對老年大鼠大腦的生化和電子顯微鏡研究表明，乙?；笮鈮A（ALC）可以抵抗與年齡有關(guān)的組織衰老，并提高脂肪酸利用率。但是，由于電子流量增加，它也可能導(dǎo)致氧化應(yīng)激增加。已顯示與抗氧化劑（例如α-硫辛酸）組合使用ALC可調(diào)節(jié)氧化效果。 12 ， 13當(dāng)組合，ALC加導(dǎo)致與線粒體膜電勢，氧的消耗年齡相關(guān)下降，以及眾多的輔因子，礦物質(zhì)和與線粒體功能和細(xì)胞呼吸相關(guān)的酶的部分改進(jìn)硫辛酸給藥。但是，單獨(dú)使用ALC時，線粒體膜電位（線粒體功能的關(guān)鍵指標(biāo)）的改善更大。 13 ， 15

與未經(jīng)治療的老年大鼠的大腦相比，ALC加α-硫辛酸處理的老年大鼠大腦中的神經(jīng)元線粒體顯示線粒體結(jié)構(gòu)評分（ P = 0.02）和完整的線粒體數(shù)量（ P <0.001）有顯著改善；治療后，老年大鼠的線粒體超微結(jié)構(gòu)模式與年輕大鼠（治療和未治療）相似。 13這些結(jié)果類似于在老年和年輕大鼠的肝細(xì)胞線粒體活性研究中發(fā)現(xiàn)的結(jié)果，其中ALC（第1至4周）和硫辛酸（第3至4周）的組合改善了與年齡相關(guān)的氧化應(yīng)激增加（ P = 0.0001），并減少線粒體代謝的下降（ P = 0.02）。處理過的老大鼠的氧化應(yīng)激水平與未處理過的年輕大鼠的氧化應(yīng)激水平?jīng)]有顯著差異。另外，與未處理的老年大鼠相比，經(jīng)處理的老年大鼠的活動能力下降了3倍（ P = 0.03），表明代謝活動的生理參數(shù)得到了改善。對于大齡大鼠，ALC加硫辛酸的劑量分別約為0.75和0.075 g / kg /天，對于小齡大鼠，其劑量分別為1.2和0.12 g / kg /天。 15

衰老過程是帕金森氏病發(fā)展的最大風(fēng)險因素。在正常的衰老組織中也發(fā)現(xiàn)了一些與帕金森病有關(guān)的中樞神經(jīng)系統(tǒng)變化（即，多巴胺減少，谷胱甘肽減少，氧化應(yīng)激標(biāo)記增加，α突觸核蛋白，淀粉樣蛋白，線粒體DNA缺失）。營養(yǎng)補(bǔ)品（包括乙酰基左旋肉堿）處理這些衰老危險因素的能力通過抗氧化劑響應(yīng)元件Keap / Nrf2途徑的基因表達(dá)以及調(diào)節(jié)能量代謝，線粒體生物發(fā)生的基因表達(dá)調(diào)控的轉(zhuǎn)錄共激活因子來支持。 ，以及線粒體的結(jié)構(gòu)完整性–過氧化物酶體增殖物激活受體gamma共同激活劑1 alpha。 12進(jìn)行了一項(xiàng)隨機(jī)，雙盲，安慰劑對照的2期研究，以確定L-肉堿對70名100-106歲的西西里百歲老人的生理和心理疲勞以及認(rèn)知功能的功效，并隨機(jī)接受口服左旋肉堿2克/天或安慰劑，持續(xù)6個月，并另外隨訪6個月。補(bǔ)充左旋肉堿可改善總脂肪量，總肌肉量，血漿總?cè)鈮A，血漿長鏈和短鏈?；鈮A，總膽固醇，步行6分鐘的運(yùn)動后的身體疲勞，精神疲勞，疲勞嚴(yán)重程度，日?；顒釉u估，以及迷你精神狀態(tài)檢查。兩組之間的尿肉堿水平?jīng)]有差異。左旋肉堿耐受性良好； 1名患者因腹瀉的不良影響退出治療組。 16

抗氧化劑

因?yàn)檠a(bǔ)充乙酰基-L-肉堿已經(jīng)顯示出增加的ATP線粒體電子轉(zhuǎn)運(yùn)活性和生產(chǎn)，事件可能增加氧化應(yīng)激， 12給藥通常以組合進(jìn)行與抗氧化劑（即，硫辛酸）。 12 ， 13 ， 15

一項(xiàng)臺灣冠狀動脈疾病且至少一條大動脈狹窄程度為50％的臺灣患者的單盲，隨機(jī)，安慰劑對照試驗(yàn)（N = 47）顯示，氧化應(yīng)激的生物標(biāo)志物有所改善，并且抗氧化酶的數(shù)量增加了每天兩次，補(bǔ)充12周500毫克左旋肉堿。這些數(shù)據(jù)建立在較早的臨床試驗(yàn)的基礎(chǔ)上，表明較高劑量的左旋肉堿（至少2,000 mg /天）對患有心肌缺血的患者的心臟代謝和功能具有保護(hù)作用。沒有觀察到嚴(yán)重的不良事件。 2

惡病質(zhì)

一項(xiàng)前瞻性，多中心，雙盲，隨機(jī)，對照試驗(yàn)比較了左旋肉堿和安慰劑對72例IV期胰腺癌患者惡病質(zhì)的影響（CARPAN試驗(yàn)）。每天口服4克左旋肉堿補(bǔ)充劑可使肉堿血清血漿水平在第6周增加至基本值的60％，而在安慰劑組中則略有下降。與左旋肉堿組的基線相比，在第12周時，BMI，身體細(xì)胞質(zhì)量和體脂增加；而安慰劑組的BMI降低。與安慰劑組相比，接受左旋肉堿的患者的認(rèn)知功能，整體健康狀況和胃腸道癥狀均有改善。但是，兩組之間在疲勞，生存獲益或住院時間方面均未見差異。左旋肉堿耐受性良好，兩組之間的不良反應(yīng)沒有差異。 56

心血管的

截止到2013年11月，對隨機(jī)對照試驗(yàn)（RCT）進(jìn)行了系統(tǒng)回顧和薈萃分析，評估了心肌梗塞情況下左旋肉堿的各種劑量。五項(xiàng)試驗(yàn)（N = 3,108）符合納入標(biāo)準(zhǔn)；所有試驗(yàn)均質(zhì)量好，異質(zhì)性低。每日維持劑量為2至6克口服左旋肉堿，給藥期最長為12個月； 3個試驗(yàn)在5到7天內(nèi)使用了6或9 g /天的口服或IV負(fù)荷劑量。在報告特定心血管事件（即不穩(wěn)定）的研究中，使用4種每日口服維持劑量（2、3、4、6 g）的受試者之間或使用2和6 g /日劑量的受試者之間，沒有觀察到全因死亡率的差異。心絞痛，心力衰竭，心肌梗塞）。參與者之間的微不足道的趨勢傾向于每天3 g的劑量。 3

在雙盲，交叉試驗(yàn)（N = 36）中，與α-硫辛酸聯(lián)合使用，ALC的使用顯著降低了患有穩(wěn)定冠心病的至少55歲成年人的動脈張力（ P = 0.008）。但是，只有收縮壓（SBP）高于中值（大于135 mm Hg）的亞組和代謝綜合征的亞組在治療后SBP有所改善（兩者均為P = 0.01）。終止治療后，導(dǎo)致2名患者退出的不良反應(yīng)（瘙癢性皮疹和惡心）得以解決。 17

