Resuscitative Effect of Centhaquine (Lyfaquin®) in Hypovolemic Shock Patients: A Randomized, Multicentric, Controlled Trial

Gulati, Anil; Jain, Deepak; Agrawal, Nilesh; Choudhuri, Rajat; Das, Sudipta; Dhibar, Deba Prasad; Prabhu, Madhav; Haveri, Sameer; Agarwal, Rohit; Lavhale, Manish S

doi:10.1007/s12325-021-01760-4

Cited by 10 publications

(12 citation statements)

References 47 publications

(69 reference statements)

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“…The results from this randomized multicenter trial suggest that centhaquine is an effective resuscitative agent for hypovolemic shock. Its resuscitative action is based upon stimulation of venous α 2B adrenergic receptors to produce constriction and increase venous return to the heart, cardiac preload, cardiac output, and tissue perfusion [ 34 , 37 , 42 ]. It has no beta-adrenergic activity, mitigating the risk of arrhythmias.…”

Section: Discussionmentioning

confidence: 99%

“…This was a prospective, multicenter, randomized, placebo-controlled, double-blinded phase III clinical study of centhaquine in patients with hypovolemic shock receiving the best SOC. Centhaquine was found to be efficacious in a phase II study, with statistically significant improvements in blood lactate levels ( p = 0.0012), base deficit ( p < 0.0001), and blood pressure ( p < 0.0001) and a trend towards reduced mortality [ 34 ]. Therefore, in consultation and agreement with regulatory authorities, patients were randomized in a 2:1 ratio either to receive centhaquine 0.01 mg/kg by intravenous infusion along with SOC or to receive SOC plus saline.…”

Section: Methodsmentioning

confidence: 99%

“…The sample size was calculated according to the results of our phase II trial (CTRI/2017/03/008184, NCT04056065) [ 34 ]. In the phase II study, SBP in the centhaquine group improved from 87.3 mmHg at baseline to 121.4 mmHg (39.5% increase) at 48 h of resuscitation, whereas, in the control group, SBP improved from 90.4 mmHg at baseline to 108.8 mmHg (25.4% increase) at 48 h of resuscitation.…”

Section: Methodsmentioning

confidence: 99%

“…Stimulation of α 2B adrenergic receptors, located on the smooth muscle cells [ 32 ], produced dose-dependent constriction of human veins [ 33 ]. Centhaquine is a novel first-in-class resuscitative agent that acts on α 2B adrenergic receptors to produce venous constriction and increase venous return to the heart, resulting in increased cardiac output [ 34 , 35 ]. It also has little action on α 2A adrenergic receptors to reduce sympathetic drive and decrease systemic vascular resistance [ 36 ], contributing to improved tissue blood perfusion.…”

Section: Introductionmentioning

confidence: 99%

“…The safety and efficacy of centhaquine were evaluated extensively in preclinical models [ 37 – 41 ], healthy volunteers [ 42 ], and patients [ 34 ]. Centhaquine was safe and effective in a phase II study and significantly improved blood lactate levels, base deficit, and blood pressure [ 34 , 42 ]. Based on these highly encouraging data, we undertook a phase III study, the results of which are described here.…”

Section: Introductionmentioning

confidence: 99%

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A Multicentric, Randomized, Controlled Phase III Study of Centhaquine (Lyfaquin®) as a Resuscitative Agent in Hypovolemic Shock Patients

Gulati¹,

Choudhuri

Gupta³

et al. 2021

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Introduction Centhaquine (Lyfaquin ® ) showed significant safety and efficacy in preclinical and clinical phase I and II studies. Methods A prospective, multicentric, randomized phase III study was conducted in patients with hypovolemic shock, systolic blood pressure (SBP) ≤ 90 mmHg, and blood lactate levels ≥ 2 mmol/L. Patients were randomized in a 2:1 ratio to the centhaquine group ( n = 71) or the control (saline) group ( n = 34). Every patient received standard of care (SOC) and was followed for 28 days. The study drug (normal saline or centhaquine 0.01 mg/kg) was administered in 100 mL of normal saline infusion over 1 h. The primary objectives were to determine changes (mean through 48 h) in SBP, diastolic blood pressure (DBP), blood lactate levels, and base deficit. The secondary objectives included the amount of fluids, blood products, and vasopressors administered in the first 48 h, duration of hospital stay, time in intensive care units, time on ventilator support, change in acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), and the proportion of patients with 28-day all-cause mortality. Results The demographics of patients and baseline vitals in both groups were comparable. The cause of hypovolemic shock was trauma in 29.4 and 47.1% of control group and centhaquine group patients, respectively, and gastroenteritis in 44.1 and 29.4%, respectively. Shock index (SI) and quick sequential organ failure assessment at baseline were similar in the two groups. An equal amount of fluids and blood products were administered in both groups during the first 48 h of resuscitation. A lesser amount of vasopressors was needed in the first 48 h of resuscitation in the centhaquine group. An increase in SBP from baseline was consistently higher up to 48 h (12.9% increase in area under the curve from 0 to 48 h [AUC 0–48 ]) in the centhaquine group than in the control group. A significant increase in pulse pressure (48.1% increase in AUC 0–48 ) in the centhaquine group compared with the control group suggests improved stroke volume due to centhaquine. The SI was significantly lower in the centhaquine group from 1 h ( p = 0.032) to 4 h ( p = 0.049) of resuscitation. Resuscitation with centhaquine resulted in a significantly greater number of patients with improved blood lactate (control 46.9%; centhaquine 69.3%; p = 0.03) and the base deficit (control 43.7%; centhaquine 69.8%; p = 0.01) than in the control group. ARDS and MODS improved with centhaquine, and an 8.8% absolute reduction in 28-day all-cause mortality was observed in the centhaquine group. Conclusion Centhaquine is an efficacious resuscitative agent for treating hypovolemic shock. The e...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Multicentric, Randomized, Controlled Phase III Study of Centhaquine (Lyfaquin®) as a Resuscitative Agent in Hypovolemic Shock Patients

