－体分流（porto-systemicvenous shunting）所引起的，以代谢紊乱为基础的神经精神方面的异常。临床表现可以是仅仅用智力测验或电生理检测方法才能检测到的轻微异常，也可表现为行为异常、意识障碍，甚至昏迷。过去所称的肝性昏迷只是肝性脑病中程度严重的一期。仅用心理学检测方法才能检测到的轻微异常的肝性脑病又称为亚临床型肝性脑病（subclinical hepatic encephalopathy, SHE）或轻微肝性脑病（minimal hepatic encephalopathy, MHE） Malaguarnera et al - Effects of L-Carnitine in patients with hepatic encephalopathy 可益能在肝性脑病患者中的效果 Study evaluated the influence of L-Carnitine on mental conditions and ammonia effects on patients with hepatic encephalopathy (HE) 研究评价了可益能对肝性脑病患者的精神状况和氨的作用的影响；Dose used: 4 g/d os, 3-months 患者: 150 人 结果: After 1-months of L-Carnitine treatment (4 g/d, os) serum ammonia levels is significantly reduced in patients with Minimal Hepatic Encephalopathy, and in patients with Hepatic Encephalopathy grade 1 and grade 2 一个月可益能治疗后，轻微肝性脑病和1级、2级肝性脑病患者的血清氨水平显著下降 After 2-months and 3-months of treatment, a persistent trend of decreased ammonia serum levels is observed 2-3个月的治疗，可观察到持久的血清氨水平的降低趋势 A significant therapeutic effect of L-Carnitine was also observed in psychometric tests for the assessment of mental function 可益能在精神功能评价的心理计量测试中也有显著治疗效果 Conclusions: L-Carnitine treatment may have a protective effect against ammonia-precipitated encephalopathy in cirrhotic patients. 可益能治疗对在肝硬化病人的氨沉积引起的脑病具有保护作用

8 可益能：在丙戊酸诱导的肝中毒中的合理性 丙戊酸广泛用于治疗癫痫症并在肝脏线粒体中代谢 丙戊酸以丙戊酰卡尼汀的形式从肾脏清除
丙戊酰基对线粒体有毒，被卡尼汀清除，因此导致了卡尼汀存储的消耗 卡尼汀缺乏引起高血氨症并引起肝和脑功能紊乱并导致肝性脑病 补充卡尼汀恢复左卡尼汀的缺乏起到排毒作用从而恢复线粒体的性能 丙戊酸(Valproate)是治疗小儿癫痫常用药物之一。在使用中可发生两种类型的肝中毒。一种是与剂量有关的由于药物直接的损害,另一种是特发性原因不明的致死性损害。与剂量有关的肝中毒特点是在治疗的最初3个月期间,血清转氨酶(SGOT、SGPT)活性和血氨浓度短暂地升高,可占44%以上,常常没有症状,但亦可有恶心和萎靡,并不致死。另一类致死者与药物剂量无关而可能是由于特发性的反应,常是不可逆性损伤,肝功监测亦不易早期发现。至1982年为止。已知有62例因使用丙戊酸治疗而致肝中毒死亡。 Valproic Acid (VA) is widely used in epilepsy and is metabolized in the liver mitochondria. 丙戊酸广泛用于癫痫症并在肝脏线粒体中代谢 VA is eliminated by the kidney as Valproyl-carnitine. 丙戊酸以丙戊酰卡尼汀的形式从肾脏清除 Valproyl moyety is toxic for the mitochondria and is cleared by carnitine thus inducing a depletion of carnitine storage. 丙戊酰基对线粒体有毒，被卡尼汀清除，因此导致了卡尼汀存储的消耗 Carnitine deficiency induces hyperammonemia which is responsible for liver and brain dysfunction thus leading to hepatic encephalopathy.卡尼汀缺乏引起高血氨症并引起肝和脑功能紊乱并导致肝性脑病 Carnitine supplementation restoring the occurred depletion acts as a detoxifying agent thus restoring mitochondria performance. 补充卡尼汀恢复左卡尼汀的缺乏起到排毒作用从而恢复线粒体的性能 Valproate-induced hepatotoxicity (VHT) 丙戊酸诱导的肝中毒

