WO2008070995A1

WO2008070995A1 - Methods and treatments for prevention of acute renal failure following cardiac surgery

Info

Publication number: WO2008070995A1
Application number: PCT/CA2007/002261
Authority: WO
Inventors: Marjorie Zettler; Albert Friesen
Original assignee: Medicure International Inc.
Priority date: 2006-12-12
Filing date: 2007-12-12
Publication date: 2008-06-19

Abstract

Methods and treatments of prevention of, or reduction of risk of incidence of, acute renal failure following cardiac surgery, through administration of pyridoxal-5'-phosphate, pyridoxine, pyridoxal, pyridoxamine or a pyridoxal analogue, before, during or after the surgery. Of particular interest is when the cardiac surgery is Coronary Artery Bypass Grafting (CABG)

Description

METHODS AND TREATMENTS FOR PREVENTION OF ACUTE RENAL FAILURE FOLLOWING CARDIAC SURGERY

Field of the Invention

This invention relates to methods and treatments for prevention of, or reduction of risk of incidence of, acute renal failure following cardiac surgery. In particular, the invention relates to the administration of pyridoxal-5'- phosphate, pyridoxine, pyridoxal, pyridoxamine, or a pyridoxal analogue, before, during or after the surgery, to prevent or reduce the risk of incidence of acute renal failure arising therefrom.

Background of Invention

Acute renal failure (ARF) can be identified as the inability of the kidneys to function as they previously had. This includes inability to concentrate urine, maintain fluid balance, maintain electrolyte balance, and a reduction or loss in the ability to excrete wastes (Schrier et ah, 2004). These events may develop over the course of a few hours or their development may require a few days and lead to certain conditions known as metabolic acidosis, volume overload and hyperkalemia (Hilton, 2006).

Specific determinations and diagnoses of whether a person has acute renal failure are well known to those skilled in the art. These include an increase in serum urea (Hilton, 2006), an increase in creatinine by >0.5 mg per deciliter over the baseline value, creatinine increase of >50% of the baseline, reduced creatinine clearance of 50% and of course requirement of dialysis due to decreased function (Thadhani et al., 1996).

There are many possible causes of kidney damage causing acute renal failure, including decreased blood flow (caused by trauma, surgery, serious illnesses, septic shock, hemorrhage, burns or dehydration), acute glomerulonephritis, interstitial nephritis, acute tubular necrosis (including necrosis caused by ischemia or by toxins), certain infections, urinary tract obstruction, autoimmune kidney disease, and clotting of the thin blood vessels of the kidney. Ischemia is responsible for the majority of cases of ARF followed by toxins, interstitial nephritis and acute glomerulonephritis (Thadhani et ai, 1996).

The only known and effective treatment for severe acute renal failure, once it occurs, is dialysis. Acute renal failure is often fatal.

Despite the advent of excellent pharmaceutical compounds for the prevention of many cardiovascular diseases, cardiac surgery remains a common therapeutic intervention. There are several types of cardiac surgery, the most common being coronary artery bypass grafting (CABG).

CABG is used to effectively relieve angina, resulting in longer survival, and a better quality of life in specific subgroups of patients with obstructive coronary artery disease. Due to the high incidence of coronary artery disease worldwide, as well as the effectiveness of this surgical procedure, CABG surgery makes up one of the top ten most frequently performed procedures in North America and Europe. In the year 2000, the total volume of bypass surgery was over 280,000 in the 15 European Union countries according to the European Heart Survey and the National Registries of Cardiovascular Diseases and Patient Management. In the United States, it is estimated that over 700,000 CABG procedures are performed every year.

Despite the benefits of CABG surgery, patients undergoing these procedures may also suffer serious adverse outcomes including operative mortality, myocardial infarction, acute coronary syndrome, unstable angina, ventricular failure, life-threatening arrhythmia, acute renal failure, cognitive decline, and stroke. Some of the proposed causes of cardiovascular morbidity and mortality after CABG include perioperative ischemia, inadequate myocardial protection, and reperfusion injury. The impact of these serious complications is significant: The overall mortality after open-heart surgery ranges between 2 and 8% (Conlon, 1999, JoIm, 1999, Abel, 1996).

