Zōprinol Provisional Patent Application
Genotec Nutritionals Methods and Composition For The Prevention and Treatment Of Cardiovascular Disorders, Hepatopathology, Glaucomatous Optic Neuropathy and Exercise Overstrain.

Abstract

The inventive subject matter relates to the administration of inosine (hypoxathine riboside) in combination with orotic acid or its mineral orotates, in the embodiment of an oral dosing form trademarked as Zôprinol™, to treat or prevent cardiovascular conditions and neuropathies including but not limited to: congestive heart failure, cardiomyopathy, coronary artery disease, hypertensive left ventricular hypertrophy, myocardial infarction, angina pectoris, arrhythmias, reperfusion injury after interventional coronary angioplasty, pulmonary hypertension, hepatopathology, retinal ganglion/nerve fiber layer regeneration and visual enhancement in glaucomatous optic neuropathy and other ischemic neuropathies, adriamycin induced cardiotoxicity and fibromyalgia and chronic fatigue syndrome.

DESCRIPTION OF INVENTION

Inosine is a purine nucleoside widely found in plants, animals and other forms of living matter consisting of the purine base hypoxanthine and the five carbon sugar D-ribose. Inosine itself has been used as a pharmaceutical agent. In France, inosine (Trophicardyl) was used to treat cardiovascular indications and in Russia, inosine (Riboxin) is currently in use for the same conditions.

Inosine has an extensive literature database supporting its putative cardioprotective/cardiorestorative, neuroprotective/neurorestorative and immunomodulatory effects. The actions of inosine’s cardiovascular effects are diverse and include the following:  positive inotropic effect, anti-ischemic/anti-hypoxic effect, cellular and extra-cellular regeneration effect, mild coronary vasodilation activity, increasing nucleic acid and protein production, restoration of normal gene expression in chronic heart overload.

Research supports the theory of inosine’s ability to restore ventricular heart-pump function and structure by preventing the diminution of the effective contractile proteins in the myocyte and restoring normal cell structure.  The end stage of congestive heart failure is characterized by anatomic remodeling from the concentric form of heart hypertrophy (CHH) to the eccentric form of heart hypertrophy (EHH). EHH is accompanied by morphological (cell loss) and biochemical changes (cardio-myofibrils are depleted of the normal a-myosin heavy chain and instead replaced with the non-functional ß-myosin heavy chain). This pathologic remodeling leads to mechanical insufficiency and the depression of heart pump performance (ventricular ejection fraction) which often results in rapid death.

The literature shows the cellular regenerative properties of inosine/orotate in restoring normal mitochondrial and myofybril structure and function in the myocardium in experimental aortic stenosis-induced chronic overload in the myocardium. The endpoint of improving myocardial myocyte structure is the significant increase in ventricular ejection fraction following the administration of Zôprinol™.  It has been reported in many publications in the last decade that the progressive development of EHH in chronic heart overload leads to abnormal gene expression in the myocardium. We believe that inosine’s/orotate’s cardiovascular properties are attributable to its ability to prevent abnormal gene expression and pathologic heart remodeling to EHH.

Inosine contributes to the to the high-energy phosphate pool (ATP) of cardiac muscle cells and favorably affects bioenergetics generally.  Inosine  also enhances the myocardial uptake of carbohydrates relative to free fatty acids as well as glycolysis.  It is this property of inosine which may be responsible for its anabolic action in enhancing exercise and athletic performance and diminishing fatigue in fibromyalgia and chronic fatigue. Inosine’s neuro-restorative properties are based upon its documented axon-promoting effects in vivo following transection of the corticospinal tracts of rats and axotomy of gold fish retinal ganglion cells.  Inosine may also serve as a neurotropin (nerve growth factor) or actually augment neuritogenesis to restore essential neuronal circuitry after CNS injury.

In cell culture studies, inosine has been found to inhibit the production, in the immunostimulated macrophages and spleen cells, of the proinflammatory cytokines, tumor necrosis factor (TNF)-alpha and interleukin (IL-1). It also suppressed proinflammatory cytokine production and mortality in a mouse endotoxemic model.

Orotic acid or its mineral forms, is a key intermediate in the biosynthesis of pyrimidine nucleotides, which are constructive elements of nucleic acids.  Research has demonstrated its favorable effects on the same aspects of the cardiovascular system as inosine and therefore, has the same aforementioned indications with respect to cardiovascular disease.