Frequently Asked Questions (FAQ)

Lyfaquin® stimulates alpha2B-adrenergic receptors which are extensively (95%) located on the venous system. Stimulation of these receptors enhances venous blood return to the heart and (according to Starling's law) more blood is pumped out of the heart. This increases stroke volume and cardiac output and that leads to an increase in blood pressure; It also acts on alpha2A-adrenergic receptors that are located in the brain to inhibit sympathetic drive and decrease arterial vascular resistance, thereby enhancing tissue blood perfusion. Lyfaquin® administered intravenously will mainly stimulate venous alpha2B-adrenergic receptors to increase stroke volume and cardiac output. A minor action is stimulation of alpha2A-adrenergic receptors in the brain to produce arterial dilatation. The net effect is an increase in blood pressure which has been observed in all the preclinical and clinical studies of hypovolemic shock.

An increase in stroke volume because of more venous blood return to the heart leads to an increase in blood pressure. An increase in systolic blood pressure is more than diastolic and therefore pulse pressure also increases. Pulse pressure is the difference between systolic and diastolic blood pressure.

Blood pressure is governed by cardiac output and arterial vascular resistance. Main action of Lyfaquin® is to increase cardiac output and minor action is to dilate arteries. An increase in cardiac output is dominant and results in increasing blood pressure in shock patients.

It is a venous constrictor due to stimulation of alpha2B-adrenergic receptors which are on the venous system. It is an arterial dilator by stimulating alpha2A-adrenergic receptors in the brain to inhibit sympathetic drive.

An increase in cardiac output by Lyfaquin® results in increase in blood flowing to the tissues resulting in improved tissue perfusion.

Compared to existing treatment, Lyfaquin® showed significant improvement in blood pressure, blood lactate, base-deficit, ARDS, and MODS in hypovolemic shock patients. Lyfaquin® limits the use of vasopressors and helps to achieve a vasopressor-free-resuscitation. It ensured a 9% absolute reduction in mortality compared to standard treatment. Lyfaquin® reduces the requirement of fluids, blood products and also showed trends of reduction for ICU/Hospital stay/duration on the ventilator. Lyfaquin® is a first-in-class product with a unique mechanism of action. When administered to patients, it acts on α2B adrenergic receptors to produce venous constriction and increase venous return to the heart, increasing cardiac output and tissue perfusion. It also acts on central α2A adrenergic receptors to reduce sympathetic drive and decrease systemic vascular resistance (SVR), leading to improved tissue blood perfusion.

It is NOT a vasopressor, Lyfaquin® is a vasoactive resuscitative agent. Lyfaquin® is a frontline resuscitative agent for the treatment of hypovolemic shock. It limits the use of vasopressors and helps to achieve a vasopressor-free-resuscitation. Lyfaquin® is a vasoactive pharmacological resuscitative agent. Lyfaquin® increases the cardiac output without increasing the heart rate. In contrast, vasopressors offer no benefit when used in the early management of hemorrhagic shock. Vasopressors constrict arteries and veins and increase heart rate. Vasopressors increase afterload due to arterial constriction and may continue tissue hypoperfusion. However, vasopressors have a role in resuscitation when vasoplegic shock develops, and blood pressure cannot be maintained. Administration of vasopressors requires dose titration and bears the risk of cardiac arrhythmias/ischemia, whereas there is no need for dose titration with Lyfaquin® and is free from any cardiac risk.

Clinical trials conducted were multicenter, randomized, controlled double blinded where the best standard of care was provided to all the patients. Therefore, patients were getting crystalloids, colloids, blood, blood products, vasopressors depending on the need of each patient. Lyfaquin® was compared to the best standard of care and proved to be superior existing treatment for hypovolemic shock.

No complication or any drug-drug interaction with standard of care is reported.

No, alpha blocker (antagonists) may block Lyfaquin®’s therapeutic effects.

Yes, in phase II and III clinical trials, patients received catecholamines as part of standard of care.

Dexmedetomidine is a specific and selective alpha-2 adrenoceptor agonist. It is used to sedate initially intubated and mechanically ventilated patients during treatment in an intensive care setting, also used for anxiety reduction and analgesia. The therapeutic effects of dexmedetomidine are at the spinal and supraspinal levels. Lyfaquin® is an agonist of alpha2B (located in the veins) and alpha2A (located in the brain) receptors. Its desired therapeutic effects are peripheral and central action on alpha receptors. Lyfaquin® selectively constricts veins (due to alpha 2B receptors on veins) and optimally dilates arteries (due to alpha 2A receptors in the brain) to increase organ perfusion in patients with hypovolemic shock. It does not produce any sedation. The possibility of interaction producing an added alpha 2A receptors response cannot be ruled out if both these agents are administered simultaneously, although no such evidence is available in our clinical trials.

