I. The Effects of Inosine and Orotic Acid in Acute and Chronic Heart Failure

In 1988 M. Parker, MD wrote that during the past 10 years more than 80 orally active vasodilator and inotropic agents have been tested to evaluate their potential in the treatment of heart failure. However, only three agents – digoxin, captopril, and enalprin – have produced consistent long-term hemodynamic and clinical benefits. To date, there has been no significant progress in creating a new class of pharmaceuticals for the treatment of heart failure. It is well documented that the end stage of chronic heart failure (CHF) is characterized by anatomical remodeling from the concentric form of heart hypertrophy (CHH) to the eccentric form (EHH). Concentric heart hypertrophy is characterized by a thickening of the myocardium without any major enlargement of the heart cavities, whereas eccentric hypertrophy – by a thinning of the myocardial wall and a considerable enlargement of the cavities. In humans, the maximal weight in which the overloaded heart remains in the condition of CHH is about 400-500 grams (critical weight). In the stage of concentric hypertrophy the myocardial cells are enlarged, and all biochemical activity – concentration of DNA and RNA, synthesis of protein are increased. Eccentric heart hypertrophy is accompanied by morphological cell loss and biochemical changes characterized by a decrease in RNA-DNA, and protein synthesis in the myocardium and replacement of the high mechanical efficiency heavy chain alpha-myosin with the poorly contractile heavy chain beta-myosin.

The medical challenge was to find compounds that can modify the anatomical and biochemical changes that leads to “abnormal gene expression” and the subsequent cascade of events that describes end stage CHF.

In the former Soviet Union, a group of purine and pyrimidine derivatives (inosine and orotic acid) were proven in animal experiments to prevent heart remodeling from concentric hypertrophy to its eccentric form and putatively prevent abnormal gene expression.

The results of these experiments (see abstracts below) were confirmed in human trials and this discovery represented an exciting new approach in the management of CHF.

 

II. The Effects of Inosine and Orotic Acid on Myocardial Infarction

Infarct of the myocardium (MI) is ischemic myocardial necrosis usually resulting from abrupt reduction of coronary flow to a segment of myocardial tissue. The ability of the heart to continue as a pump is probably related directly to the extent of the infarction zone. Necrosis is therefore, the main cause of many complications affecting the prognosis in MI including:

- Rupture of myocardium;

- Reduction of contractility of the myocardium and development of acute heart failure;

- Development of different forms of arrythmias such as a atrial fibrillation, atrial flutter and ventricular fibrillation;

- Development of dystrophic and necrotic change in the perinecrotic area.

The abstracts of experimental and clinical research presented below clearly demonstrate the therapeutic efficacy of orotic acid and inosine in treatment of MI.

The research shows that both of these neutraceuticals not only accelerates the healing of the necrosis zone, but also improves the condition of the perinecrotic zone and contributes to the development of compensatory hypertrophy of the unaffected normal zones of myocardium and ultimately prevents the development of heart failure.

III. The Effects of Inosine and Orotic Acid in  Myocardiodystrophy and Coronary Atherosclesosis

Myocardiodystrophy is one type of myocardial damage produced by many factors such as:

- arteriosclerotic heart disease, adverse effect of pharmacological therapy, action of catecholamines, deficit of magnesium or potassium, acute and chronic physical overload, chronic alcoholism or infection.  The research abstracts presented below describe the salutary effects of potassium orotate and inosine in the treatment of some forms of myocardiodystrophy

 
IV. The Effects of Inosine and Orotic Acid in Cardiosurgery

The current treatment of advanced coronary artery decease is either angioplasty or coronary artery bypass (CABG) surgery. Both of these procedures carry intraoperative risks as well as many medicals complications including ischemia/reperfusion injury and restenosis of the graft.

The number of patients undergoing this operation worldwide has increased dramatically over the last 2 decades to more than 800 000 patients annually. Mortality currently ranges from less than 1% to more than 8% and morbidity from 1% to 28% - incidences are likely to worsen given the continued aging of the population and the selection of higher risk patients for this procedure.

Although several therapeutic approaches to reduce adverse outcomes following cardiac surgery have been suggested, only one agent has been studied in large-scale clinical trials-acadesine, a purine nucleoside analogue that selectively raises tissue adenosine levels during ischemic conditions.

However, according to some recent publications this effect can be achieved by not only the purine nucleoside acadesine but also by the purine nucleoside inosine and the pyrmidine precursor orotic acid especially a complex of these two components. Results of the selected research with this product are presented below.

Abstracts of the Cardiovascular Effects of Inosine (Hypoxanthine Riboside) and Orotic Acid.


Rosenfeld FL
Metabolic supplementation with orotic acid and magnesium orotate
Cardiovasc Drugs Ter. 1998 Sept; 12 Suppl 2:147-52


Orotic cid (OA), a naturally occurring substance, is a key intermediate in the biosynthetic pathway of pyrimidines. Previous investigations in the heart suggest that orotate can protect recently infarcted hearts against a further ischemic stress and may be beneficial in certain types of experimental cardiomyopathy. At the Hamburg symposium on magnesium orotate, a number of studies of this form of metabolic supplementation were presented that indicate orotic acid and its magnesium salt have a significant beneficial effect on the myocardium under conditions of stress ranging from myocardial infarction to severe physical exercise. The following conclusions can be drawn: (1) Orotic acid can improve the energy status of the recently infarcted myocardium (rat hearts). (2) Orotic acid may improve myocardial purine and pyrimidine levels by stimulating hepatic release of uridine into the bloodstream, which in turn augments depleted myocardial pyrimidines and purines (rat heart). (3) Orotic acid improves the tolerance of the recently infarcted heart to global ischemia (rats). (4) Magnesium orotate may reduce the severity of chronic myocardial dysfunction and structural damage in cardiomyopathy (cardiomyopathic hamsters). (5) Magnesium orotate may improve exercise tolerance in patients with coronary artery disease and in trained athletes (humans). (6) Magnesium orotate has only a weak inotropic effect, if any, on normal hearts (rats). (7) Further clinical testing is indicated to determine if the effects described could be of significant clinical benefit in the treatment of heart disease.