In particular, the impact of acute renal failure is staggering: the risk of post-operative mortality in open heart surgery patients increases exponentially among patients who develop postoperative acute renal failure, with such patients exhibiting mortality rates in excess of 60% (Thakar, 2005, Chew, 2000, Vanholder, 1996, Giorgio, 1999). When defined in its most severe form (as requiring dialysis), postoperative acute renal failure is an independent risk factor of death.

Survival rate associated with postoperative acute renal failure has remained dismal; multiple attempts at therapeutic interventions have failed to demonstrate clear benefits in either amelioration of renal injury or improved survival.

Currently the best method of prevention of acute renal failure is development of a strategy to identify those individuals who are at a greater risk of contraction such as the elderly, individuals affected by hypertension or diabetes or both, or those with chronic renal failure disease. Special care must be taken to monitor patients' blood pressure and volume status as well as avoiding non-steroid anti-inflammatory drugs (NSAIDs), nephrotic agents, angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (Hilton, 2006). Unfortunately, it is common for elderly patients to be using the previously mentioned medications. This strategy imposes a judgment call to be made by the physician with the potential of a deadly outcome.

Traditional pharmacological agents, for example low dose dopamine and diuretics, administered for renal insufficiency after cardiac surgery have been disappointing; mechanical manipulations improving blood flow with Cardiopulmonary Bypass (CPB) have been ineffective to date in eliminating renal failure (Stallwood, 2004; Garwood, 2004). Other treatments have also been suggested, including diuretic agents, natriuretic agents, vasodilators, antioxidants, growth factors, anti-inflammatory drugs and anti-apoptosis agents; however, none of these agents have been found to protect against acute renal failure (Kellum et al., 2005).

It would therefore be desirable to have a treatment method that can be used to prevent, or reduce the risk of onset of, post-operative acute renal failure. Pyridoxal-5'-phosphate (3-hydroxy-2-methyl-5-[(phosphonooxy) methyl]-4-pyridine-carboxaldehyde, or "P5P") is a naturally occurring metabolite of pyridoxine (Vitamin B6) and is formed in mammalian cells by phosphorylation and oxidation reactions. While the pharmacological activity of P5P may involve multiple mechanisms, research suggests that at least part of its cardioprotective effect may be mediated through inhibitory actions on purinergic receptors. Via this mechanism, stress-induced calcium influx is reduced thereby preventing cardiomyocyte calcium overload and death. P5P has also been shown to treat or prevent hypertrophy, congestive heart failure, ischemic heart disease, myocardial infarction, acute coronary syndrome, unstable angina, ischemia in various organs and tissues, ischemia reperfusion injuries in various organs and tissues, and cellular dysfunction, including arrhythmia and heart failure subsequent to myocardial infarction. In particular, P5P has been shown to be useful in the treatment or prevention of certain post-operative complications, such as the post-operative complications arising from bypass surgery, thrombolysis, CABG, or angioplasty. Some postoperative complications shown to be preventable or treatable with P5P include hypertrophy, myocardial ischemia, organ ischemia such as kidney ischemia, tissue ischemia, acute coronary syndrome, unstable angina, ischemia reperfusion injury, arrhythmia, conjestive heart failure, contractile dysfunction, cerebral infarction (stroke), cognitive decline, and cardiovascular death.

P5P can be chemically synthesized in a number of ways, for example, by the action of ATP on pyridoxal, by the action of phosphorus oxychloride on pyridoxal in aqueous solution, and by phosphorylation of pyridoxamine with concentrated phosphoric acid followed by oxidation.

