Methods and compounds for inhibiting aldehyde dehydrogenase are disclosed. The compounds are useful as pharmaceutical compositions in methods for therapeutically treating alcohol consumption in a human.

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: EQU 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: EQU 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.
(i) Discovery of isozymes: Bosron et al., 1977, "Isolation and Characterization of an Anodic Form of Human Liver Alcohol Dehydrogenase," Biochem. Biophys. Res. Comm. 74: 85-91; Bosron et al., 1979, "Human Liver .pi.-Alcohol Dehydrogenase: Kinetic and Molecular Properties," Biochemistry 18: 1101-1105; Bosron et al., 1980, "New Molecular Forms of Human Liver Alcohol Dehydrogenase: Isolation and Characterization of ADH (Indianapolis)," Proc. Natl. Acad. Sci. USA 77: 5784-5788; Pares and Vallee, 1981, "New Human Liver Alcohol Dehydrogenase Forms with Unique Kinetic Characteristics," Biochem. Biophys. Res. Comm. 2, No. 1: 122-130.
(ii) Discovery of new Physiological and toxicological substrates: Wacker et al., 1965, "Treatment of Ethylene Glycol Poisoning with Ethyl Alcohol," JAMA 194: 1231-1233; Frey and Vallee, 1980, "Digitalis Metabolism and Human Liver Alcohol Dehydrogenase," Proc. Natl. Acad. Sci. USA 77: 924-927; Mardh et al., 1985, "Human Class I Alcohol Dehydrogenases Catalyze the Oxidation of Glycols in the Metabolism of Norepinephrine," Proc. Natl. Acad. Sci. USA 82: 4979-4982; Mardh et al., 1986a, "Testosterone Allosterically Regulates Ethanol Oxidation by Homo- and Heterodimeric .gamma.-Subunit-Containing Isozymes of Human Alcohol Dehydrogenase," Proc. Natl. Acad. Sci. USA 83: 2836-2840; Consalvi et al., 1986, "Human Alcohol Dehydrogenases and Serotonin Metabolism," Biochem. Biophys. Res. Comm. 139: 1009-1016; Mardh and Vallee, 1986b, "Human Class I Alcohol Dehydrogenases Catalyze the Interconversion of Alcohols and Aldehydes in the Metabolism of Dopamine," Biochemistry 25: 7279-7282; Mardh et al., 1986c, "Human Class II (.pi.) Alcohol Dehydrogenase Has a Redox-Specific Function in Norepinephrine Metabolism," Proc. Natl. Acad. Sci. USA 83: 8908-8912; Mardh et al., 1987, "Thyroid Hormones Selectively Modulate Human Alcohol Dehydrogenase Isozyme Catalyzed Ethanol Oxidation," Biochemistry 26: 7585-7588; McEvily et al., 1988, "3.beta.-Hydroxy-5.beta.-steroid Dehydrogenase Activity of Human Liver Alcohol Dehydrogenase Is Specific to .gamma.-Subunits," Biochemistry 27: 4284-4288; Keung, 1991, "Human Liver Alcohol Dehydrogenases Catalyze the Oxidation of the Intermediary Alcohols of the Shunt Pathway of Mevalonate Metabolism," Biochem. Biophys. Res. Comm. 174: 701-707.
(iii) Development of new methods for isolation and characterization: Lange and Vallee, 1976, "Double-Ternary Complex Affinity Chromatography: Preparation of Alcohol Dehydrogenases," Biochemistry 15: 4681-4686; Keung et al., 1985, "Identification of Human Alcohol Dehydrogenase Isozymes by Disc Polyacrylamide Gel Electrophoresis in 7M Urea," Biochem. Biophys. Res. Comm. 151: 92-96; Montavon et al., 1989, "A Human Liver Alcohol Dehydrogenase Enzyme-Linked Immunosorbent Assay Specific for Class I, II, and III Isozymes," Anal. Biochem. 176: 48-56.
