Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

General Review Article

L-carnitine: Searching for New Therapeutic Strategy for Sepsis Management

Author(s): Adeleh Sahebnasagh, Razieh Avan, Mahila Monajati, Javad Hashemi, Solomon Habtemariam, Sina Negintaji and Fatemeh Saghafi*

Volume 29, Issue 18, 2022

Published on: 14 January, 2022

Page: [3300 - 3323] Pages: 24

DOI: 10.2174/0929867328666211117092345

Price: $65

Open Access Journals Promotions 2
Abstract

In this review, we discussed the biological targets of carnitine, its effects on immune function, and how L-carnitine supplementation may help critically ill patients. L-carnitine is a potent antioxidant. L-carnitine depletion has been observed in prolonged intensive care unit (ICU) stays, while L-carnitine supplementation has beneficial effects in health promotion and regulation of immunity. It is essential for the uptake of fatty acids into mitochondria. By inhibiting the ubiquitin-proteasome system, down-regulating the apelin receptor in cardiac tissue, and reducing β-oxidation of fatty acid, carnitine may decrease vasopressor requirement in septic shock and improve clinical outcomes of this group of patients. We also reviewed animal and clinical studies that have been recruited for evaluating the beneficial effects of L-carnitine in the management of sepsis/ septic shock. Additional clinical data are required to evaluate the optimal daily dose and duration of L-carnitine supplementation.

Keywords: L-carnitine, sepsis, septic shock, critically ill, intensive care, antioxidant.

« Previous
[1]
Rhodes, A.; Evans, L.E.; Alhazzani, W.; Levy, M.M.; Antonelli, M.; Ferrer, R.; Kumar, A.; Sevransky, J.E.; Sprung, C.L.; Nunnally, M.E.; Rochwerg, B.; Rubenfeld, G.D.; Angus, D.C.; Annane, D.; Beale, R.J.; Bellinghan, G.J.; Bernard, G.R.; Chiche, J.D.; Coopersmith, C.; De Backer, D.P.; French, C.J.; Fujishima, S.; Gerlach, H.; Hidalgo, J.L.; Hollenberg, S.M.; Jones, A.E.; Karnad, D.R.; Kleinpell, R.M.; Koh, Y.; Lisboa, T.C.; Machado, F.R.; Marini, J.J.; Marshall, J.C.; Mazuski, J.E.; McIntyre, L.A.; McLean, A.S.; Mehta, S.; Moreno, R.P.; Myburgh, J.; Navalesi, P.; Nishida, O.; Osborn, T.M.; Perner, A.; Plunkett, C.M.; Ranieri, M.; Schorr, C.A.; Seckel, M.A.; Seymour, C.W.; Shieh, L.; Shukri, K.A.; Simpson, S.Q.; Singer, M.; Thompson, B.T.; Townsend, S.R.; Van der Poll, T.; Vincent, J.L.; Wiersinga, W.J.; Zimmerman, J.L.; Dellinger, R.P. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med., 2017, 43(3), 304-377.
[http://dx.doi.org/10.1007/s00134-017-4683-6] [PMID: 28101605]
[2]
Oh, T.K.; Park, H.Y.; Han, J.Y.; Song, I.A. Prior benzodiazepine use and mortality among adult patients with sepsis: a retrospective population-based cohort study in South Korea. Int. J. Clin. Pract., 2021, 75(10), e14517.
[http://dx.doi.org/10.1111/ijcp.14517] [PMID: 34133821]
[3]
Rudd, K.E.; Johnson, S.C.; Agesa, K.M.; Shackelford, K.A.; Tsoi, D.; Kievlan, D.R.; Colombara, D.V.; Ikuta, K.S.; Kissoon, N.; Finfer, S.; Fleischmann-Struzek, C.; Machado, F.R.; Reinhart, K.K.; Rowan, K.; Seymour, C.W.; Watson, R.S.; West, T.E.; Marinho, F.; Hay, S.I.; Lozano, R.; Lopez, A.D.; Angus, D.C.; Murray, C.J.L.; Naghavi, M. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet, 2020, 395(10219), 200-211.
[http://dx.doi.org/10.1016/S0140-6736(19)32989-7] [PMID: 31954465]
[4]
Angus, D.C. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med. Soc., 2001, 29(7), 1303-1310.
[http://dx.doi.org/10.1097/00003246-200107000-00002]
[5]
Lewis, R.J.; Viele, K.; Broglio, K.; Berry, S.M.; Jones, A.E. An adaptive, phase II, dose-finding clinical trial design to evaluate L-carnitine in the treatment of septic shock based on efficacy and predictive probability of subsequent phase III success. Crit. Care Med., 2013, 41(7), 1674-1678.
[http://dx.doi.org/10.1097/CCM.0b013e318287f850] [PMID: 23514753]
[6]
Puskarich, M.A.; Evans, C.R.; Karnovsky, A.; Das, A.K.; Jones, A.E.; Stringer, K.A. Septic shock nonsurvivors have persistently elevated acylcarnitines following carnitine supplementation. Shock, 2018, 49(4), 412-419.
[http://dx.doi.org/10.1097/SHK.0000000000000997] [PMID: 29384504]
[7]
Douglas, R.G.; Shaw, J.H. Metabolic response to sepsis and trauma. Br. J. Surg., 1989, 76(2), 115-122.
[http://dx.doi.org/10.1002/bjs.1800760205] [PMID: 2649205]
[8]
Biolo, G.; Toigo, G.; Ciocchi, B.; Situlin, R.; Iscra, F.; Gullo, A.; Guarnieri, G. Metabolic response to injury and sepsis: changes in protein metabolism. Nutrition, 1997, 13(9)(Suppl.), 52S-57S.
[http://dx.doi.org/10.1016/S0899-9007(97)00206-2] [PMID: 9290110]
[9]
Englert, J.A.; Rogers, A.J. Metabolism, metabolomics, and nutritional support of patients with sepsis. Clin. Chest Med., 2016, 37(2), 321-331.
[http://dx.doi.org/10.1016/j.ccm.2016.01.011] [PMID: 27229648]
[10]
Proulx, F.; Lacroix, J.; Farrell, C.A.; Lambert, M. Blood lactate and gastric intramucosal pH during severe sepsis. Crit. Care Med., 1996, 24(6), 1092.
[http://dx.doi.org/10.1097/00003246-199606000-00039] [PMID: 8681582]
[11]
Hatamkhani, S.; Karimzadeh, I.; Elyasi, S.; Farsaie, S.; Khalili, H. Carnitine and sepsis: a review of an old clinical dilemma. J. Pharm. Pharm. Sci., 2013, 16(3), 414-423.
[http://dx.doi.org/10.18433/J3JS4C] [PMID: 24021290]
[12]
Levy, E.; Slusser, R.J.; Ruebner, B.H. Hepatic changes produced by a single dose of endotoxin in the mouse. Electron microscopy. Am. J. Pathol., 1968, 52(2), 477-502.
[PMID: 5639556]
[13]
Träger, K.; DeBacker, D.; Radermacher, P. Metabolic alterations in sepsis and vasoactive drug-related metabolic effects. Curr. Opin. Crit. Care, 2003, 9(4), 271-278.
[http://dx.doi.org/10.1097/00075198-200308000-00004] [PMID: 12883281]
[14]
Jennaro, T.S. Using L-Carnitine as a Pharmacologic Probe of the Interpatient and Metabolic Variability of Sepsis. Pharmacotherapy: J. Human Pharm. Drug Ther., 2020, 40(9), 913-923.
[http://dx.doi.org/10.1002/phar.2448]
[15]
Singer, M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence, 2014, 5(1), 66-72.
[http://dx.doi.org/10.4161/viru.26907] [PMID: 24185508]
[16]
Eaton, S.; Fukumoto, K.; Stefanutti, G.; Spitz, L.; Zammit, V.A.; Pierro, A. Myocardial carnitine palmitoyltransferase I as a target for oxidative modification in inflammation and sepsis. Biochem. Soc. Trans., 2003, 31(Pt 6), 1133-1136.
[http://dx.doi.org/10.1042/bst0311133] [PMID: 14641011]
[17]
Puskarich, M.A.; Kline, J.A.; Krabill, V.; Claremont, H.; Jones, A.E. Preliminary safety and efficacy of L-carnitine infusion for the treatment of vasopressor-dependent septic shock: a randomized control trial. JPEN J. Parenter. Enteral Nutr., 2014, 38(6), 736-743.
[http://dx.doi.org/10.1177/0148607113495414] [PMID: 23851424]
[18]
Johansson, P.I.; Nakahira, K.; Rogers, A.J.; McGeachie, M.J.; Baron, R.M.; Fredenburgh, L.E.; Harrington, J.; Choi, A.M.K.; Christopher, K.B. Plasma mitochondrial DNA and metabolomic alterations in severe critical illness. Crit. Care, 2018, 22(1), 360.
[http://dx.doi.org/10.1186/s13054-018-2275-7] [PMID: 30594224]
[19]
Brealey, D.; Brand, M.; Hargreaves, I.; Heales, S.; Land, J.; Smolenski, R.; Davies, N.A.; Cooper, C.E.; Singer, M. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet, 2002, 360(9328), 219-223.