9 L-Carnitine: Rational in Valproate-induced hepatotoxicity (VHT)
可益能：在丙戊酸诱导的肝中毒中的合理性 L-Carnitine: Rational in Valproate-induced hepatotoxicity (VHT) 实验和临床证据表明早期静脉滴注可益能可以改善严重丙戊酸中毒的生存率，推荐静脉而不是口服补充可益能是为了保证较高的血液中左卡尼汀的水平 尽管人的对照研究数量有限，对严重的丙戊酸引起的肝中毒的病例评估，较高的生存率的案例以及降低的高血氨症的报告，均来自使用可益能治疗的病人 Experimental and clinical evidence suggests that early L-carnitine i.v. administration improves hepatic survival in severe VHT. Intravenous rather than oral supplementation is recommended because it is likely to ensure higher blood levels of carnitine. 实验和临床证据表明早期静脉滴注可益能可以改善严重丙戊酸中毒的生存率，推荐静脉而不是口服补充可益能是为了保证较高的血液中左卡尼汀的水平 Although the limited number of human controlled studies, evaluating cases of severe hepatotoxicity occurring during VA therapy, higher survival cases and reduced hyperammonemia have been reported mainly in those patients treated with L-carnitine. 尽管人的对照研究数量有限，严重的丙戊酸引起的肝中毒的病例评估，较高的生存率的案例以及降低的高血氨症的报告，均来自使用可益能治疗的病人

10 可益能在丙戊酸肝中毒中的作用 患者： 92 有丙戊酸中毒导致的急性有症状肝功能衰竭的患者 结果： 静脉滴注可益能后，肝病患者生存者更加普遍
Bohan et al - 可益能治疗丙戊酸肝中毒的效果 研究评估了可益能治疗是否对患有急性严重有症状的丙戊酸中毒患者生存率有好的作用 使用剂量: mg/d, os-iv, 一直用4个月 患者： 92 有丙戊酸中毒导致的急性有症状肝功能衰竭的患者 结果： 静脉滴注可益能后，肝病患者生存者更加普遍 在早期停用丙戊酸后（<5天），可益能的效果更加明显 结论： 对病毒酸诱导的肝中毒患者，可益能治疗与更高的生存率有关系 Bohan et al - Effect of L-Carnitine treatment for valproate-induced hepatotoxicity 可益能治疗丙戊酸肝中毒的效果 Study evaluated whether L-Carnitine treatment is associated with better hepatic survival of patients with acute, severe, symptomatic, valproate-induced hepatotoxicity 研究评估了可益能治疗是否对患有急性严重有症状的丙戊酸中毒患者生存率有好的作用 Dose used : mg/d, os-iv, up to Patients: 92 patients with VPA-induced acute, symptomatic hepatic failure 92 有丙戊酸中毒导致的急性症状肝功能衰竭的患者 Results:Hepatic survival was much more prevalent after iv L-Carnitine treatment 静脉滴注可益能后，肝病患者生存者更加普遍 L-Carnitine effect was most apparent when VPA was stopped early (< 5 days) 在早期停用丙戊酸后，可益能的效果更加明显 Conclusions: In patients with Valproic Acid-induced hepatotoxicity, L-Carnitine treatment is associated with better survival 对病毒酸诱导的肝中毒患者，可益能治疗与更高的生存率有关系 4 months

