WO1999021544A1 - Novel pharmaceutical alpha-keto carboxylic acid compositions, method of making and use thereof - Google Patents

Abstract

A pharmaceutical composition comprising as an active phosphorylation potential enhancing substance and an alpha-keto carboxylic acid or a pharmaceutically-acceptable salt thereof, its use and products containing the same.

Description

NOVEL PHARMACEUTICAL ALPHA-KETO CARBOXYLIC ACID COMPOSITIONS METHOD OF MAKING AND USE THEREOF

I. GOVERNMENT INTEREST

This Invention described herein may be manufactured, licensed and used by or for the United States Government without the payment of any royalties to us thereon. The Federal Government has a nonexclusive nontransferable, irrevocable, paid-up license to practice _or.have_practiced for or on behalf of the United States any subject invention throughout the world.

I . A CROSS REFERENCE

This application. is a continuation in part of U. S . Serial No . 08/239 , 635 filed May .9 , 1994 .

II. TECHNICAL FIELD QP THF INVENTION

The invention is in the field of protecting, preserving and restoring normal cell functions_. More specifically ii is in the field of using alpha-keto carboxylⁱc acⁱd compositions as prophylactic and therapeutic agents to prevent the deterioratⁱon or promo:. the restoration and preservation of normal cell functions.

HI. BACKGROUND OF THF INVENTION

Pyruvate is the key glycoivtic intermediate of all mammalian cells. As discussed ir more detail below_, this substance and pharmaceutically acceptable derivatⁱves thereo. are useful as biological stimulating agents.

1) Pvruvatc compartmentalization and cytoplasmic phosphor^ylatⁱon potentⁱal: Intracellular^* pyruvate is usually derived from glucose, i.e. it is a key glycolyt.c ⁱntermedⁱate of all mammalian cells. It can also be formed from extracellular lactate vⁱa the lactate dehydrogenase reaction. In situations where pyruvate is employed as an exogneous metabolⁱc substrate, i.e. where its extracellular concentration is sufficiently raised, pyruvate functⁱons as a precursor of lactate by reversing the lactate dehydrogenase reaction. Further ⁱn contrast to alternative metabolic fuels such as acetate and also lactate, pyruvate has recently been established by applicant as an agent that consistently improves key indⁱces of the cytoplasmⁱc phosphorylation potential of creatine phosphate (ratios of the concentratⁱons of creatⁱne phosphate (CrP) to inorganic phosphate (?d, to that of creatine (Cr), or to ft product of the concentrations of creatine and inorganic phosphate, [CrP]/([Cr]T Pι]); ¹ ι formal ly s.m.lar concentration ratio is the phosphorylation potential of ATP, [ATP]/([ADP]*[PJ), whⁱch ⁱs coupled to and in most cases in equilibrium with [CrPrøCrHPJ), an effect medⁱated by the powerful magnesium- and pH- dependent enzyme creatine kinase; this enzyme ⁱs presen ⁱn high concentrations in striated and smooth muscle (heart, vascular smooth muscle, skeletal muscle) and brain, but not in liver and kidney. [ATPJ/([ADPJ*[PJ) is a major determinant of the actual free energy available from cellular ATP hydrolysis according to the following equation:

A G_ATP= A G°_ATP+R-T-ln([ADP] fP/[ATP]) in which A G°_ATP is the (relatively constant) standard free energy change of ATP hydrolysis under conditions prevailing in vivo ( -32.35 kJ/mol, pH 7.2, free cytoplasmic magnesium concentration < 1 mM), R = gas constant (8.314 J/K*moI) and T = absolute temperature in degrees Kelvin (K). Thus, during alterations of physiologic states and under many pathophysiological states investigated so far, [ATP]/([ADP]*^rPJ) can change considerably, whereas the G°_ATP -term changes relatively little.

Pyruvate, administered in doses between 2 to 10 mM, has recently been demonstrated by applicant to raise the phosphorylation potential in a dose-dependent manner in normal, but especially in reversibly damaged (ischemia/reperfusion protocols) heart models of guinea pig, dog and pig. Thus, pyruvate administration can somewhat (by about 4 to 6 %) improve the free energy available for cellular phosphorylations and energy consuming ion transporters as well.

Pyruvate is centered at the compartmental interface between cytoplasma and mitochondria; applicant has recently shown that it is linked via the cytoplasmic NADVNADH system (which is under the joint control of two major cytoplasmic dehydrogenases, the lactate dehydrogenase and the gIyceraidehyde-3-phosphate dehydrogenase) to the cytoplasmic phosphorylation potential. Thus, pyruvate is coupled to (ATP]/([ADP]*[P_j3) in 'ts capacity as substrate of lactate dehydrogenase, which can affect the NADVNADH system which in turn is stoichiometrically coupled the combined glyceraldehyde-3-phosphate dehydrogenase/ 3-phosphoglycerate kinase reaction; the latter enzyme system involves ATP, ADP, and Pj as reactaπts, i.e. is linked directly to the cytoplasmic [ATP]/([ADP]*[Pj]) rather than the CrP phosphorylation potential, [CrP]/([Cr]*[PJ). In practice, [ATP]/([ADP]*[PJ) is usually determined using the [CrPJ/([Cr]* PJ)_f but applicant has demonstrated that it also can be estimated using the reactants of the glyceraIdehyde-3-phosphate dehydrogenase combined with those of the lactate dehydrogenase.

2) Pyruvate dehydrogenase: Pyruvate is also the immediate substrate of the powerful mkochondrial pyruvate dehydrogenase enzyme complex (PDH), the main mechanism that controls entry of carbohydrate and lactate carbon into the citric acid cycle for end-oxidation (formation of water and carbon dioxide) coupled with oxidative phosphorylation (formation of ATP from ADP and inorganic phosphate). In addition, pyruvate, not lactate or acetate, is auto-catalytically active at the PDH enzyme complex; thus pyruvate stimulates covalent modification (dephosphorylation) of the interconvertible PDH complex, which results in increased activity of the PDH; this in turn stimulates oxidative decarboxylation of pyruvate to acetyl-CoA and carbon dioxide and hence facilitates complete conversion of cellular glucose-

during ischemia [1], it becomes evident that pyruvate- vⁱa ⁱts oxy .z.n_c _- e instrumental could be instrumental in maintaining -^^ϊS^ SSS^

the cytoskeletal apparatus [17] which can jeopardize the physical ⁱntegrⁱty and sturdⁱness

normal physiologic functon. PHQSPHORYLATIO POTENTIAL

The metabolite ratio IATP]/([ADP]* [P,]), termed the phosphorylation potential, determines cellular ionic pumps/gradients and the output of mechanical muscle energy (cross-bridge cycling). These reactions always produce free inorganic phosphate thereby providing chemical energy due to hydrolysis of ATP. [ATP]/([ADPj* [P,]) influences the extent of such ender onic reactions, not the rate or velocity of these reactions. The phosphorylation potential is effective via the hydrolytic energy available from A TP, which in turn is greatly influenced by mitochondrial function in the form of oxidative phosphorylation. (ATPJ/([ADPJ* [P,]) it is not dependent upon second messengers such as cyclic nucleotides or inositol phosphates.

ATP is the immediate energy source of chemical hydrolysis energy for all major cellular activities which combine to sustain cellular sodium and calcium homeostases and specific cellular functions. For example in muscle the most important physiologic function is contraction and relaxation, in neurons and glandular cells these functions are electrical and secretory activities, in liver hepatocytes they are protein/hormone synthesis and detoxifications, in kidney it is the sodium and glucose transpoπ against concentration gradients. The actual amount of energy available from ATP under a given cellular milieu, i.e. the free energy change of ATP hydrolysis is dependent upon the energy level of ATP. This energy level is mainly determined by the phosphoiylation potential, i.e. the metabolite ratio [ATP]/([ADP]^* [P,]) according to the formula for the Gibbs-free energy of ATP hydrolysis termed ΔG_ATP :

ΔG_ATP = ΔG°_AT? + R*T*ln( [ADP]* [P,]/[ATP]) where ΔG°_A7? is the standard free energy change (-7.73 kcaI/moI=-32.3 kJ/mol at 38⁰C, ionic strength = 0.25) which is nearly constant under most physiologic conditions and likely also under many reversible pathological conditions provided intracellular free magnesium level and intracellular pH are also near normal. R=gas constant (1.98 cal/mol*K), T=absoIute temperature =273°C +37°C=3.10 K for normal body temperature.

ΔG_Aπ is normally between 55 to 60 kJ/mol in mammalian cells, while [ATP]/([ADPJ* [P,]), the phosphorylation potential, varies greatly as a function of the physiologic or pathologic states with values, in the myocardium, ranging between about 5,000 per mol during extreme stress and deenergization and 50,000 to 100,000 per mol during rest and the absence of physiologic work loads.

The phosphorylation potential, [ATP]/([ADP]* [P,]), is stoichiometrically involved in the chemical reactions of vital cellular ion pumps, especially the sodium pump (Na^*,K^*-ATPase) and the calcium pumps (Ca^2*-ATPases at sarcoplasmic reticulum and cell membrane). These reactions are not dependent on second messengers, instead they are governed by mass-action relationships. The [ATP]/([ADP]* [P,]) is thus crucial for ion homeostasis as its value is a determinant of the distribution of sodium across the cell membrane and that of calcium across the SR membrane as well. [ATP]/([ADP]* [P,]) does not determine the rates or velocity of these ion pump reactions, rather it determines the distribution of the ions across the cellular boundary at which they are strategically located. [ATP]/([ADP]* [P,]) thus determines the extent of these endergonic processes thereby creating the ionic gradients across cellular membranes.

[ATP]/([ADPj* [P,]) is also stoichiometrically involved in muscular contraction providing the energy for cross-bridge cycling and hence the energy for contractile force and hydraulic work- output of the muscle. -9- P T/US9 /16141

PROTEIN PHOSPHORYLATION

Protein phosphorylation in contrast afFects cellular metabolism and function mainly as a consequence of the activity ot second messenger-dependent kinases. These kinases alter the state of phosphorylation of target regulatory proteins (troponin I, phospholamban), key 'interconvertible' metabolic enzymes (glycogen phosphorylase, glycogen synthetase, phosphofructokinase, pyruvate dehydrogenase complex), ion channels, receptors, and contractile proteins (troponin T, myosin light chain). These kinase-dependent protein/enzyme/ receptor/channel phosphorylations are not accompanied by liberation of inorganic phosphate or free energy and, except for pyruvate dehydrogenase phosphorylation, require for maximal activity the presence of a second messenger. Phosphorylation of target proteins/key metabolic enzymes/channels/receptors usually leads to altered rates of reactions via changes in affinities (K_M) and maximum velocities (V^). Thus troponin I and phospholamban phosphorylations increase the rate of contraction in heart muscle whereas pyruvate dehydrogenase phosphorylation decreases V^ of oxidative decarboxylation of pyruvate, i.e. the rate of entry of carbohydrate carbon into the citric acid cycle. As for reasons of stoichiometry the degree of phosphorylation is also partially influenced by the level of the [ATP]/[ADP] ratio, which in turn is an integral constituent of [ATP]/([ADP]* [P,]), it is possible, if not likely that the phosphorylation potential can influence protein phosphorylation independent of second messengers. This mechanism simply follows from the mass-action equation of kinase reactions (however, to date there is only very sporadic evidence for this mechanism in the literature).