在嚴(yán)格的審查中，評估了ALC和PLC在治療心血管疾病中的有效性。 PLC被認(rèn)為可有效治療周圍動脈疾病的間歇性lau行，尤其是與運(yùn)動，脈沖性肌肉加壓療法和其他策略相結(jié)合時。在9項(xiàng)評價PLC間歇性lau行的臨床試驗(yàn)中，最大的一項(xiàng)是對485例接受口服PLC 2 g /天治療1年的患者進(jìn)行的；與安慰劑組相比，基線最大步行距離嚴(yán)重受限（小于250 m）的患者有明顯改善（分別為87％和46％； P <0.01）。 ALC或PLC對缺血性心臟?。ㄐ募∪毖┑闹委熜Ч胁幻鞔_，可能有利于預(yù)防而不是治療。同樣，支持在患有腦缺血或PLC的充血性心力衰竭患者中使用ALC的臨床數(shù)據(jù)也不充分。 18對18項(xiàng)研究進(jìn)行了系統(tǒng)評價，以評估補(bǔ)充肉堿對改善間歇性lau行患者的步行性能的作用。大多數(shù)試驗(yàn)表明，步行性能有小到中等的提高。在測試前和測試后，平行RCT和交叉RCT中，無痛步行距離分別從74提升至157 m，31提升至54 m和23提升至132 m。每個研究設(shè)計(jì)中還證明了最大步行距離的改善，分別從71到135 m，9到86 m和104 m。測試前和測試后的試驗(yàn)使用口服或靜脈內(nèi)PLC的劑量為300至2,000 mg /天，持續(xù)10至90天，而平行和交叉RCT主要使用PLC，但也使用左旋肉堿，劑量為600至3,000 mg /天，共21天。 1至1天和300至6,000 mg /天，分別為4至21天。結(jié)果大部分與證據(jù)的水平或質(zhì)量無關(guān)，一些數(shù)據(jù)支持通過口服靜脈內(nèi)給藥。 19

在患有CVD的患者中，較高的口服左旋肉堿劑量（每天超過3 g）增加了動脈粥樣硬化和心血管疾病的風(fēng)險。在進(jìn)行心臟評估的患者中，血漿左旋肉堿水平與冠狀動脈和周圍動脈疾病的風(fēng)險以及整體CVD風(fēng)險之間存在正相關(guān)，呈線性，劑量依賴性。 2013年的一項(xiàng)研究發(fā)現(xiàn)，肉堿衍生物（乙酰基和棕櫚酰-L-肉堿）的含量較高，導(dǎo)致全因死亡率和心臟移植的發(fā)生率增加。 3

肉堿缺乏癥，小學(xué)和中學(xué)

盡管與先天性代謝錯誤有關(guān)的遺傳性疾病表現(xiàn)為多種癥狀，通常在出生時或出生后不久開始出現(xiàn)，但直到成年后癥狀才變得明顯。錯誤的轉(zhuǎn)運(yùn)蛋白或酶中的缺陷會導(dǎo)致蛋白質(zhì)，碳水化合物或脂肪的合成和代謝異常以及有毒代謝產(chǎn)物的積累。 20 ， 21 ， 22 L-肉堿是由FDA批準(zhǔn)用于原發(fā)性系統(tǒng)性肉堿缺乏癥的治療批準(zhǔn)，以及用于在患者的短期和長期治療繼發(fā)肉堿缺乏癥與代謝的或終末期腎臟疾病的先天性障礙誰正在透析。先天性代謝錯誤的兩個例子包括戊二酰輔酶A脫氫酶缺乏癥和脂肪酸氧化紊亂。在前者中，L-賴氨酸，L-羥基賴氨酸和L-色氨酸的分解代謝受到影響，如果不加以治療，可能導(dǎo)致神經(jīng)系統(tǒng)疾病。治療包括限制賴氨酸飲食和補(bǔ)充左旋肉堿。推薦的補(bǔ)充劑量最初是口服左旋肉堿100 mg / kg /天，但后來進(jìn)行調(diào)整以維持正常的游離左旋肉堿水平，通常在6歲以上的患者中口服50 mg / kg /天是可能的。 21飲食中的脂肪限制和左旋肉堿的補(bǔ)充都被認(rèn)為是特定中，長鏈脂肪酸疾病以及線粒體三功能蛋白缺乏癥的治療考慮因素。但是，臨床試驗(yàn)并未顯示出肉堿補(bǔ)充的主要益處，而且潛在的不良心臟影響是接受調(diào)查的醫(yī)療服務(wù)提供者所關(guān)注的問題。 22對肉堿補(bǔ)充的先天性錯誤進(jìn)行的Cochrane薈萃分析未發(fā)現(xiàn)可比較兒童或成人肉堿與安慰劑的RCT或準(zhǔn)RCT。 20

糖尿病

PLC對胰島素抵抗的影響的第一份報告發(fā)表于2009年，并在肥胖Zucker大鼠（肥胖和胰島素抵抗的動物模型）中注意到。接受PLC的大鼠體重和食物攝入量增加，肥胖，血清胰島素，胰島素抵抗模型指數(shù)和三酰甘油肝含量提高。 18在80只Sprague Dawley大鼠的隨機(jī)對照試驗(yàn)中，與2型糖尿病大鼠相比，補(bǔ)充L-肉堿加膽鈣化固醇可以改善空腹血糖，與糖尿病對照組相比或單獨(dú)使用任一藥物的結(jié)果（ P <0.001）。與糖尿病對照組和左旋肉堿組相比，該組合還改善了空腹血漿胰島素（ P <0.001），并且與單獨(dú)使用任何一種藥物相比，胰島素抵抗也得到了改善（ P <0.001）。 23

2000年發(fā)表了第一份顯示ALC的抗糖尿病作用的報告。與安慰劑相比，靜脈推注的劑量為5 mg / kg，然后以0.025、0.1或1 mg / kg恒定輸注。與安慰劑組相比，接受ALC的2型糖尿病患者（N = 18）表現(xiàn)出劑量依賴性更高的組織葡萄糖攝取。 18一項(xiàng)2010年的隨機(jī)，雙盲，對照比較研究納入了258名肥胖的白人患者（體重指數(shù)[BMI]至少為30），患有非控制性2型糖尿?。ㄌ腔t蛋白[HbA 1c ]大于8％）；在整個試驗(yàn)過程中，患者均接受了多種抗糖尿病藥物治療?；颊弑浑S機(jī)分配接受或不接受左旋肉堿的奧利司他（每天3次，每次120毫克）（每天2次，每次2克），并接受飲食和鍛煉計(jì)劃。兩組的體重，BMI，HbA 1c ，空腹血糖，低密度脂質(zhì)（LDL）-膽固醇和胰島素抵抗均得到改善。然而，在12個月時，左旋肉堿加奧利司他組的患者比單獨(dú)接受奧利司他的患者有更大的改善（每個P <0.05）。沒有不良反應(yīng)的報道。 24 2010年另一項(xiàng)具有相同設(shè)計(jì)的研究在2型糖尿病患者（N = 254）中進(jìn)行了比較，將西布曲明（10 mg /天）與左旋肉堿和不加左卡尼丁（2 g /天）進(jìn)行了1年比較。盡管兩組的大多數(shù)參數(shù)在12個月后都有改善，但添加L-肉堿后，體重，HbA 1c ，胰島素抵抗，空腹血漿胰島素和其他胰島素抵抗參數(shù)（即視黃醇結(jié)合蛋白4）顯著改善（每個P <0.05）。然而，僅在左旋肉堿加西布曲明組中，甘油三酸酯和炎性標(biāo)志為visfatin改善（ P <0.05）。 25

