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

Abstract

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...

Role of adrenergic receptors in shock

“…A significantly greater number of patients had improved base deficit in CQ than the control group. Also, an 8.8% absolute reduction in 28-day all-cause mortality was observed in the CQ group along with improved acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS) scores ( Gulati et al, 2019 ; Gulati et al, 2020 ; Gulati et al, 2021a ; Gulati et al, 2021b ). The meta-analysis of the mortality data obtained from our phase II and III studies found that mortality was 10.71% in the control group ( N = 56) and 2.20% in the CQ group ( N = 91) ( p = 0.03), which indicated statistically significant reduction in mortality in CQ group ( Gulati et al, 2021a ).…”

“…Also, an 8.8% absolute reduction in 28-day all-cause mortality was observed in the CQ group along with improved acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS) scores ( Gulati et al, 2019 ; Gulati et al, 2020 ; Gulati et al, 2021a ; Gulati et al, 2021b ). The meta-analysis of the mortality data obtained from our phase II and III studies found that mortality was 10.71% in the control group ( N = 56) and 2.20% in the CQ group ( N = 91) ( p = 0.03), which indicated statistically significant reduction in mortality in CQ group ( Gulati et al, 2021a ). Based on these successful clinical trials Pharmazz Inc. has obtained marketing authorization to sell CQ as a drug (Lyfaquin ® ) for hypovolemic/hemorrhagic shock in India ( Gulati et al, 2020 ; Gulati et al, 2021a ), and a phase III IND application is approved by US FDA to conduct a trial on 430 patients.…”

Synthetic Approaches to the New Drugs Approved During 2020

“…In patients experiencing hypovolemic shock, centhaquine decreases blood lactate, increases blood pressure, increases cardiac output, and improves tissue perfusion. 63,64 Centhaquine citrate also restores renal blood flow and protects against tissue damage after hemorrhagic shock. 65 A synthesis of centhaquine citrate on scale has been described in the patent literature and is outlined in Scheme 12.…”

Revisión sistemática y metaanálisis sobre eficacia de las drogas vasoactivas en el shock hemorrágico en animales

“…l shock hipovolémico es una condición clínica que amenaza la vida por una inadecuada perfusión y oxigenación tisular debido a una disminución en el volumen vascular circulante de sangre [1].…”

“…La incidencia anual del shock hipovolémico en los Estados Unidos es de aproximadamente 1,5 millones y el número de muertes total debido a shock hemorrágico es de 61.000 [1]. Investigadores de la Organización Mundial de la Salud (WHO) reportaron que cerca de 5,8 millones de personal morían por trauma cada año [3] y este número se espera se incremente a 8 millones en los próximos años [4].…”