INDICATORS OF PHOSPHORYLATION POTENTIAL

[ATP]/([ADPJ* [P,]) cannot be readily and directly measured because the concentrations of ADP in the cytopiasma is below the detection limit of, e.g., nuclear magnetic resonance technology, but also below the detection limit of enzymatic-optic and HPLC techniques. Further complicating the direct measurement of [ATP]/([ADP]* [P,]) is the fact that at least in muscle most of ADP is bound to actin. Measurements of totatl muscle ADP thus grossly overestimates the thermodynamically relevant free ADP concentration, the term that appears in the [ ATP]/([ ADPJ * [P,]). However, there are at least four readily measurable indicators of [ ATP ]/([ ADPJ* [P,]) that can be used to assess the level and/or directional change of [ATPj/([ADP]* [P,]). These indicators are briefly discussed below.

1⁾ fCrPl/iTCrl* fP.l) ratio

[ATP]/([ADP]* [P,]) is stoichiometrically linked to the [CrP]/([Cr]* [P,]) ratio via the powerful creatine kinase reaction. This is true for muscle, brain and endothelium, i.e. cellular systems that contain the creatine kinase enzyme system. Therefore, in these tissues, [ATP]/([ADP]* [P,]) can be assessed by measuring the reactants of creatine kinase (creatine phosphate, creatine, H^") and inorganic phosphate.

2) rGAPl*fPYRVtT3PGl* fLACl) ratio

[ATPJ/([ADP]* [P ) is also stoichiometrically linked to glycolysis, specifically the combined GAPDH/PGK reaction. Thus, [ATP]/([ADP]* [P,]) can be assessed from the measured [GAP]*[PYR]/([3PG]* [LAC]) ratio provided glycolytic flux is relatively small and the key enzymes (glyceraldehyde phosphate dehydrogenase, phosphoglycerate kinase, lactate dehydrogenase) can therefore be assumed to catalyze a near-equilibrium reactions. This is known to obtain for heart muscle in low-metabolic rate Langendorff hearts. Further, the [GAP]*[PYR]/([3PG]* [LAC]) ratio can be applied to assess [ATP]/([ADP]* [P,]) in tissues devoid of creatine kinase such as liver and kidney, if near equilibrium conditions obtain.

4)Fxn.cellularpurine iUfiteflate _{f tion and re!}ease of ATP degradatives,

IV ST MMARV THF INVENTION

unctons.

y ηprgc- n gr T TIOr' ™> V^τ riRftWINOS

applied. Figure 3: The stunned dog heart

In a series with 13 dog hearts in situ which were stunned by five repeated ischemias of three min duration, ventricular segment shortening in the region of the left anterior descending coronary artery (LAD) was masured as an index of left ventricular globan function. Also the [CrP]/([Cr]* [P,]) ratio was measured as an index of the phosphorylation potential. The stunned heart were treated with 5 to 10 mM pyruvate anion infusion intracoronarily. The data show that the dog hearts recovered left ventricular function in parallel with the instantantenous [CrPj/([Crj* [P,]) ratio as prediceted from Fig. 1. Moreove the data showed that pyruvate treated dogs had considerably higher [CrPJ/([CrJ* [P,]) ratios than the controls in six of the eight cases tested. Overall, pyruvate raised significantly the [CrP]/([Cr]* [P,]) ratio in the stunned dog heart. Fig. 4: Purine release during low-flow ischemia

In a series with 14 isolated working guinea pig hearts, hearts were subjected to low flow ischemia (coronary flow reduced from 8 ml/min to 1 ml/min) for 45 min and perfused with either the physiological level of pyruvate anion (0.2 mM) or therapeutic doses of pyruvate (1 mM). Glucose was the co-substrate. The data show that increased levels of pyruvateattenuated the ischemic rise in production of adenosine plus inosine. This suggested that pyruvate when applied at therapeutic levels reduced the energetic depletion during moderate ischemias. Similarly, pyruvate infusion also attenuated the production of lactate during low flow ischemia, suggesting again that pyruvate raised the [ATP]/([ADP]*[P,]) ratio according to the GAPDH/PGK reaction described above.

The data also show that pyruvate at the 1 mM dose significantly reduced the basal nucleoside production in normoxia, again demonstrating that pyruvate can raise the [ATPJ/[ADP] ratio and hence the [ ATP ]/([ ADPJ* [P,]) ratio ratio also in normal normoxic heart.

VI. DETAILED DESCRIPTION OF THE INVENTION

A. Biological activity has been discovered for a pharmaceutical composition whose dominate function is to enhance the phosphorylation potential and to reduce hydrogen load within the cell thereby preventing the deterioration or promoting the restoration and preservation of normal cell functions. More precisely, applicant has discovered a pharmaceutical composition method of making and use thereof with the following attendant itemized features:

FEATURES : 1. A method for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising administering to a mammal in need thereof a pharmaceutical composition containing as an active ingredient thereof a salt of an alpha-ketocarboxylic acid having the formula R-C(O) (CO)OM wherein R is alkyl of 1 to 12 carbon atoms; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms; alkynyl of 3 to 6 carbon atoms; benzyl; substituted benzyl (wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring) ; adamantyl; phenyl; naphthyl; substituted phenyl or substituted napthyl (wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of l to 4 carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and M is a cation. 2. The method in accordance with Feature 1 wherein said cation is an alkali or alkaline earth metal, --

3. The method in accordance with Feature 2 wherein the alkali metal is sodium. --

4. The method in accordance with Feature 3 wherein R is an alkyl group containing 1 to 12 carbon atoms. --

5. The method in accordance with Feature 4 wherein the alkyl group is methyl.--

6. A method for enhancing the phosphoryla ion poten^tial within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising administering to a mammal in need thereof a perenteral fluid containing as an active ingredient thereof a salt of an alpha-ketocarboxylic acid having the formula R-C⁽O^{) (}CO⁾OM wherein R is alkyl of 1 to 12 carbon atoms; substituted alkyl of ¹ to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms; alkynyl of 3 to 6 carbon atoms; benzyl^; substituted benzyl ₍wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring⁾; adamantyl^; phenyl^; naphthyl; substituted phenyl or substituted napthyl (wherein the ring is mono-, di-, or trisubstituted and the substitutents are a_lkyl of _{1 t}o ₄ carbon a_toms , halo, alkoxy of 1 to ^{4 c}ar^bon a_toms , _phen_oxy, _tri_ha_lome_thy_l, dimethylamino, diethylamin^o, ^an^{d M} is a cation.

₇ . _A metho_d accor_din_{g to F}eature 6 wherein the per^en^ter^al f^lui^d i_s sel_ec_te_{d f}rom _the _group comprising total par^en^teral nu_tri_ti_onal f_lui_ds _; ki_dney and peritoneal dialyse^s f^lui^{ds ; vo}lum^e _an_{d p}l_asm_{a e}x_pan_din_{g f l}ui_ds ; pyruvate/acetate near-isot^onic _solu_{t io}n_{s ; lact}a_te/_ac_etate-_free pyruvate isotonic ^solu^{t io}n^{s ;} _{normal sal i}n_{e sol}u_tion_{s ; he}moglobin-substitute con^tainⁱn^g _solu_{t ions ; v}i_tami_{n suppl}ement product ; and car^dioplegic solutions .

8. A method according to Feature 6 wherein the amount of active

ingredient is effective in reducing and/or ameliorating intracellular acidosis.

9. A method according to Feature 6 wherein the amount of active ingredient is effective in neutralizing hydrogen peroxide through hydrogen peroxide-alpha-ketocarboxylate interaction to inhibit the formation of toxic-free radicals.

10. A method for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising administering to a mammal in need thereof a rehydration fluid, which may contain electrolyte balances, containing as an active ingredient thereof a salt of an alpha- ketocarboxylic acid having the formula R-C(O^{) (}CO⁾OM wherein R is alkyl of 1 to 12 carbon atoms; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms_; alkynyl of 3 to 6 atoms; benzyl; substituted benzyl (wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring); adamantyl; phenyl; naphthyl^; substituted phenyl or substituted napthyl ⁽wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylaraino, and M is a cation.

11. A method according to Feature 10 wherein the rehydration fluid contains electrolyte balances.

12. A method for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising administering to a mammal in need thereof a topical composition containing as an active ingredient thereof a salt of an alpha-ketocarboxylic acid having the formula R-C⁽O^{) (}CO)OM wherein R is alkyl of 1 to 12 carbon atoms; substituted alkyl of

1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms; alkynyl of 3 to 6 carbon atoms^; benzyl^; substituted benzyl (wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring); adamantyl^; phenyl^; naphythyl_; substituted phenyl or substituted napthyl ⁽wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of ₁ to ₄ carbons atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalo ethyl, dimethyla ino, diethylamino, and M is a cation.

₁₃. _A method according to Feature 12 wherein the topical composition is selec_ted from the group comprising m^edicinal soaps_; medicinal shampoos; sunscreens; medicinal ointmen^ts^; vitamin capsules_{; d}en_trifice; outhwash; douche solutions^; and medicinal baths .

₁₄. _A method for enhancing the phosphorylation potential wi^thin the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising administering to a mammal in need thereof a pharmaceutical composition selected from the group comprising an antibiotic and antiplogistic containing as an active ingredient thereof a salt of an alpha-ketocarboxylic acid having the formula R-_C(_{O) (C}O)_OM wherein R is alkyl of 1 to 12 carbon atoms^; substituted alkyl of ₁ to 12 carbon atoms, cyloalkyl of ³ to ¹⁰ carbon atoms, within the alkylene chain, halogen amino, alhylamino of 1 to 4 carbon atoms dialkylamino of 1 to 4 carbon atoms in each alkyl, alkenyl of 2 to 6 carbon atoms^; alkynyl of 3 to 6 carbon atoms_; benzyl; substituted benzyl ⁽wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring_{) ;} adamantyl_; phenyl; naphythyl; substituted phenyl or substituted napthyl (wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbons atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylarnino, diethylamino, and M is a cation.

₁5. The method in accordance with Feature 14 wherein said composition is administered by intramuscular injection.

₁6. The method in accordance with Feature 15 whereⁱn saιιⁱα

composition is an antibiotic.

17. The method in accordance with Feature 16 wherein said composition is an antiphylogistic.

18. A method for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising administering to a mammal in need thereof a pharmaceutical composition for the treatment of local skin disorders, selected from the group comprising an antibiotic and antiphlogiotic having as an active ingredient thereof a salt of an alpha-ketocarboxylic acid having the formula R-C⁽O^{) (}CO⁾OM wherein R is alkyl of 1 to 12 carbon atoms; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to 10^" carbon atoms, alkenyl of 2 to 6 carbon atoms_; alkynyl of 3 to 6 atoms; benzyl- substituted benzyl ₍wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring^{) ;} adamantyl^; phenyl^; naphthyl_; substituted phenyl or substituted napthyl ⁽wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of ₁ to ₄ carbon atoms, halo, alkoxy of ¹ to ⁴ carbon atoms, phenoxy, trihalomethyl, dimethylarnino, diethylamino, and M

as a cation.

