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CNS & Neurological Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Mini-Review Article

Evolutionary Unmasking Resuscitative Therapeutics Potential of Centhaquin Citrate in Hypovolemic Shock

Author(s): Ravinder Singh, Varinder Singh, Pratima Kumari, Namita Aggarwal, Muskaan Oberoi, Heena Khan and Thakur Gurjeet Singh*

Volume 23, Issue 7, 2024

Published on: 22 August, 2023

Page: [812 - 818] Pages: 7

DOI: 10.2174/1871527322666230623113013

Price: $65

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Abstract

Hypovolemic shock (HS), a clinical condition of insufficient blood perfusion and oxygenation in body tissues, is associated with immense morbidity and mortality. Treatment approaches include fluid replacement and surgical repair of reversible causes of hemorrhage; however, they cause irreversible blood perfusion loss, systemic inflammation, multiple organ failure, and death. Centhaquin citrate (CC) is an innovative centrally acting cardiovascular active agent that is initially intended as an antihypertensive drug. However, due to its positive ionotropic effect, Centhaquin citrate is being tested clinically as a resuscitative agent for the management of hypovolemic shock It acts at the α2B-adrenergic receptor to produce venous constriction followed by an increase in venous return to the heart. These actions are assumed to be capable of resuscitative activity observed by centhaquin citrate, through an increase in cardiac output and tissue perfusion. Pharmacokinetics investigations in animals and humans have shown that centhaquin citrate is well tolerated and has insignificant side effects. Therefore, centhaquin citrate seems to be a promising entity and gaining the interest of researchers to develop it as a resuscitative agent in HS. The review gives insight into the development of centhaquin citrate as a resuscitative agent and provides insight into the associated mechanism of action and molecular signalling to foster future research on CC for its clinical use in HS.

Keywords: Centhaquin, hemorrhagic shock, cardiac output, blood lactate, resuscitation agent, HIF pathway.