P5P and other related compounds such as pyridoxine, pyridoxal and pyridoxamine, have been previously shown to be effective in the treatment of hypertrophy, congestive heart failure, ischemic heart disease, ischemia reperfusion injuries in an organ, and arrhythmia and contractile dysfunction subsequent to myocardial infarction. P5P has also been used therapeutically as an enzyme cofactor vitamin. P5P is described in US Patent 6,043,259, herein incorporated by reference, as having an effective enteral or parenteral dosage range of about 0.5 to about 100 mg/kg of patient body weight, for treating hypertrophy, hypertension, congestive heart failure, ischemic heart disease, ischemia reperfusion injury and cellular dysfunction.

Analogs of P5P have also been described, for example, in US patents 6,890,943, 6,417,204, 6,548,519, 6,897,228, US patent applications 09/863093, 11/016737, 10/453414, and European patent application 05019081.8, which are incorporated herein by reference.

Summary of the Invention

According to one embodiment the present invention is a method of treating, preventing, or reducing the probability of onset of acute renal failure in a mammal at risk of or having acute renal failure, comprising administering a therapeutic amount of pyridoxine, pyridoxal-5'-phosphate, pyridoxal, a pyridoxal analogue, or pyridoxamine.

In a further embodiment, the mammal is at risk of acute renal failure, and the compound is administered prior to, following, or during cardiac surgery. For example, the cardiac surgery may be bypass surgery, thrombolysis, Coronary Artery Bypass Grafting (CABG), or angioplasty.

According to one embodiment of the present invention, the compound is P5P.

In a further embodiment, the administration is an oral administration.

In a further embodiment, wherein the administration is an oral administration, the therapeutic amount is between about 1-10 mg/kg of the mammal's body weight per day.

In yet a further embodiment, the mammal is a human, the administration is an oral administration, and the therapeutic amount is in a range of about 100 mg per day to about 1000 mg per day. In one embodiment, such amount is 200 to 300 mg per day. In another embodiment, such amount is 250 mg/day. In another embodiment, such amount is 750 mg/day.

In yet a further embodiment, the administration is a parenteral administration.

In a further embodiment, wherein the administration is a parenteral administration, the therapeutic amount is in a range of about 0.01 to about 5.00 mg/kg, preferably about 0.05 to about 2.50 mg/kg and more preferably about 0.071 to about 1.14 mg/kg of the mammal's body weight per day.

In yet a further embodiment, wherein the administration is a parenteral administration and the mammal is a human, the therapeutic amount is in a range of about 1.00 mg per day to about 100.00 mg per day, preferably about 5.00 mg per day to about 80.00 mg per day.

In a further embodiment, wherein the adminstration is a parental administration and the mammal is a human, the therapeutic amount is about 5.00 mg per day.

In a further embodiment, the parenteral administration is an intravenous administration. In a further embodiment, the intravenous administration is a bolus injection, or a continuous injection.

According to a further aspect of the present invention is the use of a compound selected from pyridoxine, pyridoxal, pyridoxal-5'-phosphate, a pyridoxal analogue, or pyridoxamine in the preparation of a medicament for use in prevention, reduction of probability of onset, or treatment of acute renal failure.

According to a further aspect of the present invention is the use of pyridoxal-5'-phosphate in the preparation of a medicament for use in the prevention of post-operative acute renal failure.

According to a further aspect of the present invention is the use of a therapeutically effective amount of a compound selected from pyridoxine, pyridoxal, pyridoxal-5'-phosphate, a pyridoxal analogue, or pyridoxamine for the treatment, reduction of probability of onset, or prevention of acute renal failure in a patient in need thereof.

According to a further aspect of the present invention is the use of a therapeutically effective amount of pyridoxal-5'-phosphate for the prevention of post-operative acute renal failure in a patient in need thereof.

According to a further aspect of the present invention is a kit comprising: (a) a pharmaceutical preparation for oral administration comprising a compound selected from pyridoxine, pyridoxal, pyridoxal-5'- phosphate, or pyridoxamine; (b) instructions for the administration of said preparation, said instructions specifying that said preparation should be administered before, during or after a heart procedure

In one embodiment of the present invention, the instructions further specify that the heart procedure is one of bypass surgery, thrombolysis, CABG, or angioplasty.

In a further embodiment of the present invention, the instructions further specify that said preparation should be administered in a dosage range of about 200 mg to about 300 mg per day.