Gulati¹,

Choudhuri

Gupta³

et al. 2021

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Synthetic Approaches to the New Drugs Approved During 2020

et al. 2022

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New drugs introduced to the market are privileged structures that have affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody–drug conjugates (ADCs), provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This Review is part of a continuing series presenting the most likely process-scale synthetic approaches to 44 new chemical entities approved for the first time anywhere in the world during 2020.

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A multicentric, randomized, controlled phase III study of centhaquine (Lyfaquin^®) as a resuscitative agent in hypovolemic shock patients

Gulati

Choudhuri

Gupta

et al. 2020

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Centhaquine is a novel, first-in-class resuscitative agent for the treatment of hypovolemic shock. Efficacy of centhaquine for the treatment of hypovolemic shock as an adjuvant to standard of care (SOC) was evaluated in a prospective, multi-center, randomized, double-blind, placebo-controlled Phase 3 study. Key inclusion criteria were; systolic blood pressure of ≤90 mm Hg, blood lactate levels of ≥2 mmol/L and patients receiving SOC in a hospital or ICU setting. Patients were randomized in a 2:1 ratio either to the centhaquine group receiving centhaquine dose of 0.01 mg/kg by IV infusion along with SOC or to the control group receiving SOC plus saline. Primary endpoints of the study were change in systolic blood pressure (SBP) and diastolic blood pressure (DBP), change in blood lactate levels and change in base deficit. Mortality through day 28 was the key secondary endpoint. A total of 197 patients were screened, of which 105 patients met the eligibility criteria and were included in the study. Out of 105 patients, 71 patients were randomized to centhaquine group and 34 patients to control group. Demographics and baseline characteristics of patients in both groups was comparable. Hemoglobin level was 9.38 ± 0.71 g/dL and 8.73 ± 0.55 g/dL in control and centhaquine groups, respectively at the time of inclusion in the study. At 24 hours of resuscitation, SBP of more than 110 mmHg was in 59.38% patients of control and 81.82% patients of centhaquine group (P=0.00842). Similarly, at 24 hours of resuscitation, DBP of more than 70 mmHg was in 50.00% patients in control group and 78.46% patients in centhaquine group (P=0.002175). The number of patients with blood lactate levels of 1.5 mmol/L or less were 46.88% in the group with standard treatment compared to 69.35% in centhaquine group (P=0.0168). The number of patients with base-deficit of less than minus 2 were 46.88% in standard treatment group compared to 68.25% in those receiving centhaquine (P=0.0217). Centhaquine treatment significantly reduced 28-day all-cause mortality. In the control group, the mortality rate was 11.76% compared to 2.94% in the centhaquine group (odds ratio: 4.4; 95% CI 0.9651 to 23.74 and P=0.037). No drug related adverse event was reported. Centhaquine (Lyfaquin®) is a highly efficacious resuscitative agent for the treatment of hypovolemic shock as an adjuvant to SOC. The study protocol (PMZ-2010/CT-3.1/2018) was approved by the Drug Controller General of India (DCGI), Ministry of Health and Family Welfare, Government of India and Institutional Ethics Committee of all the 14 Institutions.

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Resuscitative Effect of Centhaquine (Lyfaquin®) in Hypovolemic Shock Patients: A Randomized, Multicentric, Controlled Trial

Cited by 10 publications

References 47 publications

A Multicentric, Randomized, Controlled Phase III Study of Centhaquine (Lyfaquin®) as a Resuscitative Agent in Hypovolemic Shock Patients

A Multicentric, Randomized, Controlled Phase III Study of Centhaquine (Lyfaquin®) as a Resuscitative Agent in Hypovolemic Shock Patients

Synthetic Approaches to the New Drugs Approved During 2020

A multicentric, randomized, controlled phase III study of centhaquine (Lyfaquin^®) as a resuscitative agent in hypovolemic shock patients

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Resuscitative Effect of Centhaquine (Lyfaquin®) in Hypovolemic Shock Patients: A Randomized, Multicentric, Controlled Trial

Cited by 10 publications

References 47 publications

A Multicentric, Randomized, Controlled Phase III Study of Centhaquine (Lyfaquin®) as a Resuscitative Agent in Hypovolemic Shock Patients

A Multicentric, Randomized, Controlled Phase III Study of Centhaquine (Lyfaquin®) as a Resuscitative Agent in Hypovolemic Shock Patients

Synthetic Approaches to the New Drugs Approved During 2020

A multicentric, randomized, controlled phase III study of centhaquine (Lyfaquin®) as a resuscitative agent in hypovolemic shock patients

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A multicentric, randomized, controlled phase III study of centhaquine (Lyfaquin^®) as a resuscitative agent in hypovolemic shock patients