(iv) Characterization of isozymes: von Wartburg et al., 1964, "Human Liver Alcohol Dehydrogenase. Kinetic and Physicochemical Properties," Biochemistry 3: 1775-1782; Blair and Vallee, 1966, supra; Lange et al., 1976, "Human Liver Alcohol Dehydrogenase: Purification, Composition, and Catalytic Features," Biochemistry 15: 4687-4693; Wagner et al., 1983, "Kinetic Properties of Human Alcohol Dehydrogenase: Oxidation of Alcohols by Class I Isoenzymes," Biochemistry 22: 1857-1863; Wagner et al., 1984, "Physical and Enzymatic Properties of a Class III Isozyme of Human Liver Alcohol Dehydrogenase: .chi.-ADH," Biochemistry 23: 2193-2199; Ditlow et al., 1984, "Physical and Enzymatic Properties of a Class II Alcohol Dehydrogenase Isozyme of Human Liver: .pi.-ADH," Biochemistry 23: 6363-6368; Fong and Keung(a), 1987, "Substrate Specificity of Human Class I Alcohol Dehydrogenase Homo- and Heterodimers Containing the .beta..sub.2 (Oriental) Subunits," Biochem. 26: 5726-5732; Fong and Keung(b), 1987, ".beta..sub.2 (Oriental) Human Liver Alcohol Dehydrogenases Do Not Exhibit Subunit Interaction: Oxidation of Cyclohexanol by Homo- and Heterodimers," Biochem. 26: 5733-5738.
(v) Relationship of isozymes to genetics: Li et al., 1977, "Isolation of Alcohol Dehydrogenase of Human Liver: Is it a Determinant of Alcoholism?," Proc. Natl. Acad. Sci. USA 74: 4378-4381; Jornvall et al., 1984, "Human Liver Alcohol Dehydrogenase: Amino Acid Substitution in the .beta..sub.2 .beta..sub.2 Oriental Isozyme Explains Functional Properties, Establishes an Active Site Structure, and Parallels Mutational Exchanges in the Yeast Enzyme," Proc. Natl. Acad. Sci. USA 81: 3024-3028; von Bahr-Lindstrom et al., 1986, "cDNA and Protein Structure for the .alpha. Subunit of Human Liver Alcohol Dehydrogenase," Biochemistry 25: 2465-2470; Hoo et al., 1987, "Structure of the Class II Enzyme of Human Liver Alcohol Dehydrogenase: Combined cDNA and Protein Sequence Determination of the .pi. Subunit," Biochemistry 26: 1926-1932; Fong et al., 1989, "Liver Alcohol and Aldehyde Dehydrogenase Isozymes in a Chinese Population in Hong Kong," Human Heredity 39: 185-191.
(vi) Tissue distribution of isozymes: Pares et al., 1984, "Organ Specific Alcohol Metabolism: Placental .chi.-ADH," Biochem. Biophys. Res. Comm. 119: 1047-1055; Beisswenger et al., 1985, ".chi.-ADH is the Sole Alcohol Dehydrogenase Isozyme of Mammalian Brains: Implications and Inferences," Proc. Natl. Acad. Sci. USA 82: 8369-8373.
One ADH isozyme, class III or .chi.-ADH, is the only one present in brain, placenta, and testis and is least capable of oxidizing ethanol (Pares and Vallee, 1981, supra; Pares et al., 1984, supra; Beisswenger et al., 1985, supra). As a consequence, these tissues would seem to be at greatest risk with respect to the effects of ethanol. On the other hand, this circumstance also affords these tissues protection from acetaldehyde, the highly toxic oxidation product of ADH.
Alcohol abuse and alcoholism are problems unique to humans. It may not be surprising, therefore, that the complexity in other species is significantly less than in man. Such species differences extend to the catalytic preferences of ADH isozymes toward different alcohols. For example, horse ADH does not oxidize methyl alcohol and ethylene glycol while human ADH does (von Wartburg et al., 1964, supra). Large doses of ethanol administered to compete with methanol or ethylene glycol and prevent their oxidation to toxic products now constitutes the therapy for individuals poisoned with these agents (Wacker et al., 1965, supra). As a consequence of the detailed research exemplified above, much more is known about human ADH than the corresponding enzyme in other species, a unique situation quite the opposite for most other enzymes.
