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Treatment of alcohol dependence or alcohol abuse

KudZu, Treatment of alcohol dependence or alcohol abuse

Darrell Miller

05/19/05

Date: May 19, 2005 09:29 AM
Author: Darrell Miller (dm@vitanetonline.com)
Subject: KudZu, Treatment of alcohol dependence or alcohol abuse

For millennia, folk medicines have been used to treat ‘‘alcohol addiction’’ in China. A thorough literature search of the ancient Chinese pharmacopoeias revealed a long list of traditional remedies, including the 16 ‘‘stop-drinking’’ formulae of Sun Simiao (ca. 600 AD) and the ‘‘anti-alcohol addiction’’ formula of Li Dongyuan (ca. 1200 AD), 2 of the most reputed ‘‘medical doctors’’ in the history of Traditional Chinese Medicine. However, like those discovered by the ancient Romans,11 most of the ancient Chinese remedies for ‘‘alcohol addiction’’ were based on psychological aversion: to deter patients from further drinking by associating alcohol drinking with an unpleasant experience. Interestingly, as time went by, treatments based solely on psychological aversion were gradually eliminated from the ancient Chinese pharmacopoeias, presumably because of their ineffectiveness and/or undesirable side effects. The only remedies that have survived this historical trial-anderror scrutiny are those consisting the root (Radix puerariae, RP) or flower (Flos puerariae, FP) of Pueraria lobata (a medicinal plant known to the West as kudzu). It was on the basis of this historical backdrop, we initiated the search of safe and efficacious anti-dipsotropic (alcohol intake suppressive) agents from RP. This approach has led to the discovery of daidzin,12 an isoflavone that has since been shown to reduce alcohol drinking in all alcohol preferring animal models tested to date.

Alcohol abuse

Alcohol abuse and alcohol dependence (i.e., alcoholism) are serious public health problems of modern society. In the United States alone, an estimated 13 million adults exhibit symptoms of alcohol dependence due to excessive alcohol intake, and an additional 7 million abuse alcohol without showing symptoms of dependence according to U.S. Government projections from studies conducted in the mid-1980s. Alcohol dependence and abuse are very expensive: in economic and medical terms, it will cost the U.S. well over $200 billion in 1991 with no prospect of falling or leveling off. The social and psychological damages inflicted on individuals as a consequence of alcohol abuse, e.g., children born with fetal alcohol syndrome (FAS) and victims of alcohol-related accidental death, homicide, suicide, etc., are immense.

While it is generally accepted that alcoholism and alcohol abuse are afflictions with staggering international economic, social, medical, and psychological repercussions, success in preventing or otherwise ameliorating the consequences of these problems has been an elusive goal. Only very recently the public view that alcoholism and alcohol abuse are remediable solely by moral imperatives has been changed to include an awareness of alcoholism and alcohol abuse as physiological aberrations whose etiology may be understood and for which therapy may be found through scientific pursuits. Both alcohol abuse and dependence arise as a result of different, complex, and as yet incompletely understood processes. At present, alcohol research is in the mainstream of scientific efforts.

Our studies on alcohol (ethanol or ethyl alcohol) have been based on the hypothesis that its abuse can ultimately be understood and dealt with at the molecular level. Such a molecular understanding, if achieved, would provide a basis for the identification and development of appropriate therapeutic agents. Our view hypothesizes that the clinical manifestations of alcoholism and alcohol abuse are the consequence of aberrations or defects within one or more metabolic pathways, affected by the presence of ethyl alcohol. In order to test this hypothesis, our initial studies focused on physical, chemical, and enzymatic properties of human alcohol dehydrogenase (ADH), the enzyme that catalyzes alcohol oxidation according to the following reaction formula:

CH.sub.3 CH.sub.2 OH+NAD.sup.+ .fwdarw.CH.sub.3 CHO+NADH

In addition, our studies more recently have focused on the aldehyde dehydrogenases (ALDH) which catalyze the subsequent step in the major pathway of ethanol metabolism according to the following reaction formula:

CH.sub.3 CHO+NAD.sup.+ .fwdarw.CH.sub.3 COOH+NADH

Prior to our research (for example, see Blair and Vallee, 1966, Biochemistry 5:2026-2034), ADH in man was thought to exist in but one or two forms, primarily in the liver, where it was considered the exclusive enzyme for the metabolism of ethanol. Currently, four different classes of ADH encompassing over twenty ADH isozymes have been identified and isolated from human tissues. There is no reason to believe that all of these ADH isozymes are necessary to catalyze the metabolism of a single molecule, ethanol, even though all of them can interact with it. We have proposed that the normal function of these isozymes is to metabolize other types of alcohols that participate in critical, physiologically important processes, and that ethanol interferes with their function (Vallee, 1966, Therapeutic Notes 14:71-74). Further, we predicted that individual differences in alcohol tolerance might well be based on both qualitative and quantitative differences in isozyme endowment (Vallee, 1966, supra).

Our research has established the structures, properties, tissue distribution, and developmental changes for most of the ADH isozymes, which while structurally quite similar, and presumed to have evolved from a common precursor, are functionally remarkably varied. Of the more than 120 publications from our laboratory that relate to the above subjects, the following, arranged in six categories, are especially useful for instruction in the prior art.