11 可益能在丙戊酸肝中毒中的作用 Bohles et al 补充可益能对丙戊酸引起的高血氨症的作用 患者:
研究评价了补充可益能对丙戊酸治疗的病人的高血氨症的影响 采用剂量: 1 g/m2, os-iv, 一直用药 110 天 患者: 69个儿童和年轻人采用慢性丙戊酸单药治疗（15位患者采用可益能治疗） 结果： 丙戊酸诱导的高血氨症与降低的血浆卡尼汀水平有关 可益能治疗引起15.6%的血浆自由卡尼汀的增加 血氨与卡尼汀的水平显著相关 结论： 当血氨不正常升高时，应该推荐可益能治疗采用丙戊酸治疗的病人 Rational for L-carnitine in Valproate-induced hyperammonemia Carnitine supplementation (50 mg/kg per day) for 4 weeks was shown to correct both carnitine deficiency and hyperammonaemia in 14 VA-treated patients. Administration of exogenous carnitine is thought to decrease ammonia levels by binding to VA, thereby enhancing the β-oxidation process and production of acetyl-CoA, and relieving the inhibition of urea synthesis. 在14位丙戊酸治疗的病人中，补充可益能4周表现出纠正了左卡尼汀缺乏和高血氨症。外源左卡尼汀的给予被认识通过结合丙戊酸来降低血氨水平，因此加强了β氧化的进程和乙酰辅酶A的产生，并减轻了尿素合成的抑制。 Bohles investigated the effects of carnitine supplementation in 69 children and young adults treated with VA monotherapy. 研究了可益能补充给用丙戊酸单药治疗的69位儿童和青少年病人的作用 Their mean plasma ammonia concentration was within the normal range, but 24 patients (35.3%) with ammonia concentrations above 80 μg/dl were considered hyperammonaemic and 15 of these 24 (22.1%) had ammonia concentrations above 100 μg/dl. 他们平均血氨浓度在正常范围，但是24个病人的血氨浓度超过80微克/分升，被认为是高血氨，其中有15位血氨浓度超过100 Total plasma carnitine concentrations were determined in 48 out of 69 patients and were found to be rather low, as was the percentage of free carnitine. 69人中48人的确定了血浆卡尼汀浓度，结果发现非常低，像之前的自由卡尼汀。 Fourteen hyperammonaemic and one non ammonaemic patients were supplemented with L-carnitine (500 mg/m2, twice daily). Prolonged L-carnitine supplementation was associated with normalization in plasma ammonia concentrations and marked increase in carnitine concentration in all 15 patients. 14位高血氨症和一位非血氨患者给予可益能，在15为患者中，长期的可益能给予与血氨水平的正常化和左卡尼汀浓度的显著提高有关系 The plasma ammonia concentrations were significantly correlated with the percentage of free plasma carnitine in plasma (r = –0.67, P < ). These findings indicate that carnitine supplementation allows normalization of elevated plasma ammonia concentrations. However, a correlation between ammonia levels and clinical condition is not always observed. 血氨浓度显著地与自由卡尼汀在血浆中的百分比有关。这些发现表明补充可益能可以使增加的血氨浓度正常化。然而一直没有观察到血氨浓度和临床状况之间的关系。 L-carnitine dose used: Bohles: 1 g/m2, os-iv, up to 110 days 患者: 69 children and young adults under chronic Valproic Acid monotherapy (15 treated with L-Carnitine) 69个儿童和年轻人采用慢性丙戊酸单药治疗（15位患者采用可益能治疗） Results: Valproic Acid-induced hyperammonemia is associated with reduced plasma Carnitine levels 丙戊酸诱导的高血氨症与降低的血浆卡尼汀水平有关 Treatment with L-Carnitine led to median 15.6% increase in plasma free Carnitine 可益能治疗引起15.6%的血浆自由卡尼汀的增加 Plasma ammonia significantly correlated with Carnitine levels 血氨与卡尼汀的水平显著相关 Conclusions: L-Carnitine should be recommended in Valproic Acid-treated patients when plasma ammonia is inappropriately increased. 当血氨不正常增加时，可益能应该推荐治疗丙戊酸治疗的病人