Each of the human ADHs is composed of two protein subunits that form a dimeric molecule. Class I ADHs are made up of .alpha., .beta., and .gamma. subunits which combine into homodimeric and heterodimeric isozymes; class II, III and IV appear to be only homodimers (Vallee and Bazzone, in Isozymes: Current Topics in Biological and Medical Research, Rattazzi et al. (eds.) pp. 219-244, Alan R. Liss, Inc., NY, 1983; Vallee, B. L., A Novel Approach to Human Ethanol Metabolism: Isoenzymes of Alcohol Dehydroaenase. Invited Lecture, Proceedings of the 20th International European Brewery Convention, Helsinki, 1985; Pares et al., 1990, FEBS Lett. 227: 115-118). The activities of the different ADHs toward several types of substrates has been examined and is quite revealing (see, for example, Vallee, 1985, supra). Class I isozymes containing at least one .gamma.-subunit are active toward specific steroid hormones and are selectively inhibited by testosterone (Mardh et al., 1986a, supra; McEvily et al., 1988, supra). Class II ADH contains the .pi.-subunit and is the only one that acts selectively on intermediates in the metabolism of norepinephrine, a critical endocrine and neurotransmitter agent (Mardh et al., 1986c, supra). The class III (.chi.) enzyme and its unique characteristics were mentioned above. The recently discovered human class IV ADH (Moreno and Pares, 1991, J. Biol. Chem., 266: 1128-1133), found mainly in gastric mucosa, shares the general physicochemical properties of all mammalian ADHs. Kinetically, it resembles class II ADH but is chemically distinct. Since ethanol concentration in the stomachs of drinkers may be as high as 1 to 10M transiently, the moderately high K.sub.m, 41 mM, of this isozyme is nevertheless ample to allow it to have a possibly important role in the first pass metabolism of ethanol. Many alcohols other than ethanol have important physiological roles and some are likely to be substrates for one or another of the ADH isozymes. Clearly, the interference of ethanol with normal metabolic processes could have serious consequences, both acute and chronic. One of the main goals of continued research is the identification of these critical substrates.
Genetic subvariants of the .beta. and .gamma.-subunits of ADH isozymes within the general population (.beta..sub.1, .beta..sub.2, .beta..sub.3, and .gamma..sub.1, .gamma..sub.2) produce characteristic differences in individuals. The first genetic difference found between the form predominant in Caucasians (.beta..sub.1) and that predominant in Asians (.beta..sub.2) is also the most profound (Smith et al., 1971, Ann. Hum. Genet., Lond., 34: 251-271; Fukui and Wakasugi, 1972, Jpn. J. Leg. Med., 26: 46-51); the .beta..sub.1 -subunit is 100-times less effective in converting ethanol to acetaldehyde than is the .beta..sub.2 -subunit. All of the differences are now known to result from point mutations at widely different positions in the chain, e.g., .beta..sub.1 .fwdarw..beta..sub.2, R47H; .beta..sub.1 .fwdarw..beta..sub.3, R369C; .gamma..sub.1 .fwdarw..gamma..sub.2, I349V and R 271Q but all affect coenzyme binding (Jornvall et al., 1987, Enzyme 37: 5-18). Several population studies have documented striking differences in .beta..sub.1 and .beta..sub.2 frequencies among Asian and Caucasian populations. For example, in an Asian population in Hong Kong, the .beta..sub.1 form of the .beta.-subunit was present in only about 10% of the subjects; all others had the .beta..sub.2 form (Fong et al., 1989, supra). In contrast, studies on a Caucasian population in England indicated that 90% had the .beta..sub.1 form and only 10% had the .beta..sub.2 form (Smith et al., 1971, supra).
Aldehyde dehydrogenase (ALDH) is the enzyme that catalyzes the second step in the ethanol metabolic pathway (see reaction formula above). As with ADH, there are multiple forms of ALDH, but only two of these have been examined in any detail; very much less is known about the others. The first two classes, in particular, are thought to have primary responsibility for oxidizing acetaldehyde (Pietruszko, in Biochemistry and Physiology of Substance Abuse, Watson (ed.), pp. 89-127, 1989). ALDH-I is present in mitochondria, has a high affinity for acetaldehyde, and has been assigned the major role in acetaldehyde detoxification. ALDH-II, on the other hand, occurs in the cytosol and has a low affinity for acetaldehyde. It is therefore thought to be less effective in its detoxification. The amino acid sequences of both forms are now known (Jornvall et al., 1987, supra).
An important inactive dominant mutant form of ALDH-I was discovered by Goedde et al., 1979, Hum. Genet. 51: 331-334, and shown to be present in approximately 50% of major Asian populations, e.g., Chinese, Japanese and Vietnamese (Goedde and Agarwal, 1987, Enzyme, 37: 29-44). This mutant protein apparently results from at least one point mutation (K487E) (Yoshida et al., 1984, Proc. Natl. Acad. Sci. USA 81: 258-261) that abolishes enzymatic activity and therefore markedly impairs the ability of heterozygous and homozygous individuals (Goedde and Agarwal, 1990, Pharm. Ther., 45: 345-371) to metabolize a variety of aldehydes including acetaldehyde and presumably including any physiologically important aldehydes that are in the range of the specificity characteristic of native ALDH-I. Remarkably, such individuals do not display any pathologic abnormalities but do experience a sensitivity reaction when they consume alcohol. The characteristic facial flushing is the symptom of this reaction that is recognizable immediately. Still more remarkably, this mutation seems to have survival value: alcoholism and alcohol abuse virtually do not exist among Asian flushers (Ohmori et al., 1986, Prog. Neuro-Psychopharmacol. and Biol. Psychiat., 10: 229-235).
The Hong Kong study (Fong et al., 1989, supra) documents, for the first time, the joint distribution of the .beta.-ADH and ALDH-I genetic subvariants in a Chinese population. The subvariants classify into four measurably distinct subgroups: 2.2% .beta..sub.1 -ADH and active ALDH-I; 5.6% .beta..sub.1 - ADH and inactive ALDH-I; 44.4% .beta..sub.2 -ADH and active ALDH-I; and 47.8% .beta..sub.2 -ADH and inactive ALDH-I. Based on the catalytic capacities of the four phenotype varieties, one would expect subjects with .beta..sub.2 -ADH and inactive ALDH-I to be the most rapidly intolerant of alcohol; those with .beta..sub.1 -ADH and inactive ALDH-I to be intolerant of alcohol but with less rapid onset; those with .beta..sub.2 -ADH and active ALDH-I to be moderately tolerant; and, subjects with .beta..sub.1 -ADH and active ALDH-I, i.e., the predominant Caucasian type, to be tolerant.
Since the lack of ALDH-I is not known to generate other significant metabolic problems, save those which are the consequence of ethanol metabolism, it would be ideal if a drug could be found which mimics the effect of this natural genetic variant but without producing substantial toxic side effects; such a drug would clearly offer great promise for the treatment of alcoholism and alcohol abuse.
The experience of Asian flushers with alcohol is not described as "aversion," but rather as intolerance, i.e., as an inability to endure alcohol. This is an important distinction because in Western medicine the psychological setting surrounding the administration of the toxic drugs disulfiram and carbimide has been given considerable emphasis in producing a regimen leading to so-called "aversion therapy" and more recently "psychological deterrence" (Banys,. 1988, J. Psychoactive Drugs 26: 243-261).
We now describe in detail two types of treatments for alcoholism and alcohol abuse that were known long before either the enzymology or genetics of ADH and ALDH isozymes were known. Their discovery and use has been phenomenological: not based on modern rational drug discovery or design. On the one hand, Western medicine has used toxic chemicals, not further developed since discovery of their effects on exposed industrial workers decades ago, to produce sensitization to alcohol. Ancient Traditional Chinese medicine, on the other hand, has used herbal preparations to treat diseases generally, and in particular alcohol intoxication, according to a philosophy in which herbal mixtures modulate bodily functions; treatment with herbal combinations is highly individualistic both with respect to the practitioner's preferences and prescriptions for the patient; record-keeping is rare; and practice of the art is heavily influenced by oral anecdotal tradition.
The only two pharmaceuticals currently used as alcohol-sensitizing drugs are both chemically reactive species but differently so, both non-specific inhibitors and individually distinct and hence different from one another, and both shown after decades of testing and use to be toxic, unsafe and ineffective. The pharmacological basis for the action of these drugs, disulfiram and carbimide (hereinafter referred to by its chemical name, cyanamide) is thought to be inhibition of hepatic ALDHs, but neither one is selective for ALDH-I, the only ALDH known to be affected by genetic mutation.
Disulfiram
Disulfiram (tetraethylthiuram disulfide) was first proposed as an aversive agent for the treatment of alcoholism by Williams, 1937, JAMA 109: 1472-1473. He had noticed that workers in the rubber industry who had been exposed to thiuram compounds, which are used as accelerators of vulcanization, experienced unpleasant effects after consumption of alcohol. Its approved use as a drug dates from 1948.
As to chemical properties, disulfiram is a general reagent for the determination of SH groups in proteins (Neims et al., 1966, J. Biol. Chem. 241, pp. 3036-3040), and reacts with thiols to form the diethylammonium diethyldithiocarbamates, carbon disulfide and the disulfide derived from the thiol (Coffey, supra, pp. 331-332); it undergoes disulfide exchange reactions under mild conditions.
Given its chemical properties, it is not surprising to find that disulfiram is a broadly acting but non-specific inhibitor of many physiologically important sulfhydryl-containing compounds including enzymes, Wright and Moore, 1990, Am. J. Medicine, 88: 647-655 (for a review, see Banys, 1988, supra). Thus, it inhibits enzymes critical in neurotransmitter metabolism (dopamine-.beta.-hydroxylase), drug metabolism and detoxification (microsomal mixed function oxidases), and multiple pathways of intermediary metabolism. It is a potent inhibitor of many liver enzymes, including ALDH, DBH, aniline hydroxylase, nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, and cytochrome P-450. Other studies have demonstrated inhibition of glyceraldehyde-3-phosphate dehydrogenase, succinic dehydrogenase, xanthine oxidase, hexokinase, and NADPH dehydrogenase. Still other studies have established inhibition of superoxide dismutase, which is thought to be an important antioxidant defense mechanism against free radical-induced biological damage. The details of these and other instances of enzyme inhibition may be found in may be found in the references cited in Banys, 1988, supra. This lack of specificity clearly contributes to and may be largely responsible for the substantial toxicity that accompanies the therapeutic use of disulfiram.
In vitro, disulfiram (Pietruszko, 1989, supra) is a potent inhibitor of the high K.sub.m cytosolic isozyme (ALDH-II) but inhibits the major acetaldehyde oxidizing mitochondrial isozyme (ALDH-I) only slightly. However, under conditions where trace amounts of certain mercaptans such as 2-mercaptoethanol or the in vivo metabolite methanethiol are added to disulfiram to generate a mixed disulfide, the low K.sub.m mitochondrial ALDH-I isozyme, normally resistant to disulfiram, is inactivated. Thus, disulfiram directly inhibits ALDH-II, but only indirectly inhibits ALDH-I via metabolites (Pietruszko, 1989, supra).
In vivo, disulfiram acts slowly to inhibit ALDH over 12 hours, and this inhibition is irreversible (Pietruszko, 1989, supra). Restoration of ALDH activity after disulfiram administration depends upon de novo enzyme synthesis of ALDH, which requires 6 or more days. Thus, disulfiram and its metabolites have the capacity to shut down hepatic acetaldehyde oxidation via ALDH-I and ALDH-II so that in the presence of high concentrations of ethanol, high levels of acetaldehyde will rapidly accumulate. Although exogenous acetaldehyde is known to be toxic, it is not at all clear that endogenous accumulation of acetaldehyde is the only or even the main causative agent in the so-called disulfiram-alcohol reaction (DAR) described below. The direct involvement of acetaldehyde in any of the manifestations of alcohol intolerance is poorly studied, poorly understood and remains unproven.
Disulfiram is essentially the only alcohol-sensitizing agent approved and marketed for use in the U.S. by Wyeth-Ayerst as Antabuse.RTM. and has been used in alcohol-aversion and psychological deterrence therapy. In a patient who has consumed ethanol, inhibition of ALDH by disulfiram produces highly unpleasant physiological reactions, among them flushing, tachypnoea, palpitations, nausea and tachycardia (Peachey and Naranjo, 1985, Medical Progress, May:45-59). The rationale for treatment with disulfiram is that fear of these reactions will deter alcoholics from further drinking (Peachey and Naranjo, 1985, supra).
As described in the 1991 Physician's Desk Reference (Medical Economics Co., Oradell, N.J., pp. 2358-59), Antabuse.RTM. plus alcohol, even small amounts, produces flushing, throbbing in the head and neck, throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, tachycardia, hypotension, syncope, marked uneasiness, weakness, vertigo, blurred vision, and confusion (Physician's Desk Reference, 1991, supra). Significant cardiac, hepatic, and neurological toxicity, have been observed associated with disulfiram therapy. For example, in severe reactions to Antabuse.RTM., there may be respiratory depression, cardiovascular collapse, arrhythmias, myocardial infarction, acute congestive heart failure, unconsciousness, convulsions, and death (see Physician's Desk Reference, supra). These at best undesirable side effects have been attributed to inhibition of enzymes other than ALDHs, as well as inhibition of the normal physiological functions of one or more of the ALDHs. In fact, the risk of taking disulfiram is so high in the minds of many that many clinicians refuse to use this drug to deal with alcohol abuse. Moreover, many patients themselves either refuse to take it or abandon its use. Thus, the art has not yet been provided with a drug for the selective or direct reversible inhibition of ALDR-I without the undesirable side effects or toxicity which accompanies disulfiram treatment.
In fact, placebo-controlled clinical trials of Antabuse.RTM. (disulfiram) (Fuller et al., 1986, JAMA 256: 1449-1455; Fuller and Roth, 1979, Ann. Int. Med. 90: 901-904) have shown that disulfiram is no more effective than the placebo control in reducing alcohol consumption, when compared with pre-treatment levels. According to Banys, 1988, supra, although since 1948 millions of doses of disulfiram have been prescribed for the treatment of alcoholism, well-controlled studies have never demonstrated that disulfiram is more effective than placebos in producing sustained abstinence; most of the studies published in the ensuing 40 years suffer from serious flaws. In reviewing the efficacy of disulfiram, Banys, 1988, supra supports the contention of Sellers et al., 1981, N. Eng. J. Med. 305: 1255-1262, that "evidence supporting the efficacy of disulfiram is limited. Controlled clinical trials of efficacy show no improvement or short-term improvement only. Appreciable improvements (abstinence and improved social functioning) reported by chronic alcoholics during the first three months of treatment with therapeutic doses (250 mg daily) and non-therapeutic doses (1 mg daily) probably result from non-specific specific, nonpharmacologic activity of the drug. The subsequent decline from early improvement after the first three months of treatment probably reflects both the low potency of the drug and the increased importance of nonpharmacologic factors as determinants of long-term outcomes of treatment.
In accord with this, of all the numerous studies of disulfiram, according to Peachey et al.(a), 1989, Brit. J. Addict. 84: 877-887, only two properly controlled clinical trials were conducted, and the more recent of these two reported that disulfiram was no more effective than placebos in bringing about continued abstinence in alcoholic patients.
Thus, the weight of the evidence after more than fifty years of use is that disulfiram is not only toxic and unsafe but ineffective.
Cyanamide
The citrated calcium salt of cyanamide was introduced as a result of the search for an alcohol-sensitizing agent less toxic than disulf iram (Ferguson, 1956, Canad. M. A. J., 74: 79314 795; Reilly, 1976, Lancet (Apr. 24, 1976): 911-912), but even now only disulfiram has been approved for use in the United States. Citrated calcium cyanamide is hydrolyzed to free cyanamide (H.sub.2 NCN) in aqueous solution, hence the general properties of cyanamide are relevant. Like disulfiram, cyanamide's alcohol-sensitizing effect was discovered among industrial workers exposed to the substance in the workplace. Although chemically distinct from disulfiram, it is also a reactive species. Cyanamide, which readily forms compounds by addition to the cyano group, yields guanidinium compounds, O-alkylisoureas and S-alkylisothioureas when reacted with alkyl amines, alcohols and thiols, respectively (Rodd's Chemistry of Carbon Compounds, 1965, Vol. 1, Part C, Coffey, ed., Elsevier, Amsterdam, p.374), i.e., with the nucleophilic functionalities that are present in proteins. It is so reactive that at slightly alkaline pH it dimerizes to cyanoguanidine, a species that is itself reactive toward nucleophiles, e.g., alkyl amines (Rodd, 1965, supra, p. 349). Incorporation of citrate in the pharmaceutical formulation provides the slightly acid pH required for stability with respect to dimerization.
Neither ALDH-I (the low K.sub.m isozyme) nor ALDH-II (the high K.sub.m isozyme) are inhibited in vitro by cyanamide, but in vivo a reactive product of cyanamide catabolism inhibits both isozymes (Deitrich et al., 1976, Biochem. Pharmacol. 25: 2733-2737; DeMaster et al., 1982, Biochem. Biophys. Res. Comm. 107: 1333-1339). Formation of this active inhibitor was shown initially to be catalyzed by enzyme(s) present in intact mitochondria and the microsomal fraction of rat liver (DeMaster et al., 1983, Pharmacol. Biochem. Behav. 18 (Supp. 1): 273-277). More recently, mitochondrial catalase has been shown to activate cyanamide to an ALDH inhibitor (DeMaster et al., 1984, Biochem. Biophys. Res. Comm. 122: 358-365; Svanas and Weiner, 1985, Biochem. Pharmacol. 34: 1197-1204). Further, Shirota et al.(a), 1987, Alcohol & Alcoholism Supp. 1: 219-223 and Shirota et al.(b), 1987, Toxicol. Let. 37: 7-12, showed that cyanamide inhibits ALDH via a reactive species and that cyanide is generated as a product of cyanamide oxidation by catalase under conditions in which the ALDH inhibitory species is also generated. According to Shirota et al.(b), 1987, supra, this cyanide formation could serve as a basis for cyanamide toxicity in vivo. It was postulated in 1987 (Shirota et al.(b), 1987, supra) that the oxidation of cyanamide would yield nitroxyl (HNO) as a product and that this highly reactive substance is the active ALDH inhibitory species. In 1990, Nagasawa et al. (J. Med. Chem. 33: 3120-3122) presented evidence, via isotope tracer experiments, that nitroxyl was formed in the catalase-mediated bioactivation of cyanamide. They suggest that their data and those of others support nitroxyl as the active ALDH inhibitor, noting that millimolar concentrations of cyanide do not inhibit ALDH. Marchner and Tottmar, 1978, Acta Pharmacol. et Toxicol. 43: 219, have reported that inhibition of ALDH with cyanamide is maximal at 1-2 hours after drug administration and is reversible, with restoration of 80% of the ALDH activity occurring within 24 hours.
As with disulfiram, cyanamide has been used in alcohol-aversion and psychological deterrence therapy as described above (Peachey and 1Naranjo, 1985, supra). According to Peachey, 1981, J. Clin. Psychopharmacol. 1: 368-375, cyanamide has not been approved in the United States because of its significant antithyroid activity in experimental animals. Citrated calcium cyanamide is marketed in other countries as Temposil.RTM., Dipsan.RTM. and Abstem.RTM. (Shirota et al.(a), 1987, supra). "Plain" cyanamide, commonly used in Spain, is marketed as Colme.RTM. (Valerdiz and Vazquez, 1989, Appl. Pathol. 7: 344-349).
Cyanamide like disulfiram is reported to be associated with medical complications, again as might be expected from its chemical reactivity. Although fewer side effects have been reported with cyanamide than with disulfiram, cyanamide has been studied much less intensively and the information on this drug, including its side effects, especially those which are long-term, is incomplete.
There are a number of known contraindications to treatment with cyanamide. Among the toxic effects of cyanamide reported are the following: (i) allergic contact dermatitis according to Conde-Salazar et al., 1981, Contact Dermatitis 7: 329-330 and references cited therein and peripheral neuropathy (also associated with disulfiram) according to Reilly, 1976, supra, who suggests that both cyanamide and disulfiram are general metabolic poisons and may lead to the accumulation of toxic derivatives of chemicals normally metabolized by oxidative pathways; (ii) liver injury, including generation of ground-glass inclusion bodies in liver cells of alcoholics treated with cyanamide (but not disulfiram, Vazquez et al.(a), 1983, Diagnostic Histopath. 6: 29-37) as first reported by Vazquez and Cervera, 1980, Lancet 1: 361-362 using plain cyanamide and by Thomsen and Reinicke, 1981, Liver 1: 67-73 as well as Koyama et al., 1984, Acta Hepatol. Jpn. 25: 251-256 using the citrated calcium salt of cyanamide; a series of reports of hepatotoxicity, including ground-glass inclusions, inflammatory reactions associated with liver cell destruction, portal tract fibrosis that can be severe if treatment has been prolonged, scarring, even cirrhosis according to the above-cited references and Vazquez et al. (a), 1983, supra; Vazquez et al.(b), 1983, Liver 3: 225-230; Bruguera et al., 1986, Arch. Pathol. Lab. Med. 110: 906-910; Bruguera et al., 1987, Liver 7: 216-222; Valerdiz and Vazquez, 1989, supra, for cyanamide and disulfiram but not calcium cyanamide; and (iii) cardiotoxic effects, including hypotension and even cardiac death according to Rodger, 1962, Br. Med. J. 2: 989 and hazardous cardioacceleration according to Kupari et al., 1982, J. Toxicol. - Clin. Toxicol..19: 79-86; Kupari et al., 1982, supra suggest that the use of alcohol aversive drugs including disulf iram and cyanamide has been contraindicated to patients with known cardiac diseases, but point out that it is common that asymptomatic chronic alcoholics have a number of cardiac problems. Clearly, therefore such drugs may be hazardous.