In a further embodiment of the present invention, the instructions further specify that said preparation should be administered in a dosage of about 250 mg per day.

In a further embodiment of the present invention, the instructions further specify that said preparation should be administered in a dosage of about 750 mg per day.

According to a further aspect of the present invention is a kit comprising : (a) a pharmaceutical preparation for parenteral administration comprising a compound selected from pyridoxine, pyridoxal, pyridoxal-5'- phosphate, or pyridoxamine; (b) instructions for the administration of said preparation, said instructions specifying that said preparation should be administered before, during or after a heart procedure. In a further embodiment of the present invention, the instructions further specify that the heart procedure is one of bypass surgery, thrombolysis, CABG, or angioplasty.

In a further embodiment of the present invention, the instructions further specify that said preparation should be administered in a dosage range of about 1.00 mg to about 100.00 mg per day, preferably 5.00 mg to about 80.00 mg per day.

In a further embodiment of the present invention, the instructions further specify that said preparation should be administered in a dosage of about 5.00 mg per day.

According to a further aspect of the present invention is a pharmaceutical composition for administration to a patient before a cardiac surgery, comprising (a) P5P, and (b) one or more additional compounds selected from the group consisting of an adenosine diphosphate receptor antagonist, a glycoprotein Ilb/IIIa receptor antagonist and an anti-coagulant.

Detailed Description

The present inventors have surprisingly found that administration of P5P is effective in reducing incidences of post-operative acute renal failure. Specifically, the present inventors have found that administration of P5P prior to, during, and after CABG open heart surgery reduced incidences of postoperative acute renal failure. The inventors therefore have found that administration of P5P (and in another embodiment all P5P related compounds, such as pyridoxine, pyridoxal, pyridoxamine, and pyridoxal analogues) are effective in preventing, and/or reducing the probability of incidence of, post- cardiac surgery acute renal failure.

The inventors have also found that an oral administration of a dosage range of 250 mg per day, or 750 mg per day, in humans, is effective, and a dosage range of 100 mg per day to 1000 mg per day, administered orally, or a pharmacokinetically equivalent dosage administered parenterally, for example, an IV dosage providing a mean AUC_(0-24h) of about 5.00 to about 80.00 mg IV bolus, is effective in reducing post-operative acute renal failure, and morbidity and mortality caused thereby. The inventors have found that such administration is appropriate pre- and post-operative treatment protocol for any form of invasive or open heart surgery, such as CABG. Other dosage and delivery regimens, as have been taught in the art for other therapeutic uses of P5P and related compounds, are also taught. For example, oral dosages of P5P of 0.5 - 100 mg/kg/day have are also taught herein as useful for preventing acute renal failure.

"Treatment" and "treating" as used herein include preventing, inhibiting, reducing the probability of onset of, and alleviating, acute renal failure. Thus a composition of the present invention can be administered in a therapeutically effective amount to a patient before, during, and/or after acute renal failure arises. As an example, for instance, a composition of the present invention can be administered prior to open heart surgery to prevent, inhibit, reduce the probability of onset of, or protect against, acute renal failure. Dosages, and a "therapeutic amount" for P5P related compounds, such as pyridoxal, pyridoxamine and pyridoxine, can be readily determined, applying the present teachings to the known dosage and safety/effectiveness of these compounds.

In one aspect, the invention is directed to a method of treating, preventing, reducing the probability of onset of, or protecting against, acute renal failure in mammals comprising administering to the mammal a therapeutic amount of a compound selected from the group consisting of pyridoxal-5'-phosphate, pyridoxine, pyridoxal, pyridoxal analogues, and pyridoxamine. The treatment, prevention reduction of probability of onset of, or protection can be treatment, prevention or protection of acute renal failure caused by, or resulting as a complication of, surgery, for example, open heart surgery such as CABG.