[http://dx.doi.org/10.1016/S0140-6736(02)09459-X] [PMID: 12133657]
[20]
Carré, J.E.; Orban, J.C.; Re, L.; Felsmann, K.; Iffert, W.; Bauer, M.; Suliman, H.B.; Piantadosi, C.A.; Mayhew, T.M.; Breen, P.; Stotz, M.; Singer, M. Survival in critical illness is associated with early activation of mitochondrial biogenesis. Am. J. Respir. Crit. Care Med., 2010, 182(6), 745-751.
[http://dx.doi.org/10.1164/rccm.201003-0326OC] [PMID: 20538956]
[21]
Reuter, S.E.; Evans, A.M. Carnitine and acylcarnitines: pharmacokinetic, pharmacological and clinical aspects. Clin. Pharmacokinet., 2012, 51(9), 553-572.
[http://dx.doi.org/10.1007/BF03261931] [PMID: 22804748]
[22]
Tanphaichitr, V.; Broquist, H.P. Role of lysine and -N-trimethyllysine in carnitine biosynthesis. II. Studies in the rat. J. Biol. Chem., 1973, 248(6), 2176-2181.
[http://dx.doi.org/10.1016/S0021-9258(19)44202-6] [PMID: 4690599]
[23]
Famularo, G.; De Simone, C.; Trinchieri, V.; Mosca, L. Carnitines and its congeners: a metabolic pathway to the regulation of immune response and inflammation. Ann. N. Y. Acad. Sci., 2004, 1033(1), 132-138.
[http://dx.doi.org/10.1196/annals.1320.012] [PMID: 15591010]
[24]
Flanagan, J.L.; Simmons, P.A.; Vehige, J.; Willcox, M.D.; Garrett, Q. Role of carnitine in disease. Nutr. Metab. (Lond.), 2010, 7(1), 30.
[http://dx.doi.org/10.1186/1743-7075-7-30] [PMID: 20398344]
[25]
Takeyama, N.; Takagi, D.; Matsuo, N.; Kitazawa, Y.; Tanaka, T. Altered hepatic fatty acid metabolism in endotoxicosis: effect of L-carnitine on survival. Am. J. Physiol., 1989, 256(1 Pt 1), E31-E38.
[PMID: 2521428]
[26]
Gasparetto, A.; Corbucci, G.G.; De Blasi, R.A.; Antonelli, M.; Bagiella, E.; D’Iddio, S.; Trevisani, C. Influence of acetyl-L-carnitine infusion on haemodynamic parameters and survival of circulatory-shock patients. Int. J. Clin. Pharmacol. Res., 1991, 11(2), 83-92.
[PMID: 1879992]
[27]
Puskarich, M.A.; Finkel, M.A.; Karnovsky, A.; Jones, A.E.; Trexel, J.; Harris, B.N.; Stringer, K.A. Pharmacometabolomics of l-carnitine treatment response phenotypes in patients with septic shock. Ann. Am. Thorac. Soc., 2015, 12(1), 46-56.
[http://dx.doi.org/10.1513/AnnalsATS.201409-415OC] [PMID: 25496487]
[28]
Famularo, G.; De Simone, C. A new era for carnitine? Immunol. Today, 1995, 16(5), 211-213.
[http://dx.doi.org/10.1016/0167-5699(95)80159-6] [PMID: 7779248]
[29]
Nanni, G.; Pittiruti, M.; Giovannini, I.; Boldrini, G.; Ronconi, P.; Castagneto, M. Plasma carnitine levels and urinary carnitine excretion during sepsis. JPEN J. Parenter. Enteral Nutr., 1985, 9(4), 483-490.
[http://dx.doi.org/10.1177/0148607185009004483] [PMID: 3928925]
[30]
Abdollahi, H. The Effect of L-Carnitine on Mortality Rate in Septic Patients: A Systematic Review and Meta-Analysis on Randomized Clinical Trials. Endoc. Metab. Immune Disorders-Drug Targets (Formerly Current Drug Targets-Immune, Endocrine & Metabolic Disorders), 2021, 21(4), 673-681.
[31]
Levy, M.M.; Evans, L.E.; Rhodes, A. The surviving sepsis campaign bundle: 2018 update. Intensive Care Med., 2018, 44(6), 925-928.
[http://dx.doi.org/10.1007/s00134-018-5085-0] [PMID: 29675566]
[32]
Kaukonen, K-M.; Bailey, M.; Suzuki, S.; Pilcher, D.; Bellomo, R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA, 2014, 311(13), 1308-1316.
[http://dx.doi.org/10.1001/jama.2014.2637] [PMID: 24638143]
[33]
Giacomini, M.G.; Lopes, M.V.; Gandolfi, J.V.; Lobo, S.M. Septic shock: a major cause of hospital death after intensive care unit discharge. Rev. Bras. Ter. Intensiva, 2015, 27(1), 51-56.
[PMID: 25909313]
[34]
Hager, D.N.; Hooper, M.H.; Bernard, G.R.; Busse, L.W.; Ely, E.W.; Fowler, A.A.; Gaieski, D.F.; Hall, A.; Hinson, J.S.; Jackson, J.C.; Kelen, G.D.; Levine, M.; Lindsell, C.J.; Malone, R.E.; McGlothlin, A.; Rothman, R.E.; Viele, K.; Wright, D.W.; Sevransky, J.E.; Martin, G.S. The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) Protocol: a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial. Trials, 2019, 20(1), 197.
[http://dx.doi.org/10.1186/s13063-019-3254-2] [PMID: 30953543]
[35]
Masood, H.; Burki, A.M.; Sultan, A.; Sharif, H.; Ghauri, A.; Khan, S.; Qureshi, M.S.S.; Qadeer, A.; Rasheed, G. Effect of intravenous vitamin C, thiamine, and hydrocortisone (the metabolic resuscitation protocol) on early weaning from vasopressors in patients with septic shock. A descriptive case series study. Cureus, 2019, 11(6), e5016.
[http://dx.doi.org/10.7759/cureus.5016] [PMID: 31497446]
[36]
Berger, M.M.; Shenkin, A. Update on clinical micronutrient supplementation studies in the critically ill. Curr. Opin. Clin. Nutr. Metab. Care, 2006, 9(6), 711-716.
[http://dx.doi.org/10.1097/01.mco.0000247466.41661.ba] [PMID: 17053424]
[37]
Garpestad, E.; Devlin, J.W. Polypharmacy and delirium in critically ill older adults: recognition and prevention. Clin. Geriatr. Med., 2017, 33(2), 189-203.
[http://dx.doi.org/10.1016/j.cger.2017.01.002] [PMID: 28364991]
[38]
Li, S.; Tang, T.; Guo, P.; Zou, Q.; Ao, X.; Hu, L.; Tan, L. A meta-analysis of randomized controlled trials: Efficacy of selenium treatment for sepsis. Medicine (Baltimore), 2019, 98(9), e14733.
[http://dx.doi.org/10.1097/MD.0000000000014733] [PMID: 30817625]
[39]
Kong, L.; Wu, Q.; Liu, B. The impact of selenium administration on severe sepsis or septic shock: a meta-analysis of randomized controlled trials. Afr. Health Sci., 2021, 21(1), 277-285.
[http://dx.doi.org/10.4314/ahs.v21i1.36] [PMID: 34394308]
[40]
Zhao, Y.; Yang, M.; Mao, Z.; Yuan, R.; Wang, L.; Hu, X.; Zhou, F.; Kang, H. The clinical outcomes of selenium supplementation on critically ill patients: a meta-analysis of randomized controlled trials. Medicine (Baltimore), 2019, 98(20), e15473.
[http://dx.doi.org/10.1097/MD.0000000000015473] [PMID: 31096444]
[41]
Allingstrup, M.; Afshari, A. Selenium supplementation for critically ill adults. Cochrane Database System. Rev., 2015, 2015(7), CD003703.
[http://dx.doi.org/10.1002/14651858.CD003703.pub3]
[42]
Manzanares, W.; Lemieux, M.; Elke, G.; Langlois, P.L.; Bloos, F.; Heyland, D.K. High-dose intravenous selenium does not improve clinical outcomes in the critically ill: A systematic review and meta-analysis. Crit. Care, 2016, 20(1), 356.
[http://dx.doi.org/10.1186/s13054-016-1529-5] [PMID: 27788688]
[43]
Lu, C.; Sharma, S.; McIntyre, L.; Rhodes, A.; Evans, L.; Almenawer, S.; Leduc, L.; Angus, D.C.; Alhazzani, W. Omega-3 supplementation in patients with sepsis: a systematic review and meta-analysis of randomized trials. Ann. Intensive Care, 2017, 7(1), 58.
[http://dx.doi.org/10.1186/s13613-017-0282-5] [PMID: 28585162]
[44]
Pradelli, L.; Klek, S.; Mayer, K.; Omar Alsaleh, A.J.; Rosenthal, M.D.; Heller, A.R.; Muscaritoli, M. Omega-3 fatty acid-containing parenteral nutrition in ICU patients: systematic review with meta-analysis and cost-effectiveness analysis. Crit. Care, 2020, 24(1), 634.