Domingo M. Aviado.
Inosine: A Naturally Occurring Cardiotonic Agent
J. Pharmcol. (Paris), 1983, 14,suppl, pp.47-71.

Summary. For many years, Inosine was considered to be a simple metabolite of adenosine which was devoid of any cardiovascular effects. This theoretical ineffectiveness can be explained in the light of recent studies by the use of inadequate doses. In fact, higher doses of inosine, a non-toxic nucleoside, have demonstrated, experimentally, a cardiovascular activity and the pharmacological profile of this naturally occurring substance has been defined.

Like adenosine, inosine is a potent coronary vasodilator.  The vasodilation induced by inosine is only partly due to increased metabolic demands.  Inosine has a direct action on coronary artery relation independent of the inotropic effect.  It alters the balance between oxygen supply and demand which is reflected by an intramyocardial redistribution of oxygen in favor of the sub-endocardial zones.  Inosine acts on the coronary circulation like a “regulator of myocardial nutrition”, unlike adenosine, which can be thought of as a “coronary vasoregulator”.   This dissociation between the two nucleosides is apparently due to different vascular sites of action.


Mikhailets G.A., Belenky E.E., et al
Effects of riboxin (inosine) on the course of experimentally produced injuries to the cardiovascular system
Advances in antibiotic research and production; p27-50; Moscow, USSR 1980


Riboxin is a ribonucleoside formed in the process of biosynthesis by bacterial cultures of Bacillus subtilis; it is analogous to inosine, which is precursor of ATP and a natural metabolite in animal and human tissues. It has been shown that inosine is involved in nucleotide syntheses [1-2], activates intracellular redox reactions, increases the ATP content. Inosine administration into animals with experimentally produced myocardial infarction facilitates the formation of compensatory ventricle and atrium hypertrophy, promotes the reparation process in the necrotic zone [6-8]. Inosine exerts a marked antiarrhythmic effect in animals with pharmacologically induced arrhytmias [9-10].

The aim of this study was to investigate pharmacologic properties of Russia-produced preparation of riboxin. The main attention was focused on the study of riboxin effects in the course of such pathological conditions of the cardiovascular system as myocardial infarction and dystrophy, chronic cardiac failure, strophanthine-induced arrhytmias.


Summary:

The studies of riboxin effects on various “models” of cardiovascular disease showed, that this preparation:

    * activated the reparation process in the necrosis zone in myocardium infarction, increased the activity of enzymes involved in aerobic metabolism, accelerated function recovery of damaged cells in the perinecrosis zone;
    * produced marked antiarrhythmic effects in mice, rabbits, cats and guinea pigs with heart rhythm disturbances, induced with strophantine;
    * prevented the development of cardiac dilation, reduced the degree of structural alterations in the myocardium and normalized the biochemical characteristics of heart muscle state in animals given toxic doses of catecholamines;
    * stopped the development of eccentric hypertrophy of the heart in experimentally produced aortic stenosis of rats, diminished the degree of functional and structural alterations in their myocardium.

These qualities of riboxin, as well as its good tolerance shown by intact animals, allow this agent to be recommended for clinical studies in myocardial infarction and dystrophy, acute and chronic heart failure, disturbances of heart rhythm, induced by cardiac glycosides, as well as in preparing patients for cardiac surgery and in the postoperative period.

 

Stepura OB, Tomaeva FE, Zvereva TV
Orotic acid as a metabolic agent

The Paper reviews clinical and experimental studies into the mechanisms of action of orotic acid (OA). OA has been show to take an active participation in metabolic processes in the body. As a pyrimidine precursor, it plays a key role in the biosynthesis of nucleic acids and protein, regulates water-salt exchange, by increasing diuresis and reducing the volume of extracellular fluid. OA is also a cellular fixative of magnesium by producing pronounced antiarrhythmic, vasodilator, and cardioprotective effects. OA has ascertained to stimulate erythro- and leukopolesis. The involvement of OA in metabolic processes explains its cardio- and neuroprotective effects. By enhancing the resistance of myocytes to ischemia, OA favorably affects the clinical course of myocardial infarction and on manifestations of heart failure. OA has been noted to have an angioprotective action and to play an important role in the energy provision of the hypertrophic myocardium, by increasing its contractility. The ability to enhance the functional reserves of the heart adapted to higher exercises accounts for its use in sports medicine. When there are emergency emotional and vestibular stimuli, OA drugs show an antistressor action and are effective in treating patients with borderline nervous and mental disorders. Whether OA can be used to treat gastrointestinal diseases is to be clarified.


I. Abstracts of the Effects of Inosine and Orotic Acid in Acute and Chronic Heart Failure
 

Belenkii, E.E.
Effects of orotic acid and metacyl in certain physiological and pathological processes of the heart muscle
Proc. Conference on the Use of Pyrimidine Derivatives in Oncology and other Regions of Medicine, 22. to 24. May 1963, Leningrad (USSR), 1963: p.9

In vitro the sodium salt of orotic acid at concentrations of 1.10 -5 or 1.10 -6 had no noticeable effect on the action of a non-fatigued isolated heart of the frog, but stimulated it at 1.10 -4. Metacyl (1.10 -4) somewhat increased the contractility of the heart muscle. Orotic acid or metacyl (1.10 -4) restored the contractile activity of an isolated frog heart, that was impaired by prolonged work.

In vitro orotic acid in a dose of 150 mg/KG BW metacyl (75 mg/KG) administered subcutaneous promoted the development of compensatory hypertrophy in the heart in frogs with experimental aortic stenosis. On day 4 after creating aortic stenosis the weight of the ventricle of the heart in a frog given daily orotic acid or metacyl was greater than in untreated control animals (by 18% and 5%, respectively).

Orotic acid in a daily dose of 200 mg/KG, in food, allayed the course of experimentally induced epinephrine myocarditis in albino rats, as did metacyl in a dose of 40mg/KG. On the day 24 following induction of the myocarditis, the control animals showed an increased weight of the heart, morphological alterations in the myocardium, and a delayed growth rate. In animals treated with the pyrimidines these changes were definitely smaller.