A "therapeutic amount" as used herein can include a prophylactic amount, for example, an amount effective for preventing or protecting against acute renal failure, and amounts effective for alleviating or healing acute renal failure. Orally administering a therapeutic amount of the compound for treating acute renal failure can be in any known therapeutic dosage range, for example, in the range of about 0.5-100 mg/kg of a patient's body weight per day, for example, 1-10 mg/kg of a patient's body weight, such as in the range of about 100-1000 mg, per daily dose, the range of about 200-300 mg per daily dose, about 250 mg per daily dose, or about 750 mg per daily dose.

Parenterally administering a therapeutic amount of the compound for treating acute renal failure can be in any known therapeutic dosage range, for example, in the range of about 0.01 to about 5.00 mg/kg, preferably about 0.05 to about 2.50 mg/kg and more preferably about 0.071 to about 1.14 mg/kg of a patient's body weight, such as in the range of about 1.00 mg to about 100.00 mg per day, preferably about 5.00 mg to about 80.00 mg per daily dose or about 5.00 mg per daily dose.

The compound may be administered for periods of short and long durations depending on the condition treated. The compound can be administered prior to, during, or after the surgery. The compound may, for example, be administered for the remaining life of the patient, or administration may stop shortly after surgery.

By way of illustration, the following describes administration to a human of a pharmaceutical composition containing P5P for prevention of acute renal failure. When a human is presented for a heart procedure, for example, bypass surgery, CABG, thrombolysis, or angioplasty, or for a procedure requiring interruption of blood flow to an organ, an aqueous solution comprising P5P in a therapeutic amount can be given intravenously, immediately prior to surgery and then throughout a patient's hospitalization. Alternatively, a pharmaceutical composition comprising P5P can be given immediately prior to surgery via oral administration and then continuously for up to 30 days following surgery via oral administration.

For example, the composition comprising P5P can be combined with a known cocktail of drugs to be administered to a patient prior to, during or after a cardiac surgery. Similarly, a patient may be administered an oral or parenteral dose of P5P beginning with the onset of symptoms of acute renal failure through the surgical procedure. Furthermore, a person known to be at risk for acute renal failure for any other reason, such as ischemia, exposure to a toxin, or low blood pressure, may be administered a regular oral or patenteral dose of P5P to protect against, or decrease the risk of onset of, acute renal failure.

A pharmaceutical composition of the present invention is directed to a composition suitable for the prevention of onset, reduction in the probability of onset, or treatment of acute renal failure. A pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound selected from the group consisting of pyridoxal-5'-phosphate, pyridoxine, pyridoxal, pyridoxal analogues, and pyridoxamine. A pharmaceutically acceptable carrier includes, but is not limited to, physiological saline, ringers, phosphate buffered saline, and other carriers known in the art. Pharmaceutical compositions may also include stabilizers, anti-oxidants, colorants, and diluents.

Pharmaceutically acceptable carriers and additives are chosen such that side effects from the pharmaceutical compound are minimized and the performance of the compound is not canceled or inhibited to such an extent that treatment is ineffective. A selected compound may be P5P. Advantageous pharmaceutical compositions include those that are made specifically for the oral treatment dosage levels discovered herein, for example, a pharmaceutical composition for oral administration comprising about 250 mg of P5P or an other compound of the invention, a pharmaceutical composition for oral administration comprising about 750 mg of P5P or another compound of the invention, or a pharmaceutical composition for oral administration comprising about 100 to about 1000 mg of P5P or another compound of the invention.

Other advantageous pharmaceutical compositions include those that are made specifically for the parenteral treatment dosage levels discovered herein, for example, a pharmaceutical composition for parenteral administration comprising preferably about 5.00 mg of P5P or another compound of the invention, or a pharmaceutical composition for parenteral administration comprising preferably about 5.00 mg per day to about 80.00 mg of P5P or another compound of the invention.

Pharmaceutical compositions may be administered orally and parenterally. Parenteral administration includes subcutaneous, intramuscular, intradermal, intramammary, intravenous, and other administrative methods known in the art. Parenteral administration may be bolus or continuous infusion. Oral administration includes enteral administration of solution, tablets, sustained release capsules, enteric coated capsules, and syrups. When administered, the pharmaceutical composition should be at or near body temperature.

