The 700,000 Americans diagnosed with sepsis each year might have a better chance of reversing the dramatic and often fatal blood pressure drop that typically accompanies septic shock if new treatments are developed based on an animal study reported in today's Proceedings of the National Academy of Sciences.
Sepsis has a 30 to 50 percent mortality rate and is the leading cause of death in non-coronary intensive care units. Septic shock represents an extreme situation in which the body's immune system goes into overdrive and attacks an infection with all possible means. Damaged in the process is the body's vascular pressure maintenance system.
Researchers at Saint Louis University School of Medicine and MetaPhore Pharmaceuticals confirmed that free radicals – particularly superoxide anions – produced in large quantities during septic shock deactivate dopamine, norepinephrine and epinephrine destroying their biological activity and often leading to a free fall in blood pressure. Together, dopamine, norepinephrine and epinephrine are known as catecholomines, a class of chemically similar small molecules that are derived from the amino acid tyrosine.
Confirmation of free radicals' role in septic shock came after researchers administered a MetaPhore superoxide dismutase (SOD) mimetic (M40403) to a rat model of septic shock to remove excess superoxide free radicals. The treatment with the SOD mimetic restored the ability of norepinephrine to constrict blood vessels and reversed hypotension, i.e. low blood pressure.
"The use of an SOD mimetic represents a new paradigm for the treatment of septic shock. Removing superoxide free radicals protects catecholamines like dopamine, norepinephrine and epinephrine from deactivation, restoring reactivity, reversing low blood pressure and resulting in higher survival in rats," observed Heather Macarthur, Ph.D., of the Saint Louis University Medical School and Daniela Savemini, Ph.D. of MetaPhore Pharmaceuticals. Other members of the research team include Dennis P. Riley of MetaPhore, Thomas P. Misko of Pharmacia and Thomas C. Westfall of Saint Louis University Medical School.
Standard treatment for septic shock consists of prompt initiation of antibiotic therapy and in addition, any rapid fall in blood pressure is addressed by the administration of fluids intravenously and of catecholamines such as dopamine and norepinephrine in an attempt to prevent the fall in blood pressure thus augmenting blood flow to vital organs. However, the additional catecholamines that are administered are frequently destroyed by the huge excess of superoxide free radicals, produced as the body fights the infection.
Despite such aggressive therapy, successful outcomes are limited because the loss of normal responses to dopamine and norepinephrine hampers the ability of the clinician to sustain blood pressure. Death from septic shock often comes despite the administration of progressively larger doses of dopamine and norepinephrine because the inability to maintain appropriate blood pressure leads to severe reduced blood flow to critical organs and eventually death.
"If development of sepsis-related low vascular responsiveness to norepinephrine therapy could be overcome, the therapeutic administration of norepinephrine would effectively maintain blood pressure," wrote Drs. Macarthur and Salvemini, noting that administration of the SOD mimetic had that effect in the rat model of septic shock.
The MetaPhore SOD mimetic was given in a therapeutic mode several hours after the septic shock condition was established in the test animals. The research team showed that the free radical fighting ability of MetaPhore's SOD mimetic was capable of reversing life-threatening blood pressure decline at relatively low doses.
MetaPhore has subsequently discovered even more potent SOD mimetics and more extensive studies of another of MetaPhore's compounds in septic shock are underway at the National Institutes of Health and the Saint Louis University School of Medicine.
Background on Metaphore's SOD Mimetic
The MetaPhore SOD mimetic simulates – or mimics -- the natural enzyme superoxide dismutase (SOD), which combats superoxide ions. Superoxide is a free radical arising from oxygen metabolism in activated white cells. SOD catalyses the removal of superoxide radicals providing a major protective effect in our bodies.
Unlike the natural enzyme, the mimic of SOD is well suited for use as a drug because it has a low molecular weight, as well as remarkable oxidative and kinetic stability. The SOD mimic used in this research is not a protein like the natural form, but instead is a specially constructed manganese-based compound.
Attempts to use natural, bovine-derived SOD enzyme in clinical applications have been frustrated by the natural form's inherent instability and the body's allergic reaction to its introduction. It also had a very short half-life, lasting intact in the body only about fifteen minutes.
"Mimics of SOD have major medical potential. For over twenty years we have understood the inflammation fighting power of the SOD enzyme but we have been unable to reproduce the beneficial effect in a stable drug form. We have now achieved this and can safely and dependably reproduce the superoxide fighting effect in numerous animal models, enabling us to address a myriad of therapeutic areas", said Dennis Riley, MetaPhore's Vice President of Research & Development.
In October 1999, Science Magazine published research documenting that MetaPhore's mimic of SOD substantially reduced tissue damage due to inflammation and reperfusion – the latter involving the return of blood flow to a surgical site following a surgical procedure. These results provided a scientific rationale for an entirely new class of molecules based on the mimic of SOD to treat inflammation, pain, shock, arthritis and the side effects associated with chemo and radiation therapy.
Located in St. Louis, MetaPhore Pharmaceuticals, Inc., is applying its metal-based technology platform to develop novel therapeutics addressing significant unmet medical needs. The company's proprietary expertise in rational drug design and metal-based therapeutics has been used to explore novel approaches to iron-overload, antibiotics and antioxidants. The company's most advanced program is in the antioxidant area with proprietary mimics of the body's own radical fighting enzyme, superoxide dismutase. MetaPhore is moving its superoxide dismutase mimetics forward for inflammation and pain, dermatitis, refractory hypotension and reperfusion injury. MetaPhore believes its approach to superoxide dismutase mimetics could result in treatments with unmatched therapeutic value and minimal side effects. Additional information is available at www.metaphore.com.
The Company intends to initiate Phase I clinical trials for one of its leading drug candidates at the end of this year, with two other drug candidates scheduled to enter Phase I trials in the first of half of 2001 - all of which are in applications for conditions other than septic shock. The SOD mimetics family has shown promise in treating numerous disease states including in numerous disease states including inflammation, pain, cancer, rheumatoid arthritis and reperfusion injury and stroke. Metaphore Pharmaceuticals SOD mimetic family is protected by an extensive patent estate around the world.
Statements in this press release that are not strictly historical are "forward looking" statements as defined in the Private Securities Litigation Reform Act of 1995. The actual results may differ from those projected in the forward looking statement due to risks and uncertainties that exist in the company's operations, development efforts and business environment.
MetaPhore Pharmaceuticals Contact:
Punnie Donohue
314-290-2014 or 314-496-9620
Saint Louis University School of Medicine Contact:
Shawn Tate
314-977-8016
Journal
Proceedings of the National Academy of Sciences