Czarnecki W, Czarnecki A
Haemodynamic effects of inosine. A new drug for failing human heart?
Pharmacol Res. 1989 Sep-Oct;21(5):587-94
 

Haemodynamic effects of inosine were studied in intact dogs and subsequently in patients suffering from prolonged otherwise intractable cardiogenic shock. The nucleoside significantly improved myocardial performance in patients with an extremely low cardiac index by 63 +/- 29% as well as animals with no signs of haemodynamic deterioration, increasing cardiac output by 12.2 +/- 4.3%. These results suggest that inosine may become a promising inotropic agent. Further studies though are necessary to elucidate the mechanism of inosine action.

 
Belenkii, E.E., Pogosova A.C, Tunitskaia TA, Borisova TA
Effect of orotic acid and purinor on the myocardium in compensatory hypertrophy and hyperfunction of heart, caused by experimental stenosis of aorta
Farmakol Toxicol; Nov – Dec 1966; 29(6):685-8 Russian

 

Investigations on 40 rats with experimental aortic stenosis kept under observation for 8 months after surgery demonstrated, that as a result of a prolonged compensatory hyperfunction in 50% of them the condition of the heart changed from concentric over to eccentric hypertrophy.

In animals whose hearts were in the state of concentric hypertrophy (50%) one could see against the background of reduced performance capacity, an intensified methionine-S35 incorporation in the myocardium with DNA and RNA concentration in the myocardium continuing to be normal.

In animals with eccentric hypertrophy of the heart (50% of animals) a greater drop of performance capacity, reduced DNA and RNA concentrations in the myocardium, along with a relatively diminished methionine-S35 incorporation in the myocardium. The extent of histological alterations in this animal group was also more pronounced.

Daily administration of the orotic acid or Purinor started 1 ½ months after surgery in a dose of 100mg/kg prevented the decrease of work capacity development, morphological change and the devolpment of eccentric hypertrophy in 90% of the animals. At the same time methionine incorporation in the myocardium was close to normal.

The animals treated with orotic acid or Purinor increased the “critical weight” of heart (weight in which the heart continues to stay in “concentric” form).

 
Belenki E.E., Sokolov I.K., Kleimenova N.N., Suzdalnitskii R.S., Tuniskay T.A.
Prevention of chronic experimental heart insufficiency by inosine.
Cor Vasa, 1975;17(1):57-65

The administration of inosine dosed 25 mg/kg/daily starting 45 days after operation and for 10 ½ months prevented the development of eccentric cardiac hypertrophy on the background of experimental aortic stenosis in rats, reduced the lowering of the working capacity of the animals, and partially inhibited the full development of functional and morphological myocardial changes, detected by electrocardiographic, vectorcardiographic, microscopic, and electronmicroscopic examinations. Differences were found in the relative weights of the heart, thymus, liver and other organs; there findings attested to an anabolic activity of inosine. The results obtained justify the application of inosine for the prevention of eccentric hypertrophy and decompensation of the heart in cardiac failures varying in etiology; any deficient preventive measure is of importance, because the degree of eccentric hypertrophy is a factor influencing the survival of the patients.


Belenky Y,
Reduction of Ventricular Overload to Prevent Abnormal Gene Expression and Heart Failure
New Americans’ collected scientific reports, 1991;I; p.169-172

Observations of rats with experimental aortic stenosis for 12 months after surgery demonstrated that, as a result of a prolonged compensatory hyperfunction in 80% of them, the condition of the heart changed from concentric to eccentric hypertrophy.

In animals whose hearts were in the state of concentric hypertrophy, one could see an intensified methionine-S35 incorporation in the myocardium and its nuclei, as well as in the tissue of most internal and endocrine organs, with DNA and RNA concentration in the myocardium continuing to be normal.

Animals with eccentric hypertrophy of the heart showed a greater drop of performance capacity, reduced DNA and RNA concentration in the myocardium and a relatively diminished methionine-S35 incorporation in the myocardium, its nuclei, and other organs. The extent of histological alterations in this animal group was also more pronounced.

Daily administration of 50 mg/kg of Purinor (orotic acid, adenine, xanthine, hypoxanthine) started 8 months after surgery raised the muscular performance and prevented the development of eccentric hypertrophy in most animals. At the same time methionine-S35 incorporation in the proteins of the myocardium and other organs remained normal. The animals treated with Purinor showed a much better histology of the myocardium than the respective controls. It can be suggested that this effect of a complex of pyrimidine (orotic acid) and purine (adenine, xanthine and hypoxantine) is a result of its prevention of abnormal gene expression in the overloaded heart.


Maslyuk V.I, V.G. Popov, T.A. Popova, V.P. Litvintsev
Treatment of Cardiac Insufficiency with Cardiac Glycosides in Combination with Agents Influencing Nucleic Acid Synthesis and Energy Formation
Kardiologia (Moscow) 1972; Vol. XII, No. 1,45-52

 

The authors observed 500 patients suffering from rheumatic heart disease with circulatory insufficiency of grades IIA, IIB and III. The patients were allocated into four groups: the first one received cardiac glycosides, the second - potassium orotate (5 g daily), the third group – cardiac glycoside plus ATP and vitamin B12, the fourth group- cardiac glycosides and calcium pantothenate. Results of the treatments were evaluated by clinical indices, analysis of the systolic phase, determination of the cardiac output, circulating blood volume, circulation rate, venous pressure and ECG. Therapy with the drug complex produced a much better response than glycoside and diuretics given alone, particularly with regard to myocardial contractile function, hemodynamic trends, and reduction in cardiac glycoside toxicity. This allows the authors to recommend the use of the complex of medicines employed for the treatment of grades IIB and III circulatory insufficiency in patients with rheumatic heart disease.

Bondarenko I.P.
Riboxin (inosine)-induced changes in hemodynamic parameters of patients with chronic circulatory failure
Ischemic Heart Disease, Khar’kov 1983, pp. 84-86 (in Russian)

Chronic heart failure (CHF) is one of the common complications of cardiac disease. It was observed clinically 112 patients with ischemic heart disease- CHF (grades IIB and III), 64 of whom formed Group 1 (treatment), taking oral riboxin 0.4 g tid, together with the conventional strophantin and diuretics therapy (hypothiazide, furosemide).

The other 48 patients made Group 2 (controls) and received strophantin and diuretics only, without riboxin. The treatment duration was 3 to 4 weeks in both the groups. Prior to and after the therapy the patients had repeated ECGs and assessments of mycocardial contractility (by names of polycardiography) and central and peripheral hemodynamics (rheovasographically and thermagraphcally).

Following the treatment period, Group 1 showed a good response in 36 (56.3%) patients, and no response in 2 (3.1%,with grade III CCF). Stenocardia (angina) attacks ceased in 75% of patients.

In Group 2 good response was observed in 20 (41.6%) patients, and no change was seen in 6 (12.5%). Angina attacks disappeared in 50% of patients.

In Group 2 the number of cased with tachiarrhythmic atrial fibrillation dropped from 32 to 15 (by 53.1% versus 71% in Group 1).

An analysis of the evidence obtained allows to suppose that inclusion of riboxin (inosine) into the traditional combined drug therapy of ischemic heart disease (IHD) with severe CHF can improve cardiac contractility and central and peripheral hemodynamics, and correct systemic and pulmonary microcirculation. As a result the clinical efficacy of the traditional medicines for IHD can be improved.

 

 

II. Abstracts of the Effects of Inosine and Orotic Acid on Myocardial Infarction

Belenkii E.E., Runikhin IuA, Tunitskaia TA
Effect of orotic acid and methyluracil (methacil) on the restorative processes in experimental infarct in rabbits
Patol Fixiol Eksp Ter. 1966 Sep-Oct; 10(5):62-4. Russian

 

The experiments were carried out on 38 rabbits which were distributed into 4 groups. Group 1 consisted of intact animals; group 2 included control animals with experimental myocardial infarction; group 3 and 4 of animals with experimental myocardial infarction treated with orotic acid 200mg/ kg BW or methyluracil 100mg / kg BW administered daily until the animals sacrifice on experimental day 7 and 14.

The control animals with extensive myocardial infarctions showed disseminated necroses on the 7th experimental day. On the 14th experimental day the necroses were detected in 50% of the animals. The administration of orotic acid or methyluracil resulted in necrosis elimination in half of the animals on the 7th day and in two thirds of the animals on the 14th experimental day.

It deserves mention that the area of necrosis in the animals treated with the drug was 4-fold smaller in size, as compared with the controls. The experimental rabbits had a more pronounced (as compared with the controls) increase in the number of poorly-differentiated young intensely basophilic fibroblasts and less marked infiltration in the area of the cicatrix being formed and in the adjacent areas.


 
Kleimenova NN, Alekseeva SP, Belenkii E.E.
The effect of potassium orotate on the ultrastructure of cardiac muscle cells in experimental myocardial infarct.
Biull Eksp Biol Med. 1973 Apr; 75(4):105-9. Russian.

 
Changes produced in the ultrastructure of the ventricular muscle cells of the heart by potassium orotate in normal rabbits and in rabbits with experimental myocardial infarction were studied. On the 7th day of administration of potassium orotate (200 mg/kg) considerable accumulation of glycogen and activation of the muscle cell nuclei were observed. The number of nucleoli in the nucleus was increased and binuclear muscle cells were found. The decrease in the glycogen content and marked increase in elements of the rough endoplasmic reticulum and membranous structures, and the increased density of the matrix of the mitochondria observed on the 14th day of potassium orotate administration are the ultrastructural reflection of activation of the synthetic function of the muscle cells. This effect was particularly pronounced in the perinecrotic zone of the infarct.  The glycogen accumulation effect perhaps lies at the basis of the beneficial action of potassium orotate on the clinical course of myocardial infarction during the first days of disease.

 

Nikolaeva L.F., Cherpachenko N.M., Sokolova R.I., Veselova S.P., Golikow P.P.,
Effects of anabolic agents on cardiac muscle reparation in experimental myocardial infarction
“Kardiologia”, 1975, v. XY, No. 7, 78-83. Russia.


Experimental myocardial infarction by ligating the anterior descending branch of the coronary artery was produced in 276 mal Shinshilla rabbits with initial weights of 2.5 – 3.0 kg. Then, 56 animals were given inosine intravenously, 20 mg/kg once daily (first injection 2 hours post operation, the last dose – two hours prior to sacrifice); 55 rabbits received a combination of the so-called stimulants of nucleic acid syntheses (Potassium orotate 100 mg/kg a day by mouth, vitamin B12 100 mcg/kg intramuscularly, and Aminasol 35 mg/kg by intravenous drip infusion). 43 animals were given retabolil, 0.8 mg/kg intramuscularly, once or twice. 120 rabbits operated upon served as controls. The animals were sacrificed by decapitation 1, 3 or 7 days postoperatively.

Examinations: 1) nine tissue enzymes were determined histochemically in the myocardium necrosis zone and beyond it, 2) tissue histology by light microscopy and electron microscopy (the last – in 6 treated and 3 control animals); 3) myocardium catecholamine levels; 4) electrocardiography; 5) left ventricular and aortic pressure measurements. The study results demonstrated that potassium orotate, potassium orotate, and especially inosine, stimulated the reparation process in the necrosis zone due to more rapid resorption of the necrosis mass and maturation of connective tissue elements.
At the same time, an increased activity of a number of enzymes of the aerobic metabolism was observed in both perinecrotic and apparently not infarcted myocardium areas, in all the three treatment groups, these alterations being most pronounced in animals given inosine.


Zharov E.I.
The use of co-factors and precursors of nucleic acid synthesis in patients with myocardial infarction
Kardiologia (Moscow) 1971: Vol. XI, No. 11, 21-25


The study treats one of the most urgent problems of cardiology, namely the elaboration of effective means for preventing and treating cardiac failure in macrofocal myocardial infarction. Therefore patients with the disease were given a number of agents (potassium orotate 1.5 g daily, vitamin B12, and folic acid), whose beneficial action on heart contractility was ascertained in laboratory animals with experimentally induced infarctions. The patients were divided into two roughly similar groups. Those in the first one (n=101) received the co-factors and precursors of nucleic acid synthesis for two months (in addition to the conventional drug therapy), while 115 patients in the second group were given only the conventional medicines. The author employed radiocardiography to record the changes of basic hemodynamic indices. The results were obviously better in the first group that was given the additional agents. In particular there was a more rapid restoration of myocardial contractility, and lethality rate here was 15.8% against 27% in the second group

 

Kheinonen I.M., G.K. Makeeva
The influence of potassium orotate on the course of myocardial infarction
Kardiologia (Moscow) 1970; Vol. X, No. 2, 31-35


Potassium orotate (mostly combined with folic acid) was given to 40 patients (Group 1) with transmural or macrofocal myocardial infarctions, since the first few days of disease for a period of one to two months, in addition to the traditional drug therapy. The controls (Group 2) consisted of 22 similar patients and received only the conventional therapy. Improvement in myocardial contractility was more marked and rapid in the Group 1, as evidenced from clinical signs and the heart phase analysis. Significant differences in the length of the isometric contraction phase, ejection period, and intrasystolic index were noted from the 14th day, and in the values of Blumberger’s mechanical coefficient from the 21st day of the study. The more favorable clinical course and outcomes in Group 1 were corroborated by the dynamics of ECG and the death rate was comparatively lower (4.9 % in the patient treated with potassium orotate than in the control group (13.6 %)).

 
Nikolaeva L.F., Lysenko L.T., Makarova T.E.
Effects of inosine on the course of myocardial infarction
Clinic Medicine 1975, v.53, #7:50-56 Moscow


The study was performed in 150 consecutive patients with acute myocardial infarction (AMI). 72 of these received inosine (group A), and the other 78 formed the control (group B). In the initial 2 days all the patients were given the conventional pharmacological treatment.

 Tablets of inosine were used from the 1st day of the disease, 600 mg 3 times a day for 30 days. One of the tasks of this experiment was the evaluation of the action of inosine on the development of circulatory failure (CF) in patients with AMI.

The efficacy was assessed by means of clinical, electrocardiographical, radiocardiographical, and biochemical testing.

By the 10th day of the disease the proportion of patients with circulatory failure in group A decreased more significantly than in group B.

On day 1-2, 69.4% of patients in group A developed CF, in group B 61.3%.

On day 10, signs of CF was discovered in only 35.5% of patients in group A (decrease of 31.3%), and 50.2% in group B (decrease of only 11.1%).

This effect of inosine was more significant in patients over 60 years or with recurrent MI, or with pre-existing arterial hypertension.

On day 10, the percent cause of CF disease in patients over 60 years old dropt from 88.4% to 44.2%; in group B from 75% to 62.5%, respectively. 

In patients of group A with recurrent myocardial infarctions the incidence of CF diminished from initial 66.5% to 43.3% (23.3%) on day 10; in group B from 78.6% to 75% (3.6%).

In patients with pre-existing arterial hypertension of group A the CF developed in 11 of 20 persons (55%). On day 10 only 3 of them (15%) had signs of CF. In group B the corresponding values were 11 of 22 (50%) and on day 10 the CF was discovered by 7 patients (31.8%). Also, abnormalities of cardiac rhythm and intracardial conductivity recovered earlier and fuller, and cardiac and systolic indexes increased more in group A, than in group B. After 40 days mortality in group A was 5.5% (and not because of CF); in group B it was 10.2% (3 out of 8 died from CF (37.5% of all mortality).

Conclusions:

1. Inosine effectively contributed to the prevention and treatment of cardiac failure in myocardial infarction,

2. Inosine was particularly effective in myocardial infarction of aged persons, in recurrent infarction, and infarction superimposed on arterial hypertension.

                                         

N.N. Kipshidze, N.V. Murmanishvili
Indications for the use of inosine in myocardial infarction (Clinical and experimental study)
Kardiologia 1978, 18, 18-29


The effect of the nucleoside inosine on the intracardiac hemodynamics and the contraction and relaxation of a diseased myocardium was studied in the clinic and in experiments. An examination was made of  102 patients with macrofocal myocardial infarction (22 received inosine by intravenous drip in a single dose of 200 mg in the acute stage of infarction; 60 patients were given inosine pills in a daily dose of 800 mg in the restoration period for one month, and 20 patients were given placebo. Comparative appraisal of treatment in the period of rehabilitation showed prevailing improvement in the condition of individuals treated with inosine, positive ECG dynamics, increase of cardiac output and decrease of peripheral resistance. In experiments on 28 dogs with a model of acute myocardial ischemia a noticeable improvement in myocardial contraction and relaxation in the absence of negative ECG dynamics was recorded after intravenous infusion of inosine.  Inosine achieves maximum effect by 60-90 minutes after the beginning of infusion.


Golikov A.P., V.A. Karev
Stimulation of repair in myocardial infarction; comparative assessment of the effects of piracetam and inosine
Kardiologia (Moscow) 1988: Vol. XXVIII, No. 11, 46-56


A study of 102 patients with primary macrofocal myocardial infarction admitted to hospital within the first 6 hours after the onset of disease, and experimental evidence gained from 110 Wistar rats are reported. In the control group of myocardial infarction patients, collagen synthesis was depressed in the presence of activated free-radical lipid oxidation and circulatory hypoxia. Inosine treatment was associated with inhibition of the free-radical lipid oxidation and reduction of hypoxia, increased collagenogenesis and accelerated postinfarction scar formation.  Inosine, had a marked stimulating effect on the development of compensatory myocardial hypertrophy, thus contributing to sooner recovery of cardiac contractility and reducing manifestations of circulatory insufficiency.



III. Abstracts of the Effects Inosine and Orotic Acid in   Myocardiodystrophy and Coronary Atheriosclesosis

 
Belenkii, E.E., Sokolov IK, Lantsberg LA, Tunitskaia TA, Kalugina GE
Prevention of experimental adrenaline damage to the myocardium with potassium orotate
Farmakol Toksikol, 1973 May-June; 36(3):301-4. Russian


Effects of potassium orotate on some functional and morphological characteristics of the heart muscle were studied in rats with experimental epinephrine-induced myocardial damage. It was shown that previous intragastric administration of potassium orotate (100 mg/kg BW/day for 14 days) reduced animal mortality substantially and was able to prevent an increase in the heart weight, changes in the ECG and the degree of myocardial dystrophy, a drop in swimming capability, and led to normalization of the potassium and sodium levels in the cardiac tissues. Potassium chloride given in doses equal in their potassium content to the potassium orotate, failed to reproduce the effects of the latter.

 

Proschek J.
Effect of orotic acid and magnesium orotate on the development and progression of the UM-X7.1 hamster hereditary cardiomyopathy
Cardiovascular Drugs and Therapy 1998; 12:189-195; U.S.A.


This study deals with the potential therapeutic effect of orotic acid and magnesium Orotate (MgO) on myocardial degeneration and the development of congestive heart failure in cardiomyopathic (CM) hamsters.  Two major age groups (group I, < 30 days and group II > 180 days old) were used in these experiments, which lasted 30 and 50 days respectively; the orotic salts were incorporated (10%) into Purina Dog Chow. Macroscopic and microscopic assessment of pathologic changes together with ECG recordings revealed that Mg treatment significantly reduces myocardial damage. ECG recording clearly demonstrated a significant shortening of QTc and PR intervals, resulting in partial electrical stabilization of failing hearts, with a significant delay in systemic cell changes. The prevention of heart lesions was less evident in animals receiving OA, but both preparations proved to be equally efficient in prolonging survival of the CM hamsters.



Ignat’ev M.V.
Therapeutic application of potassium orotate
Kardiologia (Moscow): 1969, Vol. 9, No.12, p.91-92


Potassium orotate was used in the treatment of 23 patients (11 men and 12 women) with coronary sclerosis. Three patients were aged 50 and 59 years, and 20 patients 60 to 69 years. 22 patients had cardiac pains, the frequency and intensity of which were not constant. In 21 patients, the coronary atherosclerosis was combined with atherosclerosis of the cerebral arteries; 8 patients had a history of myocardial infarction. All the patients showed no pronounced circulatory insufficiency, particularly no liver congestion.

Potassium orotate was given in a dose of 500 mg three times a day for 20 days. Before the treatment with potassium orotate phase analyses of the heart systole and ECG recording in 12 leads were performed in each patient in the morning on an empty stomach. Then blood was taken for cholesterol analysis. These examinations were repeated on completion of the treatment course. General self-feeling, complaints of heart pains, and drug tolerance were followed during the entire course of the treatment.

According to the data of the systole phase analysis about 1/3 of the patients (8 persons) had, in the end of the treatment course, an improvement of the myocardium contractility (greater Blumberger’s mechanical coefficient, normalization of the periods of prolonged expulsion and prolonged blood pressure elevation, lowering of the elevated intrasystolic index). According to the ECG data in 3 patients, the S-T interval and the T wave returned to normal in the end of the treatment. The general self-feeling improved in 10 patients while in 13 it did not change noticeably. The cardiac pains disappeared in 7 patients and in 7 other patients they became less frequent and less intense.The patients tolerated the drug well. No side effects attributable to potassium orotate were observed.

 


Graevskaya N.D., Agranenko V.S., Belenky Y.Y., Stepanova Y.S. Yastchuk A.M.
Potassium Orotate in the Management of Cardiac Overstrain
Theoria, Practika Physich Culture 1970, 8, 29-32 (Moscow)


In view of substantial increase in exercise loads during training sessions, the sports medicine is facing the problem of identifying and preventing early abnormalities of health in athletes. [In recent years researchers concentrate their attention on the ECG syndrome of chronic cardiac overstrain (CCOS) in sports.]

 An examination of 219 leading athletes who were preparing for important competitions revealed 32 subjects with electrocardiographic and, in some cases, with clinical signs of myocardial overstrain. The relatively high percentage of subjects with the myocardial overstrain might be accounted for by intensive training in middle mountains.

Potassium orotate, 1 gm three times daily was given to 10 athletes (group 1) with electrocardiographic signs of chronic myocardial overstrain. 7 athletes present a control group.

All athletes were exposed to a complex clinical and instrumental examination with the use of electrocardiography and biochemical tests. The patients were examined 12 days after the first comprehensive examination and 9-10 days after the administration of potassium orotate. The athletes complained of poor night sleep, drowsiness, sensation of fatigue in the morning. The response to graded functional exercise remained atypical in 4 athletes. The ECG findings showed a distinct deterioration in 2, and a negligible improvement in 3 subjects. Since no distinct positive changes were attained in the athletes of this group the training intensity had to be greatly lowered in them. The ECG of the athletes of group 1 exhibited clear-cut positive changes: the voltage of the R and T waves greatly heightened in the standard and thoracic leads (for example, the mean sum of the waves in the standard leads amounted to 24 instead of 19 mm before treatment). Changes in the terminal part of the ventricular complex markedly diminished or disappeared.

The phase analysis showed an improved myocardial contractility (shortening of the phases of isometric contraction and expulsion, decreased index of myocardial effort, increased index of intrasystolic expulsion and mechanical difference).

Thus the observations reported have shown that administration of potassium orotate is conductive to elimination of ECG signs of myocardial overstrain in training athletes. It deserves mention that attempts to eliminate this overstrain with other rehabilitative measures had failed.

 


Mikunis R.I., R.Z. Morozova
The use of precursors of pyrimidine bases in patients with continuous recurrent course of rheumatism
Problems of Rheumatism 1971; No. 1, 83-86, Russia


A comparative assessment was made of two groups of patients: the one was given the conventional antirheumatic therapy including cardiac glycosides, diuretics, calcium chloride, and antibiotics. Those in the second group received the same treatment supplemented with the stimulators of nucleic acid synthesis – orotic acid, folic acid and vitamin B12. Chronocardiometric data and the dynamics of blood amino acid composition were taken as criteria in the assessment. The results obtained showed that the stimulators and precursors of nucleic acid synthesis had a favorable effect on the blood levels of the amino acids asparaginic acid and glutamine that are known to be closely associated with oxidative phosphorylation and regeneration of the myofibril apparatus of the myocardium. The significant improvement observed in the indices of phasal analysis of ventricular systole in the patients of the second group corresponded to these findings.

 

Gorbachev V.V., G.A. Vechersky, L.G. Baranov
Effect of potassium orotate on the contractile function of the myocardium in patients with coronary atherosclerosis
Clinich Medicine (Moscow) 1975; vol. LIII, No. 1, 86-90


The rheopolygraphic method was used to study the contractile function of the left and right cardiac ventricles in 130 persons including 46 healthy individuals aged 17-59 years, and 84 patients with coronary atherosclerosis aged 33-70. In 26 patients with coronary atherosclerosis the phasal structure of the ventricular systole was studied before and after treatment with potassium orotate for two to four weeks, 1,5 gm a day. A significant pre-study deterioration of the contractile function of the heart was revealed in those with coronary atherosclerosis, especially of the right ventricle, that was associated with substantial lengthening of the tension phase and shortening of the ejection phase. Potassium orotate produced a normalizing effect on the cardiac contractility in the patients. The duration of the asynchronous and isometric contraction phases, and the phase of tension decreased. The normalization of the ejection phase, accompanied by lengthening of the maximal ejection phase, and a distinct shortening of the residual ejection phase occurred. There was also a regular increase in the mechanical and electromechanical systole of the right ventricle. The Blumberger index and hemodynamic coefficient became normal.

 

Kuz’ko N.V.
The effectiveness of inosine derivatives in patients with ischemic heart disease (IHD)
Vrachednoye Delo; 1977, #8, p.9, 25-28: Kiev, USSR


The present study aimed at fining out the effects of inosine in ischemic heart disease. A total of 32 patients with IHD were included. All 32 had various grades of coronary insufficiency, complained of cardiac palpitations and intermissions, had a periodic dyspnea while fast walking or going upstairs, had nocturnal dyspnea.

Electrocardiography showed the presence of ventricular and politope extrasystoles in 8 patients. 6 had constant or paroxysmal cardiac fibrillation. 69% of the patients had deformities of the T-wave, displaced S-T intervals or diminished voltage of the R-wave. Evaluation of the contractile function of the heart revealed abnormalities in the phase structure of the left ventricular systole. Although the majority took medicines improving coronary circulation, there was no noticeable positive response.

Hypoxanthine riboside (inosine) was given in tablets of 200 mg in individually adjusted doses ranging from 600 mg to 1600 mg per day depending upon the response for 4 – 5 weeks.

By the end of the course an improvement was noted in 28 patients, which manifested itself by cessation or significant reduction of pains over the cardiac region, palpitations, dyspnea, better tolerance of physical exercise. The electrocardiograms showed increased voltage of T-waves and R-waves (in some patients), normalization of the S-T interval. 6 patients (of 8) had a cessation of ventricular and politope extrasystoles. And it was particularly noted that inosine increased the therapeutic effectiveness of cardiac glycosides. Four patients with frequent paroxysms if cardiac fibrillation had their total elimination by the end of a four-week combined treatment with inosine and cardiac glycosides, and these attacks did not reappear for 6 months of the follow-up.

Positive trends were also seen in the above parameters of the phase structure of the left ventricle contraction, indicating better myocardial contractility.

The effects of HR were earlier and more pronounced in patients with uncomplicated IHD, and also in those taking daily 1200 mg or more inosine. Severe cases of IHD required 1600-200 mg inosine a day.

It is also important to point out that inosine was more effective when combined with agents improving coronary circulation, cardiac glycosides and potassium salts (in cases with cardiac arrhythmisas).

These results suggest that inosine may be beneficial in IHD.



R.I. Mikunis, E.E. Belenky, V.K. Serkova, Yu.I. Monastyrsky (Vinnitsa)
Use of Riboxin (inosine) in the complex treatment of patients with ischemic heart disesase
Vrachebnoye Delo, 1982, 3, p 38-41

 
The authors carried out a complex clinical, biochemical and instrumental investigation of 32 patients with ischemic heart disease before and after riboxin (inosine) treatment. The biochemical indices tended to normalize.

Most patients showed a reduction of stenocardia (angina) attack incidence, disappearance of extrasystole.  Riboxin is indicated in the treatment of ischemic heart disease.

 

Geiss KR, Sterglou N, Neuenfeld HU, Jester HG
Effects of magnesium orotate on exercise tolerance in patients with coronary heart disease
Cardiovascular Drugs Therapy. 1998 Sep; 12 Suppl 2:153-6


In a pilot study at 14 patients with coronary heart disease (CHD) and left-ventricular dysfunction with ventricular enddiastolic volume [LVEDV] > or = 100ml), who actively participated in an cardiac sports group, left ventricular endsystolic volume (LVESV), LVEDV and duration on heart function analyzed by echocardiographic and ergometric tests. An initial workup was followed by a 4 week double blind treatment phase, in which 3 grams/day magnesium orotate given additionally to medication taken prior to the study. At the end of this phase a conclusion was performed. Magnesium orotate decreased significantly LVESV, increased ejection fraction EF, decreased LVEDV and increased significantly exercise duration. The study gives references to favorable effects of oral magnesium orotate to heart function and exercise tolerance in patients with CHD.

 


IV. Abstracts of the Effects of Inosine and Orotic Acid in Cardiosurgery

Munsch C, Williams J.F., and Rosenfeld F.L.
The impaired Tolerance of the Recently Infarcted Rat Heart to Cardioplegic Arrest: The Protective Effect of Orotic Acid
Journal of Molecular and Cellular Cadiology 21, 751-754 (1989)


After myocardial infaction, a reduced mass of non-infarcted myocardium remains to maintain cardiac output. This acutely stressed, non-infarcted myocardium exhibits many metabolic disturbances, and undergoes a process of acute hypertrophy. These stress-induced disturbances may reduce the tolerance of the heart to the global ischemia of caridoplegic arrest and may explain the increased mortality and morbidity associated with cardiac surgery in patients with recent myocardial infarction.

We postulated that orotic acid, a pyrimidine precursor which augments the rate of protein synthesis during hypertrophy, might improve the response of the recently infarcted heart to cardioplegic arrest.

Myocardial infarction was induced in rats by coronary ligation, and after 2 days or 3 days the hearts were excised and perfused on the working heart apparatus. After measurement of work capacity, the hearts underwent 1 hour of hypothermic cardioplegic arrest. Post-arrest function was then measured and expressed as a percentage of the pre-arrest value. A group of sham-operated, non-infarcted hearts served as controls. There were two distinct findings:

(1) when subjected to hypothermic cardioplegic arrest 2 days after myocardial infarction, hearts recovered only 49% of pre-arrest function, compared with 80% recovery in non-infarcted controls (P<0.001). Three days after infarction, recovery had improved to 68% (P<0.01 vs. days, P<0.05 vs. non-infarcted).

(2) Treatment with oral orotic acid following infarction augmented recovery from cardioplegic arrest to 83%, 2 days after infarction (P<0.001 vs. untreated) and to 87%, 3 days after infarction (P<0.01 vs. untreated).

 These findings indicate that the recently infarcted heart has reduced tolerance to global ischaemia, that orotic acid therapy improves this tolerance and hence may improve the results of urgent cardiac surgery in patients with acute myocardial infarction.


Selizarova NO, Eliseev VV, Krylova IB
Effect of purine nucleosides on the contractile function of the rat heart in ischemia and reperfusion
Patol Fiziol Eksp Ter 1994 Oct-Dec;(4):11-3


The Langendorf isolated rat hearts underwent 30-minute total ischemia followed by 60-minute reperfusion. Adenosine, inosine or guanosine was added at a concentration of 50 mumol/l into the perfusate in the first 30 minutes. The nucleotides significantly increased the developed pressure and them maximum left ventricular contractility rate. The most effective agent was adenosine which also made blood flow higher. Guanosine was more effective than adenosine and inosine in protecting the heart from ischemic contracture. At the same time adenosine augmented the arrhythmogenic effect of reperfusion, by significantly elevating the cardiac levels of diene conjugates and malonic dialdehyde. It is suggested that the arrhythmogenic effect of adenosine is the result of activated lipid peroxidation due to adenosine exchange via the xanthine reaction during nucleotide-induced vasodilation.


T. Yeh, Jr., MD, I.M. Rebeyka, MD, E.R. Jakoi, PhD, D.E. Johnson, MD, R.J. Dignan, MD, C.M. Dyke, MD, and A.S. Wechsler, MD
Orotic Acid Improves Left Ventricular Recovery Four Days After Heterotopic Transplantation


Orotic acid accelerates compensatoy myocardial hypertrophy after regional ischemia and improves left ventricular function acutely after global ischemia. In this study, the effect of orotic acid on left ventricular functions was investigated 4 days after global ischemia (75 minutes) using heterotopically transplanted rabbit hearts. Experimental animals received daily 100 mg/kg of intraperitoneally administered orotic acid, starting 1 day before transplantation, and showed a threefold disease in the serum level of orotic acid by 4 days. After four days of reperfusion, the developed pressure was depressed in both the control and experimental groups; however, 4 days later, the developed pressure in control animals was decreased by 3 ± 3 mm HG while the developed pressure in experimental animals was significantly increased by 25 ± 8 mm Hg. Heterotopically transplanted hearts manifested diminished systolic function (stemming from ischemia and unloading) as well as decreased expression of adult myosin. Because orotic acid has been observed to produce an increase in protein synthesis in other models, we investigated whether this improvement in systolic function resulted from an orotic acid-medicated augmentation (or preservation) of normal adult myosin expression. Both orotic acid-treated and untreated hearts manifested decreased expression of the ß-myosin heavy chain expression, an alternate mechanism underlying orotic acid-medicated improvement in function is implicated. Nevertheless, orotic acid may be therapeutic agent facilitating long-term recovery from global ischemia.

Fazekas T., Kadar E.
Effects of orotic acid on ischemic/reperfused myocardial function and glycogen isolated working rat hearts
Pharmacol Res. 1998 Feb; 37(2):111-4

 

The present study was carried out to investigate the effect of orotic acid on ischemic/reperfusion on myocardial function and cardiac glycogen content in isolated working rat hearts. Rats were treated intravenously with 0.01 mg/ -1 for 4 days. Hearts were then isolated and subjected to 30 min of global no-flow ischemia followed by 10 min of reperfusion. Orotic acid treatment significantly improved post-ischemic myocardium and increased pre-ischemic and post-ischemic glycogen content of the heart and left ventricular function.

Branea I, Socoteanu I, Mancas S, Sarau CA
Benefit of treatment with magnesium orotate in patients with chronic heart failure postoperative period after coronary artery by-pass grafting.
Gavan N. Hjertforum, 2001 Aug; 14(3):78

Background: Previous studies demonstrated that magnesium orotate is useful in patients with artery disease. The aim of the study is to observe the effect of magnesium orotate early postoperative period after coronary artery bypass grafting (CABG) in patients with heart failure.

Methods: We evaluated 32 patients (25 males, 7 females, 53 ±6 years old) with similar xxx parameters: left ventricular ejection fraction 25-35%, in relatively stable condition, 24-4xx CABG (6 with 2 grafts, 17 with 3 grafts, 9 with 4 grafts). The study was randomized, placebo-controlled. After inclusion, the patients were divided into 2 groups: Group A with standard medication and placebo and Group B which received standard medication plus 2 gr. magnesium orotate daily. All the patients were addressed to the cardiac rehabilitation clinic training. During the follow-up period (8 weeks), we evaluated functional capacity (Heart Failure Questionnaire and “Dyspnea-Fatigue Index”), exercise capacity (ergospirometric parameter), echocardiographic data (left ventricular ejection fraction and incidence of cardiac arrhythmia (Holter monitoring). There were no significant differences in groups regarding the baseline data.

Results: The main improvement induced by magnesium orotate is the increase in exercise duration (15.6 ±1.4 in Group B vs. 11.3-1.3 min in Group A, p<0.05). We noticed also, only in Group B, a significant decrease in the irregular of premature ventricular beats (1.9±0.4, baseline, vs. 0.7±0.3, final, p<0.05).

Conclusion: It is clear that the fragile equilibrium of hemodynamics, early postoperative ischemia, reperfusion syndrome, and the ionic imbalance by high dose of diuretics claim treatment- and this study suggests the benefit of magnesium orotate added to classical therapy in this special group of patients.