Methods of preparing pharmaceutical compositions containing a pharmaceutically acceptable carrier and a therapeutic compound selected from P5P, pyridoxine, pyridoxal and pyridoxamine are known to those of skill in the art and described in US patent applications 11/288971, and 60/785,594, and PCT patent applications PCT/CA2005/001810 and PCT/CA2006/000467, which are included herein by reference.

The invention also includes pharmaceutically acceptable salts of the compounds of the invention. The compounds of the invention are capable of forming both pharmaceutically acceptable acid addition and/or base salts. Pharmaceutically acceptable acid addition salts of the compounds of the invention include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and di-carboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate, n-methyl glucamine, etc. (see Berge et al., J. Pharmaceutical Science, 66: 1-19 (1977). The term "pharmaceutically acceptable salts" also includes any pharmaceutically acceptable base salt including, but not limited to, amine salts, trialkyl amine salts and the like. Such salts can be prepared by those skilled in the art using standard techniques.

The acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention. Base salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines are N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms which may be defined in terms of absolute stereochemistry as (R)- or (S)-. The present invention is meant to include all such possible diastereomers and enantiomers as well as their racemic and optically pure forms. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise all tautomeric forms are intended to be included. U.S. Patent No. 6,339,085 and U.S. Patent No. 6,861,439 are herein incorporated by reference.

As an illustration, a method of preparing a pharmaceutical composition containing P5P will be described. Generally, a P5P solution may be prepared by simply mixing lyophilized P5P with water for injection at a temperature of at least room temperature and under sterile conditions. Preferably, a P5P solution is prepared immediately prior to administration to the mammal. However, if a P5P solution is prepared at a time more than immediately prior to the administration to the mammal, the prepared solution should be stored under sterile, refrigerated conditions. Furthermore, because P5P is light sensitive, a P5P solution should be stored in containers suitable for protecting a P5P solution from the light, such as amber-colored vials or bottles or syringes with sticker or opaque coverings. Each amber colored vial or bottle can contain P5P or another compound of the invention, for example, 250 mg, or 750 mg or from about 200 to about 1000 mg of P5P or another compound of the invention, for oral use. Alternatively, for parenternal use, each amber colored bottle or vial can contain P5P or another compound of the invention, for example, preferably about 5.0 mg, or preferably from about 5.00 to about 80.00 mg of P5P or another compound of the invention.

For illustrative purposes, a beneficial effect of administering P5P is demonstrated in the specific examples detailed below. Although the examples below discuss "high risk" patients, in another embodiment, the invention is useful for all patients.

Examples

Example 1 : Ability of P5P to protect against acute renal failure following cardiac surgery

The ability of P5P to protect against acute renal failure following CABG surgery was evaluated.

A randomized, double-blind placebo-controlled, dose-ranging, parallel- arm multi-center study was undertaken, on high-risk patients undergoing

CABG surgery with cardiopulmonary bypass-MEND-CABG (Tardiff et al., 2007) Patients were identified as "high risk" if they had two or more of the following risk factors:

Age greater than 65 years

Diabetes mellitus

History of congestive heart failure

History of a previous non-disabling stroke, transient ischemic attack, or carotid endarterectomy

Prior CABG surgery

Urgent CABG intervention defined as the need to stay in the hospital (although the patient may be operated on whithin a normal scheduling routine).

History of myocardial infarction that occurred more than 48 hours but less than 6 weeks prior to CABG surgery

Presence of at least one asymptomatic carotid artery stenosis (>50% ) either in one or two carotid arteries.

Approximately 900 high risk pre-CABG patients in 42 different treatment centers in North America were screened and randomized to three groups of approximately 300 patients each, prior to their bypass surgery, as follows. Patients were either placed in a control group (placebo), treated with 250 mg/day of P5P, (250 mg/day), or treated with 750 mg/day of P5P (750 mg/day).