₁9. A method for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising administering to a mammal in need thereof an aerosolized pharmaceutical composition containing as an active ingredient thereof a salt of an alpha-ketocarboxylic acid having the formula R-C₍O_{) (}CO)OM wherein R is alkyl of 1 to 12 carbon atoms_; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, ₍carboxyalkylene of 1 to 20 carbon atoms within the alkylene chain, halogen amino, alkylamino of 1 to 4 carbon atoms, dialkylamino of 1 to 4 carbon atoms in each alkyl group or phenyl_); alkenyl of 2 to 6 carbon atoms^; alkynyl of 3 to 6 atoms_; benzyl_; substituted benzyl (wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring⁾; adamantyl; phenyl_; naphthyl; substituted phenyl or substituted napthyl ₍wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylarnino, diethylamino, and M is a cation alone or in combination with a bronchodilating agent.

20. A method in accordance with Feature 19 resulting in the amelioration or prevention of the onset of abnormal respiratory conditions caused by a reactive airway disease.

21. A method in accordance with Feature 20 wherein said reactive airway disease is selected from the group comprising asthma and bronco-pulmony dyplasia.

22. A method for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of. normal cell functions comprising perfusion of a mammalian organ in need thereof with pharmaceutical composition containing as an active ingredient thereof a salt of an alpha-ketocarboxylic acid having the formula R-C₍O_{) (}CO₎OM wherein R is alkyl of 1 to 12 carbon atoms^; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms; alkynyl of 3 to 6 carbon atoms_; benzyl_; substituted benzyl (wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring^); adamantyl_; phenyl_; naphthyl; substituted phenyl or substituted napthyl ₍wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylarnino, diethylamino, and M is a cation.

23. The method in accordance with Feature 22 wherein said mammalian organ is selected from the group comprising heart, liver, kidney, brain, spleen vessels, arteries, .endothelium, pancreas and glands.

24. A method for enhancing the phosphorylation potential within bacterial or viral cells in culture or cloning media in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising adding to the incubation solution for said cells a pharmaceutical composition containing as an active ingredient thereof a salt of an alpha- ketocarboxylic acid having the formula R-C⁽O^{) (}CO⁾OM wherein R is alkyl of 1 to 12 carbon atoms; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms; alkynyl of 3 to 6 carbon atoms^; benzyl^; substituted benzyl ₍wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring⁾; adamantyl^; phenyl^; naphthyl; substituted phenyl or substituted napthyl ⁽wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylarnino, diethylamino, and M is a cation.

25. A method for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions thereby enhancing physical endurance or refreshment comprising administering to a mammal in need thereof a food product containing a pharmaceutical composition having as an active ingredient thereof a salt of an alpha-ketocarboxylic acid having the formula R-C(O) (CO)OM wherein R is alkyl of 1 to 12 carbon atoms_; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms^; alkynyl of 3 to 6 carbon atoms_; benzyl; substituted benzyl ⁽wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring_{) ;} adamantyl; phenyl; naphthyl; substituted phenyl or substituted napthyl (wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylarnino, diethylamino, and M is a cation. 26. The method in accordance with Feature 25 wherein said food product is a beverage drink.

27. The method in accordance with Feature 26 wherein said food product is a confectionery food.

28. The method in accordance with Feature 27 wherein said food product is selected from the group comprising candies and pastries .

29. A method for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising administering to a mammal in need thereof a pharmaceutical composition containing ⁽¹⁾ a thiamine ₍Bl₎ vitamin capsule and (2) a therapeutically-effective amount of a salt of an alpha-ketocarboxylic acid having the formula R-C₍O_{) (}CO₎OM wherein R is alkyl of 1 to 12 carbon atoms^; substituted alkyl of ₁ to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms; alkynyl of 3 to 6 carbon atoms_; benzyl_; substituted benzyl (wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring⁾; adamantyl_; phenyl_; naphthyl; substituted phenyl or substituted napthyl ₍wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylarnino, diethylamino, and M is a cation.

30. A composition of matter for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising a therapeutically effective amount of a salt of an alpha-ketocarboxylic acid having the formula R-C₍O_{) (}CO₎OM wherein R is alkyl of 1 to 12 carbon atoms^; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to ¹0 carbon atoms, alkenyl of 2 to 6 carbon atoms^; alkynyl of 3 to 6 carbon atoms_; benzyl_; substituted benzyl (wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring^{) ;} adamantyl_; phenyl_; naphthyl; substituted phenyl or substituted napthyl ₍wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of ₁ to 4 carbon atoms, phenoxy, trihalomethyl, dimethylarnino, diethylamino, and M is a cation.

31. A perenteral fluid useful for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising a therapeutically-effective amount of a salt of an alpha-ketocarboxylic acid having the formula R-C₍O_{) (}CO₎OM wherein R is alkyl of 1 to 12 carbon atoms^; substituted alkyl of ₁ to ₁2 carbon atoms, cyloalkyl of ³ to .⁰ carbon atoms, alkenyl of ₂ to 6 carbon atoms, alkynyl of 3 to . carbon atoms_; benzyl.- substituted benzyl ⁽wherein the su^bstituent is methyl, phenyl on the alpha carbon atom or the substituent x. methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring^{) ;} adamantyl_; phenyl_; naphthyl; substituted pheny! or substituted j;. _αr trisubstituted and napthyl ₍wherein the ring is mono-, ^d , or ^tn^s the su_bstitutents are _• a ilkyli _n of _l 1 _t ^too •> . carbon atoms, halo, alkoxy of ₁ to ₄ carbon atoms, p _Lhenox ..y., » t-.r-ii _hhaa_l ^l _nomee^tt_hnvylⁱ., dimethylarnino,

diethylamino, and M is a cation.

3₂. Λ co position according to Feature 31 wherein ^the peren^teral flui_d is selec_ted from the group comprising total parenteral nutritional fluids._; kidney and peritonea! dialys s fluids^; voi me an_d plasma expanding flui_ds_; pyruvate/acetate near-isotomc solu_tions_; lactate/acetate-free pyruvate isotonic solutions^; normal saline solutions_; hemoglobin-substitute containing

SO lutions_; vitamin supplement product; an^d card oplegic

solutions .

33 _A rehydration fluid, which may contain electrolyte ^balances, useful for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising a therapeutically-effective amount of a salt of an R is alkyl of 1 to 12 carbon atoms; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms; alkynyl of 3 to 6 atoms; benzyl; substituted benzyl (wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring); adamantyl; phenyl; naphthyl; substituted phenyl or substituted napthyl (wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylarnino, diethylamino, and M is a cation.

34. A composition according to Feature 33 wherein the rehydration fluid contains electrolyte balances.

35. A medicinal composition useful for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising a therapeutically effective amount of thereof a salt of an alpha- ketocarboxylic acid having the formula R-C(O) (CO)OM wherein R is alkyl of 1 to 12 carbon atoms; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms; alkynyl of 3 to 6 carbon atoms; benzyl; substituted benzyl (wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring⁾; adamantyl^; phenyl^; naphythyl_; substituted phenyl or substituted napthyl ⁽wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbons atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylarnino, diethylamino, and M is a cation.

36. A composition according to Feature 35 is selected from the group comprising medicinal soaps; medicinal shampoos^; sunscreens^; medicinal ointments_; vitamin capsules; dentrifice^; mouthwash^; douche solutions; and medicinal baths.

37. An antibiotic or antiphylogistic composition useful for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising a therapeutically effective amount of a salt of an alpha- ketocarboxylic acid having the formula R-C⁽O^{) (}CO⁾OM wherein R is alkyl of 1 to 12 carbon atoms; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, within the alkylene chain, halogen amino, alhylamino of 1 to 4 carbon atoms dialkylamino of 1 to 4 carbon atoms in each alkyl, alkenyl of 2 to 6 carbon atoms; alkynyl of 3 to 6 carbon atoms^; benzyl^; substituted benzyl ₍wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring⁾; adamantyl^; phenyl; naphythyl_; substituted phenyl or substituted napthyl ⁽wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of ₁ to ₄ carbons atoms, halo, alkoxy of ¹ to ⁴ carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and M is a cation.

₃₈. The composition according to Feature 3⁷ wherein said composition is administered by intramuscular injection.

₃₉. _The composition according to Feature 3⁸ wherein said composi_tion is an antibiotic.

₄₀. _The me_tho_d in accordance with Feature ³⁹ w^herein sai^d composition is an antiphylogistic .

₄₁. _An aeroso _ιli •z _÷e*d _n p_hha-r_rmm_aa_rc_ee_uu_ttiiccaall

for enhancing ^the phosphoryla_tion po_tential within the cells of a mammal in order to prevent the deterioration or promote the res^toration and preservation of normal cell functions comprising a therapeutically effective amount of a salt of an alpha- ketocarboxylic acid having the formula R-C⁽O^{) (CO)O}M wherein R is alkyl of ₁ to ₁₂ carbon atoms; substituted alkyl of 1 to 12 carbon atoms, cy ,loa _nliky -li _« o_ff 3 ■_» to 1 ιo⁰ _c caarrboo^onⁿ a ^αtoms, (carboxyalkylene of ₁ to ₂₀ carbon atoms within the alkylene chain, halogen amino, alkylamino of 1 to ₄ carbon atoms, dialkylamino of ¹ to ⁴ carbon atoms in each alkyl group or phenyl) ; alkenyl of 2 to ⁶ carbon atoms; alkynyl of 3 to 6 atoms; benzyl; substituted benzyl ₍wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring); adamantyl; phenyl^; naphthyl^; substituted phenyl or substituted napthyl ⁽wherein the .ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and M is a cation alone or in combination with a bronchodilating agent.

42. A perfusion fluid for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising a therapeutically effictive amount of a salt of an alpha-ketocarboxylic acid having the formula R-C₍O_{) (}CO₎OM wherein R is alkyl of 1 to ¹2 carbon atoms^; substituted alkyl of ₁ to 12- carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms^; alkynyl of 3 to 6 carbon ato.s_; benzyl_; substituted benzyl ⁽wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring^{) ;} adamantyl_; phenyl_; naphthyl; substituted phenyl or substituted napthyl ₍wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and M is a cation. 43. An incubation solution for enhancing the phosphorylation potential within bacterial or viral cells in culture or cloning media in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising a salt of an alpha-ketocarboxylic acid having the formula E- C₍0_{) (}CO)OM wherein E is alkyl of 1 to 12 carbon atoms; substituted alkyl of X to U carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to « carbon atoms^; alkynyl of 3 to 6 carbon atoms_; benzyl_; substituted benzyl ⁽wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring^); adamantyl_; phenyl_; naphthyl; substituted phenyl or substituted napthyl ₍wherein the ring is mono-, di-, or trisubstituted anc the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to ₄ carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and M is a cation.

4₄. A food product for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions thereby enhancing physical endurance or refreshment comprising a pharmaceutical composition having as an active ingredient thereof a salt of an alpha-ketocarboxylic acid having the formula R-C(O) (CO)OM wherein E is alkyl of 1 to 12 carbon atoms_; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms; alkynyl of 3 to 6 carbon atoms; benzyl; substituted benzyl ₍wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring); adamantyl; phenyl^; naphthyl^; substituted phenyl or substituted napthyl ⁽wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and M is a

cation.