[http://dx.doi.org/10.1186/s13054-020-03356-w] [PMID: 33143750]
[45]
Chen, H.; Wang, S.; Zhao, Y.; Luo, Y.; Tong, H.; Su, L. Correlation analysis of omega-3 fatty acids and mortality of sepsis and sepsis-induced ARDS in adults: data from previous randomized controlled trials. Nutr. J., 2018, 17(1), 57.
[http://dx.doi.org/10.1186/s12937-018-0356-8] [PMID: 29859104]
[46]
Colunga Biancatelli, R.M.L.; Berrill, M.; Mohammed, Y.H.; Marik, P.E. Melatonin for the treatment of sepsis: the scientific rationale. J. Thorac. Dis., 2020, 12(Suppl. 1), S54-S65.
[http://dx.doi.org/10.21037/jtd.2019.12.85] [PMID: 32148926]
[47]
Tang, Z.; Wei, Z.; Wen, F.; Wu, Y. Efficacy of zinc supplementation for neonatal sepsis: a systematic review and meta-analysis. J. Matern. Fetal Neonatal Med., 2019, 32(7), 1213-1218.
[http://dx.doi.org/10.1080/14767058.2017.1402001] [PMID: 29103346]
[48]
Rouhani, P.; Rezaei Kelishadi, M.; Saneei, P. Effect of zinc supplementation on mortality in under 5-year children: a systematic review and meta-analysis of randomized clinical trials. Eur. J. Nutr., 2022, 61(1), 37-54.
[PMID: 34120246]
[49]
Cherukuri, L.; Gewirtz, G.; Osea, K.; Tayek, J.A. Vitamin A treatment for severe sepsis in humans; a prospective randomized double blind placebo-controlled clinical trial. Clin. Nutr. ESPEN, 2019, 29, 49-51.
[http://dx.doi.org/10.1016/j.clnesp.2018.10.011] [PMID: 30661700]
[50]
Ponnarmeni, S.; Kumar Angurana, S.; Singhi, S.; Bansal, A.; Dayal, D.; Kaur, R.; Patial, A.; Verma Attri, S. Vitamin D deficiency in critically ill children with sepsis. Paediatr. Int. Child Health, 2016, 36(1), 15-21.
[http://dx.doi.org/10.1179/2046905515Y.0000000042] [PMID: 26120004]
[51]
Keane, C.; Jerkic, M.; Laffey, J.G. Stem cell–based therapies for sepsis. Anesthesiology, 2017, 127(6), 1017-1034.
[http://dx.doi.org/10.1097/ALN.0000000000001882] [PMID: 28872482]
[52]
Zhang, X.; Yang, K.; Chen, L.; Liao, X.; Deng, L.; Chen, S.; Ji, Y. Vitamin A deficiency in critically ill children with sepsis. Crit. Care, 2019, 23(1), 267.
[http://dx.doi.org/10.1186/s13054-019-2548-9] [PMID: 31370866]
[53]
Langlois, P.L.; Szwec, C.; D’Aragon, F.; Heyland, D.K.; Manzanares, W. Vitamin D supplementation in the critically ill: A systematic review and meta-analysis. Clin. Nutr., 2018, 37(4), 1238-1246.
[http://dx.doi.org/10.1016/j.clnu.2017.05.006] [PMID: 28549527]
[54]
Wei, X.B.; Wang, Z.H.; Liao, X.L.; Guo, W.X.; Wen, J.Y.; Qin, T.H.; Wang, S.H. Efficacy of vitamin C in patients with sepsis: an updated meta-analysis. Eur. J. Pharmacol., 2020, 868, 172889.
[http://dx.doi.org/10.1016/j.ejphar.2019.172889] [PMID: 31870831]
[55]
Workneh Bitew, Z.; Worku, T.; Alemu, A. Effects of vitamin D on neonatal sepsis: a systematic review and meta-analysis. Food Sci. Nutr., 2020, 9(1), 375-388.
[http://dx.doi.org/10.1002/fsn3.2003] [PMID: 33473300]
[56]
de Haan, K.; Groeneveld, A.B.; de Geus, H.R.; Egal, M.; Struijs, A. Vitamin D deficiency as a risk factor for infection, sepsis and mortality in the critically ill: systematic review and meta-analysis. Crit. Care, 2014, 18(6), 660.
[http://dx.doi.org/10.1186/s13054-014-0660-4] [PMID: 25475621]
[57]
Upala, S.; Sanguankeo, A.; Permpalung, N. Significant association between vitamin D deficiency and sepsis: a systematic review and meta-analysis. BMC Anesthesiol., 2015, 15(1), 84.
[http://dx.doi.org/10.1186/s12871-015-0063-3] [PMID: 26041306]
[58]
Dang, H.; Li, J.; Liu, C.; Xu, F. The association between vitamin E deficiency and critically Ill children with sepsis and septic shock. Front. Nutr., 2021, 8, 648442.
[http://dx.doi.org/10.3389/fnut.2021.648442] [PMID: 34222298]
[59]
Lewis, E.D.; Meydani, S.N.; Wu, D. Regulatory role of vitamin E in the immune system and inflammation. IUBMB Life, 2019, 71(4), 487-494.
[http://dx.doi.org/10.1002/iub.1976] [PMID: 30501009]
[60]
Kanchanasurakit, S.; Suthumpoung, P.; Santimaleeworagun, W.; Nakaranurack, C.; Huynh, N.S.; Srisawat, C.; Nunta, M.; Chirakan, V.; Saokaew, S. Effectiveness of thiamine therapy in mortality rate in patients with septic shock: A systematic review and meta-analysis. Int. J. Crit. Illn. Inj. Sci., 2021, 11(2), 86-94.
[http://dx.doi.org/10.4103/IJCIIS.IJCIIS_159_20] [PMID: 34395210]
[61]
Fong, K.M.; Au, S.Y.; Ng, G.W.Y. Steroid, ascorbic acid, and thiamine in adults with sepsis and septic shock: a systematic review and component network meta-analysis. Sci. Rep., 2021, 11(1), 15777.
[http://dx.doi.org/10.1038/s41598-021-95386-9] [PMID: 34349184]
[62]
Byerly, S.; Parreco, J.P.; Soe-Lin, H.; Parks, J.J.; Lee, E.E.; Shnaydman, I.; Mantero, A.; Yeh, D.D.; Namias, N.; Rattan, R. Vitamin C and thiamine are associated with lower mortality in sepsis. J. Trauma Acute Care Surg., 2020, 89(1), 111-117.
[http://dx.doi.org/10.1097/TA.0000000000002613] [PMID: 32039973]
[63]
Harun, N.F. Intravenous thiamine as an adjuvant therapy for hyperlactatemia in septic shock patients. Crit. Care Shock, 2019, 22(6)
[64]
Qian, X.; Zhang, Z.; Li, F.; Wu, L. Intravenous thiamine for septic shock: A meta-analysis of randomized controlled trials. Am. J. Emerg. Med., 2020, 38(12), 2718-2722.
[http://dx.doi.org/10.1016/j.ajem.2020.08.050] [PMID: 33036854]
[65]
Toyosawa, T.; Suzuki, M.; Kodama, K.; Araki, S. Highly purified vitamin B2 presents a promising therapeutic strategy for sepsis and septic shock. Infect. Immun., 2004, 72(3), 1820-1823.
[http://dx.doi.org/10.1128/IAI.72.3.1820-1823.2004] [PMID: 14977995]
[66]
Toyosawa, T.; Suzuki, M.; Kodama, K.; Araki, S. Effects of intravenous infusion of highly purified vitamin B2 on lipopolysaccharide-induced shock and bacterial infection in mice. Eur. J. Pharmacol., 2004, 492(2-3), 273-280.
[http://dx.doi.org/10.1016/j.ejphar.2004.04.004] [PMID: 15178375]
[67]
Prauchner, C.A. Oxidative stress in sepsis: Pathophysiological implications justifying antioxidant co-therapy. Burns, 2017, 43(3), 471-485.
[http://dx.doi.org/10.1016/j.burns.2016.09.023] [PMID: 28034666]
[68]
Hong, G.; Zheng, D.; Zhang, L.; Ni, R.; Wang, G.; Fan, G.C.; Lu, Z.; Peng, T. Administration of nicotinamide riboside prevents oxidative stress and organ injury in sepsis. Free Radic. Biol. Med., 2018, 123, 125-137.
[http://dx.doi.org/10.1016/j.freeradbiomed.2018.05.073] [PMID: 29803807]
[69]
Danielski, L.G.; Giustina, A.D.; Goldim, M.P.; Florentino, D.; Mathias, K.; Garbossa, L.; de Bona Schraiber, R.; Laurentino, A.O.M.; Goulart, M.; Michels, M.; de Queiroz, K.B.; Kohlhof, M.; Rezin, G.T.; Fortunato, J.J.; Quevedo, J.; Barichello, T.; Dal-Pizzol, F.; Coimbra, R.S.; Petronilho, F. Vitamin B 6 reduces neurochemical and long-term cognitive alterations after Polymicrobial Sepsis: involvement of the kynurenine pathway modulation. Mol. Neurobiol., 2018, 55(6), 5255-5268.