Graphical Abstract
[1]
Gulati A, Choudhuri R, Gupta A, et al. A multicentric, randomized, controlled phase III study of centhaquine (Lyfaquin®) as a resuscitative agent in hypovolemic shock patients. Drugs 2021; 81(9): 1079-100.
[http://dx.doi.org/10.1007/s40265-021-01547-5] [PMID: 34061314]
[2]
Prabhakar NK, Khan H, Grewal AK, Singh TG. Intervention of neuroinflammation in the traumatic brain injury trajectory: In vivo and clinical approaches. Int Immunopharmacol 2022; 108: 108902.
[http://dx.doi.org/10.1016/j.intimp.2022.108902] [PMID: 35729835]
[3]
Kobayashi L, Costantini TW, Coimbra R. Hypovolemic shock resuscitation. Surg Clin North Am 2012; 92(6): 1403-23.
[http://dx.doi.org/10.1016/j.suc.2012.08.006] [PMID: 23153876]
[4]
Gould SA, Sehgal LR, Sehgal HL, Moss GS. Hypovolemic shock. Crit Care Clin 1993; 9(2): 239-59.
[http://dx.doi.org/10.1016/S0749-0704(18)30195-7] [PMID: 8490762]
[5]
Lavhale MS, Havalad S, Gulati A. Resuscitative effect of centhaquin after hemorrhagic shock in rats. J Surg Res 2013; 179(1): 115-24.
[http://dx.doi.org/10.1016/j.jss.2012.08.042] [PMID: 22964270]
[6]
O’Donnell JN, O’Donnell EP, Kumar EJ, et al. Pharmacokinetics of centhaquin citrate in a dog model. J Pharm Pharmacol 2016; 68(6): 803-9.
[http://dx.doi.org/10.1111/jphp.12554] [PMID: 27109141]
[7]
Papapanagiotou P, Xanthos T, Gulati A, et al. Centhaquin improves survival in a swine model of hemorrhagic shock. J Surg Res 2016; 200(1): 227-35.
[http://dx.doi.org/10.1016/j.jss.2015.06.056] [PMID: 26216751]
[8]
Murti A, Bhandari K, Ram S, et al. ChemInform Abstract: Synthesis and QSAR of 1-Aryl-4-(β-2-quinolyl/1-isoquinolylethyl)piperazines and some related compounds as hypotensive agents. ChemInform 1990; 21(9)
[http://dx.doi.org/10.1002/chin.199009348]
[9]
Carpy AL, Saxena AK. Structure of 1-(3-methylphenyl)-4-(2-β-quinolylethyl) piperazine: Centhaquin. Acta Crystallogr C Struct 1991; 47(1): 227-9.
[http://dx.doi.org/10.1107/S0108270190007211]
[10]
Srimal RC, Mason DF, Dhawan BN. Studies on 2-(2-(4-(3-methylphenyl) 1-piperazinyl) ethyl quinoline (centhaquin), a centrally acting antihypertensive. II, Effect on cardiohaemodynamics. Asian Pac J 1990; 5(3): 185-90.
[http://dx.doi.org/10.1016/1043-6618(90)90729-W]
[11]
Gaur SP, Puri VN, Asthana OP. Effect of centhaquin on renal functions of normal human subjects. Indian J Chem 1995; 27: 56.
[12]
Srimal RC, Gulati K, Nityanand S, Dhawan BN. Pharmacological studies on 2-(2-(4-(3-methylphenyl)-1-piperazinyl)ethyl) quinoline (centhaquin). I. hypotensive activity. Pharmacol Res 1990; 22(3): 319-29. [b
[13]
Gulati A, Hussain G, Srimal RC. Effect of repeated administration of centhaquin, a centrally acting hypotensive drug, on adrenergic, cholinergic (muscarinic), dopaminergic, and serotonergic receptors in brain regions of rat. Drug Dev Res 1991; 23(4): 307-23.
[http://dx.doi.org/10.1002/ddr.430230404]
[14]
Briyal S, Lavhale M, Gulati A. Repeated administration of centhaquin to pregnant rats did not affect postnatal development and expression of endothelin receptors in the brain, heart or kidney of pups. Arzneimittelforschung 2012; 62(12): 670-6.
[http://dx.doi.org/10.1055/s-0032-1329985] [PMID: 23154885]
[15]
Briyal S, Gandhakwala R, Khan M, Lavhale MS, Gulati A. Alterations in endothelin receptors following hemorrhage and resuscitation by centhaquin. Physiol Res 2018; 67(S1): S199-214.
[http://dx.doi.org/10.33549/physiolres.933856] [PMID: 29947540]
[16]
Khan H, Kashyap A, Kaur A, Singh TG. Pharmacological postconditioning: A molecular aspect in ischemic injury. J Pharm Pharmacol 2020; 72(11): 1513-27.
[http://dx.doi.org/10.1111/jphp.13336] [PMID: 33460133]
[17]
Gulati A, Pais G, Mulloy N, Zhang Z. Resuscitative efficacy of centhaquin in a rabbit model of uncontrolled hemorrhagic shock with tissue injury. Crit Care Med 2013; 41(12): A130-1.
[http://dx.doi.org/10.1097/01.ccm.0000439677.20938.e9]
[18]
Gulati A, Jain D, Agrawal NR, et al. Resuscitative effect of centhaquine (Lyfaquin®) in hypovolemic shock patients: A randomized, multicentric, controlled trial. Adv Ther 2021; 38(6): 3223-65.
[http://dx.doi.org/10.1007/s12325-021-01760-4] [PMID: 33970455]
[19]
Gulati A, Lavhale MS, Garcia DJ, Havalad S. Centhaquin improves resuscitative effect of hypertonic saline in hemorrhaged rats. J Surg Res 2012; 178(1): 415-23.
[http://dx.doi.org/10.1016/j.jss.2012.02.005] [PMID: 22487389]
[20]
Safar ME, Levy BI, Struijker-Boudier H. Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases. Circulation 2003; 107(22): 2864-9.
[http://dx.doi.org/10.1161/01.CIR.0000069826.36125.B4]
[21]
Sheng Y, Zhu L. The crosstalk between autonomic nervous system and blood vessels. Int J Physiol Pathophysiol Pharmacol 2018; 10(1): 17-28.
[PMID: 29593847]
[22]
Bonanno F. Physiopathology of shock. J Emerg Trauma Shock 2011; 4(2): 222-32.
[http://dx.doi.org/10.4103/0974-2700.82210] [PMID: 21769210]
[23]
Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 1990; 348(6303): 730-2.