The first dose of study medication was administered at 3-10 hours prior to CABG surgery. In the event of surgery delay or rescheduling, a second preoperative dose of P5P was administered so that all patients received study medication 3-10 hours before surgery. Treatment continued for 30 days after surgery (post operative day (POD) 30). Patients received follow-up evaluations up to and including postoperative day (POD) 4, on POD 30 and on POD 90. Incidences of acute renal failure reported as serious adverse effects were tabulated. A person was characterized as having acute renal failure if a serum creatinine value of > 250 micromol/L or > 2.8 mg/dL was measured. Patients in the 250 mg/day group exhibited approximately 50% lower total incidences of acute renal failure than those in the placebo group. Patients in the 750 mg/day group exhibited approximately 66% lower total incidences of acute renal failure than those in the placebo group.

The Example showed that administration of P5P reduced the total incidences of acute renal failure. See Table 1

Table 1 : Acute Renal Failure

References:

Abel RM et al., Etiology, incidence and prognosis of renal failure following cardiac operations, results of a prospective analysis of 500 consecutive patients. J. Thorac Cardiovasc Surg 1996:71 :323-3

Chew ST et al., Preliminary report ono the association of apolipoprotein E polymorphisms, with postoperative peak creatinine concentrations in cardiac surgical patients. Anethesiology 2000; 93(2):325-31

Conlon, PI et al. Acute renal failure following cardiac surgery. Nephrol Dial Transplant 1999: 14(5): 115-9

Giorgio et al. Acute renal failure in the patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1999; 107(6): 1489-95. JoIm et al., Management of acute renal failure complicating cardiac surgery. Crit Care Med 1999; 8(10) :562-9

Tardiff, Jean-Claude;Carrier, Michel; Kandzari, David E; Emory, Rober; Cote, Robert; Heinonen, Therese; Zettler, Marjorie; Hasselblad, Vic; Guertin, Marie Claude; and Harrington, Robert A. Effects of pyridoxal 5'-phosphate (MC-I) in patients undergoing high-risk coronary artery bypass surgery: Results of the MEND-CABG randomized study. J Thorac Cardiovasc Surg (2007); 133: 1604- 11.

Thakar et al., A clinical score to predict acute renal failure after cardiac surgery. J Am Soc Nephrol. 16: 162-168, 2005

Vanholder R et al. Pathophysiology of acute renal failure. In: Choice of dialysis membranes for acute renal failure. International yearbook of nephrology 1996: 12: 107-116

Claims

We claim:

1. A method of treating, preventing, or reducing the probability of onset of acute renal failure in a mammal at risk of or having acute renal failure, comprising administering a therapeutic amount of a compound selected from the group consisting of pyridoxine, pyridoxal-5'-phosphate, pyridoxal, a pyridoxal analogue, and pyridoxamine.

2. The method of claim 1, wherein the mammal is at risk of acute renal failure, and said compound is administered prior to or during cardiac surgery.

3. The method of any one of claims 1-2, wherein the mammal is at risk of acute renal failure, and said compound is administered following cardiac surgery.

4. The method of any one of claims 2-3, wherein the cardiac surgery is selected from the group consisting of bypass surgery, thrombolysis, Coronary Artery Bypass Grafting (CABG), and angioplasty.

5. The method of claim 4, wherein the cardiac surgery is CABG.

6. The method of any one of claims 1-5, wherein the compound is pyridoxal-5'-phosphate.

7. The method of any one of claims 1-6, wherein administration is an oral administration.

8. The method of claim 7, wherein said therapeutic amount is between about 1-10 mg/kg of the mammal's body weight per day.

9. The method of claim 8, wherein the mammal is a human and said therapeutic amount is in a range of about 100 mg per day to about 1000 mg per day.

10. The method of claim 9, wherein said therapeutic amount is in a range of about 200 mg per day to about 300 mg per day.

11. The method of claim 10, wherein said therapeutic amount is about 250 mg per day.

12. The method of claim 9, wherein said therapeutic amount is about 750 mg per day.

13. The method of any one of claims 1-7, wherein the administration is a parenteral administration.

14. The method of claim 13, wherein said therapeutic amount is in a range of about 0.01 to about 5.00 mg/kg of the mammal's body weight.