[http://dx.doi.org/10.1007/s12035-017-0706-0] [PMID: 28879460]
[70]
Vickers, N.J. Animal communication: when i’m calling you, will you answer too? Curr. Biol., 2017, 27(14), R713-R715.
[http://dx.doi.org/10.1016/j.cub.2017.05.064] [PMID: 28743020]
[71]
Tattevin, P.; Monnier, D.; Tribut, O.; Dulong, J.; Bescher, N.; Mourcin, F.; Uhel, F.; Le Tulzo, Y.; Tarte, K. Enhanced indoleamine 2,3-dioxygenase activity in patients with severe sepsis and septic shock. J. Infect. Dis., 2010, 201(6), 956-966.
[http://dx.doi.org/10.1086/650996] [PMID: 20151841]
[72]
Lambden, S.; Creagh-Brown, B.C.; Hunt, J.; Summers, C.; Forni, L.G. Definitions and pathophysiology of vasoplegic shock. Crit. Care, 2018, 22(1), 174.
[http://dx.doi.org/10.1186/s13054-018-2102-1] [PMID: 29980217]
[73]
Patel, J.J.; Venegas-Borsellino, C.; Willoughby, R.; Freed, J.K. High-dose vitamin B12 in vasodilatory shock: a narrative review. Nutr. Clin. Pract., 2019, 34(4), 514-520.
[http://dx.doi.org/10.1002/ncp.10327] [PMID: 31187494]
[74]
Romain, M.; Sviri, S.; Linton, D.M.; Stav, I.; van Heerden, P.V. The role of Vitamin B12 in the critically ill-a review. Anaesth. Intensive Care, 2016, 44(4), 447-452.
[http://dx.doi.org/10.1177/0310057X1604400410] [PMID: 27456173]
[75]
Rigault, C.; Mazué, F.; Bernard, A.; Demarquoy, J.; Le Borgne, F. Changes in l-carnitine content of fish and meat during domestic cooking. Meat Sci., 2008, 78(3), 331-335.
[http://dx.doi.org/10.1016/j.meatsci.2007.06.011] [PMID: 22062286]
[76]
Tein, I.; Bukovac, S.W.; Xie, Z-W. Characterization of the human plasmalemmal carnitine transporter in cultured skin fibroblasts. Arch. Biochem. Biophys., 1996, 329(2), 145-155.
[http://dx.doi.org/10.1006/abbi.1996.0203] [PMID: 8638946]
[77]
Vaz, F.M.; Wanders, R.J. Carnitine biosynthesis in mammals. Biochem. J., 2002, 361(Pt 3), 417-429.
[http://dx.doi.org/10.1042/bj3610417] [PMID: 11802770]
[78]
Durazzo, A.; Lucarini, M.; Nazhand, A.; Souto, S.B.; Silva, A.M.; Severino, P.; Souto, E.B.; Santini, A. The nutraceutical value of carnitine and its use in dietary supplements. Molecules, 2020, 25(9), 2127.
[http://dx.doi.org/10.3390/molecules25092127] [PMID: 32370025]
[79]
Stephens, F.B.; Constantin-Teodosiu, D.; Greenhaff, P.L. New insights concerning the role of carnitine in the regulation of fuel metabolism in skeletal muscle. J. Physiol., 2007, 581(Pt 2), 431-444.
[http://dx.doi.org/10.1113/jphysiol.2006.125799] [PMID: 17331998]
[80]
Rosca, M.G.; Lemieux, H.; Hoppel, C.L. Mitochondria in the elderly: is acetylcarnitine a rejuvenator? Adv. Drug Deliv. Rev., 2009, 61(14), 1332-1342.
[http://dx.doi.org/10.1016/j.addr.2009.06.009] [PMID: 19720100]
[81]
Bersani, G.; Meco, G.; Denaro, A.; Liberati, D.; Colletti, C.; Nicolai, R.; Bersani, F.S.; Koverech, A. L-Acetylcarnitine in dysthymic disorder in elderly patients: a double-blind, multicenter, controlled randomized study vs. fluoxetine. Eur. Neuropsychopharmacol., 2013, 23(10), 1219-1225.
[http://dx.doi.org/10.1016/j.euroneuro.2012.11.013] [PMID: 23428336]
[82]
Karlic, H.; Lohninger, A. Supplementation of L-carnitine in athletes: does it make sense? Nutrition, 2004, 20(7-8), 709-715.
[http://dx.doi.org/10.1016/j.nut.2004.04.003] [PMID: 15212755]
[83]
Orer, G.E.; Guzel, N.A. The effects of acute L-carnitine supplementation on endurance performance of athletes. J. Strength Cond. Res., 2014, 28(2), 514-519.
[http://dx.doi.org/10.1519/JSC.0b013e3182a76790] [PMID: 24263659]
[84]
Colombani, P.; Wenk, C.; Kunz, I.; Krähenbühl, S.; Kuhnt, M.; Arnold, M.; Frey-Rindova, P.; Frey, W.; Langhans, W. Effects of L-carnitine supplementation on physical performance and energy metabolism of endurance-trained athletes: a double-blind crossover field study. Eur. J. Appl. Physiol. Occup. Physiol., 1996, 73(5), 434-439.
[http://dx.doi.org/10.1007/BF00334420] [PMID: 8803503]
[85]
Kraemer, W.J.; Spiering, B.A.; Volek, J.S.; Ratamess, N.A.; Sharman, M.J.; Rubin, M.R.; French, D.N.; Silvestre, R.; Hatfield, D.L.; Van Heest, J.L.; Vingren, J.L.; Judelson, D.A.; Deschenes, M.R.; Maresh, C.M. Androgenic responses to resistance exercise: effects of feeding and L-carnitine. Med. Sci. Sports Exerc., 2006, 38(7), 1288-1296.
[http://dx.doi.org/10.1249/01.mss.0000227314.85728.35] [PMID: 16826026]
[86]
Kraemer, W.J. L-carnitine supplementation: a new paradigm for its role in exercise. Monatshefte für Chemie/Chemical Monthly, 2005, 136(8), 1383-1390.
[http://dx.doi.org/10.1007/s00706-005-0322-y]
[87]
Spiering, B.A.; Kraemer, W.J.; Hatfield, D.L.; Vingren, J.L.; Fragala, M.S.; Ho, J.Y.; Thomas, G.A.; Häkkinen, K.; Volek, J.S. Effects of L-carnitine L-tartrate supplementation on muscle oxygenation responses to resistance exercise. J. Strength Cond. Res., 2008, 22(4), 1130-1135.
[http://dx.doi.org/10.1519/JSC.0b013e31817d48d9] [PMID: 18545197]
[88]
Evans, M.; Guthrie, N.; Pezzullo, J.; Sanli, T.; Fielding, R.A.; Bellamine, A. Efficacy of a novel formulation of L- Carnitine, creatine, and leucine on lean body mass and functional muscle strength in healthy older adults: a randomized, double-blind placebo-controlled study. Nutr. Metab. (Lond.), 2017, 14(1), 7.
[http://dx.doi.org/10.1186/s12986-016-0158-y] [PMID: 28115977]
[89]
Fielding, R.; Riede, L.; Lugo, J.P.; Bellamine, A. L-carnitine supplementation in recovery after exercise. Nutrients, 2018, 10(3), 349.
[http://dx.doi.org/10.3390/nu10030349] [PMID: 29534031]
[90]
Varney, J.L.; Fowler, J.W.; Gilbert, W.C.; Coon, C.N. Utilisation of supplemented l-carnitine for fuel efficiency, as an antioxidant, and for muscle recovery in Labrador retrievers. J. Nutr. Sci., 2017, 6, e8.
[http://dx.doi.org/10.1017/jns.2017.4] [PMID: 28620483]
[91]
Owen, K.Q.; Jit, H.; Maxwell, C.V.; Nelssen, J.L.; Goodband, R.D.; Tokach, M.D.; Tremblay, G.C.; Koo, S.I. Dietary L-carnitine suppresses mitochondrial branched-chain keto acid dehydrogenase activity and enhances protein accretion and carcass characteristics of swine. J. Anim. Sci., 2001, 79(12), 3104-3112.
[http://dx.doi.org/10.2527/2001.79123104x] [PMID: 11811466]
[92]
Calder, P.C.; Carr, A.C.; Gombart, A.F.; Eggersdorfer, M. Reply to “Overstated Claims of Efficacy and Safety. Comment On: Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections. Nutrients 2020, 12, 1181”. Nutrients, 2020, 12(9), 2696.
[http://dx.doi.org/10.3390/nu12092696] [PMID: 32899398]
[93]
Childs, C.E.; Calder, P.C.; Miles, E.A. Diet and immune function; Multidisciplinary Digital Publishing Institute, 2019.
[94]
Alesci, S.; Gerschenson, M.; Ilias, I. L-carnitine, immunomodulation, and human immunodeficiency virus (HIV)-related disorders. Monatshefte für Chemie/Chemical Monthly, 2005, 136(8), 1493-1500.