2013年的系統(tǒng)綜述和薈萃分析評估了安慰劑對照試驗(yàn)，以評估補(bǔ)充左旋肉堿在2型糖尿病中的代謝作用。有4項(xiàng)試驗(yàn)（N = 284）符合納入標(biāo)準(zhǔn)，其中1項(xiàng)給藥3 g /天，而其他3項(xiàng)試驗(yàn)給藥2 g /天。盡管未發(fā)現(xiàn)對甘油三酸酯，脂蛋白（a），HbA 1c或總膽固醇有顯著影響，但口服左旋肉堿（12至52周內(nèi)每天2或3 g）可改善空腹血糖（ P = 0.002），LDL-膽固醇（ P <0.0001），載脂蛋白AI（ P = 0.008）和載脂蛋白B100（ P = 0.013）。當(dāng)排除每天3 g的研究時，每天2 g的合并效應(yīng)不再顯著。異質(zhì)性不顯著。 26還顯示靜脈內(nèi)施用L-肉堿4 g /天，連續(xù)7天，可以減輕空腹引起的饑餓感并改善空腹引起的疲勞，膽固醇異常（總膽固醇和LDL-膽固醇），肝代謝變化（AST，ALT，γ一項(xiàng)小型（N = 30）單盲隨機(jī)，安慰劑對照先導(dǎo)研究中的代謝綜合征患者的體重減輕和體重減輕。 27

血脂異常

一項(xiàng)2010年的隨機(jī)，雙盲，對照比較研究納入了258名肥胖的高加索白種人病患者（BMI≥30），患有2型糖尿?。℉bA 1c > 8％）。在整個試驗(yàn)過程中，患者服用了多種抗糖尿病藥物?；颊弑浑S機(jī)分配接受或不服用左旋肉堿的奧利司他（120 mg，每天3次）（每天2g，一次），并按飲食和運(yùn)動計(jì)劃進(jìn)行治療。在研究期間，兩組在體重，BMI，HbA 1c ，空腹血糖和胰島素抵抗方面均表現(xiàn)出顯著改善。 LDL-膽固醇也顯著降低。然而;在12個月時，左旋肉堿加奧利司他組的結(jié)果優(yōu)于單獨(dú)使用奧利司他的結(jié)果（每個P <0.05）。沒有重大不良事件的報道。 24

高甘油三酸酯血癥在社會經(jīng)濟(jì)地位低至中等的黎巴嫩男性中非常普遍（52％），這與谷物含量高而動物產(chǎn)品含量低的飲食有關(guān)。在一項(xiàng)為期12周的隨機(jī)，安慰劑對照試驗(yàn)（N = 85）中，社會經(jīng)濟(jì)地位低，甘油三酯血癥高（TG> 150 mg / dL）的成年黎巴嫩男性接受了賴氨酸（1 g /天），維生素B6（50 mg /天），賴氨酸加維生素B6或肉堿（1克/天）補(bǔ)充劑，以確定對血糖和脂質(zhì)的影響。補(bǔ)充維生素B6可以改善總膽固醇和高密度脂蛋白（HDL）膽固醇，但肉堿或賴氨酸組未見變化。 28

對來自12個RCT的數(shù)據(jù)進(jìn)行了薈萃分析，以確定補(bǔ)充L-肉堿對血液透析患者血脂水平的影響（N = 391）。大多數(shù)研究質(zhì)量低下。左旋肉堿的總劑量為1.5克/周至3克/天，持續(xù)約12周至6年。根據(jù)8個報告LDL-膽固醇的試驗(yàn)的數(shù)據(jù)，補(bǔ)充左旋肉堿與LDL-膽固醇的改善有關(guān)，尤其是在使用靜脈內(nèi)給藥超過16周的研究中。但是，未發(fā)現(xiàn)對甘油三酸酯，總膽固醇，HDL或極低密度脂蛋白膽固醇有影響?；诘乩砦恢玫膩喗M分析表明，在每個研究的國家中都沒有差異。 29

左旋肉堿（每天兩次，每次500 mg）治療12周可顯著改善HDL-膽固醇（平均值，+ 0.18 mmol / L； P = 0.03）和載脂蛋白A1（平均值，+ 0.12 g / L； P = 0.02）。以及在冠心病患者進(jìn)行的單盲，隨機(jī)，平行，安慰劑對照研究（n = 47）中，與安慰劑相比，抗氧化酶的活性有所改善。排除對象包括但不限于患有糖尿病，肝臟或腎臟疾病的患者，或接受大劑量他汀類藥物治療的患者。沒有觀察到甘油三酸酯（TG），總膽固醇，LDL-膽固醇或載脂蛋白B（apo-B）的顯著變化。發(fā)現(xiàn)左旋肉堿水平與TG之間以及超氧化物歧化酶活性與TG，總膽固醇和載脂蛋白B之間存在顯著的負(fù)相關(guān)。 64

運(yùn)動表現(xiàn)/不寬容/疲勞

一項(xiàng)雙盲，安慰劑對照，劑量反應(yīng)，交叉研究評估了L-肉堿3和4 g劑量對26位健康男性運(yùn)動員耐力表現(xiàn)的短期影響。在乳酸水平為2至4 mmol / L的情況下，左旋肉堿劑量為3 g和安慰劑的運(yùn)行速度存在顯著差異。左旋肉堿4 g劑量和安慰劑在乳酸水平3.5和4 mmol / L時也發(fā)現(xiàn)了顯著差異。在兩個補(bǔ)充組中發(fā)現(xiàn)的差異表明，體育鍛煉前服用3或4克左旋肉堿會延長疲勞程度。此外，與安慰劑相比，左旋肉堿組的乳酸和跑步速度心率均得到改善。在兩個測試組中，測試期間每次速度增加之前對困難的主觀感覺也有所改善。 4

疲勞是多發(fā)性硬化癥（MS）最令人衰弱的癥狀，據(jù)報道，多達(dá)40％的患者患有疲勞。 2012年的Cochrane干預(yù)審查發(fā)現(xiàn)，有2個RCT評估了MS患者的左卡尼汀。在審查時唯一完成的研究中，一項(xiàng)交叉試驗(yàn)中，36例患有復(fù)發(fā)緩解型和繼發(fā)性進(jìn)行性MS的成年人接受乙?；?L-肉堿2 g /天治療3個月，然后金剛烷胺200 mg /天治療3個月后3個月的淘汰期。對MS相關(guān)疲勞的影響尚不清楚。沒有嚴(yán)重不良反應(yīng)的報道。 30

在補(bǔ)充左旋肉堿的癌癥患者中，疲勞也是最常見的癥狀。癌癥相關(guān)的疲勞會嚴(yán)重削弱人的活力，休息通常無法緩解。 31 ， 32 A 4周，3期臨床試驗(yàn)隨機(jī)分配L-肉堿2克/天或安慰劑至367名癌癥患者的侵入性惡性腫瘤和疲勞;然而，無論基線肉堿水平如何，治療組和安慰劑組之間的不良反應(yīng)（即疲勞，抑郁，疼痛）在統(tǒng)計(jì)學(xué)上均無顯著差異。 31 2015年的Cochrane綜述和對包括癌癥在內(nèi)的晚期疾病患者的姑息治療疲勞治療的薈萃分析發(fā)現(xiàn)，有限證據(jù)支持任何特定治療的建議。具體與左旋肉堿有關(guān)的證據(jù)薄弱且無定論。 32綜合腫瘤學(xué)會關(guān)于在乳腺癌患者中采用綜合療法作為支持治療的臨床實(shí)踐指南（2014年）不建議使用乙?；鵏-肉堿來治療疲勞，原因是缺乏療效（中等到高）。 33 2018年，美國臨床腫瘤學(xué)會（ASCO）批準(zhǔn)了綜合腫瘤學(xué)會（SIO）循證指南，對乳腺癌治療后使用綜合療法進(jìn)行了指導(dǎo)，指出不應(yīng)建議使用乙?；鵏-肉堿來改善治療期間疲勞（D級）。 68

間歇性lau行引起的運(yùn)動能力有限在周圍動脈疾病患者中很常見。運(yùn)動引起的短暫性缺血會導(dǎo)致肉堿代謝的改變，并導(dǎo)致肉堿水平和骨骼肌能量供應(yīng)的消耗。對18項(xiàng)研究的數(shù)據(jù)進(jìn)行系統(tǒng)回顧，評估了補(bǔ)充肉堿在改善間歇性lau行患者的步行性能中的作用。大多數(shù)試驗(yàn)表明，步行性能有小到中等的提高。在測試前和測試后，平行RCT和交叉RCT中，無痛步行距離分別從74至157 m，31至54 m和23至132 m改善。每個研究設(shè)計(jì)中的最大步行距離也分別從71 m提升至135 m，9 m提升至86 m和104 m。試驗(yàn)前和試驗(yàn)后口服或靜脈PLC的劑量為300至2,000 mg /天，范圍為10至90天；平行和交叉RCT主要使用PLC，也使用左旋肉堿，劑量分別為600至3,000 mg /天（21天至1年）和300至6,000 mg /天（4至21天）。結(jié)果大部分與證據(jù)的水平或質(zhì)量無關(guān)，一些數(shù)據(jù)表明與口服相比，靜脈給藥更具益處。 19顧問公司和Sigma-Tau公司（PLC的制造商和主要開發(fā)商）的雇員對使用口服PLC評估間歇性lau行患者的步行性能的影響進(jìn)行了系統(tǒng)的回顧和薈萃分析。在6項(xiàng)Sigma-Tau 3期研究（N = 867）的初步分析中，與安慰劑相比，采用2 g / day PLC的峰值步行距離凈提高了16 m，與之相比，結(jié)果相似（凈提高了45米）薈萃分析包括另外7個RCT（總共13項(xiàng)研究；總共1,854例患者）。 6到12個月的劑量范圍為1-4克/天（中值2克/天），耐受性良好，PLC干預(yù)組與安慰劑/比較組之間無治療相關(guān)差異。死亡發(fā)生率分別為1.6％和1.4％。作者否認(rèn)有任何行業(yè)，機(jī)構(gòu)和公共資金來源。 34美國心臟病學(xué)會基金會/美國心臟協(xié)會針對外周動脈疾病的治療指南指出，PLC在改善間歇性lau行患者步行距離方面的有效性尚未確立（證據(jù)水平：有限）。 35

運(yùn)動不耐受也是線粒體肌病（MM）患者的主要癥狀，最常見的表現(xiàn)為慢性進(jìn)行性外眼肌麻痹（CPOE;眼瞼下垂），伴有相對較低的勞累水平的過度疲勞。一項(xiàng)隨機(jī)，雙盲，安慰劑對照的交叉試驗(yàn)，對12位MM和CPOE患者以及10位年齡和性別相匹配的健康對照進(jìn)行了研究，記錄了補(bǔ)充L-肉堿的MM患者運(yùn)動耐受性和耗氧量的改善（3 g /天）與接受安慰劑的人相比。與對照組相比，MM患者的平均外周肌力量，身高，體重和無脂肪量較低。 36

血液學(xué)疾病

一項(xiàng)前瞻性，隨機(jī)，開放標(biāo)簽的試驗(yàn)招募了69位慢性丙型肝炎成人，以評估4克/天左旋肉堿與不治療對藥物性貧血的影響；兩組患者均接受標(biāo)準(zhǔn)α-干擾素聯(lián)合利巴韋林治療。 12個月后，接受左旋肉堿的患者的肝酶參數(shù)（即AST，ALT），病毒血癥，血紅蛋白和血細(xì)胞計(jì)數(shù)（即紅細(xì)胞，白細(xì)胞，血小板）均有改善。左旋肉堿組的持續(xù)病毒學(xué)應(yīng)答和復(fù)發(fā)率也有所改善。兩組均未發(fā)現(xiàn)嚴(yán)重不良事件。 57在接受維持性血液透析的腎功能不全患者中，接受乙酰-L-肉堿至少2周的患者與接受安慰劑的患者之間的血紅蛋白，血細(xì)胞比容或促紅細(xì)胞生成素之間沒有差異，對49項(xiàng)RCT進(jìn)行系統(tǒng)回顧和薈萃分析（ N = 1,734）。 53

由于證據(jù)不足（非常低），KDIGO慢性腎臟病貧血臨床實(shí)踐指南（2012年）不建議使用左旋肉堿作為輔助療法。 55

肝毒性

過量的丙戊酸不會產(chǎn)生容易識別的氧化反應(yīng)，但可能會耗盡肝左旋肉堿的儲存，從而削弱線粒體通過肉堿穿梭的運(yùn)輸。因此，盡管數(shù)據(jù)有限，但左旋肉堿被認(rèn)為是恢復(fù)線粒體功能，減少有毒代謝產(chǎn)物的產(chǎn)生以及抵消或逆轉(zhuǎn)丙戊酸毒性作用的潛在解毒劑。一項(xiàng)系統(tǒng)的審查僅鑒定了成人和兒童中丙戊酸急性暴露的8例（7種單一療法，1種多藥），以及1篇報道674名患者安全性數(shù)據(jù)的文章。靜脈內(nèi)給藥是首選方法，因?yàn)樽笮鈮A的口服生物利用度低。此外，大多數(shù)用藥過量的患者都會服用活性炭，這會使口服左旋肉堿無效。根據(jù)這些病例的數(shù)據(jù)和毒理學(xué)參考資料，最常用的負(fù)載劑量是左旋肉堿100 mg / kg。建議每8小時服用50 mg / kg的維持劑量（最大3 g /劑量）以治療由于丙戊酸持續(xù)或延遲吸收引起的毒性。盡管數(shù)據(jù)有限且懷疑存在出版偏倚，但作者認(rèn)為左旋肉堿的給藥對表現(xiàn)出意識水平下降的急性藥物過量患者是合理的。 10還有一個病例報道，使用L-肉堿成功治療PEG-天冬酰胺酶誘導(dǎo)的急性淋巴細(xì)胞白血病患者的肝毒性。 58

一項(xiàng)雙盲，隨機(jī)，安慰劑對照試驗(yàn)評估了口服肉堿在預(yù)防新診斷，初治的伊朗結(jié)核病患者中抗結(jié)核藥引起的肝毒性（ATDH）的潛在益處（N = 182）。發(fā)現(xiàn)結(jié)核?。═B）患者中的肉堿缺乏癥比健康對照者更為普遍。所有結(jié)核病患者均按方案接受一線抗結(jié)核治療方案（異煙肼，利福平，乙胺丁醇，吡嗪酰胺），并隨機(jī)分配給左旋肉堿2 g /天，共4周或安慰劑。在為期2.5年的研究期內(nèi)，發(fā)生過ATDH的25％的患者中，左旋肉堿組為16.7％，而安慰劑組為32.3％（ P = 0.049）。基于多元邏輯回歸的ADTH易感因素包括年齡大于35歲的糖尿病，HIV感染和安慰劑治療的患者。 59

不孕癥

氧化應(yīng)激被認(rèn)為在男性不育癥中起重要作用，并且已經(jīng)表明，成熟的，形態(tài)學(xué)上正常的精子比未成熟的形式產(chǎn)生的活性氧種類（ROS）少。在附睪，精漿和精子中都發(fā)現(xiàn)了酶促（例如谷胱甘肽過氧化物酶，超氧化物歧化酶）和非酶促（例如肉堿，谷胱甘肽，類胡蘿卜素）的抗氧化活性。在正常條件下，這些氧化和抗氧化過程保持平衡，但是過量的ROS會導(dǎo)致廣泛的精子功能障礙和DNA結(jié)構(gòu)破壞。與減少攝入量相比，增加飲食中的抗氧化劑攝入量可以改善精液質(zhì)量。 37 ， 38在子宮內(nèi)膜異位癥，在卵泡液ROS可能影響胚胎的質(zhì)量和發(fā)育以及卵母細(xì)胞，其是對氧化應(yīng)激極為敏感的減數(shù)分裂紡錘體的結(jié)構(gòu)。 39 2014年Cochrane對男性不育癥中使用的抗氧化劑的系統(tǒng)評價和薈萃分析得出的結(jié)論是，僅有異質(zhì)性低的肉堿的唯一數(shù)據(jù)可以通過分析得出與肉堿（即乙酰基-L-肉堿，乙?；?肉堿，左旋肉堿）和與安慰劑相比在6個月時的有益精子濃度（2個試驗(yàn)，116名男性）。數(shù)據(jù)不適合總結(jié)對精子活力的影響。 65歲

在一項(xiàng)實(shí)驗(yàn)研究中，探討了抗氧化劑，L-肉堿和N-乙酰半胱氨酸（NAC）在預(yù)防由輕度子宮內(nèi)膜異位癥的不育女性的卵泡液引起的減數(shù)分裂卵母細(xì)胞損傷中的潛在保護(hù)作用。從BMI小于30，年齡38歲以下，患有子宮內(nèi)膜異位相關(guān)性不育癥（n = 11，測試組）或輸卵管或男性因素相關(guān)性不育癥的婦女中收集卵泡液（FF）樣品（N = 22） （n = 11，控制）。與無FF或?qū)φ誇F中成熟的卵母細(xì)胞產(chǎn)生的百分比相比，子宮內(nèi)膜異位FF中牛卵母細(xì)胞的體外成熟產(chǎn)生的減數(shù)分裂正常卵母細(xì)胞的百分比更低（中期II中存在正常的紡錘體）。當(dāng)評估抗氧化劑單獨(dú)使用或與0.6 mg / mL左旋肉堿組合使用對子宮內(nèi)膜異位癥-FF成熟的卵母細(xì)胞的作用時，與不添加左旋肉堿的卵母細(xì)胞相比，左旋肉堿產(chǎn)生的正常卵母細(xì)胞百分比更高（80.61％vs 51.35 ％），與無FF組（86.36％）和對照組FF（83.52％）相似。與單獨(dú)使用左旋肉堿相比，添加NAC（1.5 mmol / L）和左旋肉堿加NAC的組合所產(chǎn)生的正常成熟百分比略低（分別為62.22％和61.40％）。 39

在一項(xiàng)評估L-肉堿對環(huán)磷酰胺引起的不育癥的保護(hù)作用的實(shí)驗(yàn)研究中，雄性大鼠接受IP環(huán)磷酰胺（CP）35 mg / kg，CP加L-肉堿21 mL / kg /天或鹽溶液（對照）。治療3周后，與CP組相比，給予L-肉堿的大鼠精子活動力，活力和睪丸激素水平增加。與CP組相比，L-肉堿組的睪丸凋亡細(xì)胞也減少。 Immunohistochemistry revealed nearly normal seminiferous tubules with the quality of spermatogenic cells improved with L-carnitine supplementation. 40

A systematic review of 17 randomized trials (N = 1,665 men) assessed the effects of oral antioxidants, including carnitine, on sperm quality in infertile men and pregnancy rates in partners; heterogeneity in clinical methods prevented a meta-analysis from being performed. Over 50% of studies used a combination of antioxidants (vitamin C and E, zinc, selenium, folic acid, carnitine, N-acetyl-cysteine, astaxanthin); monotherapy with carnitine was most frequently studied, with 4 studies that enrolling 365 patients with asthenozoospermia or oligoasthenozoospermia. Although some benefit has been reported, clinical data are lacking. Supplementation with carnitine 2 g/day, L-carnitine 2 to 3 g/day, and/or acetyl-L-carnitine 0.5 to 3 g/day for up to 26 weeks resulted in improvements in sperm motility in 3 studies, improved pregnancy rates in 2 studies, and improved sperm concentration and morphology in 1 study. 41 A randomized, double-blind, controlled trial (N = 52) in Iran compared the effects of L-carnitine with clomiphene citrate, an anti-estrogen commonly prescribed for male infertility, on idiopathic male infertility. Patients received either clomiphene citrate 25 mg/day or L-carnitine 2 g/day for 3 months. Compared with baseline, semen volume, sperm count, and motility improved with L-carnitine. Compared with clomiphene citrate, L-carnitine resulted in increased semen volume and equal improvements in sperm motility, but not sperm morphology. 38 L-carnitine 1 g/day was used as a positive control in a 12-week, RCT that evaluated the effects phosphodiesterase-5 inhibitors on Leydig cell secretory function in men with oligoasthenospermia (N = 75). Although mean sperm concentration, percent motile spermatozoa, percent morphologically normal spermatozoa, and insulin-like 3 peptide levels were improved after treatment with vardenafil or sildenafil, no differences were seen with the positive control (L-carnitine) or negative control (untreated infertile men with oligoasthenospermia). 37

Migraine prophylaxis

Because mitochondrial phosphorylation potential was reduced between headaches in migrainous patients, a single-blind, randomized, controlled clinical trial was conducted to investigate the effects of L-carnitine 500 mg/day and/or magnesium oxide 500 mg/day on migraine prophylaxis (N = 133). Conventional treatment and migraine elimination diet were continued throughout the study. After 12 weeks, L-carnitine supplementation produced the highest reductions in mean migraine days/month and the magnesium supplemented group produced the most improvements in the mean number of frequency, severity, and index. Overall, the effects of magnesium on all migraine indicators were more than those of L-carnitine, and the effects of routine treatments on all migraine indicators were more than those of the supplements. 60

Muscle cramps

A prospective uncontrolled, nonrandomized study evaluated the effects of 2 doses of L-carnitine to reduce muscle cramps in cirrhosis patients; patients with ongoing symptoms of painful, involuntary contraction of skeletal muscles at rest or that woke them from sleep at least 3 times in the previous month were included. L-carnitine 300 mg 3 times daily (900 mg/day) or 4 times daily (1,200 mg/day) was provided for 8 weeks. Muscle cramp frequency and duration was assessed with questionnaires and severity was assessed by visual analog scale (VAS). Overall, 88.1% of patients experienced a reduction in cramping and 28.6% had complete elimination of cramps; mean VAS scores improved from 69.9 at baseline to 26.2 by the end of the study. A dose-response was observed, with 43.5% compared with 10.5% experiencing fewer cramps in the 1,200 mg/day and 900 mg/day groups, respectively. The higher dose also resulted in improved VAS scores (mean 9.9 vs 39.6, respectively).沒有不良反應(yīng)的報道。 61

