MTR-105 - VasoplegicSyndrome

Hypotension following Cardiac Surgery (Vasoplegic Syndrome)

Hypotension within the first 24 hours after cardiac surgery is very common in almost all patients.[1] It could begin with a benign, routine passing symptom, or it could signal the onset of a sequela that could endanger the patient's life. The condition merits thorough, prompt consideration and treatment, as the human brain can withstand only four minutes of hypoxia before suffering severe damage. Transient hypotension that occurs frequently after heart surgery may also lead to acute renal failure.

Hypotension due to vasodilation is observed in post-cardiac surgery patients where body temperature during surgery was maintained at 35°C; as body temperature approaches normal, peripheral vasodilatation may cause relative changes in the intravascular volume, resulting in hypotension. Several other factors, such as major fluid shifts during cardiopulmonary bypass, or the inflammatory process initiated by the release of various cytokines, are also implicated in the pathogenesis of hypotension.

1 Borgdorff P, Fekkes D, Tangelder GJ. Hypotension caused by extracorporeal circulation: serotonin from pump-activated platelets triggers nitric oxide release. Circulation. 2002 Nov 12;106(20):2588-93.

2000-2001:Phase I clinical trial in Germany This study was conducted in order to evaluate the safety of MTR-105 when administered to healthy volunteers, in accordance with ICH guidelines and FDA requirements.A request to support an Investigational New Drug (IND) application was submitted to the FDA Center for Drug Evaluation and Research and, in 2003, the IND approval was granted.

2001: Separate from the FDA Phase I study, Phase II clinical trial completed in Moldova

With the consideration of the 1999-2000 Phase I clinical trial and a full summary of previous human experience gained through the clinical studies completed in Moldova (including Phase II clinical study n-36 open-heart surgery patients), the IND (number 66,505) was approved by the FDA in 2003.

Second Section, Intradialytic Hypotension

Dialysis is required when the kidneys can no longer fulfill their role of removing waste (diffusion) and unwanted water (ultrafiltration) from the blood, a condition known as End Stage Renal Disease (ESRD). Hemodialysis is a clinical procedure which substitutes for the normal function of the kidneys, removing waste products, excess fluid and toxic substances from the bloodstream. This process is essential for the survival of ESRD patients whose kidneys are no longer able to perform their crucial function.

Intradialytic hypotension (IDH) is defined as a decrease in systolic blood pressure or in mean arterial pressure, a common adverse event that occurs in 10-30% of all dialysis treatments. Dialysis hypotension usually presents in one of two ways: either episodic hypotension or chronic, persistent hypotension. The latter condition is more commonly recognized in patients who have been on dialysis for a number of years. Both conditions present therapeutic challenges, as ultrafiltration requirements are difficult to achieve within the context of hemodynamic instability.

Intradialytic hypotension is a major source of morbidity for ESRD patients. Few pharmaceutical solutions have been provided to date for treatment of the condition. Current common options include:

  • Dialysate temperature adjustments (from 37 to 35°)
  • Dialysate calcium adjustments
  • Sodium modeling
  • Ultrafiltration modeling

These common treatment modalities can produce unwanted side effects, such as significant weight gain, and often require interrupting the hemodialysis treatment or increasing the dialysis time. Additionally, they seldom address the symptoms associated with intradialytic hypotension, which require a substantial amount of medical and nursing care before and during dialysis in order to control.

Chronic hypotension is characterized hemodynamically by generally preserved cardiac index, heart rate or stroke volume, juxtaposed with reduced total peripheral vascular resistances. Although its pathophysiology is not well defined, a reduced cardiovascular response to vasopressor agents (such as norepinephrine and angiotensin II), associated with a down-regulation of their receptors, as well as an increased production of vasodilators (such as nitric oxide or adrenomedullin), are possibly involved. The treatment of this complication is not well defined, and the measures recommended (contention in the lower limbs or the sympathomimetic agent Midodrine) are of limited benefit.[1] This is a clear indication of the unmet medical need in this market segment.

In a most promising development, intradialytic hypotension has recently been officially designated by the FDA as an "orphan disease" opening the way for increased funding and research possibilities.

1 Cases A. and Coll E. J Nephrol 2002 Jul-Aug;15(4):331-5    Division of Nephrology, IDIBAPS, University of Barcelona, Catalonia, Spain