[95]
Arafa, H.M.; Abd-Allah, A.R.; El-Mahdy, M.A.; Ramadan, L.A.; Hamada, F.M. Immunomodulatory effects of L- carnitine and q10 in mouse spleen exposed to low-frequency high-intensity magnetic field. Toxicology, 2003, 187(2-3), 171-181.
[http://dx.doi.org/10.1016/S0300-483X(03)00050-7] [PMID: 12699906]
[96]
Thangasamy, T.; Subathra, M.; Sittadjody, S.; Jeyakumar, P.; Joyee, A.G.; Mendoza, E.; Chinnakkanu, P. Role of L- carnitine in the modulation of immune response in aged rats. Clin. Chim. Acta, 2008, 389(1-2), 19-24.
[http://dx.doi.org/10.1016/j.cca.2007.11.013] [PMID: 18083121]
[97]
Izgüt-Uysal, V.N.; Agaç, A.; Karadogan, I.; Derin, N. Peritoneal macrophages function modulation by L-carnitine in aging rats. Aging Clin. Exp. Res., 2004, 16(5), 337-341.
[http://dx.doi.org/10.1007/BF03324561] [PMID: 15636457]
[98]
Montecino-Rodriguez, E.; Berent-Maoz, B.; Dorshkind, K. Causes, consequences, and reversal of immune system aging. J. Clin. Invest., 2013, 123(3), 958-965.
[http://dx.doi.org/10.1172/JCI64096] [PMID: 23454758]
[99]
Haghi Aminjan, H.; Abtahi, S.R.; Hazrati, E.; Chamanara, M.; Jalili, M.; Paknejad, B. Targeting of oxidative stress and inflammation through ROS/NF-kappaB pathway in phosphine-induced hepatotoxicity mitigation. Life Sci., 2019, 232, 116607.
[http://dx.doi.org/10.1016/j.lfs.2019.116607] [PMID: 31254582]
[100]
Franceschi, C.; Cossarizza, A.; Troiano, L.; Salati, R.; Monti, D. Immunological parameters in aging: studies on natural immunomodulatory and immunoprotective substances. Int. J. Clin. Pharmacol. Res., 1990, 10(1-2), 53-57.
[PMID: 2387663]
[101]
Hao, J.; Shen, W.; Tian, C.; Liu, Z.; Ren, J.; Luo, C.; Long, J.; Sharman, E.; Liu, J. Mitochondrial nutrients improve immune dysfunction in the type 2 diabetic Goto-Kakizaki rats. J. Cell. Mol. Med., 2009, 13(4), 701-711.
[http://dx.doi.org/10.1111/j.1582-4934.2008.00342.x] [PMID: 18410524]
[102]
Şener, G.; Ekşioğlu-Demiralp, E.; Cetiner, M.; Ercan, F.; Sirvanci, S.; Gedik, N.; Yeğen, B.C. L-Carnitine ameliorates methotrexate-induced oxidative organ injury and inhibits leukocyte death. Cell Biol. Toxicol., 2006, 22(1), 47-60.
[http://dx.doi.org/10.1007/s10565-006-0025-0] [PMID: 16463019]
[103]
Diodato, M.; Chedrawy, E.G. Chedrawy, Coronary artery bypass graft surgery: the past, present, and future of myocardial revascularisation. Surgery Res. Practice, 2014, 2014
[http://dx.doi.org/10.1155/2014/726158]
[104]
Aldemir, M.; Pektaş, M.B.; Parlar, A.İ.; Akcı, Ö.; Emren, S.V.; Tecer, E.; Adalı, F.; Yüksel, Ş.; Darçın, O.T. L-carnitine supplementation reduces short-term neutrophil-lymphocyte ratio in patients undergoing coronary artery bypass grafting. Int. Surg., 2015, 100(7-8), 1160-1168.
[http://dx.doi.org/10.9738/INTSURG-D-15-00071.1] [PMID: 25951165]
[105]
Shankar, K.; Mehendale, H.M. Oxidative stress. Encycl. Toxicol., 2014, 735-737.
[http://dx.doi.org/10.1016/B978-0-12-386454-3.00345-6]
[106]
Aziz, M.A.; Diab, A.S.; Mohammed, A.A. Antioxidant Categories and Mode of Action In: Antioxidants; Intech: UK, 2019.
[http://dx.doi.org/10.5772/intechopen.83544]
[107]
Gülçin, I. Antioxidant and antiradical activities of L-carnitine. Life Sci., 2006, 78(8), 803-811.
[http://dx.doi.org/10.1016/j.lfs.2005.05.103] [PMID: 16253281]
[108]
Kolodziejczyk, J.; Saluk-Juszczak, J.; Wachowicz, B. L- Carnitine protects plasma components against oxidative alterations. Nutrition, 2011, 27(6), 693-699.
[http://dx.doi.org/10.1016/j.nut.2010.06.009] [PMID: 20869209]
[109]
Şener, G.; Paskaloğlu, K.; Satiroglu, H.; Alican, I.; Kaçmaz, A.; Sakarcan, A. L-carnitine ameliorates oxidative damage due to chronic renal failure in rats. J. Cardiovasc. Pharmacol., 2004, 43(5), 698-705.
[http://dx.doi.org/10.1097/00005344-200405000-00013] [PMID: 15071358]
[110]
Al-Eisa, R.A.; Al-Salmi, F.A.; Hamza, R.Z.; El-Shenawy, N.S. Role of L-carnitine in protection against the cardiac oxidative stress induced by aspartame in Wistar albino rats. PLoS One, 2018, 13(11), e0204913.
[http://dx.doi.org/10.1371/journal.pone.0204913] [PMID: 30403670]
[111]
Surai, P.F. Antioxidant action of carnitine: molecular mechanisms and practical applications. EC Vet. Sci., 2015, 2(1), 66-84.
[112]
Li, J-L.; Wang, Q.Y.; Luan, H.Y.; Kang, Z.C.; Wang, C.B. Effects of L-carnitine against oxidative stress in human hepatocytes: involvement of peroxisome proliferator-activated receptor alpha. J. Biomed. Sci., 2012, 19(1), 32.
[http://dx.doi.org/10.1186/1423-0127-19-32] [PMID: 22435679]
[113]
Mohammadi, H.; Djalali, M.; Daneshpazhooh, M.; Honarvar, N.M.; Chams-Davatchi, C.; Sepandar, F.; Fakhri, Z.; Yaghubi, E.; Zarei, M.; Javanbakht, M.H. Effects of L-carnitine supplementation on biomarkers of oxidative stress, antioxidant capacity and lipid profile, in patients with pemphigus vulgaris: a randomized, double-blind, placebo-controlled trial. Eur. J. Clin. Nutr., 2017, 72(1), 99-104.
[http://dx.doi.org/10.1038/ejcn.2017.131] [PMID: 28832573]
[114]
Rajasekar, P.; Anuradha, C.V. Effect of L-carnitine on skeletal muscle lipids and oxidative stress in rats fed high- fructose diet. Experim. Diabet. Res., 2007, 2007
[http://dx.doi.org/10.1155/2007/72741]
[115]
Uysal, N.; Yalaz, G.; Acikgoz, O.; Gonenc, S.; Kayatekin, B.M. Effect of L-carnitine on diabetogenic action of streptozotocin in rats. Neuroendocrinol. Lett., 2005, 26(4), 419-422.
[PMID: 16135998]
[116]
Solarska, K.; Lewińska, A.; Karowicz-Bilińska, A.; Bartosz, G. The antioxidant properties of carnitine in vitro. Cell. Mol. Biol. Lett., 2010, 15(1), 90-97.
[http://dx.doi.org/10.2478/s11658-009-0036-y] [PMID: 19936630]
[117]
Ribas, G.S.; Vargas, C.R.; Wajner, M. L-carnitine supplementation as a potential antioxidant therapy for inherited neurometabolic disorders. Gene, 2014, 533(2), 469-476.
[http://dx.doi.org/10.1016/j.gene.2013.10.017] [PMID: 24148561]
[118]
Fathizadeh, H.; Milajerdi, A.; Reiner, Ž.; Amirani, E.; Asemi, Z.; Mansournia, M.A.; Hallajzadeh, J. The effects of L-carnitine supplementation on indicators of inflammation and oxidative stress: a systematic review and meta-analysis of randomized controlled trials. J. Diabetes Metab. Disord., 2020, 19(2), 1879-1894.
[http://dx.doi.org/10.1007/s40200-020-00627-9] [PMID: 33520867]
[119]
Jing, L.; Zhou, L.J.; Li, W.M.; Zhang, F.M.; Yuan, L.; Li, S.; Song, J.; Sang, Y. Carnitine regulates myocardial metabolism by Peroxisome Proliferator-Activated Receptor-α (PPARalpha) in alcoholic cardiomyopathy. Med. Sci. Monit., 2011, 17(1), BR1-BR9.
[http://dx.doi.org/10.12659/MSM.881311] [PMID: 21169901]
[120]
Broderick, T.L. ATP production and TCA activity are stimulated by propionyl-L-carnitine in the diabetic rat heart. Drugs R D., 2008, 9(2), 83-91.