There is no direct effect on vascular tone because dobutamine has opposing effects of each enantiomer: (-)-dobutamine is a vasoconstrictor, and (+)-dobutamine is a vasodilator. Dobutamine used is mixture of both forms. Lyfaquin® has no isomers. Lyfaquin® is not a vasopressor it has completely different mechanism of action to increase cardiac output by enhancing venous blood return to the heart. If used with dobutamine it can augment improvement of blood perfusion to the tissues and prevent end organ failure. We should keep in mind that dobutamine is β1-agonist and increases heart rate, leading to an increase in oxygen demand. Lyfaquin® does not act on β-adrenergic receptors which is a significant advantage because of minimal risk to produce cardiac complications.

Lyfaquin® shall be administered with precautions in decompensated heart failure patient as safety and efficacy of Lyfaquin® has not been established in these cases.

Yes, Lyfaquin® is a frontline resuscitative agent and should be administered immediately to hypovolemic shock patients along with SOC.

Postpartum cases were included in clinical studies and Lyfaquin® showed significant clinical improvement. A female patient with blood lactate level of more than 17.41 and hemoglobin of 3.60 survived because that patient was in Lyfaquin® group. While another female patient with blood lactate level of 11.18 with hemoglobin of 9.30 at the time of enrollment fell in control group with standard of care and did not survive.

In our Phase II and Phase III trials there were cases which were quite serious and their MODS, ARDS scores were high. Lyfaquin® provided improvement in ARDS and MODS in those severe cases.

Yes, if the head injury patient is in hypovolemic shock, you can use Lyfaquin®. Lyfaquin® should be administered as a frontline treatment with fluids in patients with hypovolemic shock. After administration of the first dose, the next dose of Lyfaquin® should be administered only if the patient’s systolic blood pressure falls ≤90 mmHg. If the blood pressure improved and remains normal after the first dose, no subsequent doses are required. The time duration between two doses should be a minimum of 4 hours.

When the patient with hypovolemic shock gets hospitalized, his venous reserve (unstressed volume) is relatively higher than the arterial side (stressed volume) irrespective of his time of hospitalization after injury. When such patients received Lyfaquin® and the standard of care, the unstressed venous blood volume gets converted into stressed blood volume, optimizing cardiac output to maintain blood circulation.

Blood is circulating in a closed compartment, and arterial blood shall return to the venous compartment. Lyfaquin® improves cardiac output, systemic circulation, and blood pressure.

Yes, Lyfaquin® can be administered in trauma patients with high injury scores.

Lyfaquin® is frontline resuscitative agent to be used with SOC for hypovolemic shock. Shock due to other causes such as septic shock has been studied in preclinical models and Lyfaquin® improved cardiac output. Its use in other shock states is under investigation and is not yet approved and its use is left at the discretion of the Physician.

We do not anticipate any adverse effects of Lyfaquin® in CKD patients. The preclinical studies showed that Lyfaquin® restores renal blood flow and protects tissue damage after hemorrhagic shock and renal ischemia. These preclinical findings are supported with the data from our clinical studies, where Lyfaquin® improved renal function (creatinine, blood urea nitrogen, and GFR) in patients of hypovolemic shock. Lyfaquin® has a high safety margin (MTD 0.1 mg/kg body weight) and a short half-life. The possibility of its accumulation in the body and producing any toxicity at a therapeutic dose (0.01 mg/kg body weight) is extremely low.

Lyfaquin® is approved as an add-on resuscitative agent in hypovolemic shock. Lyfaquin® has only been studied in animal models of septic shock. It increased cardiac output in animals with LPS induced septic shock. However, during clinical studies in hypovolemic shock patients, few patients developed sepsis. Lyfaquin® reduced mortality, reduced requirement of vasopressors, improved base-deficit and blood pressure in these patients.

Yes, it can be used in immunocompromised patients as no interaction of Lyfaquin® is reported with any immune response.