₄5. The food product in accordance with Feature 44 wherein said food product is a beverage drink.

₄6. The food product in accordance with Feature 45 wherein said food product is a confectionery food.

4₇. The food product in accordance with Feature 44 wherein said food product is selected from the group comprising candies and

pastries .

48. A vitamin supplement product for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions hereby enhancing physical endurance or refreshment comprising a therapeutically effective amount of a salt of an alpha-ketocarboxylic acid having the formula R-C₍O) (CO)OM wherein R is alkyl of 1 to 12 carbon atoms^; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms; alkynyl of 3 to 6 carbon atoms_; benzyl_; substituted benzyl (wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring^{) ;} adamantyl; phenyl; -naphthyl; substituted phenyl or substituted napthyl ₍wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of _l to 4 carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and M is a cation.

VII EXAMPLES

The herein offered examples of compositions provide methods for illustrating without implied limitation, formulations contemplated within the scope of this invention for activating the phosphorylation potential of cells.

The representative compositions are exemplary in nature to illustrate these compositions within the scope of this invention.

All temperatures not otherwise indicated are in degrees celsius (°C) and parts of percentages are given by weight. A: intravenous solutions

Example (1): i.v. Ringer's lactate augmented with pyruvate (near-isotonic): per 100 ml solution:

600 mg sodium chloride USP

30 mg potassium chloride USP

310 mg sodium lactate

310 mg sodium pyruvate ^*

20 mg calcium chloride USP pH 6.5 (6.0 - 7.5) lactate 28 mEq/1 pyruvate 28 mEq/1 osmolarity about 300 mOsmol/1 (calculated) purified (quartz-double-distilled and sterilized) water

Example (2): i.v. lactate-/acetate-free Ringer's fortified with pyruvate ⁽isotonic): per 100ml solution:

600 mg sodium chloride USP

30 mg potassium chloride USP

310 mg sodium pyruvate

20 mg calcium chloride USP pH 6.5 (6.0 - 7.5) osmolarity about 273 mOsmol/1 (calculated) purif_ied (quartz-double-distilled and sterilized) water

Example (3): i.v. 5 % Dextrose solution fortified with pyruvate (hypertonic): per 100ml solution:

5 g Dextrose hydrous USP

287 mg sodium chloride USP

310 mg sodium pyruvate pH 4 (3.5 - 6.5) hypertonic osmolarity about 406 mOsmol/1 (calculated) purified (quartz-double-distilled and sterilized) water

Example (4): i.v. 5% Dextrose in water fortified with pyruvate (isotonic): per 100ml solution: 5 g Dextrose hydrous USP

310 mg sodium pyruvate pH 4 (3.5 - 6.5) hypertonic osmolarity about 280 mOsmol/1 (calculated) purified (quartz-double-distilled and sterilized) water

Example (5): i.v 0.45% sodium chloride solution fortified with pyruvate (hypotonic): per 100ml solution:

450 mg sodium chloride USP

310 mg sodium pyruvate pH 4 (3.5 - 6.5) hypotonic osmolarity about 182 mOsmol/1 (calculated) purified (quartz-double-distilled and sterilized) water

B: Peritoneal Dialysis (PD) solutions

Example (5): PD solution fortified with pyruvate (isotonic): final concentrations in dialysate: sodium 132 mEq/1 calcium 2 mEq/1 magnesium 1.0 mEq/1 chloride 105 mEq/1 pyruvate 30 mEq/1

Example (6): PD solution fortified with pyruvate and 1-4 % dextrose (slightly hypeπonic): final concentrations in dialysate: sodium 132 mEq/1 calcium 2 mEq/1 magnesium 1.0 mEq/1 chloride 105 mEq/1 pyruvate 30 mEq/1 glucose (Dextrose) 1-4 g/ 100 ml

C: Hemodialysis (HD) solutions .

Concentrations of anions and cations similar to PD solutions, fortified with sodⁱum pyruvate and glucose

D: Cardioplegic solutions

Example (7): University of Wisconsin solution augmented with pyruvate (near-isotonic): solution contains high potassium (30 mEq/1) _Λj_„„_Λ, „_β all major extracellular electrolytes in normal concentrations plusl mmol/1 adenosⁱne

5 mmol/1 pyruvate pH adjusted to 7.4 equilibrated with 95% oxygen/5% carbon dioxide purified (quartz-double-distilled and sterilized) water

E: Oral Rehydration

Example (8): for an oral rehydration fluid augmented with pyruvate:

(modified world health organization (WHO) solution) glucose 2 g/dl pyruvate sodium salt 1 g/dl sodium 90 mEq/1 potassium 20 mEq/1 chloride 80 mEq/1 bicarbonate 30 mEq/1

F. Oil/Water Ointment

Example (9): for a universal oil/water ointment augmented with pyruvate: calcium citrate 0.05 g sodium alginate 3.00 g

Methylparaben 0.20 g

Glycerin 45.00g sodium pyruvate 0.05 g^* double distilled water to make 100.00 g pH not known, probably about 6.0

^" *=_ use pyruvic acid, if pH is alkaline

G. Emulsifiable Ointment

Example (10): for a water-removable, emulsifiable ointment augmented with pyruvate: polyethylene glycol 4000 Jj^* J ^g polyethylene glycol 400 ^{υ" g}

Sorbitan Monapalmitate (Span 40(Atlas)) 0 05 * sodium pyruvate o 0 _P double distilled water ^δ pH not known, probably about 6.0

*= use pyruvic acid, if relatively low pH is desired H. Injectable Antibiotic

Example (11): for an injectable antibiotic augmented with pyruvate ceftriaxone sodium (Rocephin) 250 mg water °-^{9 ml} sodium pyruvate (final cone 4.5 mmol/1) 0.5 mg vial should contain these ingredients and should then be reconstituted wⁱth water

I. Medicinal Aerosol

Example (12): for a Medicinal aerosol for relief of asthma, augmented with pyruvate

particle size ^{3 t0 6 micron} water/ethanol ^{! 1 b}y ^{v0, u me} epinephrine HCl or isoprotereno! HCl sodium pyruvate to final concentration of 0.5 mg/ml propellant 3 to 15 %

J. Scientific Perfusion Solution

A method of using the composition of Feature 1 as scientific perfusion solution for isolated animal organs comprising the heart, liver, kidney, brain, spleen, any vessel, pancreas and other endocrine glands.

Example (13): for a modified Krebs-Henseleit solution augmented with pyruvate sodium chloride H6 mmol/l sodium bicarbonate 26 mmol/1 potassium chloride 3.5 mmol/1 potassium dihydrogen phosphate 1.2 mmol/1 calcium chloride 1.0 mmol/1 magnesium sulfate 0.6 mmol/1 glucose (dextrose) 5.0 mmol/1 sodium pyruvate ⁵-° ^mmol/1 solution equilibrated with Oxygen/Carbon dioxide = 95%/5% temperature 37 Celsius pH 7.4-7.45 osmolarity ²⁸° m°^{smol 1} double distilled water must be used

K. Scientific Incubation Medium A method of using the composition of claim 1 as ^^fifi ^S^!^ ^d other isolated from heart, liver, kidney, brain, spleen, any vessel, endothelⁱum, pancreas and endocrine glands.

L. Scientific Cloning Medium

_seeded scientific cloning Studies or as a superfusing solution of cells plated on Petπ dⁱs es or on latex particles. with pyruvate

^%

and vitamins will have to be

added to prevent growth limitation due to lack of essential nutrients and mⁱnerals Antⁱbⁱotⁱcs may have to be used to prevent unwanted bacterial growth. Osmolaπty ⁱncreases due addⁱtⁱon of aminoacids and vitamins will be balanced by appropriate iso-osmolar reductⁱons ⁱn sodⁱum chloride.

M. Diagnostic Agar Culture Media

Example (16): for a method of using the composition of Feature 1 as diagnostic agar or culture media for bacterial growth.

Agar or culture media will be fortified with 5 M glucose plus 5 mM sodium pyruvate.

N. Metabolic Acidosis

Example (17): for a clinical method of reducing or ameliorating the level of metabolic acidosis in a patient using an effective dose of the compositⁱon of claⁱm 1.

Use of an i.v. solution fortified with pyruvate; examples are given in Feature 3, ^"intravenous solutions".

O. Preventing or Reducing Formation of Hydrogen Peroxide-Dependent Formation of toxic free radicals

Example ( 18): for a clinical method of preventing or reducing the formation of hydrogen peroxide -dependent formation of toxic free radicals (superoxide an.on hydroxyl radⁱcal) ⁱn a patient recovering from an ischemic insult (stroke, thrombosis, myocardⁱal ⁱnfarct) usⁱng an effective dose or infusion of the composition of Feature 1.

Use of an i.v. solution fortified with pyruvate; examples are given in Feature 3, "intravenous solutions".

P. Refreshments and Energizing Drinks

Commercial refreshments and energizing drinks usually contain sugar, protein, fat and a number of essential vitamins and minerals.

Example (19): meal replacement drink (milk-shake-type): A 12 FI OZ (355 ml) can containing additional

200 mg sodium pyruvate ( about 5 mmol/l)

Example (20): thirst quencher drink which does not contain fat and protein( Gatorade-type): A 32 FI OZ (946 ml) bottle containing additional

533 mg sodium pyruvate ( about 5 mmol/l)

Example (21): nutritional water-soluble energizing powder which does not contain fat and protein: , .

A 21 OZ (6g) bag (for 6 OZ (178 ml) water) containing addⁱtⁱonal

825 mg sodium pyruvate ( about 7.4 mmol/178 ml = 42 mmol/l)

with the following standard ingredients: . .. vitamin C 2000 mg, potassium 400 mg, sodium 120 mg, calcium 100 mg, magnesⁱum 40 mg, manganese 3 mg, zinc-ascorbate 4 mg, chromium-picolinate-ascorbate 20 mⁱcro g, vitamin Bl 0.75 mg, vitamin B2 0.85 mg, niacin-niacinamide 10 mg, vⁱtamⁱn B6 20 mg, vitamin B12 50 mg, panthothenic acid 5 mg. Fructose (better glucose) as a sweetener ⁱn a base of citric, tartaric, aspartic, and malic acid. Lemon flavors added plus potassⁱum phosphate to adjust pH to near normal.

Q. Cereal Bars and Freeze-Dried Food Products

Commercial cereal bars and freeze-dried food products often contain complex carbohydrates simple sugars, protein, saturated and unsaturated fats and a number of essentⁱal vⁱtamⁱns and minerals as well.

Example (22): breakfast replacement bar (cereal -type): A 40 g bar containing additional

5.5 g sodium pyruvate ( about 50 mmol)

Example (23): freeze-dried action food for endurance hikers and military in the field: A lOOg bag containing additional

14 g sodium pyruvate ( about 126 mmol)

R. Vitamin Capsules

Commercial vitamin capsules are widely available. Especially vitamin Bl thiamine is absolutely essential for oxidative decarboxylation of pyruvate by pyruvate dehydrogenase s ⁱn mammalian as well as yeast cells (alcoholic fermentation). Thus, for a composⁱtⁱon a cord ng to Feature 1 to work efficiently, the water-soluble vitamin Bl must be present ⁱn suffⁱcⁱent concentrations. To enhance the effect of Feature 1 compositions, pyruvate and congeners wⁱll be combined with thiamine preparations. Accordingly applicant contemplates the use of Pyruvated capsules that contain vitamin Bl or a multi vitamin B system where thⁱamⁱne ⁱs a main constituent.

Example (24): pyruvated vitamin Bl:

A capsule containing 250 mg vitamin B plus additional

550 mg sodium pyruvate ( about 5 mmol)

Example (25): pyruvated vitamin B complex:

A capsule containing all major vitamin B s plus additional

550 mg sodium pyruvate ( about 5 mmol)

S. Dentrifice Products

Pyruvate added to tooth pastes may help roborize the gingiva, especially when suffering from gingivitis or other tooth-decaying diseases. Accordingly tooth pastes enhanced with compositions according to Feature 1 are claimed.

Example (26): pyruvated tooth paste without vitamin B l : A tooth paste, 5 g, containing additional

550 mg sodium pyruvate ( about 5 mmol)

Example (27): pyruvated tooth paste with vitamin B I : A tooth paste, 5 g, containing 250 mg vitamin B 1 plus additional 550 mg sodium pyruvate ( about 5 mmol)

T. Hair Products

Hair shampoos containing pyruvate compositions may strengthen hair health and growth by roborizing the hair follicles. A shampoo fortified by pyruvate is claimed.

Example (28): pyruvated hair shampoo without vitamin Bl: A hair shampoo, 5 g, containing additional

550 mg sodium pyruvate ( about 5 mmol)

Example (29): pyruvated hair shampoo with vitamin B 1: A hair shampoo, 5 g, containing 250 mg vitamin B 1 plus additional 550 mg sodium pyruvate ( about 5 mmol) The above-mentioned compositions illustrate the advantageous use of pyruvate over presently known agent where pyruvate applications/supplementations/substitutions appear to be superior to or could markedly enhance current practices and clinical routines. yiH . CONTEMPLATED CLINICAL APPLICATIONS FOR PYRTTVAT ?

A. ADVANTAGES OVER PRESENTLY KNOWN AGENTS

1) Cardiac ischemia/reperfusion damage, heart transplantation, and cardiopulmonary bypass: Pyruvate improves and accelerates recovery of cellular phosphorylation potential and ventricular function and inotropic state. In contrast, traditional clinical lactate/glucose drips (infusions) are either without effect or likely even damaging to the phosphorylation potential and reperfusion function; this is the case because the recovering but still damaged cell needs to release, not take up, lactate in an effort to remove intracellular H⁺ and to reduce the concentration of NADH. In the blood-perfused heart in situ, for example, a net release of lactate is usually a sign of hypoxia, ischemia, extreme metabolic stress. Thus, infusing lactate into an organ that is attempting to remove its own endogenous lactate waste is clearly not optimal.

With regard to acetate, this compound is kno n to lower the phosphorylation potential in experimental hearts and has also been found to impair reperfusion recovery in experimental situations. As for clinical solutions containing aspartate or glutamate, both of which have been" reported to be beneficial under some conditions, their mechanism is far from understood or proven; in particular, there are no known well characterized transporters on the plasma membrane that would allow efficient movement of these highly polar dicarboxylates into the cell. In contrast, there is a high-capacity monocarboxylate transport system for pyruvate (and lactate) which, at least in heart and liver, has the capacity to transport pyruvate into and out of the cell and the mitochondria at rates that are more than sufficient under most, if not all conditions in health and disease.

2) Post-surgical clinical stunned myocardium: Pyruvate likely improves the prolonged dysfunction and low-contractility state of the postischemic ventricle via enhancing the phosphorylation potential and possibly via removing intracellular H⁺. Also the specific anaplerotic (replenishing) effect on mitochondrial malate and oxaloacetate pools can only be considered desirable for the stunned myocardium. Pyruvate, unlike the clinically used adenosine (University of Wisconsin solution has 1 mM adenosine; adenosine is routinely injected to treat supraventricular tachycardia and other forms of arrhythmias), has no known serious hypotensive or bradycardic effects; pyruvate unlike adenosine is not a potent vasodilator and hence does not dangerously lower peripheral resistance of the circulation. Adenosine, in contrast to pyruvate, does not replenish the crucial mitochondrial metabolite pools. Pyruvate, in contrast to the clinically widely used inotropic "support" by adrenergic agonists (epinephrine, dobutamine) or vagus blockade by atropine, is not forcing restoration of postischemic function at low-ischemic phosphorylation potentials. Experimental data fro guinea pigs and pigs show that norepinephrine, calcium-agonists (BayK 8644), hypercalcemia, and dobutamine as well, all normalize reperfusion function of the stunned heart, but this improvement consistently occurs without restoration or enhancement of the phosphorylation potential, which is in marked contrast to pyruvate therapy. In guinea pig myocardium reperfused after a 45 min low-flow ischemia, these traditional inotropic interventions restored function only at the expense of the cytoplasmic phosphorylation potential.

Pyruvate can thus be seen as a novel class of inotropes, the metabolic inotropes, which produce a gentle and yet robust improvement of postischemic function, and that as permitted by or in accordance with the real-time cellular energy state. This is the principal difference with respect to current clinical adrenergic (inotropic) drug routines which force normalization of function of the damaged and/or disease-weakened heart (which, without the drugs, would be in a state of hemodynamic failure or stunning); but these inotropic regimens do not reenergize the cells nor do they create an anabolic situation to replenish crucial myocardial metabolite pools depleted by the prior damaging stimuli. Such forced restoration of performance can therefore occur at a potentially dangerous cost, a deleterious change in key metabolite levels resulting in a further fall in cellular energy level (phosphorylation potential); this will likely have obligatory but adverse consequences in cellular sodium homeostasis and calcium handling, which eventually likely combine to accelerate the development of acute and complete, and perhaps also essentially irreversible failure.

Current clinical "inotropic support" for postoperative cardiac patients (who usually have aged or pre-damaged/weak hearts which probably function already at below-physiologic phosphorylation potentials) is essentially only a symptomatic or "cosmetic" treatment of ventricular function, without appropriate concern for correcting the underlying cause of the precarious energy balance and/or the associated Na⁺ and Caⁱ⁺ ionic imbalances and/or the reduced Ca³⁺ sensitivities of the excitation-contraction process. Indeed, adrenergic agonists have long been recognized to lower the Ca²⁺-sensitivity of the myofilaments in the myocardium, a situation which makes it virtually impossible to rationalize the use of adrenergic support in stunned heart, as stunning is typically associated with exactly this type of reduced calcium sensitivity at the myofilament level [14-16]. It comes therefore as no surprise that many cardiac surgeons view customary inotropic drug regimens, when applied to the stunned or spontaneously failing human heart, with concern and skepticism. ,

Pathophysiologically it is important to understand that inotropic drug therapy in the cardiac patient shifts the energy demand/ supply balance toward higher demand; in aged hearts this may well occur in the presence of preexisting energy depletion/ion imbalance and/or a compromised coronary circulation (chronic ischemic coronary disease of the aged heart). This could put more myocytes at risk, at a moment when their recovery process has not yet begun or not yet been completed. In marked contrast, pyruvate metabolic inotrope therapy shifts the energy demand/supply balance in favor of larger supply; the ensuing functional improvements are spontaneous, a natural consequence of improved cellular energy status, redox status, and ion homeostasis; all subsequent improvements of function are fully commensurate with and supported by the existing intrinsic energy supply status of the heart.

Again, adrenergic inotropic drugs can cause desensitization towards calcium of the contractile elements, a shift toward the left in the tension/pCa^{+ +} curve of the contractile elements [14]; myocardial stunning also is often associated with a similar calcium desensitization [15,16]. Consequently, it would not seem justified to continue the practice of indiscriminate use of adrenergic inotropic "support" in the post-surgical cardiac patient with the stunned heart syndrome. Pyruvate as a metabolic inotrope would seem the more appropriate choice, even if it were only used in combination with classical adrenergic support in order to reduce the requisite dose of adrener *g»i*c agents.

3) Metabolic acidosis: The unique and special aspects of cellular pyruvate-H⁺ symport and metabolic pathways will help lower the size of the intracellular H^* ion pool. Since all vital organs have substantial amounts of pyruvate transporters, lactate and pyruvate dehydrogenases and also mitochondria, pyruvate can be expected to counteract cellular acidosis body-wide, especially in heart, liver, lung, kidney, brain, and skeletal muscle. This antiacidotic effect of exogenous pyruvate principally occurs according to the following mechanism: when one pyruvate anion enters the cell, it will be obligatorily accompanied by one hydrogen ion; this hydrogen ion will then be used in the lactate dehydrogenase reaction to form the lactate anion (without H^*); the lactate anion will then be exported from the cell together with one hydrogen ion; this latter hydrogen ion comes of course from the global cellular hydrogen ion pool, thus reducing cellular acidification. The net effect is removal of one intracellular hydrogen ion per one pyruvate taken up and reduced to lactate or oxidized to carbon dioxide and water.

Conversely, lactate infusion is contraindicated during systemic metabolic acidosis because lactate is a metabolic waste product under these conditions and produces rather than removes intracellular hydrogen ions. The mechanism is as follows: when one molecule of lactate enters the cell, it takes one hydrogen ion with it (much as pyruvate); then lactate will be oxidized to pyruvate generating rather than consuming another intracellular hydrogen ion (lactate dehydrogenase reaction). Thus, lactate oxidation to pyruvate via lactate dehydrogenase generates cytoplasmic hydrogen ions, whereas pyruvate reduction to lactate by reversal of lactate dehydrogenase removes cytoplasmic hydrogen ions. Lactate infusion can therefore only exacerbate a preexisting cellular acidosis, while pyruvate infusion will likely ameliorate it. This beneficial effect of pyruvate can be established of course only when there is some residual organ/cellular perfusion. 4) Diabetic ketoacidosis and/or coma: Pyruvate infusion will ameliorate the metabolic acidosis as explained. Pyruvate will also directly improve cellular oxidative carbohydrate metabolism. The pyruvate dehydrogenase is inhibited in ketosis due to the high blood concentration of beta-hydroxybutyrate [17]. This mitochondrial enzyme inhibition can be overcome simply by raising blood pyruvate concentration, the mechanism being the allosteric effect of pyruvate on PDH phosphorylation as explained above.

Pyruvate infusion during diabetic ketosis will not have the complications of insulin therapy: 1) Pyruvate's half live in blood is on the order of minutes, i.e. much shorter than that of insulin (order of 1/2 to 1 hour), as virtually all organs readily metabolize pyruvate. 2) Pyruvate will also not drastically lower blood sugar levels, as the glucose transport per se into skeletal and heart muscle as well as liver and kidney is not stimulated or inhibited directly by pyruvate. 3) Thus, dangerous hypoglycemia will not be a complication of systemic pyruvate administration to keto-acidotic diabetics.

Alternatively, if insulin treatment proves indispensable for some keto-acidotic or comatose patients, it would appear that the dose of insulin could be lowered by co-application of sufficient pyruvate. Thus pyruvate has the potential to substantially lower the dose and hence the risks of acute insulin administration during emergency medical care situations involving the diabetic patient.

5) Hypovolemic shock (auto accident, combat casualty, extensive internal or external bleeding): Hypovolemic shock is often associated with or progresses to systemic metabolic acidosis and a genera! deenergization of all organs; this will eventually lead to multiple organ failure and hardly manageable end-stage situations. Pyruvate as a natural alkalinizer that simultaneously enhances ^'recovery of rephosphorylation of the cell and stabilizes the physiologic reduced state of vital -SH enzymes and transporters, can be expected to be much more effective than the traditional glucose, gluconate, lactate, or calcium drips alone. Combined with human full blood, pyruvate supplementation can be expected to enhance all known parenteral drip regimens.

6) Cardiogenic shock: The acutely or chronically failing heart is likely deenergized (low phosphorylation potential) and pyruvate metabolic inotrope therapy has the potential to bring about and/or expedite recovery from failure by reestablishing the cytoplasmic phosphorylation potential, the ion homeostasis and by mitigating any existing residual acidosis.

7) Other forms of shock: Anaphylactic shock, endotoxin shock. Pyruvate is an ideal agent to improve oxidative energy and hydrogen metabolism of the heart and all major organs that contain lactate dehydrogenase and more than trace amounts of mitochondrial pyruvate dehydrogenase/ carboxylase (heart, brain, lung, liver, kidney, skeletal muscle, smooth muscle).

8) Hemosiderosis: Pyruvate could be beneficial here too because it would be expected to possibly reduce the concentration of free iron in the cells; this can take place because pyruvate would reduce the concentration of [NADH]*[H⁺] which would attenuate, if not completely blunt the already mentioned reductive release of iron from binding sites such as ferritin, haem-protein or myoglobin. Consequently, the damaging Fenton-type reactions could possibly be attenuated thus reducing the chronic overall cellular damage by toxic oxygen-derived free radicals.

9) Strenuous exercise, physical exertion, endurance: Probably skeletal muscle and heart in particular, but perhaps also other organs, suffer from energetic exhaustion Gow phosphorylation potential) due to prolonged strenuous/excessive physical stress. Such a condition appears to be ideal for application of pyruvate metabolic inotropic therapy, since restoration of the phosphorylation potential and anaplerotic replenishment of key mitochondria] metabolites would be expedited and is of primary concern in such conditions. Pyruvate, by effectively competing with lactate for transport into heart, liver, skeletal muscle and likely other organs will additionally alleviate intracellular hydrogen load thus enhancing the recovery process.

10) Acute sickle cell crisis: Systemic hemolysis and local microembolism with .. subsequent ischemia are wide-spread. The resulting anemia could favorably respond to pyruvate because, when applied in combination with adenine or inosine (two degradation products of ATP), levels of 2,3-diphosphoglycerate would increase in the remainder but still intact red cells; such a mechanism will certainly improve oxygen delivery to the tissues suffering from acute anemia combined with multiple microembolism and microiπfarctions. Thus, the need to immediately infuse donor blood or red cell concentrates with its associated problems (blood group incompatibilities) and risks of pathogens (e.g. hepatitis, AIDS) may well be reduced.

The other complication,, multiple systemic and organ-wide microembolism, will also probably be responsive to pyruvate, because pyruvate reduces the complications of ischemia itself and also those of subsequent reperfusion (after dissolution/ organization/ recanalization of the microemboli) as discussed above.

11) Kidney dialysis (inpatient, outpatient, home) and peritoneal dialysis: Combat acidosis and maintain cells functional by optimizing energy status and hydrogen ions homeostasis in face of pathological concentrations of urea, creatinine, etc..

12) Organ preservation and transplantation: Immediately after organ harvesting an initial perfusion with pyruvate-containing salt solutions/plasma expanders/hemoglobin substitutes instead of current pyruvate-free solutions (to remove cellular elements and clotting factors) would be superior; this is the case because pyruvate would- reduce the amount of intracellular NADH, raise the phosphorylation potential, and optimize cellular ionic homeostasis combined with a stabilization of the membrane potential. Also, since the procedures to collect and store donor organs usually create an ischemia/reperfusion-type condition which is typically followed by hypothermic storage and metabolic arrest, pyruvate therapy would be useful, since it is also directed at hydrogen peroxide-dependent hydroxyl radical damage. Further, during cold storage of the organs, the presence of high levels of pyruvate would further minimize gradual accumulation of reducing equivalents, which in turn would minimize the reductive release of ferritin Fe^ϊ+ and hence reduce the probability of rewarming and reperfusion damage due to Fenton-type reactions. In this regard the currently often used University of Wisconsin-Solution and St. Thomas Solution could be enhanced by adding, e.g., 2-5 M pyruvate.

13) Medical emergency resuscitation: Shock-like situations, hypotonia, blood loss, extensive burns and similar conditions can be expected to respond favorably to pyruvate metabolic and anaplerotic treatment. Quick reestablishments of cellular energy states, of crucial metabolite pools and transmembrane ion gradients, combined with gentle reduction of intracellular acidosis would be the main beneficial mechanisms. Conventional lactate or acetate containing solutions cannot effectively combat intracellular acidosis; adenosine containing solutions would be contraindicated because of the danger of adverse cardiovascular side effects. Pyruvate solutions would also avoid the potentially hazardous lowering of myocardial energy state that is likely to occur with catecholamine containing injectates. At the minimum, pyruvate therapy would promise to reduce the dosage of adrenergic inotropic drugs and also of bicarbonate and thus lower their potentially damaging side effects on cellular energetics and ionic homeostasis.

14) Status asthmnticus: Any bronchiolar smooth muscle spasm is prone to cause secondary lung ischemia and certainly ventilation/perfusion imbalances in the lung. This can lead to systemic hypoxemia and respiratory acidosis in severe cases. Current standard therapy is inhalation of aerosols usually containing a b-agonist such as albuterol or other congeners of isoproterenol, all of which are broncho dilators (smooth muscle relaxants). It seems possible that aerosolized pyruvate might also be efficacious, as pyruvate would help maintain the smooth muscle_'s metabolic phosphorylation potential and hence also its electrical membrane potential. The combined effect of these changes could favor bronchiolar relaxation (a complete relaxation of precontracted smooth muscle via this mechanism appears not impossible at this time, but remains purely speculative). Pyruvate could also be benefⁱcial in combination therapies with albuterol, perhaps allowing the patient to inhale smaller amounts of adrenergic drugs at reduced frequency; the mechanism of such a pyruvate effect could again be the overall metabolic and energetic improvement of the bronchial smooth muscle.

B. PRO_BΓ.EMS WHICH CAN BE SOLVED BY CLINICAL USE OF PYRUVATE

In principal, the clinical utility of pyruvate metabolic therapy is in the area of correcting cellular acidosis, hypoxia and ischemia prior to as well as during reperfusion, intracellular overload with reducing equivalents and H⁺, mitochondrial metabolite exhaustion, _•and cytoplasmic energy deficiencies. Pyruvate restores faster than normal cellular energy state, ionic homeostasis, membrane potential; in consequence of these changes pyruvate will likely improve both the basal cellular functions and their organ-specific function; in addition there will likely be an improved metabolic status during cellular recovery from damage or during repair. With regard to the stunned heart muscle pyruvate is a metabolic inotrope without the problematic side effects of the traditional adrenergic or pharmacologic inotropes. With regard to all cells and organs that contain mitochondrⁱa, W^ ^ ^ ⁰^ agent, s e it helps maintain crucial cytoplasmic and ^^^^ ^ This future required for maintenance of normal function and metabolⁱc/ υ c ona V"^ ™ ^feature would seem to be important in situations during and after non- ethal reve sⁱble n^uⁱy- Pyruvate also acts as a natural antidote for hydrogen peroxide (and hence ^ forn^ w ox'ygen-derived free radicals) which can produce wide-sprea in race! J|^ «to^uta damage. Some major clinically relevant examples are presented in, but are not lⁱmⁱte^d those conditions discussed in section A 1) to A 14) above.

r ^ n P_QSSTTT - — — P"" AND TMILAR ALPH.^ - VFTO Cm CONGENERS

1) Antihypertensive

2) Examples of section A 1) to A 14)

adjunct to current well tried treatment regimens.

5₎ Blood banking: high concentrations of pyruvate combined with adenine, inosine, and phosphate can raise red cell 2,3-DPG and rejuvenate stored blood.

7) Refreshments and commercial sport drinks: any type of refreshment J^ Tor enhanced by the inclusion of pyruvate replacing currently used ^'J™^ £ other poorly metabolizable carbohydrates. ^^^^ ^ ^ S∞ enhanced by inclusion of pyruvate. Pyruvate used as an enhancement of oral rehy^dratⁱon therapy would also fall into this category.

drinks should probably also contain adenine and or inosⁱne ⁱn VP^ «™ ^ to a potential for acute flatulence, since the hydrochloric acid of the tomach ^ P^ /^ pyruvic acid which may not be completely absorbed into the portal system, ώe ⁱntestⁱnal bacterial flora will likely quickly convert pyruvate to water and carbon dⁱoxⁱde or alternatively perhaps decarboxylate it to acetate.

9) Antiobesity Diets: Supplement to dietary food formulations.

10) Psychotic crises: Since the brain has substantial amounts of PDH-and I lactate dehydrogenase and because the blood-brain barrier may not be completely t ' ^f°^r ™⁸" (nothing concrete is known about the latter issue), acute psychⁱatrⁱc ^d'^sord^ treatable by parenteral or better intrathecal applicatⁱon °[ ^^ ^X^ _{out of} Certainly, classical lactate containing solution are co raindicated, sⁱnce a bra h^; t » s o ut of its fine-tuned electrical and transmitter balance would probably have one or rr u uple foe. of neurons and/or supporting glia whose energetic and ionic ^us .s abnormal^ ch hypothetical foci would be the target of metabolic pyruvate treatment. Pyruvate applⁱed intrathecally may also be considered in such situatⁱons.

11) Total parenteral nutrition PN): pyruvate appears a reasonable supplement to current TPN solutions, since it furthers replenishment of mitochondrⁱal f ™^ ' *^ virtually universally cellular energy status, removes ^. ^Λm∞ ? ^^y ^}^m^ ^ allosterically relieving PDH inhibition caused by ketosis and hⁱgh blood fatty acⁱd concentrations.

can be expected to be beneficial.

13) Disseminated intravascular coagulation: The consequences of the : U ta loss : of blood, hypotonia, anemia, all can be expected to respond favorably to pyruvate treatment. IX. SUMMARY OF NOVEL FEATURES

intrinsic natural antioxidant defense, that pyruvate itself can act as a hydrogen peroxⁱ e

and supported by the real-time cellular energetics.

IX. REFERENCES

1. Mallet RT et al. 1993: In: Interactive Phenomena in the Cardiac System, Sideman S.. Beyar R. edts.. Plenum Publishing Corp. , in press

2. Nohl et al, Free Rad Res Comms 1993; 18: 127-137 3. Downey JM Annu Rev Physiol 1990;52:487-504

4. Paller MS et al. J Clin Invest 1984;74: 1 156-1 164

5. Camporti M Lab Invest 1985;53:599-623

6. Salahudeen AK et al. J Clin Invest 1991 ;88: 1886-1893

7 Nico_tera et al Dru<* Metabolism Rev 1989;20; 193- ^{U 1} ,_{J O} A _0A,

I Cohen G .985 In: Handbook of Methods for oxygen radical research. Green ald RA ed,„

CRC Press, pp. 55-64

9. Funk et al. Eur J Bioche 1985; 152: 167-172

10. Voogd A. et al. J Clin Invest 1992; 90:2050-2055

11. Reed DJ Annu Rev Pharmacol Toxicol 1990;30:603-631

12. Zimmer HG et al. J Mol Cell Cardiol 1981; 13:531-535

13. Duhm J Biochim Biophys Acta 1 74;343:89-100

14. Holroyde MJ et al. Biochim Biophys Acta 1979;586:63-6y

15. Kusuoka H et al. Circ Res 1990;66:, 1268-1276

16. Hofman PA et al. Circ Res 1993;72:50-56

17. Bϋnger R et al. Eur J Physiol 1983;397;214-219

Claims

hat is Claimed is:

1. A method for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising administering to a mammal in need thereof a pharmaceutical composition containing as an active ingredient thereof a salt of an alpha-ketocarboxylic acid having the formula R-C₍O_{) (}CO₎OM wherein R is alkyl of 1 to 12 carbon atoms^; substituted alkyl of ₁ to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms; alkynyl of 3 to 6 carbon atoms_; benzyl_; substituted benzyl (wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring^{) ;} adamantyl_; phenyl_; naphthyl; substituted phenyl or substituted napthyl ₍wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of ₁ to 4 carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and M is a cation.

2. The method in accordance with Claim 1 wherein said cation is an alkali or alkaline earth metal, --

3. The method in accordance with Claim 2 wherein the alkali metal is sodium.--

4. The method in accordance with Claim 3 wherein R is an alkyl group containing 1 to 12 carbon atoms. --

thod in accordance with Claim 4 wherein the alkyl group

5. The me is methyl .

6. A method for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of. normal cell functions comprising administering to a mammal in need thereof a perenteral fluid containing as an active ingredient thereof a salt of an alpha-ketocarboxylic acid having the formula R-CO, ,CO,OM wherein R is alkyl of ₁ to ₁2 carbon atoms.- substituted .alkyl of 1 to ¹2 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to

6 carbon atoms.- alkynyl of 3 to 6 carbon atoms,- benzyl^; substituted benzyl ₍wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring,,- adamantyl^; phenyl^; naphthyl_; substituted phenyl or substituted napthyl ⁽wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy. trihalomethyl, dimethylamino, diethylamino, and M

is a cation.

7. A method according to Claim 6 wherein the perenteral fluid is selected from the group comprising total parenteral nutritional fluids_; kidney and peritoneal dialyses fluids^; volume and plasma expanding fluids; pyruvate/acetate near-isotonic solutions; lactate/acetate-free pyruvate isotonic solutions; normal saline solutions; hemoglobin-substitute containing solutions; vitamin supplement product; and cardioplegic solutions.

8. A method according to Claim 6 wherein the amount of active ingredient is effective in reducing and/or ameliorating intracellular acidosis.

9. A method according to Claim 6 wherein the amount of active ingredient is effective in neutralizing hydrogen peroxide through hydrogen peroxide-alpha-ketocarboxylate interaction to inhibit the formation of toxic-free radicals.

10. A method for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising administering to a mammal in need thereof a rehydration fluid, which may contain electrolyte balances, containing as an active ingredient thereof a salt of an alpha- ketocarboxylic acid having the formula R-C(O) (CO)OM wherein R is alkyl of 1 to 12 carbon atoms; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms; alkynyl of 3 to 6 atoms; benzyl; substituted benzyl (wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring); adamantyl; phenyl; naphthyl; substituted phenyl or substituted napthyl ⁽wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and M is a

cation.

11. A method according to Claim 10 wherein the rehydration fluid contains electrolyte balances.

12. A method for enhancing the phosphorylation potential within- ■ _Λ-_{H*» t}o nrevent the deterioration or the cells of a mammal in order to preveⁿ

_{A es}ervation of normal cell functions promote the restoration and preserva^tion compri _•si_•ng a_Hd_rm_ni_nniisstteerriinn_qg t<-ou a mammal in need thereof a topical composition containing as an active ingredient thereof a salt of an alpha-ketocarboxylic acid having the formula R-C⁽0^{) (}CO»OM

_• ^ ι _{of i} to ₁2 carbon atoms; substituted alkyl of wherein R is alkyl of 1 to ι ca _ιΛaι ι _of 3 to 1₀ carbon atoms, alkenyl 1 to 12 carbon atoms, cyloalkyl ot _{al vnvl} of 3 to 6 carbon atoms; benzyl^; of 2 to 6 carbon atoms; alkyny^l or

. ,_{hβ sub}stituent is methyl, phenyl on substituted benzyl (wherein the substⁱtuen^t the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring^{) ;} adamantyl; phenyl^; naphythyl; substituted phenyl or substituted napthyl ⁽wherein the stituted and the substitutents are

alkyl of 1 to carbons atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalo ethy! , dimethylamino, diethylamino, and M

is a cation.

1 . A method according to Claim 12 wherein the topical composition is selected from the group comprising medicinal soaps_; medicinal shampoos_; sunscreens; medicinal ointments^; vitamin capsules_; dentrifice; mouthwash; douche solutions; and medicinal baths .

14. A method for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration a _„njd _np„res=.errvvaat^tiⁱoonn of normal cell functions comprising administering to a mammal in need thereof a pharmaceutical composition selected from the group comprising an antibiotic and antiplogistic containing as an active ingredient thereof a salt of an alpha-ketocarboxylic acid having the formula R-C₍O_{) (}CO)OM wherein _πR i■;s c-xιlιk,_vyιl _oofr ₁ ⁱ tco^u 12 carbon atoms^; substituted alkyl of ₁ to 12 carbon atoms, cyloalkyl of 3 to ¹0 carbon atoms, within the alkylene chain, halogen amino, alhylamino of 1 to ₄ carbon atoms dialkylamino of ¹ to 4 carbon atoms in each alkyl, alkenyl of 2 to S carbon atoms^; alkynyl of 3 to 6 carbon atoms; benzyl_; substituted benzyl ⁽wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring_); adamantyl; phenyl; naphythyl; substituted phenyl or substituted napthyl (wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbons atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and H is a cation.

15. The method in accordance with Claim 14 wherein said composition is administered by intramuscular injection.

16. The method in accordance with Claim 15 wherein said composition is an antibiotic.

17. The method in_. accordance with Claim 16 wherein said composition is an antiphylogistic.

₁8. A method for enhancing the phosphorylation potential within the cells of^' a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising administering to a mammal in need thereof a pharmaceutical composition for the treatment of local skin disorders, selected from the group comprising an antibiotic and antiphlogiotic having as an active ingredient thereof a salt of an alpha-ketocarboxylic acid having the formula R-C⁽0^{) (}CO⁾OM wherein R is alkyl of ₁ to ₁2 carbon atoms; substituted alkyl of

1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms_; alkynyl of 3 to 6 atoms^; benzyl^; substituted benzyl ₍wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring⁾; adamantyl; phenyl^; naphthyl_; substituted phenyl or substituted napthyl ⁽wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and N

is a cation.

19. A method for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising administering to a mammal in need thereof an aerosolized pharmaceutical composition containing as an active ingredient thereof _.a salt of an alpha-ketocarboxylic acid having the formula R-C<0_{) (}CO)OM wherein R is alkyl of 1 to 12 carbon atoms_; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to ₁0 carbon atoms, ₍carboxyalkylene of 1 to 20 carbon atoms within the alkylene chain, halogen amino, alkylamino of ¹ to ⁴ carbon atoms, dialkylamino of 1 to 4 carbon atoms in each alkyl group or phenyl_{) ;} alkenyl of 2 to 6 carbon atoms^; alkynyl of 3 to 6 atoms_; benzyl_; substituted benzyl (wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring⁾ , adamantyl; phenyl_; naphthyl; substituted phenyl or substituted

^•i _t-risubstituted and napthyl ₍wherein the ring is mono-, di-, or tnsu^Dsc the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl. dimethylamino, diethylamino, and M is a cation alone or in combination with a bronchodilating agent.

₂₀. _A method in accordance with Claim 19 resulting in the amelioration or prevention of the onset of abnormal respiratory conditions caused by a reactive airway disease.

2₁. _A method in accordance with Claim 20 wherein said reactive airway disease is selected from the group comprising asthma and bronco-pulmony dyplasia.

₂₂. _A method for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promo_te the res_toration an_d preservation of normal cell func^tions comprising perfusion of a mammalian organ in nee^{d t}hereof wi^th pharmaceu_tical composi_tion containing as an active ingre^dient thereof a sal_t of an alpha-ketocarboxylic acid having ^the formula R-_{C(O) (CO)O}M wherein R is alkyl of 1 to 12 carbon atoms^; substituted alkyl of ₁ to 12 carbon atoms, cyloalkyl of ^{3 t}o ¹⁰ carbon a_toms, alkenyl of 2 to 6 carbon atoms; alkynyl of ³ to ⁶ carbon a_toms_{; b}enzyl_; su_bstituted benzyl (wherein ^the su^bsti^tuent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring^{) ;} adamantyl_; phenyl_; naphthyl; substituted phenyl or su^bstituted napthyl ₍wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of ₁ to 4 carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and M is a cation.

23. The method in accordance with Claim 22 wherein said mammalian organ is selected from the group comprising heart, liver, kidney, brain, spleen vessels, arteries, endothelium, pancreas and glands.

24. A method for enhancing the phosphorylation potential within bacterial or viral cells in culture or cloning media in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising adding to the incubation solution for said cells a pharmaceutical composition containing as an active ingredient thereof a salt of an alpha- ketocarboxylic acid having the formula R-C⁽O^{) (}CO⁾OM wherein R is alkyl of ₁ to 1₂ carbon atoms; substituted alkyl of ¹ to ¹2 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms_; alkynyl of 3 to 6 carbon atoms^; benzyl^; substituted benzyl ₍wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring^{) ;} adamantyl^; phenyl^; naphthyl_; substituted phenyl or substituted napthyl ⁽wherein the ring _is mono-, _Λdi_i-, _oorr tcrriιssuubost-tι-it^t-ute=d and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and M

is a cation.

25. A method for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions thereby enhancing physical endurance or refreshment comprising administering to a mammal in need thereof a food product containing a pharmaceutical composition having as an active ingredient thereof a salt of an alpha-ketocarboxylic acid having the formula R-C₍O_{) (}CO)OM wherein R is alkyl of 1 to 12 carbon atoms_; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms^; alkynyl of 3 to 6 carbon atoms_; benzyl_; substituted benzyl ⁽wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring_{) ;} adamantyl_; phenyl; naphthyl; substituted phenyl or substituted napthyl (wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of ¹ to ⁴ carbon atoms, halo, alkoxy of ₁ to 4 carbon atoms, phenoxy, trihalomethyl, dimethylamino. diethylamino. and M is a e.txon.

26. The method in accordance with Claim 25 wherein said food product is a beverage drink.

27. The method in accordance with Claim 26 wherein said food product is a confectionery food.

28. The method in accordance with Claim 27 wherein said food product is selected from the group comprising candies and

pastries.