[http://dx.doi.org/10.2165/00126839-200809020-00003] [PMID: 18298127]
[121]
Felix, C.; Gillis, M.; Driedzic, W.R.; Paulson, D.J.; Broderick, T.L. Effects of propionyl-L-carnitine on isolated mitochondrial function in the reperfused diabetic rat heart. Diabetes Res. Clin. Pract., 2001, 53(1), 17-24.
[http://dx.doi.org/10.1016/S0168-8227(01)00240-6] [PMID: 11378209]
[122]
Calò, L.A.; Pagnin, E.; Davis, P.A.; Semplicini, A.; Nicolai, R.; Calvani, M.; Pessina, A.C. Antioxidant effect of L- carnitine and its short chain esters: relevance for the protection from oxidative stress related cardiovascular damage. Int. J. Cardiol., 2006, 107(1), 54-60.
[http://dx.doi.org/10.1016/j.ijcard.2005.02.053] [PMID: 16337498]
[123]
Calabrese, V.; Scapagnini, G.; Ravagna, A.; Bella, R.; Butterfield, D.A.; Calvani, M.; Pennisi, G.; Giuffrida Stella, A.M. Disruption of thiol homeostasis and nitrosative stress in the cerebrospinal fluid of patients with active multiple sclerosis: evidence for a protective role of acetylcarnitine. Neurochem. Res., 2003, 28(9), 1321-1328.
[http://dx.doi.org/10.1023/A:1024984013069] [PMID: 12938853]
[124]
Genga, K.R.; Russell, J.A. Update of sepsis in the intensive care unit. J. Innate Immun., 2017, 9(5), 441-455.
[http://dx.doi.org/10.1159/000477419] [PMID: 28697503]
[125]
Takashima, H.; Maruyama, T.; Abe, M. Significance of levocarnitine treatment in dialysis patients. Nutrients, 2021, 13(4), 1219.
[http://dx.doi.org/10.3390/nu13041219] [PMID: 33917145]
[126]
Zhou, Z.; Qiu, C.; Chen, C.; Wang, L.; Chen, J.; Chen, M.; Guan, X.; Ouyang, B. Related factor of serum carnitine deficiency and influence of its deficiency on the length of hospital stay in critical ill patients. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue, 2014, 26(12), 890-894.
[PMID: 25476082]
[127]
Oami, T. L-Carnitine in critically ill patients - a case series study. Renal Replacement Ther., 2018, 4(1), 1-8.
[http://dx.doi.org/10.1186/s41100-018-0158-7]
[128]
Wennberg, A.; Hyltander, A.; Sjöberg, A.; Arfvidsson, B.; Sandström, R.; Wickström, I.; Lundholm, K. Prevalence of carnitine depletion in critically ill patients with undernutrition. Metabolism, 1992, 41(2), 165-171.
[http://dx.doi.org/10.1016/0026-0495(92)90146-2] [PMID: 1736038]
[129]
Santiago, M.J.; López-Herce, J.; Urbano, J.; Solana, M.J.; del Castillo, J.; Ballestero, Y.; Botrán, M.; Bellón, J.M. Complications of continuous renal replacement therapy in critically ill children: a prospective observational evaluation study. Crit. Care, 2009, 13(6), R184.
[http://dx.doi.org/10.1186/cc8172] [PMID: 19925648]
[130]
Bonafé, L.; Berger, M.M.; Que, Y.A.; Mechanick, J.I. Carnitine deficiency in chronic critical illness. Curr. Opin. Clin. Nutr. Metab. Care, 2014, 17(2), 200-209.
[http://dx.doi.org/10.1097/MCO.0000000000000037] [PMID: 24500444]
[131]
Rabito, E.I.; Leme, I.A.; Demenice, R.; Portari, G.V.; Jordão, A.A., Jr; dos Santos, J.S.; Marchini, J.S. Lower carnitine plasma values from malnutrition cancer patients. J. Gastrointest. Cancer, 2013, 44(3), 362-365.
[http://dx.doi.org/10.1007/s12029-013-9497-3] [PMID: 23609166]
[132]
Endo, K.; Ueno, T.; Ishikawa, K.; Nakanishi, Y.; Kondo, S.; Wakisaka, N.; Yoshizaki, T. Effects of l-carnitine administration on health-related quality of life during cisplatin-based chemoradiotherapy in patients with head and neck squamous cell carcinoma. Auris Nasus Larynx, 2019, 46(3), 431-436.
[http://dx.doi.org/10.1016/j.anl.2018.10.007] [PMID: 30442437]
[133]
Hooke, M.C. Fatigue, physical performance, and carnitine levels in children and adolescents receiving chemotherapy; University of Minnesota, 2009.
[134]
Iwase, S.; Kawaguchi, T.; Yotsumoto, D.; Doi, T.; Miyara, K.; Odagiri, H.; Kitamura, K.; Ariyoshi, K.; Miyaji, T.; Ishiki, H.; Inoue, K.; Tsutsumi, C.; Sagara, Y.; Yamaguchi, T. Efficacy and safety of an amino acid jelly containing coenzyme Q10 and L-carnitine in controlling fatigue in breast cancer patients receiving chemotherapy: A multi-institutional, randomized, exploratory trial (JORTC- CAM01). Support. Care Cancer, 2016, 24(2), 637-646.
[http://dx.doi.org/10.1007/s00520-015-2824-4] [PMID: 26105516]
[135]
Kraft, M.; Kraft, K.; Gärtner, S.; Mayerle, J.; Simon, P.; Weber, E.; Schütte, K.; Stieler, J.; Koula-Jenik, H.; Holzhauer, P.; Gröber, U.; Engel, G.; Müller, C.; Feng, Y.S.; Aghdassi, A.; Nitsche, C.; Malfertheiner, P.; Patrzyk, M.; Kohlmann, T.; Lerch, M.M. L-Carnitine-supplementation in advanced pancreatic cancer (CARPAN)-a randomized multicentre trial. Nutr. J., 2012, 11(1), 52.
[http://dx.doi.org/10.1186/1475-2891-11-52] [PMID: 22824168]
[136]
Piva, S.; Fagoni, N.; Latronico, N. Intensive care unit-acquired weakness: unanswered questions and targets for future research. F1000 Res., 2019, 8, 8.
[http://dx.doi.org/10.12688/f1000research.17376.1] [PMID: 31069055]
[137]
Saccheri, C.; Morawiec, E.; Delemazure, J.; Mayaux, J.; Dubé, B.P.; Similowski, T.; Demoule, A.; Dres, M. ICU-acquired weakness, diaphragm dysfunction and long-term outcomes of critically ill patients. Ann. Intensive Care, 2020, 10(1), 1.
[http://dx.doi.org/10.1186/s13613-019-0618-4] [PMID: 31900667]
[138]
Judemann, K.; Lunz, D.; Zausig, Y.A.; Graf, B.M.; Zink, W. Intensive care unit-acquired weakness in the critically ill : critical illness polyneuropathy and critical illness myopathy. Anaesthesist, 2011, 60(10), 887-901.
[http://dx.doi.org/10.1007/s00101-011-1951-7] [PMID: 22006117]
[139]
Koukourikos, K.; Tsaloglidou, A.; Kourkouta, L. Muscle atrophy in intensive care unit patients. Acta Inform. Med., 2014, 22(6), 406-410.
[http://dx.doi.org/10.5455/aim.2014.22.406-410] [PMID: 25684851]
[140]
Calò, L.A.; Vertolli, U.; Davis, P.A.; Savica, V. L carnitine in hemodialysis patients. Hemodial. Int., 2012, 16(3), 428-434.
[http://dx.doi.org/10.1111/j.1542-4758.2012.00679.x] [PMID: 22360675]
[141]
Moukas, M. Is muscular mass affected by L-Carnitine levels in critically ill patients? In: Critical Care; Springer, 2000.
[142]
Allard, M.L.; Jeejeebhoy, K.N.; Sole, M.J. The management of conditioned nutritional requirements in heart failure. Heart Fail. Rev., 2006, 11(1), 75-82.
[http://dx.doi.org/10.1007/s10741-006-9195-3] [PMID: 16819580]
[143]
Ferrari, R.; Merli, E.; Cicchitelli, G.; Mele, D.; Fucili, A.; Ceconi, C. Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: a review. Ann. N.Y. Acad. Sci., 2004, 1033(1), 79-91.
[http://dx.doi.org/10.1196/annals.1320.007] [PMID: 15591005]
[144]
Ruggenenti, P.; Cattaneo, D.; Loriga, G.; Ledda, F.; Motterlini, N.; Gherardi, G.; Orisio, S.; Remuzzi, G. Ameliorating hypertension and insulin resistance in subjects at increased cardiovascular risk: effects of acetyl-L-carnitine therapy. Hypertension, 2009, 54(3), 567-574.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.109.132522] [PMID: 19620516]
[145]
Volek, J.S.; Judelson, D.A.; Silvestre, R.; Yamamoto, L.M.; Spiering, B.A.; Hatfield, D.L.; Vingren, J.L.; Quann, E.E.; Anderson, J.M.; Maresh, C.M.; Kraemer, W.J. Effects of carnitine supplementation on flow-mediated dilation and vascular inflammatory responses to a high-fat meal in healthy young adults. Am. J. Cardiol., 2008, 102(10), 1413-1417.