Yes, Lyfaquin® can be used in arterial injury along with damage control surgery. In clinical settings, Lyfaquin® has been found to reduce fluid discharge following surgeries and help in maintaining clot strength.

Lyfaquin® is administrated along with damage control resuscitation to stop bleeding. Lyfaquin® produces only a limited increase in blood pressure and comes under permissive hypotension guidelines, which avoids dislodging the clot and recurrence of bleeding. Lyfaquin® helps to achieve better hemostasis with a survival benefit.

Lyfaquin® is a novel resuscitative agent with a short half-life, i.e., 0.71-1.62 hours. Lyfaquin® is administered along with damage control resuscitation. Lyfaquin® does not have any deleterious effect on blood coagulation profile and its parameters. It should be readministered after a gap of 4 hours if indicated and bleeding continues.

Accidental rapid infusion of complete 1.0 mg vial of Lyfaquin® should not cause any adverse effect as the maximum tolerated dose (MTD) established for Lyfaquin® is 0.1 mg/kg body weight. This MTD cannot be achieved with a single vial of Lyfaquin®. If any adverse effect is observed with rapid infusion of complete 1.0 mg vial, it can be managed symptomatically.

We recommend Lyfaquin® as a frontline treatment to patients with hypovolemic shock. It is better to prevent the worsening of the condition of the patient.

No adverse reactions due to Lyfaquin® has been reported till date. It is very safe drug to be used in critical care setting. Lyfaquin® is well tolerated and has wide safety margin.

In our clinical trial, a repeat dose if needed was administered to the patient if the condition of the patient did not improve. The next dose of Lyfaquin® should be administered if systolic blood pressure remains ≤ 90 mmHg or as per discretion of treating physician. A maximum of 3 dose in 24 hours and 6 doses in 48 hours have been approved. An interval of at least 4 hours is kept between each dose.

In our Phase 2 and Phase 3 studies, Lyfaquin® was used in conjunction with Standard of Care (SOC). The results of our study showed efficacy and safety of Lyfaquin® as a frontline adjuvant to SOC with significant reduction in mortality as compared to SOC alone.

Current standard of care (SOC) is not adequate and has high mortality. Present standard of care is based on resuscitative agents developed more than 5 decades ago and no new agent has been developed to treat this life-threatening condition. The addition of Lyfaquin® to SOC has been shown to improve blood pressure, base deficit and decrease blood lactate levels. Most importantly a decrease in mortality.

Centhaquine is not protein, but sensitive to light, heat, and moisture. The purpose of the “cold chain” is to maintain product quality, prevent any degradation and improve the shelf life of the drug.

Centhaquine has a short half-life i.e. 0.71-1.62 hrs with a large volume of distribution and no accumulation has been reported. It is metabolized in liver and has urinary and fecal excretion.

Lyfaquin® is safe for use in humans. Its antidote is not available; however, the patient can be managed symptomatically in case of overdose or toxicity.

Clinical outcome of patients is most important. The price is decided based on research, patent protection, and derived from expenses incurred on patients in ICU without Lyfaquin®. In clinical trials, we found that the average number is about 1.2 vials used per patient. We can safely say that on an average one vial will be used in each patient. Lyfaquin® is optimally priced as a novel first-in-class resuscitative agent that has been shown to improve clinical outcome and decrease mortality.

A: The current standard of care is inadequate and resuscitative agents are decades old. Attempts to develop an effective resuscitative agent have not been successful. Agents that could decrease metabolic activity to reduce oxygen demand were studied, but none was promising. Haemoglobin-based blood substitutes were effective in animal models but failed in phase III clinical trial and were dropped from further development. Lyfaquin® is a new chemical entity and has to be evaluated from a risk-benefit perspective. A balance is maintained when clinical trials are conducted with a new study intervention. The sample size used in these studies (25 volunteers in phase I, 50 patients in phase II, and 105 patients in phase III) was good enough to prove the study outcomes. Proper power analysis was performed to calculate the sample size using primary blood pressure and blood lactate endpoints. The clinical study protocols were approved by the regulatory agency and the ethics committees of every institution before the conduct of trials. We have initiated a phase IV clinical study involving 400 patients with hypovolemic shock. Lyfaquin® is approved for use, and several hundred patients have benefited from its use.

This is available from DCGI website and can be provided on request.

Phase II studies have been published in “Advances in Therapy” and phase III manuscript is under review and is available at https://www.medrxiv.org/content/10.1101/2020.07.30.20068114v4