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Hypovolemic Shock

We pioneered studies using low doses of PMZ-2010, which significantly reduced the mortality, decreased blood lactate, and increased mean arterial pressure, pulse pressure and cardiac output in hemorrhagic shock.

We have carried out comparative studies between PMZ-2010 and status quo resuscitative agents grouped into 3 different categories: (a) fluids such as Lactated Ringer’s, hypertonic saline; (b) adrenergic agents such as norepinephrine; and (c) fresh blood. Our results using (i) a rat model of fixed pressure blood loss, (ii) a rabbit model of uncontrolled bleeding with trauma, and (iii) a pig model of massive blood loss, indicate that PMZ-2010 is highly effective in reducing the mortality following hypovolemic shock.

PMZ-2010 acts through a unique mechanism of action that is completely different from any of the existing drugs or investigational products. It is NOT a vasopressor, however, it increases blood pressure and cardiac output by augmenting venous blood return to the heart (alpha2B-adrenergic stimulation), and it enhances tissue perfusion by arterial dilatation (alpha1-adrenergic block). Enhancing tissue perfusion is a significant advantage in reducing the adverse effects of existing vasopressors. Moreover, it does not act on beta-adrenergic receptors, and therefore the risk of arrhythmias is mitigated.

Patents issued in Australia, Japan, India, China and European Union.

Clinical stage – Phase I (CTRI/2014/06/004647) completed; Phase II ongoing (CTRI/2017/03/008184).

Status of Hypovolemic Shock

Product
Pre-Clinical
Clinical

phase 1

phase 2

phase 3

market

Hypovolemic Shock (PMZ-2010)

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Publications

  • Papapanagiotou, P., Xanthos, T., Gulati, A., Chalkias, A., Papalois, A., Kontouli, Z., Alegakis, A., and Iacovidou, N. (2016) Centhaquin improves survival in a swine model of hemorrhagic shock. J Surg Res 200, 227-235
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  • O'Donnell, J. N., O'Donnell, E. P., Kumar, E. J., Lavhale, M. S., Andurkar, S. V., Gulati, A., and Scheetz, M. H. (2016) Pharmacokinetics of centhaquin citrate in a dog model. J Pharm Pharmacol 68, 803-809
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  • O'Donnell, J. N., Gulati, A., Lavhale, M. S., Sharma, S. S., Patel, A. J., Rhodes, N. J., and Scheetz, M. H. (2016) Pharmacokinetics of centhaquin citrate in a rat model. J Pharm Pharmacol 68, 56-62
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  • Gulati, A., Goyal, A. O., and Lavhale, M. S. (2016) Human Pharmacokinetics of Centhaquin Citrate, a Novel Resuscitative Agent. Circulation 134:A16607
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  • Leonard, M., Zhang, Z., Briyal, S., Pais, G., Patel, S., and Gulati, A. (2016) Centhaquin Citrate Improves Cerebral Blood Flow and Reduces Oxidative Stress Following Hemorrhagic Shock in Rats. Circulation 134:A16059
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  • Gulati, A. (2016) Vascular Endothelium and Hypovolemic Shock. Curr Vasc Pharmacol 14, 187-195
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  • Goyal, A. O., Lavhale, M. S., and Gulati, A. (2015) Safety and Efficacy of Centhaquin as a Novel Resuscitative Agent for Hypovolemic Shock. Circulation 132:A17521
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  • Reniguntala, M. S., Lavhale, M. S., Andurkar, S. V., and Gulati, A. (2015) Synthesis and characterization of centhaquin and its citrate salt and a comparative evaluation of their cardiovascular actions. Drug Res (Stuttg) 65, 184-191
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  • Gulati, A., and Lavhale, M. (2014) Repositioning of Centhaquin as a Novel Resuscitative Agent. Basic Clin Pharmacol 115, 43-43
  • Lavhale, M. S., Havalad, S., and Gulati, A. (2013) Resuscitative effect of centhaquin after hemorrhagic shock in rats. J Surg Res 179, 115-124
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  • Gulati, A., Mulloy, N., Zhang, Z., and Pais, G. (2013) Resuscitative efficacy of centhaquin in a rabbit model of uncontrolled hemorrhagic shock. Crit Care Med 534
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  • Gulati, A., Zhang, Z., Murphy, A., and Lavhale, M. S. (2013) Efficacy of centhaquin as a small volume resuscitative agent in severely hemorrhaged rats. Am J Emerg Med 31, 1315-1321
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  • Gulati, A., Pais, G., Mulloy, N., and Zhang, Z. (2013) Effect of Centhaquin Resuscitation on Coagulation in a Rabbit Model of Uncontrolled Hemorrhagic Shock. Clin Pharmacol in Drug Develop 1710539
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  • Pais, G., and Gulati, A. (2012) Effect of Centhaquin on the Coagulation cascade using Thromboelastography (TEG). Crit Care Med 40, 181
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  • Lavhale, M. S., and Gulati, A. (2012) Effect of Centhaquin resuscitation on cardiovascular functions and plasma cytokines of hemorrhaged rats. Clin Pharmacol in Drug Develop 1, 215
  • Lavhale, M. S., and Gulati, A. (2012) Centhaquin resuscitation improves survival of hemorrhaged rats. Indian J Pharmacol 44, S80
  • Gulati, A., Voshtina, E., Zhang, Z., and Murphy, M. (2012) Alpha adrenergic receptors mediate resuscitative effect of Centhaquin in hemorrhaged rats. Crit Care Med 40(12), 587
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  • Gulati, A., Lavhale, M. S., Garcia, D. J., and Havalad, S. (2012) Centhaquin improves resuscitative effect of hypertonic saline in hemorrhaged rats. J Surg Res 178, 415-423
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  • Gulati, A. (2012) Pharmacology and toxicology of centhaquin: A resuscitative agent. The 32nd Annual Conference of Society of Toxicology (STOX), CSIR-Indian Institute of Toxicology Research, Lucknow.
  • Briyal, S., Lavhale, M. S., and Gulati, A. (2012) 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 62, 670-676
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  • Gulati, A., Zhang, Z., and Arshad, K. (2011) Centhaquin Decreases the Requirement of Norepinephrine, Maintains Blood Pressure and Improves Survival Following Resuscitation of Hemorrhaged Rats. Crit Care Med 39, 114
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  • Tolentino, S., Havalad, S., Gulati, A., and Lavhale, M. (2011) Role of Centhaquin in the Resuscitation of Hemorrhagic Shock. Chest 140, 318A
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  • Gulati, A., Lavhale, M. S., and Havalad, S. (2011) Role of centhaquin in the resuscitation of hemorrhagic shock. J Clin Pharmacol 51, 1349-1349
  • Gulati, A., Hussain, G., and Srimal, R. C. (1991) 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 Develop Res 23, 307-323
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  • Srimal, R. C., Gulati, K., Nityanand, S., and Dhawan, B. N. (1990) Pharmacological studies on 2-(2-(4-(3-methylphenyl)-1-piperazinyl)ethyl) quinoline (centhaquin). I. Hypotensive activity. Pharmacol Res 22, 319-329
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