12 可益能在丙戊酸肝中毒中的作用 Cuturic et al -有明确可益能缺乏症的住院精神病患者的临床结局和低剂量补充可益能：一个回顾性的图表总结 为了评价有明确低卡尼汀症的住院精神病患者可益能治疗的临床结局 患者：38为精神疾病患者 结果： 长期丙戊酸（血管纤维蛋白溶酶原激活剂）并不是单一的左卡尼汀缺乏的原因，29%的病人从没用过VPA治疗 明确左卡尼汀缺乏的病人，低剂量口服补充可益能与总体改善的行为、认知以及运动等有关系 在大多数病人中，细微神经检查获得改善和正常化，这纠正了最初被诊断给痴呆的病人的诊断 副作用较轻，不需要停止使用可益能的补充 结论： 通过补充可益能纠正左卡尼汀的消耗加强了低卡尼汀症的恢复，低卡尼汀症与精神病人的脑病有关 Rational for L-carnitine in Valproate-induced hyperammonemia Carnitine supplementation (50 mg/kg per day) for 4 weeks was shown to correct both carnitine deficiency and hyperammonaemia in 14 VA-treated patients. Administration of exogenous carnitine is thought to decrease ammonia levels by binding to VA, thereby enhancing the β-oxidation process and production of acetyl-CoA, and relieving the inhibition of urea synthesis. Bohles investigated the effects of carnitine supplementation in 69 children and young adults treated with VA monotherapy. Their mean plasma ammonia concentration was within the normal range, but 24 patients (35.3%) with ammonia concentrations above 80 μg/dl were considered hyperammonaemic and 15 of these 24 (22.1%) had ammonia concentrations above 100 μg/dl. Total plasma carnitine concentrations were determined in 48 out of 69 patients and were found to be rather low, as was the percentage of free carnitine. Fourteen hyperammonaemic and one non ammonaemic patients were supplemented with L-carnitine (500 mg/m2, twice daily). Prolonged L-carnitine supplementation was associated with normalization in plasma ammonia concentrations and marked increase in carnitine concentration in all 15 patients. The plasma ammonia concentrations were significantly correlated with the percentage of free plasma carnitine in plasma (r = –0.67, P < ). These findings indicate that carnitine supplementation allows normalization of elevated plasma ammonia concentrations. However, a correlation between ammonia levels and clinical condition is not always observed. L-carnitine dose used: Bohles:1 g/m2, os-iv, up to 110 days Cuturic et al - Clinical Outcomes and Low-Dose Levocarnitine Supplementation in Psychiatric Inpatients with Documented Hypocarnitinemia: A Retrospective Chart Review；有明确左卡尼汀缺乏症的住院精神病患者的临床结局和低剂量补充可益能：一个回顾性的图表总结 To evaluate the clinical outcomes in L-carnitine treated hospitalized psychiatric patients with documented hypocarnitinemia 为了评价有低卡尼汀症的住院精神病患者可益能治疗的临床结局 Results: Chronic VPA therapy did not appear as the sole cause of hypocarnitemia, as 29% of the patients had not been treated with VPA at any point 慢性丙戊酸（血管纤维蛋白溶酶原激活剂）并不是一个单一的左卡尼汀缺乏的原因，29%的病人从没用过VPA治疗 In patients with documented hypocarnitemia, a low-dose oral L-carnitine supplementation, was associated with overall improved behavioural, cognitive, and motor functioning 明确左卡尼汀缺乏的病人，低剂量口服补充可益能与总体改善的行为、认知以及运动等有关系 Mini-Mental State examination (MMSE) improved/normalize in most of the patients(mean improvement 5.5 points, p<0.0001). This allowed a correction of the diagnosis in some patients (8 of 14) who had initially been diagnosed with dementia 在大多数病人中，细微神经检查获得改善和正常化，这纠正了最初被诊断给痴呆的病人的诊断 Adverse effects were mild and did not require discontinuation of L-carnitine supplementation 副作用较轻，不需要停止使用可益能的补充 Conclusion: Correction of carnitine depletion by L-carnitine supplementation may enhance recovery from hypocarnitemia-associated encephalopathy in psychiatric patients 通过补充可益能纠正左卡尼汀的消耗加强了低卡尼汀症的恢复，低卡尼汀症与精神病人的脑病有关