[http://dx.doi.org/10.1038/348730a0] [PMID: 2175396]
[24]
Goto K, Kasuya Y, Matsuki N, et al. Endothelin activates the dihydropyridine-sensitive, voltage-dependent Ca2+ channel in vascular smooth muscle. Proc Natl Acad Sci 1989; 86(10): 3915-8.
[http://dx.doi.org/10.1073/pnas.86.10.3915] [PMID: 2542956]
[25]
Gulati A, Srimal RC. Endothelin antagonizes the hypotension and potentiates the hypertension induced by clonidine. Eur J Pharmacol 1993; 230(3): 293-300.
[http://dx.doi.org/10.1016/0014-2999(93)90564-X] [PMID: 8440307]
[26]
Sandoo A, Veldhuijzen van Zanten JJCS, Metsios GS, Carroll D, Kitas GD. The endothelium and its role in regulating vascular tone. Open Cardiovasc Med J 2010; 4(1): 302-12.
[http://dx.doi.org/10.2174/1874192401004010302] [PMID: 21339899]
[27]
Bourque SL, Davidge ST, Adams MA. The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives. Am J Physiol Regul Integr Comp Physiol 2011; 300(6): R1288-95.
[http://dx.doi.org/10.1152/ajpregu.00397.2010] [PMID: 21368267]
[28]
Chaudry IH, Ayala A, Ertel W, Stephan RN. Hemorrhage and resuscitation: Immunological aspects. Am J Physiol Regul Integr Comp Physiol 1990; 259(4): R663-78.
[http://dx.doi.org/10.1152/ajpregu.1990.259.4.R663] [PMID: 2145776]
[29]
Kowalczyk A, Kleniewska P, Kolodziejczyk M, Skibska B, Goraca A. The role of endothelin-1 and endothelin receptor antagonists in inflammatory response and sepsis. Arch Immunol Ther Exp 2015; 63(1): 41-52.
[http://dx.doi.org/10.1007/s00005-014-0310-1] [PMID: 25288367]
[30]
Gulati A, Singh R, Chung SM, Sen AP. Role of endothelin-converting enzyme in the systemic hemodynamics and regional circulatory effects of proendothelin-1 (1-38) and diaspirin cross-linked hemoglobin in rats. J Lab Clin Med 1995; 126(6): 559-70.
[PMID: 7490515]
[31]
Holmquist-Mengelbier L, Fredlund E, Löfstedt T, et al. Recruitment of HIF-1α and HIF-2α to common target genes is differentially regulated in neuroblastoma: HIF-2α promotes an aggressive phenotype. Cancer Cell 2006; 10(5): 413-23.
[http://dx.doi.org/10.1016/j.ccr.2006.08.026] [PMID: 17097563]
[32]
Nissanka N, Moraes CT. Mitochondrial DNA damage and reactive oxygen species in neurodegenerative disease. FEBS Lett 2018; 592(5): 728-42.
[http://dx.doi.org/10.1002/1873-3468.12956] [PMID: 29281123]
[33]
Ranjan AK, Zhang Z, Briyal S, Gulati A. Centhaquine restores renal blood flow and protects tissue damage after hemorrhagic shock and renal ischemia. Front Pharmacol 2021; 12: 616253.
[http://dx.doi.org/10.3389/fphar.2021.616253] [PMID: 34012389]
[34]
Ahmed SMU, Luo L, Namani A, Wang XJ, Tang X. Nrf2 signaling pathway: Pivotal roles in inflammation. Biochim Biophys Acta Mol Basis Dis 2017; 1863(2): 585-97.
[http://dx.doi.org/10.1016/j.bbadis.2016.11.005] [PMID: 27825853]
[35]
Breuiller-Fouché M, Moriniere C, Dallot E, et al. Regulation of the endothelin/endothelin receptor system by interleukin-1β in human myometrial cells. Endocrinology 2005; 146(11): 4878-86.
[http://dx.doi.org/10.1210/en.2005-0250]
[36]
Kim JY, Kawabori M, Yenari MA. Innate inflammatory responses in stroke: Mechanisms and potential therapeutic targets. Curr Med Chem 2014; 21(18): 2076-97.
[http://dx.doi.org/10.2174/0929867321666131228205146] [PMID: 24372209]
[37]
Khan H, Grewal AK. kumar M, Singh TG. Pharmacological postconditioning by protocatechuic acid attenuates brain injury in ischemia-reperfusion (I/R) mice model: Implications of nuclear factor erythroid-2-related factor pathway. Neuroscience 2022; 491: 23-31.
[http://dx.doi.org/10.1016/j.neuroscience.2022.03.016] [PMID: 35314251]
[38]
Khan H, Bangar A, Grewal AK, Bansal P, Singh TG. Caspase-mediated regulation of the distinct signaling pathways and mechanisms in neuronal survival. Int Immunopharmacol 2022; 110: 108951.
[http://dx.doi.org/10.1016/j.intimp.2022.108951] [PMID: 35717837]
[39]
Rani R, Kumar A, Jaggi AS, Singh N. Pharmacological investigations on efficacy of Phlorizin a sodium-glucose co-transporter (SGLT) inhibitor in mouse model of intracerebroventricular streptozotocin induced dementia of AD type. J Basic Clin Physiol Pharmacol 2021; 32(6): 1057-64.
[http://dx.doi.org/10.1515/jbcpp-2020-0330] [PMID: 33548170]
[40]
Chadha S, Behl T, Kumar A, Khullar G, Arora S. Role of Nrf2 in rheumatoid arthritis. Curr Res Transl Med 2020; 68(4): 171-81.
[http://dx.doi.org/10.1016/j.retram.2020.05.002] [PMID: 32620467]
[41]
Grewal AS, Thapa K, Bansal A, Deepshikha N, Sharma N, Singh S. Therapeutic role of nuclear factor erythroid-2 related factor 2 (Nrf2) in liver disorders. Res J Pharm Technol 2020; 13(8): 3952-6.
[http://dx.doi.org/10.5958/0974-360X.2020.00699.X]
[42]
Boiko DI, Shkodina AD, Hasan MM, et al. Melatonergic receptors (Mt1/Mt2) as a potential additional target of novel drugs for depression. Neurochem Res 2022; 47(10): 2909-24.
[http://dx.doi.org/10.1007/s11064-022-03646-5] [PMID: 35689787]

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