[http://dx.doi.org/10.1016/j.amjcard.2008.07.022] [PMID: 18993165]
[146]
Galloway, S.D.; Craig, T.P.; Cleland, S.J. Effects of oral L-carnitine supplementation on insulin sensitivity indices in response to glucose feeding in lean and overweight/obese males. Amino Acids, 2011, 41(2), 507-515.
[http://dx.doi.org/10.1007/s00726-010-0770-5] [PMID: 20963457]
[147]
Lohninger, A.; Radler, U.; Jinniate, S.; Lohninger, S.; Karlic, H.; Lechner, S.; Mascher, D.; Tammaa, A.; Salzer, H. Relationship between carnitine, fatty acids and insulin resistance. Gynakol. Geburtshilfliche Rundsch., 2009, 49(4), 230-235.
[http://dx.doi.org/10.1159/000301075] [PMID: 20530934]
[148]
Pistone, G.; Marino, A.; Leotta, C.; Dell’Arte, S.; Finocchiaro, G.; Malaguarnera, M. Levocarnitine administration in elderly subjects with rapid muscle fatigue: effect on body composition, lipid profile and fatigue. Drugs Aging, 2003, 20(10), 761-767.
[http://dx.doi.org/10.2165/00002512-200320100-00004] [PMID: 12875611]
[149]
Rahbar, A.R.; Shakerhosseini, R.; Saadat, N.; Taleban, F.; Pordal, A.; Gollestan, B. Effect of L-carnitine on plasma glycemic and lipidemic profile in patients with type II diabetes mellitus. Eur. J. Clin. Nutr., 2005, 59(4), 592-596.
[http://dx.doi.org/10.1038/sj.ejcn.1602109] [PMID: 15741989]
[150]
Spagnoli, A.; Lucca, U.; Menasce, G.; Bandera, L.; Cizza, G.; Forloni, G.; Tettamanti, M.; Frattura, L.; Tiraboschi, P.; Comelli, M. Long-term acetyl-L-carnitine treatment in Alzheimer’s disease. Neurology, 1991, 41(11), 1726-1732.
[http://dx.doi.org/10.1212/WNL.41.11.1726] [PMID: 1944900]
[151]
Freddi, R. Behaviour and Degenerative Changes in the Basal Forebrain Systems of Aged Rats (12 Months Old) after Levo-Acetyl-Carnitine Treatments. J. Behav. Brain Sci., 2012, 2(1), 18-25.
[152]
Winter, B.K.; Fiskum, G.; Gallo, L.L. Effects of L-carnitine on serum triglyceride and cytokine levels in rat models of cachexia and septic shock. Br. J. Cancer, 1995, 72(5), 1173-1179.
[http://dx.doi.org/10.1038/bjc.1995.482] [PMID: 7577464]
[153]
Ercan, U.; Kiraz, A.; Çikman, Ö.; Türkön, H.; Kilinç, N.; Otkun, M.T.; Özkan, Ö.F.; Kiraz, H.A.; Karaayvaz, M. The effect of systemic carnitine administration on colon anastomosis healing in an experimental sepsis model. J. Invest. Surg., 2015, 28(6), 334-340.
[http://dx.doi.org/10.3109/08941939.2015.1029652] [PMID: 26270147]
[154]
Ruggiero, V.; D’Urso, C.M.; Albertoni, C.; Campo, S.; Foresta, P.; Martelli, E.A. LPS-induced serum TNF production and lethality in mice: effect of L-carnitine and some acyl-derivatives. Mediators Inflamm., 1993, 2(7), S43-S50.
[http://dx.doi.org/10.1155/S0962935193000754] [PMID: 18475570]
[155]
Gallo, L.L.; Tian, Y.; Orfalian, Z.; Fiskum, G. Amelioration of popolysaccharide-induced sepsis in rats by free and esterified carnitine. Mediators Inflamm., 1993, 2(7), S51-S56.
[http://dx.doi.org/10.1155/S0962935193000766] [PMID: 18475572]
[156]
Hayashi, N.; Yoshihara, D.; Kashiwabara, N.; Takeshita, Y.; Handa, H.; Yamakawa, M. Effect of carnitine on decrease of branched chain amino acids and glutamine in serum of septic rats. Biol. Pharm. Bull., 1996, 19(1), 157-159.
[http://dx.doi.org/10.1248/bpb.19.157] [PMID: 8820932]
[157]
Linz, D.N.; Garcia, V.F.; Arya, G.; Hug, G.; Tombragel, E.; Landrigan, E.; Chuck, G.; Tsoras, M.; Ryan, M.; Ziegler, M.M. Weanling and adult rats differ in fatty acid and carnitine metabolism during sepsis. J. Pediatr. Surg., 1995, 30(7), 959-965.
[http://dx.doi.org/10.1016/0022-3468(95)90321-6] [PMID: 7472953]
[158]
Yamakawa, M.; Maeda, J.; Nakamura, T.; Mimura, Y.; Sugisaki, K.; Fujita, T.; Hayashi, N.; Kondo, Y.; Oohara, T. Distribution of endogenous and exogenous carnitine in rats with sepsis and acute liver failure. Clin. Nutr., 1996, 15(3), 133-140.
[http://dx.doi.org/10.1016/S0261-5614(96)80038-0] [PMID: 16844016]
[159]
Zambrano, S.; Blanca, A.J.; Ruiz-Armenta, M.V.; Miguel- Carrasco, J.L.; Revilla, E.; Santa-María, C.; Mate, A.; Vázquez, C.M. The renoprotective effect of L-carnitine in hypertensive rats is mediated by modulation of oxidative stress-related gene expression. Eur. J. Nutr., 2013, 52(6), 1649-1659.
[http://dx.doi.org/10.1007/s00394-012-0470-x] [PMID: 23223967]
[160]
Carlsson, M.; Forsberg, E.; Thörne, A. Observations during L-carnitine infusion in two long-term critically ill patients. Clin. Physiol., 1984, 4(4), 363-365.
[http://dx.doi.org/10.1111/j.1475-097X.1984.tb00811.x] [PMID: 6432422]
[161]
Jones, A.E.; Puskarich, M.A.; Shapiro, N.I.; Guirgis, F.W.; Runyon, M.; Adams, J.Y.; Sherwin, R.; Arnold, R.; Roberts, B.W.; Kurz, M.C.; Wang, H.E.; Kline, J.A.; Courtney, D.M.; Trzeciak, S.; Sterling, S.A.; Nandi, U.; Patki, D.; Viele, K. Effect of levocarnitine vs placebo as an adjunctive treatment for septic shock: the Rapid Administration of Carnitine in Sepsis (RACE) randomized clinical trial. JAMA Netw. Open, 2018, 1(8), e186076-e186076.
[http://dx.doi.org/10.1001/jamanetworkopen.2018.6076] [PMID: 30646314]
[162]
Puskarich, M. Pretreatment Acetyl-Carnitine Levels Predict Mortality Benefit from L-Carnitine Treatment in Sepsis: A Pharmacometabolomics Based Clinical Trial Enrichment Strategy In: A103. SEPSIS: TRANSLATIONAL STUDIES; American Thoracic Society, 2020; p. A2604.
[http://dx.doi.org/10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A2604]
[163]
Evans, C.R.; Karnovsky, A.; Puskarich, M.A.; Michailidis, G.; Jones, A.E.; Stringer, K.A. Untargeted metabolomics differentiates L-carnitine treated Septic shock 1-year survivors and nonsurvivors. J. Proteome Res., 2019, 18(5), 2004-2011.
[http://dx.doi.org/10.1021/acs.jproteome.8b00774] [PMID: 30895797]
[164]
Jennaro, T.S.; Puskarich, M.A.; McCann, M.R.; Gillies, C.E.; Pai, M.P.; Karnovsky, A.; Evans, C.R.; Jones, A.E.; Stringer, K.A. Using l-carnitine as a pharmacologic probe of the interpatient and metabolic variability of sepsis. Pharmacotherapy, 2020, 40(9), 913-923.
[http://dx.doi.org/10.1002/phar.2448] [PMID: 32688453]
[165]
Gibault, J.P.; Frey, A.; Guiraud, M.; Schirardin, H.; Bouletreau, P.; Bach, A.C. Effects of L-carnitine infusion on intralipid clearance and utilization. Study carried out in septic patients of an intensive care unit. JPEN J. Parenter. Enteral Nutr., 1988, 12(1), 29-34.
[http://dx.doi.org/10.1177/014860718801200129] [PMID: 3343797]
[166]
Mohammadzadeh, A. Clinical effects of carnitin supplementation on hypoglycemia, apnea and sepsis in very low birth weight neonates. Iran. J. Neonatol, 2011, 2(1), 18-21.
[167]
Li, L.; Wang, F. Effect of L-carnitine injection on platelet and mitochondria of patients with septic shock. J. Pract. Med., 2018, 34(4), 627-629.