13 可益能在丙戊酸肝中毒中的作用 Perrott et al -可益能对急性丙戊酸用药过量：发表案例的系统综述
治疗建议： 以下病人可能会考虑给使用可益能 大量急性的酸摄入(i.e., >100 mg/kg 表现出意识水平下降 可益能推荐的剂量: 初始治疗：可益能100mg/kg 静注(大剂量给药2-3分钟或灌注15-30分钟) 维持治疗：之后每8小时，可益能50mg/kg静注（最大剂量3g）（大剂量给药2-3分钟或间歇灌注15-30分钟）， 需要持续给予可益能直到氨的水平降低，一直要可益能给药4天，病人会表现为临床改善； 结论: 急性丙戊酸用药过量表现出意识水平下降的病人需考虑使用可益能 Rational for L-carnitine in Valproate-induced hyperammonemia Carnitine supplementation (50 mg/kg per day) for 4 weeks was shown to correct both carnitine deficiency and hyperammonaemia in 14 VA-treated patients. Administration of exogenous carnitine is thought to decrease ammonia levels by binding to VA, thereby enhancing the β-oxidation process and production of acetyl-CoA, and relieving the inhibition of urea synthesis. Bohles investigated the effects of carnitine supplementation in 69 children and young adults treated with VA monotherapy. Their mean plasma ammonia concentration was within the normal range, but 24 patients (35.3%) with ammonia concentrations above 80 μg/dl were considered hyperammonaemic and 15 of these 24 (22.1%) had ammonia concentrations above 100 μg/dl. Total plasma carnitine concentrations were determined in 48 out of 69 patients and were found to be rather low, as was the percentage of free carnitine. Fourteen hyperammonaemic and one non ammonaemic patients were supplemented with L-carnitine (500 mg/m2, twice daily). Prolonged L-carnitine supplementation was associated with normalization in plasma ammonia concentrations and marked increase in carnitine concentration in all 15 patients. The plasma ammonia concentrations were significantly correlated with the percentage of free plasma carnitine in plasma (r = –0.67, P < ). These findings indicate that carnitine supplementation allows normalization of elevated plasma ammonia concentrations. However, a correlation between ammonia levels and clinical condition is not always observed. L-carnitine dose used: Bohles:1 g/m2, os-iv, up to 110 days Perrott et al - L-Carnitine for Acute Valproic Acid Overdose: A Systematic Review of Published Cases 可益能对急性丙戊酸用药过量：系统的发表案例的综述 治疗建议： 可能会考虑给以下病人使用可益能 With large, acute ingestions acid(i.e., >100 mg/kg) 大量急性的酸摄入 Demonstrating decreased level of consciousness 表现出意识水平下降 L-carnitine reccomended dosage: Initiating therapy: L-carnitine 100 mg/kg iv (bolus over 2-3 minutes or infusion over minutes) 初始治疗：可益能100mg/kg (大剂量给药2-3分钟或灌注15-30分钟) Maintence therapy: L-carnitine 50 mg/kgiv (to a maximum of 3g/dose) (bolus 2-3 minutes or intermittent infusion over minnutes) every 8 hours thereafter 维持治疗：可益能50mg/kg（最大剂量3g）（大剂量给药2-3分钟或间歇灌注15-30分钟），之后每8小时 L-carnitine should be continued until ammonia levels are decreasing and patient demonstrates signs of clinical improvement-up to 4 days of L-carnitine therapy is required 需要持续给予可益能直到氨的水平降低，一直要可益能给药4天，病人会表现为临床改善， 结论: L-carnitine may be considered for the treatment of patients with acute overdose of valproic acid who demonstrate decreased level of consciousness 急性丙戊酸用药过量表现出意识水平下降的病人需考虑使用可益能

14 销售大纲

15 可益能/脂肪肝 开场 主题 毫无疑问您有过使用降脂药来治疗脂肪肝的经历，这种情况往往由HCV（丙型肝炎）、NASH（非酒精性脂肪变性肝炎）、肝硬化等疾病引起。 基于之前的发现表明左卡尼汀（一种参与脂肪酸氧化的内源性物质）具有抗高脂血症作用 On the basis of previous findings indicating an antihyperlipidemic effect of L-carnitine, an endogenous substance involved in fatty acid oxidation,…

16 结果：卡尼汀血浆水平 基于HCV患者存在左卡尼汀缺乏的事实
空白对照和患有慢性丙型肝炎或肠易激综合症的患者中调节脂肪量的循环自由卡尼汀和总卡尼汀水平的比较 基于HCV患者存在左卡尼汀缺乏的事实 对照和患有慢性丙型肝炎或肠易激综合症的患者的调节脂肪量的循环自由卡尼汀和总卡尼汀的水平的比较

17 结果：可益能治疗12个月 数据显示，12个月的可益能治疗慢性HCV，显著抵消了干扰素和病毒唑引起的高血脂效果。
从病理学中获得了一些有意思的结果 对HCV患者，Romano团队将可益能加入到干扰素和病毒唑的联合用药中，来评价减轻脂肪肝的效果 interesting results have been obtained in these pathologies.获得一些有意思的病理学结果 In HCV patients, the team of Romano, added L-carnitine to the association interferon plus ribavirin, to evaluate its effect in reducing hepato-steatosis.对HCV患者，Romano团队将可益能加入到干扰素和病毒唑的联合用药中，来评价减轻脂肪肝的效果 Data showed that 12-months treatment of chronic Hepatitis C patients (n=70), with L-carnitine (2g/d os) significantly counteracted the hyper-lipidemic effect exerted by interferon plus ribavirin alone. 数据显示，12个月的可益能治疗慢性HCV，显著抵消了干扰素和病毒唑引起的高血脂效果。 ALT(肝酶/谷丙转氨酶) 数据显示，12个月的可益能治疗慢性HCV，显著抵消了干扰素和病毒唑引起的高血脂效果。