神經(jīng)病學(xué)

Animal studies have demonstrated improved antioxidant activity of acetyl-L-carnitine over L-carnitine in the brain. Although L-carnitine and acetyl-L-carnitine both increased ambulatory activity, carnitine plasma levels, and brain levels in older rats, acetyl-L-carnitine provided greater improvements in biomarkers of oxidative damage (lipid peroxidation, hippocampal and cortical oxidized nucleotides, as well as hippocampal and white matter nitrotyrosine) in older rat brains compared with L-carnitine. 6 The combination of acetyl-L-carnitine plus N-acetyl-cysteine also delayed degeneration of sensory neurons, reduced early retrograde death of spinal motor neurons, attenuated neuroinflammation, promoted axonal sprouting in injured cord segment, and produced an anti-apoptotic effect in segments rostral to injury sites. 42

Neuronal loss and brain atrophy are hallmarks of AIDS-related dementia complex. Treatment strategies target the reduction of glutamate levels in the brain, which appears to be involved in the pathogenesis. In a small experimental study (N = 12) conducted in male AIDS patients with higher mean glutamate levels than those of controls, administration of IV acetyl-L-carnitine 3 g/day for 4 weeks reduced mean levels of glutamate compared with baseline (137 vs 246 micromol/L, respectively). A case of improved memory and attention after 12 weeks with acetyl-L-carnitine supplementation was also reported in a 37-year-old female AIDS patient admitted with abrupt onset of cognitive and motor symptoms associated with a fall in blood (201 to 41 micromol/l) and CSF (60 to 11 micromol/L) glutamate levels. 43 A systematic review of 7 RCTs (N = 660) evaluated the effect of acetyl-L-carnitine in patients with hepatic encephalopathy. Administration of acetyl-L-carnitine 2 g/day was consistently associated with improvement in serum ammonia levels compared with those of placebo; however, heterogeneity was found among studies. 44

The American Academy of Neurology (AAN) practice parameter for the management of dementia (2001) found the evidence to be incomplete or conflicting for the use of acetyl-L-carnitine as a cognitive-enhancing agent in patients with Alzheimer disease or mixed dementia. 66

Because bipolar depression may also be associated with mitochondrial dysfunction, 40 patients with bipolar depression with incomplete responses to standard therapy were enrolled in a 12-week, double-blind, randomized, placebo-controlled, parallel-group, flexible-dose study of acetyl-L-carnitine (1 to 3 g/day) plus alpha-lipoic acid (0.6 to 1.8 g/day) as adjunctive therapy. Although supplementation reduced phosphocreatine levels in the parieto-occipital cortex, no differences were found between groups in depression scores compared with baseline in any outcome measure. Adverse effects were generally minor with diarrhea, foul-smelling urine, rash, constipation, and dyspepsia reported more frequently with supplementation than with placebo. 45

The Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder (MDD) in adults (2016) recommend acetyl-L-carnitine as third-line monotherapy for mild to moderate MDD (Level 2). 67

In a double-blind, randomized clinical trial comparing the effect of oral ALC 1 g 3 times daily to fluoxetine 20 mg/day in 80 elderly patients with dysthymic disorder, ALC resulted in improved depression scores (Hamilton depression, Hamilton anxiety, Beck depression inventory) and attention performance scores. The latter did not reach significance in the fluoxetine group. ALC achieved a higher tolerance profile than that of fluoxetine. 46

Acetyl-L-carnitine has been shown to virtually eliminate sensory neuronal death and possibly improve regeneration after primary nerve repair. Enhanced regenerative capacity of neurons that survive peripheral nerve trauma has been demonstrated in animal studies. Rats treated with a 6-week regimen of 50 mg/kg/day acetyl-L-carnitine after unilateral sciatic nerve graft repairs were performed, increasing the total area of regenerating nerve fibers (2,242% increase) and Schwann cells (722% increase) in the grafts. 47 Similarly, faster recovery of regenerated axons as well as increased number and diameter of resulting myelinated fibers were observed with supplementation of acetyl-L-carnitine in a rat sciatic nerve regeneration model. 8

An analysis of 2 multicenter, double-blind, randomized, placebo-controlled trials evaluated the effects of 2 doses of acetyl-L-carnitine (1.5 and 3 g/day) administered over 1 year on clinical diabetic neuropathy in adults with type 1 and 2 diabetes (N = 1,346). Centers in the US and Canada (USC) participated in one study while those in the US, Europe, and Canada (USEC) participated in the second study. Demographic differences were evident among the 2 studies: weight and BMI were higher in the UCS group, while the UCES group included primarily white participants with a larger proportion of type 1 diabetic patients and a longer disease duration. Compared with the placebo group, sural nerve fiber numbers and regenerating clusters increased in patients receiving 1.5 g/day (500 mg 3 times daily) but not in the 3 g/day (1 g 3 times daily) group. Vibration perception improved in the fingers in both groups and in the toes of those receiving 3 g/day. Significantly greater reductions were also seen in UCS subgroups of patients younger than 55 years who had a BMI less than or equal to 30, type 2 diabetes, and HbA 1c less than 8.5%. Mean clinical scores of both groups were improved compared with those of the placebo group, but not among groups. No differences were found in electrophysiological parameters. The greatest pain reduction was observed with 3 g/day after 1 year in type 2 diabetic patients with adequate drug compliance and HbA 1c greater than 8.5%. Fewer patients taking 3 g/day reported pain, paresthesia, and hyperesthesia compared with those taking placebo; no other differences were observed in adverse events among groups. 48 Data from the patients in these 2 studies was retrospectively examined to identify risk factors associated with sural nerve degeneration. Three risk groups were created based on the change in myelinated fiber density: "regenerators" (top 16 percentiles), "degenerators" (bottom 16 percentiles), and intermediate. Baseline HbA 1c was the only factor that differed across the 3 groups with a mean of 8.3% (± 1.6%) for regenerators and 9.2 (± 1.8%) for degenerators. 49

A systematic review was conducted to evaluate the potential use of nutraceuticals, including acetyl-L-carnitine, as adjuvant cancer therapy for treatment or prophylaxis of chemotherapy-induced peripheral neuropathy (CIPN). A total of 24 randomized, controlled, open-label, and retrospective trials were identified and results were equivocal. Insufficient data were available to recommend any of the 10 nutraceuticals reviewed. Acetyl-L-carnitine was reported as a possible treatment option for paclitaxel- and cisplatin-induced peripheral neuropathy based on data from 2 open-label studies, while a phase 3 trial demonstrated no positive prophylactic benefit. Adverse events were only reported for acetyl-L-carnitine and included mild nausea and insomnia. 50 A negative effect of 3 g/day acetyl-L-carnitine was demonstrated at 24 weeks, but not at 12 weeks, on CIPN in women with a history of stage I to III breast cancer undergoing taxane-based treatment in a double-blind, randomized, placebo-controlled trial (N = 409). Grade 3 to 4 neuropathy was reported in 8 cases in the acetyl-L-carnitine group and 1 case in the placebo group ( P = 0.46). 51

The Society for Integrative Oncology clinical practice guidelines for the use of integrative therapies as supportive care in patients treated for breast cancer (2014) recommends against the use of acetyl-L-carnitine for the prevention of neuropathy in breast cancer patients due to adverse events (moderate to high). 33 In 2018, the American Society of Clinical Oncology (ASCO) endorsed the Society for Integrative Oncology (SIO) evidence-based guideline for the use of integrative therapies after breast cancer treatment, stating that acetyl-L-carnitine is not recommended for the prevention of chemotherapy-induced peripheral neuropathy in patients with breast cancer due to potential harm (Grade H). Lyman 2018 The ASCO clinical practice guidelines for prevention and management of CIPN in survivors of adult cancers (2014) strongly advised against the use of acetyl-L-carnitine for the prevention of CIPN in patients undergoing treatment with neurotoxic agents. An increase in incidence of CIPN has been documented at 24 weeks in a phase 3 trial in women with breast cancer receiving acetyl-L-carnitine versus placebo (high-quality evidence; strong recommendation). No recommendation could be made regarding use of acetyl-L-carnitine for treatment of CIPN based on inconclusive data (low-quality evidence, inconclusive). 52

Renal disease

A systematic review and meta-analysis was conducted to confirm or refute previous data indicating the beneficial effect of L-carnitine on hemoglobin and erythropoietin dose in maintenance hemodialysis patients. A total of 49 RCTs (N = 1,734) comparing acetyl-L-carnitine with placebo or no treatment for at least 2 weeks were included; those that compared different doses, routes, or durations were excluded. Although LDL-cholesterol and C-reactive protein improved by L-carnitine supplementation, no significant differences were identified in any other lipid parameters, hemoglobin, hematocrit, albumin, or the required erythropoietin dose. The improvement in LDL-cholesterol was not considered to be clinically important.沒有不良反應(yīng)的報道。 53 Because approximately 95% of hemodialysis patients have been found to have carnitine deficiency, L-carnitine supplementation is used frequently as adjuvant therapy. However, because its use is controversial, another meta-analysis sought to assess the clinical benefit of L-carnitine on hemodialysis patients. The 25 eligible RCTs spanned more than 20 years, with sample sizes ranging from 10 to 113 patients (N = 1,172) and study durations ranging from 3 weeks to 36 months. Both oral and IV routes were used at doses ranging from 1 to 3 g/day and 10 to 20 mg/kg/hemodialysis treatment. L-carnitine supplementation was not associated with changes in any of the inflammation, oxidative stress, nutrition, anemia, dyslipidemia, or quality of life outcomes measured. 54

The Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guideline for the anemia in chronic kidney disease (2012) does not recommend use of L-carnitine as adjuvant therapy due to insufficient evidence (very low). 55

加藥

Oral carnitine supplements are metabolized by microbiota prior to absorption; bioavailability of 1 to 6 g doses ranges from 5% to 18%. Certain gut microbiota species (eg, Gammaproteobacteria, Betaproteobacteria, and Firmicutes, including Acinetobacter species) can adversely affect the bioavailability of L-carnitine supplementation. The dynamics of skeletal muscle carnitine may also influence the metabolism of L-carnitine supplementation. 3

Anemia, drug-induced

Improvements in hemoglobin, blood cell counts, viremia, and liver enzymes were achieved with supplemental L-carnitine 2 g twice a day for 12 months in a small study of patients with chronic hepatitis C treated with standard interferon-alfa plus ribavirin receiving. 57

Cachexia

An oral liquid dose of L-carnitine 4 g/day for 12 weeks increased BMI, body cell mass, and body fat in patients with cachexia and stage IV pancreatic cancer (CARPAN trial). 56

Cardiovascular disease, secondary prevention

L-carnitine 2 to 6 g/day oral maintenance doses for up to 12 months have been used in clinical studies with some trials administering oral or IV loading doses of 6 or 9 g/day for 5 to 7 days. An insignificant trend favored the 3 g/day dose in terms of all-cause mortality. Doses higher than 3 g/day oral L-carnitine are not recommended; higher doses of carnitine derivatives (acetyl- and palmitoyl-L-carnitine) have been shown to increase atherogenesis, CVD risk, all-cause mortality, and heart transplantations in patients with CVD. 3 L-carnitine is often used in combination with an antioxidant, such as alpha-lipoic acid.

Carnitine deficiency, primary and secondary

L-carnitine is approved by the FDA for treatment of primary systemic carnitine deficiency, and for short- and long-term treatment of patients with an inborn error of metabolism or with end-stage renal disease on dialysis that results in a secondary carnitine deficiency. Maintenance doses for adults range from 1 to 3 g/day given as a once or twice daily divided dose. Refer to prescribing information for specific dosing recommendations.

Type 2 diabetes mellitus

Administration of L-carnitine 2 g once daily for 1 year to patients also receiving either orlistat or sibutramine demonstrated greater improvements in body weight, BMI, HbA 1c , plasma glucose, LDL-cholesterol, and insulin resistance compared with antidiabetic medication alone. 24 , 25

Acetyl-L-carnitine also improved tissue glucose uptake as a 5 mg/kg IV bolus loading dose followed by 0.025, 0.1, or 1 mg/kg constant infusion in a small group of type 2 diabetic patients. 18歲

血脂異常

The addition of L-carnitine 2 g once daily to orlistat in adults with type 2 diabetes resulted in lower LDL-cholesterol than did either drug alone; however, other studies failed to find an effect on lipid parameters or triglycerides. 24 , 28 , 29

Dysthymic disorder

Oral acetyl-L-carnitine 1 g 3 times daily administered for 7 weeks to patients over the age of 65 years with dysthymic disorder resulted in improved depression scores and attention performance. 46

Fatigue

Limited data show use of a 3 or 4 g dose of L-carnitine prolonged time to exhaustion in 26 healthy male athletes. 4

L-carnitine 3 g once daily for 2 months improved limits of tolerance, oxygen consumption, and constant work rate in a small group (N = 12) of patients with mitochondrial myopathy. 30

Effects on multiple sclerosis-related fatigue are unclear. 30

The Society for Integrative Oncology clinical practice guideline for the use of integrative therapies as supportive care in patients treated for breast cancer does not recommend the use of acetyl-L-carnitine for the treatment of fatigue. 33

Hepatotoxicity, drug-induced

Data are limited on the use of L-carnitine as a valproic acid overdose antidote. A systematic review identified only 8 cases of acute exposure to valproic acid (7 monotherapy, 1 polydrug) in adults and children. Intravenous administration is the preferred route. A loading dose of L-carnitine 100 mg/kg was most commonly used; a maintenance dose of 50 mg/kg (to a maximum of 3 g/dose) administered every 8 hours was recommended to treat toxicity due to ongoing or delayed absorption of valproic acid. 10

Carnitine deficiency was found to be more prevalent in TB patients than in healthy controls. Adjunctive administration of oral carnitine (1 g twice daily for 4 weeks) was used to reduce antituberculosis drug-induced hepatotoxicity resulting from first-line, anti-TB regimen (isoniazid, rifampin, ethambutol, pyrazinamide). 59

Infertility, male

Carnitine 2 g/day, L-carnitine 2 to 3 g/day, acetyl-L-carnitine 0.5 to 3 g/day for up to 26 weeks has been used successfully to improve sperm parameters and fertilization in men with oligoasthenozoospermia or asthenozoospermia. 38 , 41

Intermittent claudication, treatment

Propionyl-L-carnitine 2 g once daily is likely effective for treatment of intermittent claudication in patients with peripheral artery disease, especially when combined with exercise and other strategies. Administration for up to 1 year was most effective in patients with severely limited baseline maximum walking distance (less than 250 m). 18 Dosages of propionyl-L-carnitine 300 mg/day to 2 g/day of PLC orally or IV ranging from 10 to 90 days, and L-carnitine at dosages of 300 mg/day to 6 g/day for 4 days to 1 year have improved walking distance, with some data supporting more benefit with IV administration compared with oral. 19 The American College of Cardiology Foundation/American Heart Association guideline for the management of peripheral artery disease states that the effectiveness of propionyl-L-carnitine as a therapy to improve walking distance in patients with intermittent claudication is not well established. 35

Migraine prophylaxis

Compared with magnesium, oral L-carnitine 500 mg/day for 12 weeks produced the highest reductions in mean migraine days/month. The magnesium-supplemented group experienced the most improvements in migraines for the mean number of frequency, severity, and index. Overall, the effects of magnesium on all migraine indicators were higher than those of L-carnitine, and the effects of routine treatments on all migraine indicators were higher than those of supplements. 60

Muscle cramps

L-carnitine 300 mg 3 times daily (900 mg/day) or 4 times daily (1,200 mg/day) for 8 weeks was administered to patients with cirrhosis and ongoing symptoms of painful, involuntary contraction of skeletal muscles at rest or that woke them from sleep at least 3 times in the previous month. A dose-response was observed with 43.5% compared with 10.5% experiencing fewer cramps in the 1,200 and 900 mg/day groups, respectively. The higher dose also resulted in improved VAS scores (mean 9.9 vs 39.6, respectively). 61

Neuropathy, central

Neuronal loss and brain atrophy are hallmarks of AIDS-related dementia complex. Administration of IV acetyl-L-carnitine 3 g/day for 4 weeks reduced mean levels of glutamate compared with baseline in a small experimental study (N = 12). A case report also documented improvement in memory and attention after 12 weeks of acetyl-L-carnitine supplementation in a 37-year-old female AIDS patient, subsequently diagnosed with AIDS dementia, who was admitted with abrupt onset of cognitive and motor symptoms associated with decreased blood (201 to 41 micromol/l) and CSF (60 to 11 micromol/L) glutamate levels. 43

Acetyl-L-carnitine 1 to 3 g/day plus alpha-lipoic acid 0.6 to 1.8 g/day as adjunctive therapy for 12 weeks failed to improve depression scores compared with baseline in a small (N = 40) study of patients with bipolar depression. 45

Neuropathy, peripheral

Acetyl-L-carnitine 1.5 and 3 g/day administered over 1 year to treat diabetic neuropathy in adults with type 1 and 2 diabetes (N = 1,346) increased in sural nerve fiber numbers and regenerated clusters in patients receiving 1.5 g/day (500 mg 3 times daily) but not in those receiving 3 g/day (1 g 3 times daily) compared with the placebo group. Vibration perception improved in the fingers in both treatment groups and in the toes of those receiving 3 g/day. Greater reductions were seen in the US-Canada subgroups of younger than 55 years and who had a BMI less than or equal to 30, type 2 diabetes, and HbA 1c less than 8.5%. The greatest pain reduction was observed with 3 g/day after 1 year in type 2 diabetic patients with adequate drug compliance and HbA 1c greater than 8.5%. Fewer patients taking 3 g/day reported pain, paresthesia, and hyperesthesia compared with those receiving placebo. Baseline HbA 1c was the only factor that identified "regenerators" and "degenerators." 48 ， 49

The Society for Integrative Oncology clinical practice guidelines for the use of integrative therapies as supportive care in patients treated for breast cancer do not recommend use of acetyl-L-carnitine for the prevention of neuropathy in breast cancer patients due to harm (moderate to high). 33

The American Society of Clinical Oncology clinical practice guidelines for prevention and management of CIPN in survivors of adult cancers strongly advise against the use of acetyl-L-carnitine for the prevention of CIPN in patients undergoing treatment with neurotoxic agents. An increase in incidence of CIPN has been documented at 24 weeks in a phase 3 trial in women with breast cancer receiving acetyl-L-carnitine vs placebo (high-quality evidence; strong recommendation). No recommendation could be made regarding use of acetyl-L-carnitine for treatment of CIPN based on inconclusive data (low-quality evidence, inconclusive). 52

Pregnancy / Lactation

避免使用。 L-carnitine is assigned the pregnancy Category B by the FDA; L-carnitine supplementation in breast-feeding mothers has not been clinically studied.

Reproductive studies have been performed in rats and rabbits at doses of up to 3.8 times the human dose on the basis of surface area and have revealed no evidence of impaired fertility or harm to the fetus due to L-carnitine.

Studies in dairy cows indicate that the concentration of levocarnitine in milk is increased following exogenous administration of levocarnitine.

由于動物繁殖研究并不總是能夠預(yù)測人的反應(yīng)，因此只有在明確需要的情況下，才應(yīng)在懷孕期間使用這種藥物。 In breast-feeding mothers receiving levocarnitine, any risks to the child need to be weighed against the benefits of levocarnitine supplementation to the mother. 62 Discontinuation of levocarnitine in breast-feeding mothers should be considered.

Interactions

Carbamazepine, phenobarbital, phenytoin, and valproic acid may decrease blood concentrations of carnitine in children treated for convulsions. 1 , 63

Pivampicillin and other pivalate-conjugated antibiotics may decrease blood concentrations of carnitine and limit fatty acid oxidation. 1

不良反應(yīng)

Nausea, vomiting, abdominal cramps, diarrhea, and a "fishy" body odor can occur with doses of about 3 g/day. Less common adverse effects have included pruritic rash, muscle weakness in uremic patients, and seizures in patients with seizure disorders. Administering the daily dose in 3 divided doses may help reduce some adverse effects, such as nausea and vomiting. 1 , 2 , 17 Some evidence suggests that intestinal bacteria metabolize carnitine to form trimethylamine-N-oxide, a substance that may increase cardiovascular risk, particularly in omnivores who consume meat versus in vegans or vegetarians. 1

A systematic review of nutraceuticals used for chemotherapy-induced peripheral neuropathy identified 2 open-label studies and a phase 3 trial that investigated the use of acetyl-L-carnitine. Mild nausea (n = 2) and insomnia (n = 1) were reported in 2 trials (N = 52). 39 In a fatigue treatment trial, adverse events including insomnia and nervousness led to withdrawal of 1 patient with multiple sclerosis who received acetyl-L-carnitine 1 g twice/day for 3 months. 32

In patients with cardiovascular disease, higher oral doses of L-carnitine (more than 3 g/day) increased the risk of atherogenesis and CVD. A linear, dose-dependent association was found between plasma L-carnitine levels and risks of coronary and peripheral artery disease, as well as overall CVD risk in patients undergoing cardiac evaluation. A 2013 study also found increased rates of all-cause mortality and heart transplantation with higher levels of carnitine derivatives (acetyl- and palmitoyl-L-carnitine). 3

Toxicology

The IV median lethal dose (LD 50 ) of levocarnitine in rats is 5.4 g/kg, and the oral LD 50 of levocarnitine in mice is 19.2 g/kg. There have been no reports of a levocarnitine overdosage; however, large doses may cause diarrhea. 62

參考文獻(xiàn)

1. National Institutes of Health. Office of Dietary Supplements. Carnitine Fact Sheet for Health Professionals. Carnitine: What is it? https://ods.od.nih.gov/factsheets/Carnitine-HealthProfessional/ . Updated February 11, 2016. Accessed November 8, 2015.

2. Lee BJ, Lin JS, Lin YC, Lin PT. Effects of L-carnitine supplementation on oxidative stress and antioxidant enzymes activities in patients with coronary artery disease: a randomized, placebo-controlled trial. Nutr J . 2014;13:79.2509210810.11

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