[168]
Hogan, P.; Plourde, R.; Fortier, M.; Brindamour, D.; Lagrenade-Verdant, C.; Demers-Marcil, S.; Dupuis, S. Refractory hyperlactatemia after a septic shock in a patient with carnitine deficiency: a case report. J. Pharm. Pract., 2020, 33(1), 113-116.
[http://dx.doi.org/10.1177/0897190018782012] [PMID: 29905091]
[169]
Yahyapoor, F. L-Carnitine Effects on Clinical Status and Mortality Rate in Septic Patients: A Systematic Literature Review. J. Nutri. Fasting Health, 2021, 9(1), 14-22.
[170]
Hill, M.A.; Meininger, G.A. Arteriolar vascular smooth muscle cells: mechanotransducers in a complex environment. Int. J. Biochem. Cell Biol., 2012, 44(9), 1505-1510.
[http://dx.doi.org/10.1016/j.biocel.2012.05.021] [PMID: 22677491]
[171]
Le Gouill, E.; Jimenez, M.; Binnert, C.; Jayet, P.Y.; Thalmann, S.; Nicod, P.; Scherrer, U.; Vollenweider, P. Endothelial nitric oxide synthase (eNOS) knockout mice have defective mitochondrial β-oxidation. Diabetes, 2007, 56(11), 2690-2696.
[http://dx.doi.org/10.2337/db06-1228] [PMID: 17682093]
[172]
Palipoch, S.; Koomhin, P. Oxidative stress-associated pathology: a review. Sains Malays., 2015, 44(10), 1441-1451.
[http://dx.doi.org/10.17576/jsm-2015-4410-09]
[173]
Chiong, M.; Cartes-Saavedra, B.; Norambuena-Soto, I.; Mondaca-Ruff, D.; Morales, P.E.; García-Miguel, M.; Mellado, R. Mitochondrial metabolism and the control of vascular smooth muscle cell proliferation. Front. Cell Dev. Biol., 2014, 2, 72.
[http://dx.doi.org/10.3389/fcell.2014.00072] [PMID: 25566542]
[174]
Salvemini, D.; Cuzzocrea, S. Oxidative stress in septic shock and disseminated intravascular coagulation. Free Radic. Biol. Med., 2002, 33(9), 1173-1185.
[http://dx.doi.org/10.1016/S0891-5849(02)00961-9] [PMID: 12398925]
[175]
Shakeri, A.; Tabibi, H.; Hedayati, M. Effects of L-carnitine supplement on serum inflammatory cytokines, C-reactive protein, lipoprotein (a), and oxidative stress in hemodialysis patients with Lp (a) hyperlipoproteinemia. Hemodial. Int., 2010, 14(4), 498-504.
[http://dx.doi.org/10.1111/j.1542-4758.2010.00476.x] [PMID: 20812958]
[176]
Bilodeau, P.A.; Coyne, E.S.; Wing, S.S. The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation. Am. J. Physiol. Cell Physiol., 2016, 311(3), C392-C403.
[http://dx.doi.org/10.1152/ajpcell.00125.2016] [PMID: 27510905]
[177]
Hnia, K.; Clausen, T.; Moog-Lutz, C. Shaping striated muscles with ubiquitin proteasome system in health and disease. Trends Mol. Med., 2019, 25(9), 760-774.
[http://dx.doi.org/10.1016/j.molmed.2019.05.008] [PMID: 31235369]
[178]
Yamazaki, O.; Hirohama, D.; Ishizawa, K.; Shibata, S. Role of the ubiquitin proteasome system in the regulation of blood pressure: a review. Int. J. Mol. Sci., 2020, 21(15), 5358.
[http://dx.doi.org/10.3390/ijms21155358] [PMID: 32731518]
[179]
Keller, J.; Ringseis, R.; Koc, A.; Lukas, I.; Kluge, H.; Eder, K. Supplementation with l-carnitine downregulates genes of the ubiquitin proteasome system in the skeletal muscle and liver of piglets. Animal, 2012, 6(1), 70-78.
[http://dx.doi.org/10.1017/S1751731111001327] [PMID: 22436156]
[180]
Nagano, K.; Ishida, J.; Unno, M.; Matsukura, T.; Fukamizu, A. Apelin elevates blood pressure in ICR mice with L-NAME-induced endothelial dysfunction. Mol. Med. Rep., 2013, 7(5), 1371-1375.
[http://dx.doi.org/10.3892/mmr.2013.1378] [PMID: 23525196]
[181]
Mughal, A.; O’Rourke, S.T. Vascular effects of apelin: Mechanisms and therapeutic potential. Pharmacol. Ther., 2018, 190, 139-147.
[http://dx.doi.org/10.1016/j.pharmthera.2018.05.013] [PMID: 29807055]
[182]
Rikitake, Y. The apelin/APJ system in the regulation of vascular tone: Friend or foe? J. Biochem., 2021, 169(4), 383-386.
[http://dx.doi.org/10.1093/jb/mvaa129] [PMID: 33169143]
[183]
Ranjbar Kohan, N.; Tabandeh, M.R.; Nazifi, S.; Soleimani, Z. L-carnitine improves metabolic disorders and regulates apelin and apelin receptor genes expression in adipose tissue in diabetic rats. Physiol. Rep., 2020, 8(23), e14641.
[http://dx.doi.org/10.14814/phy2.14641] [PMID: 33278072]
[184]
Ranjbar Kohan, N.; Nazifi, S.; Tabandeh, M.R.; Ansari Lari, M. Effect of l-carnitine supplementation on apelin and apelin receptor (Apj) expression in cardiac muscle of obese diabetic rats. Cell J., 2018, 20(3), 427-434.
[PMID: 29845798]
[185]
Abdul-Razzaka, F.S.; Mohammed, M.J.; Mustafaa, E.M. Synergistic effect of l-carnitine, omega-3 with metformin on the level of apelin-36 and some hormones in rabbits induced with diabetes. Asian J. Microbiol. Biotech., 2019, 21(1), 38-45.
[186]
Council, N.R. Recommended dietary allowances; National Academies Press, 1989.
[187]
Alesci, S. Carnitine: Lessons from one hundred years of research. Ann. N. Y. Acad. Sci., 2004, 1033, ix-xi.
[http://dx.doi.org/10.1196/annals.1320.019]
[188]
Institute of Medicine (US) Subcommittee on Interpretation and Uses of Dietary Reference Intakes; Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. DRI Dietary Reference Intakes: Applications in dietary assessment. 2000.
[189]
Hathcock, J.N.; Shao, A. Risk assessment for carnitine. Regul. Toxicol. Pharmacol., 2006, 46(1), 23-28.
[http://dx.doi.org/10.1016/j.yrtph.2006.06.007] [PMID: 16901595]
[190]
Maurice, E.S. Modern Nutrition in Health and Disease, 9th edition; OkDoKeY, 2019.
[191]
Cho, S.; Park, Y.; Cha, Y. Plasma and urinary carnitine concentrations in pregnant Korean women. FASEB J., 2003.
[192]
Keller, U.; van der Wal, C.; Seliger, G.; Scheler, C.; Röpke, F.; Eder, K. Carnitine status of pregnant women: effect of carnitine supplementation and correlation between iron status and plasma carnitine concentration. Eur. J. Clin. Nutr., 2009, 63(9), 1098-1105.
[http://dx.doi.org/10.1038/ejcn.2009.36] [PMID: 19491916]
[193]
Cruciani, R.A.; Dvorkin, E.; Homel, P.; Malamud, S.; Culliney, B.; Lapin, J.; Portenoy, R.K.; Esteban-Cruciani, N. Safety, tolerability and symptom outcomes associated with L-carnitine supplementation in patients with cancer, fatigue, and carnitine deficiency: a phase I/II study. J. Pain Symptom Manage., 2006, 32(6), 551-559.
[http://dx.doi.org/10.1016/j.jpainsymman.2006.09.001] [PMID: 17157757]
[194]
Rubin, M.R.; Volek, J.S.; Gómez, A.L.; Ratamess, N.A.; French, D.N.; Sharman, M.J.; Kraemer, W.J. Safety measures of L-carnitine L-tartrate supplementation in healthy men. J. Strength Cond. Res., 2001, 15(4), 486-490.
[PMID: 11726261]
[195]
Davani-Davari, D.; Karimzadeh, I.; Sagheb, M.M.; Khalili, H. The renal safety of L-carnitine, L-arginine, and glutamine in athletes and bodybuilders. J. Ren. Nutr., 2019, 29(3), 221-234.
[http://dx.doi.org/10.1053/j.jrn.2018.08.014] [PMID: 30341034]
[196]
Sundar, K.M.; Sires, M. Sepsis induced immunosuppression: Implications for secondary infections and complications. Indian J. Crit. Care Med., 2013, 17(3), 162-169.
[http://dx.doi.org/10.4103/0972-5229.117054] [PMID: 24082613]
[197]
van Gestel, A.; Bakker, J.; Veraart, C.P.; van Hout, B.A. Prevalence and incidence of severe sepsis in Dutch intensive care units. Crit. Care, 2004, 8(4), R153-R162.
[http://dx.doi.org/10.1186/cc2858] [PMID: 15312213]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy