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  Pharmaceutical Patents  

 

Title:  Method for the accelerated in vivo removal of ethanol
United States Patent: 
7,323,452
Issued: 
January 29, 2008

Inventors: 
Bowen, Jr.; Ward B. (Brockport, NY), Daniel; Daniel S. (Rochester, NY)
Assignee: 
Wardan, L.L.C. (Fairport, NY)
Appl. No.: 
11/017,387
Filed: 
December 20, 2004


 

Pharm Bus Intell & Healthcare Studies


Abstract

A method for accelerating the process of removing ethanol from the blood through the use of certain additives that accelerate the metabolic oxidation of ethanol, and others which in addition act as catalysts or "pseudo" enzymes for the oxidation. These additives include multivalent transition metal ions, as well as complexes thereof, and NAD.sup.+ which enhance the oxidation reaction. The method described can act as a sobriety inducer and/or as an effective palliative for the unpleasant effects of overuse of ethanol.

Description of the Invention

FIELD OF INVENTION

This invention relates to compositions and processes which accelerate the oxidation of alcohol in human blood. More particularly, the invention provides for the enhanced in vivo oxidation of ethanol and/or methanol.

BACKGROUND OF THE INVENTION

Alcohol consumption and its consequences have long been a challenge to the statutes that govern our society. High levels of ethanol in the blood have far reaching consequences to the user and society, as indicated by 16000 highway deaths and 1.6 million drinking related arrests per year in the United States.

Therefore there is a need to provide a remedy which can be administered to accelerate removal of alcohol from an individual's bloodstream and therefore to shorten the period during which the individual is impaired.

There is also a need to provide a remedy to an individual who is affected by alcohol to such a degree that medical intervention is required.

The source of oxygen, both mechanical and chemical (including the use of catalase in combination with hydrogen peroxide) is an essential part of the process, both these enzymes are not oxygen dependent but rather use NAD.sup.+ as the oxidizing agent.

Even though the combination can include other enzymes, which regenerate NADH to NAD.sup.+, using glycerol dehydrogenase/dihydroxyacetone, in the presence of a liberal supply of oxygen is an essential part of the method.

SUMMARY OF THE INVENTION

Formally, the oxidation of ethanol to acetaldehyde and then to acetic acid can be generically represented by the reactions: C.sub.2H.sub.5OH+2H.sub.2O.revreaction.CH.sub.3CHO+2H.sub.3O.sup.++2e (1) CH.sub.3CHO+4H.sub.2O.revreaction.CH.sub.3CO.sub.2.sup.-+3H.sub.3O.su- p.++2e (2)

It is therefore the object of this invention to accelerate the rates of the forward reactions in the equilibria 1 and 2, by introducing additives which catalyze the forward reactions or which remove product from the right hand side of the equilibria 1 and 2 to favor their shifting to the right.

Various additives provide a remedy through an effective and rapid reduction of the alcohol level in blood of the consumer at a reasonably short time, in essence a sobriety agent. Such remedy can take the form of a liquid, a pill, a capsule, a patch or a nasal spray or any other method known to medical science and any combination thereof. Such remedy can be self-administered or, in the same or different formulation be administered at a health care facility where it can be applied intravenously, intraperitoneally or in any other method know in medical practice. The product shall apply to all alcohol containing beverages including but not limited to all beers, wines and hard liquors now in use.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention relates to compositions which when administered to a person enhance the in vivo physiological process of removing oxidizing alcohol and particularly from the blood. In this disclosure, the term "alcohol" when used without qualification is understood to refer to ethanol. However, certain embodiments of the invention as noted will also be applicable to methanol.

As alcohol enters the blood stream, the liver begins the process of detoxification through the production of the enzyme Alcohol Dehydrogenase, ADH, which catalyzes the oxidation by Nicotinamide Adenine Dinucleotide, NAD.sup.+, of ethanol to acetaldehyde and Dihydronicotinamide Adenine Dinucleotide, NADH as shown -- see Original Patent.

The equilibrium constant of this reaction is 1, indicating that it is rather inefficient, allowing sufficient amounts of alcohol to remain in the blood and to cross the blood-brain barrier. It is the purpose of this invention to find ways of increasing the efficacy or accelerating this reaction.

In one embodiment of this invention, accelerated oxidation is accomplished by introducing a chemical accelerator of the ADH enzyme, driving the reaction toward acetaldehyde. Such accelerators include, zinc ions (as ADH is a Zinc Enzyme), pyridoxamine or pyridoxamine phosphate (formulae 1a and 1b, see Original Patent) or a combination thereof .

It is a particular advantage in the case of one of the above accelerators (zinc) that it is an essential element or a part of the Vitamin B6 system (pyridoxamine).

In another embodiment of this invention, the reversible reaction above can be shifted toward irreversibility by the removal of one or more of the products (Le Chatelier's Principle). This is accomplished through the introduction of a reactive agent that reacts with acetaldehyde, thus removing it from the equilibrium and driving the reaction forward. Such an agent includes pyridoxamine or pyridoxamine phosphate (formulae 1a and 1b, see Original Patent) or the basic amino acids lysine (formula 2, see Original Patent) and arginine (formula 3, see Original Patent). A solubilized form of "Purpald" (formula 4, see Original Patent) may also be useful. Other agents reactive with acetaldehyde include thiamine. A sufficient quantity of the reactive agent is administered to provide an in vivo concentration of the reactive agent at least chemically equivalent to an amount of acetaldehyde resulting from the oxidation.

Lysine and arginine are essential amino acids, so their introduction would not cause an undue risk to the user. Further, being basic, these amino acids can help neutralize the acid formed during the oxidation, thus further shifting the equilibrium toward product. In the presence of a base, the acetic acid produced by equilibrium (2) is neutralized, which pulls the reaction to the right. This consumes acetaldehyde from equilibrium (1), which is thus pulled to the right and consumes more ethanol.

Any base can be used provided that it is not harmful to the body. For example, the base can be sodium carbonate, sodium bicarbonate, trisodium phosphate, disodium hydrogen phosphate or tris (hydroxymethyl)-aminomethane. A sufficient quantity of the base is administered to provide an in vivo concentration of the base at least chemically equivalent to the acid resulting from the oxidation of the ethanol.

The removal of acetaldehyde can also be accomplished by its enzymatic oxidation to acetic acid as shown below in Equation (3) -- see Original Patent.

In one embodiment of the invention this can be accomplished by adding acetaldehyde dehydrogenase or an accelerator thereof or a combination of the two. When in vivo, the dehydrogenase should be present in an amount at least chemically equivalent to the amount of blood alcohol or, more precisely to acetaldehyde, the oxidation product of alcohol. This translates to a concentration in the range 0.1-10 I.U./L

Optionally the dehydrogenase may be stabilized with zinc ions since the dehydrogenase might otherwise degrade. Preferably, the concentration of zinc ions is at least 1% of the molar concentration of the dehydrogenase.

By increasing the amount of one of the reactants, the equilibrium can be shifted toward product. Thus, a formulation containing NAD.sup.+ can be useful. A sufficient quantity of NAD.sup.+ is administered to provide an in vivo concentration of NAD.sup.+ in the range of 0.05% to 5% of the maximum expected in vivo molar concentration of ethanol.

Any combination of the above may also be beneficial. Thus, a formulation containing acetaldehyde dehydrogenase, NAD.sup.+, pyridoxamine phosphate and zinc arginate or lysinate (or both) can be useful.

In another embodiment of the invention, the acetaldehyde can be chemically or enzymatically converted to an innocuous derivative, which can later be removed from the body. These derivatives include, but are not limited to, esters, ethers, acetals, ketals and urethanes.

Under proper aerobic conditions and with sufficient acid neutralizing agents, the aerobic oxidation of alcohol to acetic acid catalyzed by Alcohol Oxidase, AO, is as shown -- see Original Patent.

This may also be useful, particularly in combination with any of the above schemes.

In another embodiment of the invention, the acetic acid formed in either the acetaldehyde dehydrogenase or the alcohol oxidase reaction, or the combination of the two, can be converted to methane and carbon dioxide through a methanogenetic enzyme, thus driving the alcohol oxidation further toward irreversibility, as shown in equation (4) below: CH.sub.3CO.sub.2H.fwdarw.CH.sub.4+CO.sub.2 (4)

In another embodiment of this invention, the enzymatic reaction can be accelerated by a charge-transfer agent such as thiamine, (formula 5), retinoic acid (formula 6), an isoflavonoid or a pyranoside thereof (e.g. daidezin (formula 7) or its 7-glucoside, commonly known as aloin, (formula 8)), and 4,5-Dihydro-4,5-dioxo-1H-pyrrolo [2,3-f] quinoline-2,7,9-tricarboxylic acid, also known as either pyrroloquinolinequinone (PQQ) or methoxatin (formula 9), or any combination thereof, lipoic acid, retinoic acid, retinal, retinol, and derivatives and analogs thereof. A sufficient quantity of the charge-transfer agent is administered to provide an in vivo concentration of the charge-transfer agent in the range from 0.1% and 2% of the maximum expected in vivo molar concentration of ethanol.

In a further embodiment of the invention, various accelerants can be used to supply energy to the forward reactions of equilibria 5 and 6. Such accelerants include adenosine 5'-triphosphate, adenine-9-.beta.-D-arabinofurasnoside 5'-trophosphate 2'-deoxadenosine 5'-triphosphate, and 2',3'-dideoxyadenosine 5'-triphosphate. They also include carbohydrates such as fructose, arabinose, ribose, deoxyribose, and their phosphorylated derivatives. A sufficient quantity of the accelerant is administered to provide an in vivo concentration in the range from 1% to 100% of the maximum expected in vivo molar concentration of ethanol.

In another embodiment of this invention, a combination of some or all of the above with substances that prevent or delay the absorption of gastric alcohol into the blood is also envisaged. Such substances include unsaturated fatty acids, dietary fiber, and surfactants such as oleic acid, lecithin, the plant surfactant saponin and taurine, (formula 10, see Original Patent).

The concentration of the surfactant in the composition should be in the range 0.02% and 0.2% by volume.

Some surfactants which also act as charge transfer agents can be used. These include lipoic acid, retinoic acid, retinal, retinol, and derivatives and analogs thereof. The concentration of the combined surfactant and charge-transfer agent should be between 0.1% and 2% of the maximum molar concentration of ethanol. A sufficient quantity of the combined surfactant and charge-transfer agent is administered to provide an in vivo concentration of the surfactant and charge-transfer agent between 0.1% and 2% of the maximum expected molar concentration of ethanol.

In yet another embodiment of this invention, the acceleration is effected by multivalent transition metal ions and their derivatives capable of acting as a pseudo enzyme in a dehydrogenase reaction. The ions include, but are not limited to, ions of elements of Groups IVa through VIII of the Periodic Table and their complexes or any combination thereof.

Preferred sources of such ions include: vanadyl sulfate; potassium ferricyanide, ammonium iron (III) citrate, ammonium molybdate, ammonium phosphomolybdate, sodium tungstate, and sodium phosphotungstate. Other sources include ammonium manganese (III) sulfate, zirconium (IV) EDTA, niobium (IV) EDTA, tetratkis (tropolinato) niobium (V) chloride, tetratkis (tropolinato)tantalum (V) chloride, cobalt (III) hexammine chloride, and chromium (III) picolinate. A sufficient amount of transition metal ion administered to provide an in vivo concentration of the ion in the range 0.05% to 2% of the maximum expected in vivo molar concentration of ethanol.

In the foregoing disclosure some reactions, such as those involving the enzyme ADH, are specific to ethanol, while others may apply also to methanol. In general, the multivalent transition metal ions and their complexes mentioned above would be expected to oxidize methanol and ethanol alike, via reactions which may sometimes involve NAD.sup.+. It has been found in particular that vanadyl sulfate/NAD.sup.+ is effective in oxidizing methanol. This invention therefore encompasses the in vivo oxidation of both ethanol and methanol in the blood.

Optionally, any of the embodiments can also include dietary constituents such as dietary fiber, garlic oil and onion oil, or medications including such commonly available pain relieving ingredients as aspirin, ibuprofen and acetomenaphin.
 

Claim 1 of 71 Claims

1. A process for accelerating in vivo oxidation of alcohol, comprising the steps of: (a) preparing a composition comprising NAD+ and a catalyst comprising at least one of a species selected from the group consisting of a multivalent transition metal ion and a complex thereof, excluding manganese, iron, chromium, copper and zinc; the species being in a state selected to accelerate in vivo oxidation of alcohol in the absence of a dehydrogenase where said catalyst effects the oxidation of NADH, thus recycling NAD+, and the composition having a sufficient quantity of the transition metal ion to provide an in vivo concentration of the ion in the range of 0.05% to 2% of a maximum in vivo molar concentration of ethanol; and (b) administering the composition in vivo to a subject in need of accelerated removal of alcohol from the bloodstream.

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