18 结果：随访6个月 6个月随访,组织学上证明, 使用可益能治疗的患者，肝纤维化和脂肪变性大大降低了
After 6-months follow-up, hepatic fibrosis and steatosis, as histologically evidenced, seems to be greatly reduced in patients treated with L-carnitine 6个月随访,组织学上证明, 使用可益能治疗的患者，肝纤维化和脂肪变性大大降低了 AST：天门冬氨酸转氨酶

19 结果：24周可益能治疗 肝脂肪肝是非酒精性脂肪肝肝炎的主要特征。在这些患者(n = 36)中,Malaguarnera研究发现24周口服可益能(2 g / d)治疗,降低了肝酶,使血脂正常化, 降低血糖水平、胰岛素抵抗、肝脏炎症,… Liver steatosis is the main feature of Non Alcoholic Steato- Hepatitis. In these patients (n=36), Malaguarnera showed that 24-weeks oral L-carnitine (2g/d) treatment, reduced liver enzymes, normalized plasma lipid profile, decreased plasma glucose level, insulin resistance, hepatic inflammation, … 肝脂肪变性是非酒精性脂肪肝肝炎的主要特征。在这些患者(n = 36),Malaguarnera显示24周口服可益能(2 g / d)治疗,降低了肝酶,使血脂正常化,降低血糖水平、胰岛素抵抗、肝脏炎症,… CRP: C反应蛋白，是在感染和组织损伤时血浆浓度快速,急剧升高的主要的急性期蛋白.CRP可以激活补体和加强吞噬细胞的吞噬而起调理作用,从而清除入侵机体的病原微生物和损伤,坏死,凋亡的组织细胞,在机体的天然免疫过程中发挥重要的保护作用.关于CRP的研究已经有70多年的历史,传统观点认为CRP是一种非特异的炎症标志物,但近十年的研究揭示了CRP直接参与了炎症与动脉粥样硬化等心血管疾病,并且是心血管疾病最强有力的预示因子与危险因子。 HOMA-IR是用于评价个体的胰岛素抵抗水平的指标

20 结果：24周可益能治疗的组织学数据 肝纤维化也同样 as well as hepatic fibrosis. 纤维化评分
NASH 非酒精性脂肪肝活动指数

21 结果：血氨水平 对各种的肝性脑病分级的病人，在3个月可益能治疗后（4g/d，口服），血氨水平均显著降低
在肝硬化病人中，进行性的肝排毒功能的恶化和持续的脂肪酸变性导致高血氨，这时主要的肝性脑病的原因 关于这种致命的事件，我要给大家展示一些使用卡尼汀治疗150位肝硬化患者的有意思的结果 对各种的肝性脑病分级的病人，在3个月可益能治疗后（4g/d，口服），血氨水平均显著降低 In cirrhotic patients, the progressive deterioration of hepatic detoxifying functions and the persistent fatty degeneration lead to hyperammonemia, the main cause of hepatic encephalopathy. 在肝硬化病人中，进行性的肝排毒功能的恶化和持续的脂肪酸变性导致高血氨，这是主要的肝性脑病的原因 With regard to this often fatal event, I would like to show you some interesting results obtained by Malaguarnera with Lcarnitine treatment on one hundred and fifty cirrhotic patients. 关于这种致命的事件，我要给大家展示一些使用卡尼汀治疗150位肝硬化患者的有意思的结果， MHE，minimal hepatic encephalopathy 轻微肝性脑病；ammonia fasting：空腹血氨