29. A method for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising administering to a mammal in need thereof a pharmaceutical composition containing ⁽1⁾ a thiamine ₍Bl₎ vitamin capsule and (2) a therapeutically-effective amount of a salt of an alpha-ketocarboxylic acid having the formula R-C₍O_{) (}CO₎ ON wherein R is alkyl of 1 to 12 carbon atoms^; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms^; alkynyl of 3 to 6 carbon atoms_; benzyl_; substituted benzyl (wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituen^t is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring^{) ;} adamantyl_; phenyl_; naphthyl; substituted phenyl or substituted napthyl ₍wherein the ring is mono-, di-, or trisubstituted and the substitutents are a ,l,ky_rll _Λofc _ι1 _tt-_oo _Δ4 ccaarrbooonn a*toms, halo, alkoxy of 1 to 4 carbon atoms, ph -.enox..y., tt-vriiVniaalloommeechnvylx,. dimethylamino,

diethylamino, and M is a cation.

30. A composition of matter for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising a therapeutically effective amount of a salt of an alpha-ketocarboxylic acid having the formula R-C₍O_{) (}CO)0_M wherein is alkyl of 1 to 12 carbon atoms^; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms^; alkynyl of 3 to 6 carbon atoms; benzyl; substituted benzyl (wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring^); adamantyl; phenyl; naphthyl; substituted phenyl or substituted napthyl ₍wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and M is a cation.

3₁. A perenteral fluid useful for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising a therapeutically-effective amount of a salt of an alpha-ketocarboxylic acid having the formula R-C₍O_{) (}CO₎OM wherein R is alkyl of 1 to 12 carbon atoms^; substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms^; alkynyl of 3 to 6 carbon atoms_; benzyl_; substituted benzyl ⁽wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring^); adamantyl; phenyl; naphthyl; substituted phenyl or substituted napthyl (wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and M is a cation.

32. A composition according to Claim 31 wherein the pe^'renteral fluid is selected from the group comprising total parenteral nutritional fluids; kidney and peritoneal dialyses fluids; volume and plasma expanding fluids; pyruvate/acetate near-isotonic solutions; lactate/acetate-free pyruvate isotonic solutions^; normal saline solutions; hemoglobin-substitute containing solutions; vitamin_. supplement product; and cardioplegic solutions.

33. A rehydration fluid, which may contain electrolyte balances, useful for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising a therapeutically-effective amount of a salt of an alpha-ketocarboxylic acid having the formula R-C⁽0^{) (}CO⁾OM wherein R is alkyl of 1 to 12 carbon atoms; substituted alkyl of ¹ to ¹2 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms_; alkynyl of 3 to 6 atoms; benzyl^; substituted benzyl ₍wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring); adamantyl; phenyl^; naphthyl^; substituted phenyl or substituted napthyl ⁽wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of

1 to 4 carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and M is a

cation.

34. A composition according to Claim 33 wherein the rehydration fluid contains electrolyte balances.

35. A medicinal composition useful for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising a therapeutically effective amount of thereof a salt of an alpha- ketocarboxylic acid having the formula R-C⁽O^{) (}CO⁾OM wherein R is alkyl of 1 to ₁2 carbon atoms; substituted alkyl of ¹ to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms_; alkynyl of 3 to 6 carbon atoms; benzyl^; substituted benzyl (wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring⁾; adamantyl^; phenyl^; naphythyl_; substituted phenyl or substituted napthyl ⁽wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbons atoms, halo, alkoxy of 1 to ⁴ carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and M is a cation.

36. A composition according to Claim 35 is selected from the group comprising medicinal soaps; medicinal shampoos; sunscreens; medicinal ointments; vitamin capsules; dentrifice^; mouthwash^; douche solutions; and medicinal baths.

37. An antibiotic or antiphylogistic composition useful for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising a therapeutical^ effective amount of a salt of an alpha- ketocarboxylic acid having the formula R-C⁽O^{) (}COON wherein R is alkyl of 1 to 12 carbon atoms, substituted alkyl of 1 to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, within the alkylene chain, halogen amino, alhylamino of 1 to 4 carbon atoms dialkylamino of 1 to 4 carbon atoms in each alkyl, alkenyl of 2 to 6 carbon atoms_; alkynyl of 3 to 6 carbon atoms^; substituted benzyl ₍wherein the substituent is methyl, pheny! on the alpha carbon atom or _•t■>h,_«e s_c-_uub_hsς_ttiⁱttuueennt^t is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring^{) ;} adamantyl^; phenyl^; naphythyl_; substituted phenyl or substituted napthyl ⁽wherein the

- - „ di or trisubstituted and the substitutents are ring is mono-, α -, or u ^au^ alkyl of 1 to ₄ carbons atoms, halo, alkoxy of ¹ to ⁴ carbon atoms, Phenoxy, trihalomethyl, dimethylamino, diethylamino, and M

is a cation.

38. The composition according to Claim 37 wherein said composi _■ti_•on _•s _Madmi_inniisstteerreedd b^uy intramuscular injection^,

j» .-_^ riaim 38 wherein said

39. The composition according to Claⁱm 3⁸ composition is an antibiotic.

₄0. The method in accordance with Claim 39 wherein said composition is an antiphylogistic .

4₁. An aerosolized pharmaceutical composition for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising a therapeutically effective amount of a salt of an alpha- ketocar_boxylic aci_d having the formula H-C IO^{) (}C^{O) C}M wherein R is alkyl of ₁ to ₁₂ car_bon atoms ; substituted alkyl of ¹ to ¹² carbon atoms , cyloalkyl of ₃ to 10 carbon atoms , ⁽car^boxyalkylene of ₁ to ₂₀ carbon atoms _within the alkylene chain , halogen amino, alkylamino of ₁ to ₄ car_bon atoms, dialkylamino .of ¹ to ⁴ car^bon atoms in each alkyl group or phenyl ) ; alkenyl of ² to 6 car^bon atoms _; alkynyl of ₃ to 6 atoms ; benzyl ; substituted benzyl ₍wherein the su_bs_ti_tuent is methyl , phenyl on the alpha car^bon atom or the substituent is methyl , dimethyl , halo, dihalo, or ethoxy on the phenyl ring) ; adamantyl ; phenyl ^; naphthyl ^; su_bstituted phenyl or substituted napthyl ⁽wherein the ring is mono- , di- , or trisubstituted and the substitutents are alkyl of ₁ to ₄ carbon atoms , halo, alkoxy of 1 to 4 carbon atoms , phenoxy, trihalomethyl , dimethylamino, diethylamino, and H is a cation alone or in combination with a bronohodilating agent .

₄₂ A perfusion fluid for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising a therapeutically effictive amount of a salt of an alpha-ketocarboxylic acid having the formula R-_{C(O) (CO)O}M wherein R is alkyl of 1 to ¹2 carbon atoms^; substituted alkyl of ₁ to ₁2 carbon atoms, cyloalkyl of ³ to ¹⁰ carbon atoms, alkenyl of 2 to 6 carbon atoms^; alkynyl of ³ to ⁶ carbon atoms_; benzyl_; substituted benzyl (wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring^{) ;} a_daman_tyl_; phenyl_; naph_thyl; substituted phenyl or su^bstitu^te^d napthyl ₍wherein _the ring is mono-, di-, or trisu^bstitute^d an^d _the su_bs_ti_tu_ten_ts are alkyl of 1 to 4 carbon atoms, halo, alkoxy of ₁ to ₄ car_bon a_toms, phenoxy, trihalomethyl, .dimethylamino, diethylamino, and M is a cation.

₄3. _An incu_ba_tion solution for enhancing the phosphorylation potential within bacterial or viral cells in culture or cloning me_dia in order to prevent the deterioration or promote the restoration and preservation of normal cell functions comprising a salt of an alpha-ketocarboxylic acid having the formula R- _C(O_{) (}C_O)OM wherein R is alkyl of 1 to 12 carbon atoms^; substituted alkyl of ₁ to 12 carbon atoms, cyloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms^; alkynyl of 3 to 6 carbon atoms; benzyl_; substituted benzyl (wherein the substituent is methyl, phenyl on the alpha carbon atom or the substituent ⁱs methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring^{) ;} adamantyl_; phenyl_; naphthyl; substituted phenyl or substituted napthyl ₍wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of 1 to 4 carbon atoms, halo, alkoxy of ₁ to ₄ carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and M is a cation.

₄₄. _A food product for enhancing the phosphorylation potential within the cells of a mammal in order to prevent the deterioration or promote the restoration and preservation of normal cell functions _thereby enhancing physical en^durance or refreshmen_t comprising a pharmaceutical composition having as an active ingredien_t thereof a salt of an alpha-ketocar^boxylic aci^d having _the formula _R-_C(O) (CO)O wherein R is alkyl of ^{1 t}o ¹² carbon atoms_; su_bstituted alkyl of 1 to 12 carbon a^toms, cyloalkyl of ₃ to ₁₀ carbon atoms, alkenyl of 2 ^to ⁶ car^bon atoms_; alkynyl of ₃ to ₆ carbon atoms; benzyl; substitu^te^{d b}enzyl ₍wherein the su_bsti_tuent is methyl, phenyl on the alpha car^bon atom or the su_bstituent is methyl, dimethyl, halo, dihalo, or ethoxy on the phenyl ring); adamantyl; phenyl; naphthyl^; substituted phenyl or substituted napthyl ⁽wherein the ring is mono-, di-, or trisubstituted and the substitutents are alkyl of ₁ to ₄ carbon atoms, halo, alkoxy of 1 to 4 carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and M is a cation.

₄₅ . The food product in accordance with Claim ⁴⁴ wherein said food product is a beverage drink .

₄6 . The food product in accordance with Claim ⁴5 wherein said food product is a confectionery food.

47. The food product in accordance with Claim ⁴⁴ wherein said food product is selected from the group comprising candies and

pastries .

_{48 A} vitamin supplement product for enhancing the _phosphoryla_tion potential within the cells of a mammal n order to preven_t the _de_terioration or promote the restoration ana preservation of normal cell functions here^by enhancing phy«e.l endurance or refreshment comprising a therapeutically ef fec^tive amount of a salt of an alpha-ketocarboxylic aci^d having the formula R-C _{(O) ( C}O_{) O}H wherein B is alkyl of ¹ to ¹² carbon atoms ^; substituted alkyl of ₁ to ₁2 carbon atoms , cyloalkyl of 3 ^to ¹⁰ carbon atoms , alkenyl of 2 to 6 carbon atoms ^; alkynyl carbon atoms _; benzyl _; substituted benzyl ⁽wherein the su^bstituent is methyl , phenyl on the alpha carbon atom or the substituent is methyl , dimethyl , halo, dihalo, or ethoxy on the phenyl ring, , adamantyl _; phenyl _; naphthyl; substituted phenyl or substituted

JJ _or trisubstituted and napthyl ₍wherein the ring is mono- , dⁱ- , or

„ , „ , _{to 4} carbon atoms , halo, alkoxy the substitutents are alkyl of 1 to ⁴ caroo of ₁ to ₄ carbon atoms, phenoxy, trihalomethyl, dimethylamino, diethylamino, and M is a cation.