15. The method of claim 14, wherein said therapeutic amount is in a range of about 0.5 to about 2.50 mg/kg of the mammal's body weight.

16. The method of claim 15, wherein said therapeutic amount is in a range of about 0.071 to about 1.14 mg/kg of the mammal's body weight per day.

17. The method of claim 13, wherein the mammal is a human and said therapeutic amount is in a range of about 1.00 mg per day to about 100.00 mg per day.

18. The method of claim 17, wherein the mammal is a human and said therapeutic amount is in a range of about 5.00 mg per day to about 80.00 mg per day.

19. The method of claim 18, wherein the mammal is a human and said therapeutic amount is in a range of about 5.00 mg per day to about 40.00 mg per day.

20. The method of claim 19, wherein said therapeutic amount is about 5.00 mg per day.

21. The method of any one of claims 13-20, wherein the parenteral administration is an intravenous administration.

22. The method of claim 21, wherein the intravenous administration is a bolus injection.

23. The method of claim 21, wherein the intravenous administration is a continuous injection.

24. Use of a compound selected from the group consisting of pyridoxine, pyridoxal, pyridoxal-5'-phosphate, a pyridoxal analogue, and pyridoxamine in the preparation of a medicament for use in prevention, reduction of probability of onset, or treatment of acute renal failure.

25. Use of pyridoxal-5'-phosphate in the preparation of a medicament for use in the prevention of post-operative acute renal failure.

26. Use of a therapeutic amount of a compound selected from the group consisting of pyridoxine, pyridoxal, pyridoxal-5'-phosphate, a pyridoxal analogue, and pyridoxamine for the treatment, reduction of probability of onset, or prevention of acute renal failure in a patient in need thereof.

27. Use of a therapeutic amount of pyridoxal-5'-phosphate for the prevention of post-operative acute renal failure in a patient in need thereof.

28. A kit comprising:

(a) a pharmaceutical preparation for oral administration comprising a compound selected from the group consisting of pyridoxine, pyridoxal, pyridoxal-5'-phosphate, and pyridoxamine;

(b) instructions for the administration of said preparation,

said instructions specifying that said preparation should be administered before, during or after a heart procedure.

29. The kit of claim 28, wherein the instructions further specify that the heart procedure is one of bypass surgery, thrombolysis, CABG, or angioplasty.

30. The kit of any one of claims 28 or 29 wherein the instructions further specify that said preparation should be administered in a dosage range of about 200 mg to about 300 mg per day.

31. The kit of claim 30, wherein the instructions further specify that said preparation should be administered in a dosage of about 250 mg per day.

32. The kit of any one of claims 28 or 31, wherein the instructions further specify that said preparation should be administered in a dosage of about 750 mg per day.

33. A kit comprising :

(a) a pharmaceutical preparation for parenteral administration comprising a compound selected from the group consisting of pyridoxine, pyridoxal, pyridoxal-5'-phosphate, and pyridoxamine;

(b) instructions for the administration of said preparation,

34. The kit of claim 33, wherein the instructions further specify that the heart procedure is one of bypass surgery, thrombolysis, CABG, or angioplasty.

35. The kit of any one of claims 33 or 34, wherein the instructions further specify that said preparation should be administered in a dosage range of about 1.00 mg to about 100 mg per day.

36. The kit of claim 35, wherein the instructions further specify that said preparation should be administered in a dosage range of about 5.00 mg to about 80 mg per day.

37. The kit of claim 36, wherein the instructions further specify that said preparation should be administered in a dosage range of about 5.00 mg to about 40 mg per day.

38. The kit of claim 37, wherein the instructions further specify that said preparation should be administered in a dosage of about 5.00 mg per day.

39. A pharmaceutical composition for administration to a patient before a cardiac surgery, comprising (a) P5P, and (b) one or more additional compounds selected from the group consisting of an adenosine diphosphate receptor antagonist, a glycoprotein Ilb/IIIa receptor antagonist and an anticoagulant.