22 结果：精神心理测试 可益能治疗后，精神心理测试结果显著改善
所有的肝性脑病患者，在口服可益能3个月后（4g/d），血氨水平均显著降低，神经心理测试性能显著改善 Trial making test 连线测试; Symbol digit modalities test: 符号转换测试; block design test: 积木图案测试 Evaluates tactile(触觉) performance, tactile-visual and spatial（空间） memory, rhythm perception（知觉） and memory,intelligence, psychomotor speed, language function,grip strength and personality functioning (part A ,patients were asked to serially connect digits;Part B, patients were asked to sequentially altermate numbers and letters) Provides information on attention,concentration and processing speed. In all classes of Hepatic Encephalopathy graded patients: · Blood ammonia is significantly reduced by 3-months oral L-Carnitine treatment (4 g/d) and …· … neuro-psychometric performance was significantly improved by L-Carnitine treatment. 所有的肝性脑病患者，在口服可益能3个月后，血氨水平均显著降低，神经心理测试性能显著改善

23 总体结论 这些发现都表明可益能治疗不仅仅有助于预防脂肪肝，也可以消除疲劳、肝纤维化和高血氨，因此，改善肝病患者的生活质量；
These findings highlight that L-carnitine treatment may contribute not only in the prevention of hepato-steatosis. But it seems also to counteract fatigue, fibrosis and hyperammonemia, thus improving quality of life in liver pathologies. 这些发现都表明可益能治疗不仅仅有助于预防脂肪肝，也可以消除疲劳、肝纤维化和高血氨，因此，改善肝病患者的生活质量

24 可益能在丙戊酸引起的肝中毒中的作用 毫无疑问您很熟悉长期使用抗癫痫药物丙戊酸的病人，可能会引发严重的肝中毒伴随肝功衰竭和高血氨脑病。 开场
在低于2岁的儿童中，致命肝中毒的发生率为1/800,这很令人吃惊 然而鲜为人知的是，丙戊酸诱导了可益能的缺乏，而引发了肝中毒和高血氨。 左卡尼汀是一个内源性具有包括线粒体解毒等重要的细胞功能的物质。现在我们知道,没有一个标准的治疗高血氨的方法。 所以，可以假设通过给予可益能，补充左卡尼汀的存储可能纠正丙戊酸的肝中毒作用。 开场 主题部分 No doubt you are aware that patients chronically treated with the antiepileptic drug Valproic Acid (VPA), may experience severe hepatotoxicity with hepatic failure and hyperammonemic encephalopathy.In children younger than two years, the incidence of fatal hepatotoxicity is 1/800, it is impressive, isn’t it? 毫无疑问您很熟悉长期使用抗癫痫药物丙戊酸的病人，可能会引发严重的肝中毒伴随肝功衰竭和高血氨脑病。在低于2岁的儿童中，致命肝中毒的发生率为1/800,这很令人吃惊 However, what is less known, about Valproic Acid is that by inducing a carnitine deficiency, it discloses hepatotoxicity and hyperammonemia.然而鲜为人知的是，丙戊酸诱导了左卡尼汀的缺乏，而引发了肝中毒和高血氨。 Carnitine, as you may recall, is an endogenous substance which plays essential cellular functions including mitochondrial detoxification. Now we are aware that there isn’t a standard treatment for hyperammonemia. 左卡尼汀，你也许记得,是一个内源性具有包括线粒体解毒等重要的细胞功能的物质。现在我们知道,没有一个标准的治疗高血氨的方法。 So, it has been hypothesized that L-carnitine administration,by replenishing carnitine storages may correct Valproic Acid hepatic toxic effects. 所以，可以假设通过给予可益能，补充左卡尼汀的存储可能纠正丙戊酸的肝中毒作用。

25 结果：口服和静注可益能治疗的效果 关于肝衰竭,Bohan团队对92例患有严重丙戊酸引起的肝中毒患者做了一个回顾性研究，研究了可益能治疗和 (1g/m2,os iv,110天)与标准维持性治疗的效果。 注意看肝中毒事件后丙戊酸停用时间，患者越早停用丙戊酸，可益能治疗的效果最好； With regard to hepatic failure, the team of Bohan, in a retrospective study on 92 patients suffering from severe, Valproic Acid-induced hepatotoxicity, investigated the effect of L-carnitine (1 g/m2, os-iv, up to 110 days) vs standard supportive care. 关于肝衰竭,Bohan团队对92例患有严重丙戊酸引起的肝中毒患者做了一个回顾性研究，研究了可益能治疗和 (1g/m2,os iv,110天)与标准维持性治疗的效果。 Look to the Valproic Acid discontinuation days after hepatotoxic episodes….…the greatest effects were observed in L-carnitine treated patients, the sooner Valproate was stopped. 注意看肝中毒事件后丙戊酸停用时间，患者越早停用丙戊酸，可益能治疗的效果最好； Duration of hepatotoxic episode prior stopping VPA, 停止使用VP之前所持续的时间（VPA用药持续时间） 使用可益能对肝生存率更有效，在VPA快速停用后，可益能的益处更明显；

