Q. What is nitric oxide?

Nitric oxide (NO) is a simple gas molecule composed of one nitrogen atom and one oxygen atom. NO possesses an unpaired electron making it a reactive free radical that the body uses as a powerful signaling molecule. Until 1987, NO was known only as a toxic pollutant gas that appeared in automobile exhaust and city smog. That year, NO was discovered to be produced in the body and shown to have a signaling function in the cardiovascular system. For their seminal discoveries in 1987 concerning the physiological roles of NO, Drs. Robert Furchgott, Louis Ignarro, and Ferid Murad were awarded the 1998 Nobel Prize in Physiology or Medicine.

Q. What is a free radical?

Free radicals such as hydroxyl radical and superoxide anion radical are molecules that possess unpaired electrons. This property makes them especially reactive with other molecules. Free radicals are reactive, unstable and can cause cellular damage that leads to the pathology of strokes, heart disease, and numerous other illnesses. Unlike other free radicals, NO has both life-saving and life-taking properties. In small amounts, NO plays vital roles in many body functions including regulating blood pressure, establishing memory, and fighting pathogens. During inflammatory diseases and other disorders, NO is produced in excessive amounts and exhibits its free radical properties by injuring tissue and contributing to disease pathology.

Q. Why is nitric oxide such an important molecule?

Nitric oxide plays many important roles in the body. Under normal conditions, NO is produced in very small amounts which play crucial roles in regulating blood pressure, facilitating memory, and defending the body against pathogens. The body has natural protective mechanisms to protect itself from NO. Under pathological conditions, NO is produced in excessive amounts which can overwhelm these protective mechanisms. Excessive NO can then cause inappropriate enzyme activation and oxidative damage to vital cellular systems. Excessive NO production occurs during inflammatory conditions and is associated with numerous and diverse human diseases and disorders including intradialytic hypotension, diabetes, septic and hemorrhagic shock, stroke, allograft rejection, and Alzheimer's and Parkinson's diseases.

Q. What is the difference between nitric oxide and nitrous oxide?

Nitric oxide (NO) consists of one nitrogen atom and one oxygen atom. In contrast, nitrous oxide has two nitrogen atoms and one oxygen atom. Nitrous oxide, commonly known as "laughing gas", is an anesthetic. In addition, nitrous oxide has very different chemical properties compared to nitric oxide. Nitrous oxide is not a free radical nor is it produced in the body.

Q. How is NO synthesized in the body?

Nitric oxide is synthesized by the action of nitric oxide synthases or NOS enzymes on the amino acid L-arginine. Endothelial NOS (eNOS) of the blood vessels and neuronal NOS (nNOS) in neurons continuously produce low levels of NO that is used in blood pressure regulation and neurotransmission, respectively. The inducible NOS (iNOS) gene is expressed as a result of stimulation by inflammatory cytokines and is an important component in the body's immune defense repertoire. During inflammation, the iNOS enzyme is expressed in many tissues and produces NO at levels 1,000-times greater than nNOS or eNOS. Excessive NO production from iNOS is a major contributor to the pathology of many diseases.

Q. What are drug companies doing about excessive NO?

There are two approaches to dealing with excessive NO:

1. Enzyme inhibitors to shut down the NOS enzymes or
2. Blockers to inactivate NO.

Many drug companies are developing NOS inhibitors to turn off the enzyme thereby shutting down the excessive NO production during disease conditions. Non-specific NOS inhibitors are problematic because they eliminate excessively produced NO as well as the low levels needed for vital body functions. Side effects, which have included dangerously high systemic and pulmonary hypertension, have been reported in human clinical trials of NOS inhibitors. Specific iNOS inhibitors may reduce NO production from the high output iNOS. Unfortunately, NO from iNOS performs crucial functions such as host defense against pathogens, regulating gut motility, and as a neuroprotectant during brain injury. Therefore, shutting down iNOS activity may lead to adverse effects.

In contrast to NOS inhibitors, NO blockers bind NO directly and prevent the free radical from reacting with other molecules. Two types of NO blockers are currently under development: Medinox's low molecular weight NOX compounds and hemoglobins, which are large protein molecules. Hemoglobins bind NO with high affinity and have been shown to remove excessive NO in animal models. At present, hemoglobin is being tested in clinical studies for the treatment of septic shock. However, hemoglobin is a known vasoconstrictor and an adverse effect of hemoglobin therapy is hypertension. Furthermore, the complicated and high cost of hemoglobin manufacture represents significant barriers to the successful commercialization of hemoglobin NO blocking agents.

Q. What is Medinox's approach to excessive NO and why is it better than what other companies are doing?

Medinox's approach does not involve NOS inhibition nor does it involve large protein blockers. In contrast, Medinox's NO blocking agents are low molecular weight, highly water soluble, orally active compounds that specifically bind and block NO. After binding to a NOX compound, NO is eliminated from the body as a NO-NOX compound complex that is excreted in the urine. The excellent safety and efficacy of NOX compounds has been well established in many preclinical studies. Significantly, NOX compounds have never produced hypertension in vivo, indicating that the low-level NO production, which is required for vital physiological processes, is not affected by NOX compounds.