26 结果：口服和静注可益能治疗效果的对比 早期的关键临床情况的诊断（5天内）和快速静注可益能治疗达到致命性肝中毒的100%的存活。
In addition, an early diagnosis of the critical clinical condition (within 5 days) and a prompt i.v. L-carnitine treatment results in 100% patient survival to fatal hepatotoxicity. 早期的关键临床情况的诊断（5天内）和快速静注可益能治疗达到致命性肝中毒的100%的存活。 Hepatic survival was more evident after intravenous LC treatment 静脉给药对肝存活的效果更明显

27 结果：口服可益能的治疗效果 Bohles 回顾性揭示了可益能在69个丙戊酸引起的高血氨和高血氨性脑病的儿童和年轻患者中的作用，正如你看到的，持续的口服可益能明显地与血氨的正常化有关。 Prolonged oral LC supplementation is associated with a reduction in blood ammonia 持续的口服可益能与血氨的降低有关系 The efficacy of L-carnitine has been also retrospectively demonstrated by Bohles in 69 children and young adults with Valproate-induced hyperammonemia and fatal hyperammonaemic encephalopathy. As you may see prolonged L-carnitine oral administration is clearly associated with blood ammonia normalization. Bohles 回顾性揭示了可益能在69个丙戊酸引起的高血氨和高血氨性脑病的儿童和年轻患者中的作用，正如你看到的，持续的口服可益能明显地与血氨的正常化有关。

28 结果：对左卡尼汀水平的影响 在精神疾病的情况下如躁郁症，可发现左卡尼汀缺乏的脑病，使用低剂量可益能治疗（平均剂量660 ± 230 g/day） Well, also in psychiatric conditions such as bipolar disorders is used Valproic Acid, and hypocarnitinemic encephalopathy can be observed: Cuturic treated these psychiatric patients (n=38) with low Lcarnitine dosage (mean dosage: 660 ± 230 g/day). 在精神疾病的情况下如躁郁症，可发现左卡尼汀缺乏的脑病，使用低剂量可益能治疗（平均剂量660 ± 230 g/day） L-carnitine treatment significantly improved blood carnitine levels and… 可益能治疗显著改善了血氨水平 可益能治疗显著改善了血氨水平

29 结果：简易精神状态检查与左卡尼汀的关系 左卡尼汀改善了简易精神状态检查与步行 神经精神症状，卡尼汀有助于代谢性脑病的解决
MMSE: mini-mental state examination 简易精神状态检查；Ambulation：步行 Positive correlation between MMSE socres and total and free carnitine levels MMSE评分和总卡尼汀与自由卡尼汀的正相关关系 皮尔森相关P值 神经精神症状，卡尼汀有助于代谢性脑病的解决

30 结果总结 治疗建议： 以下情况患者要考虑使用可益能治疗： 大量急性丙戊酸摄入（〉100mg/kg） 表现为意识水平下降 可益能推荐的剂量：
初始治疗：可益能 100mg/kg iv(2-3分钟大剂量或15-30分钟灌注) 维持治疗：50mg/kg iv(最大剂量到3g/dose) 当血氨水平下降病人临床症状改善后，仍然需要继续补充可益能 在对一些病例的评价中，需要4天的持续用药 By increasing the population exposed to Valproic acid, also the potentials of Valproic acid overdose may result increased… 随着使用丙戊酸的人越来越多，丙戊酸过度用药的情况也会增加 ..and, in fact, Perrott recommends L-carnitine as antidote for the treatment of patients with acute valproic acid overdose, showing decreased level of consciousness.可益能作为表现为意识下降的丙戊酸中毒病人的解药剂

31 总的结论 考虑到这些结果，很多临床医生认为可益能在治疗丙戊酸引起的肝毒性中有较大益处