Peachey et al.(b), 1989, Brit. J. Addict. 84: 1359-1366, have conducted the only placebo-controlled, double-blind clinical trial of Temposil.RTM.. From this short-term trial, Peachey and his colleagues concluded that this drug was safe for use in alcoholics with normal thyroid function and without other serious medical conditions. Thyroid function was not altered during the short-term trial by Temposil.RTM. in patients with normal pretreatment thyroid function. However, in the trial one patient whose baseline thyroid function was decreased became hypothyroid after administration of Temposil.RTM.; thus it was concluded that for short-term use in alcoholics with normal thyroid function, the drug was safe. Peachey et al.(a), 1989, supra, report that they did not observe hepatotoxicity as measured merely by blood alkaline phosphatase. Liver biopsies were not performed, so that an assessment of histopathological liver changes in biopsies, such as those cited above with reference to hepatoxicity of cyanamide, was not done. Despite the premature conclusion of safety by Peachey et al. (a), 1989, supra, as limited by their assessment of what was measured as short-term effects, the effects of long-term treatment with cyanamide in controlled studies is still unknown.
According to Peachey, 1981, supra, in Canada and other countries, cyanamide has not been used widely because of its short duration of activity and its questionable efficacy in reducing drinking. Unfortunately, placebo-controlled clinical trials of Temposil.RTM. (chemical name: calcium cyanamide; generic name: calcium carbimide) (Peachey et al.(a), 1989, supra; Peachey et al.(b), 1989, supra) have shown that, compared with pre-treatment levels, cyanamide is only as effective as the placebo control in reducing alcohol consumption.
The weight of the evidence is that cyanamide in its various forms, like disulf iram, is not only toxic and unsafe but ineffective.
There are some reports that use of either disulfiram or cyanamide is counterproductive in treatment of alcoholism. In a double-blind study in humans, consumption of low doses of alcohol together with either disulfiram or cyanamide, induces and enhances euphoria (Brown et al., 1983, Alcoholism: Clin. Exp. Res. 7: 276-278). Brien et al., 1980, Eur. J. Clin. Pharmacol. 18: 199-205, have reported that their results with male alcoholic volunteers ingesting small amounts of ethanol after oral administration of cyanamide support the self-reports of alcoholics who state that they can circumvent a severe disulfiram-ethanol reaction by ingesting ethanol over a few hours, and thereafter drink excessively with impunity, the so-called burn-off phenomenon. If both disulfiram and cyanamide can be effectively burned-off by slow ingestion for a period followed by excessive consumption without aversion, the effectiveness of these so-called anti-alcohol drugs not only may be severely limited but even generally counterproductive.
Cyanamide has also been shown to have the undesirable effect of actually causing an increase in alcohol consumption in animals given cyanamide after alcohol deprivation (Sinclair and Gribble, 1985, Alcohol 2: 627-630). Typically cyanamide is given to alcoholics after they have been withdrawn from alcohol and are being abstinent. According to Sinclair and Gribble, 1985, supra, if this results in a potentiation of the desire for alcohol subsequent to termination of the drug, as appears to be the case in rat experiments, treatment with cyanamide would be counterproductive and should be dropped from usage altogether.
Traditional Chinese Herbal Medicine
Since ancient times, Radix Puerariae (RP), prepared from the root of Pueraria lobata Ohwi or Pueraria pseudo-hirsuta Tang et Wang (Leguminosae) and Puerariae Flos (FP), prepared from the flower of Pueraria lobata Ohwi have been known for their use in Traditional Chinese medicine. The crude drug RP was described in the first Chinese Materia Medica about 200 B.C. as something of a panacea: an antipyretic, antidiarrhetic, diaphoretic, anti-emetic agent, and, in today's parlance, a general anti-microbial agent. Sun Simiao reported the use of RP for the relief of drunkenness in his work "Beji-Qianjin-Yaofang" about 600 A.D. Presently, RP is widely used by the Chinese for the treatment of drunkenness, muscle clonus and tonus and myalgia, hypertension, migraine, angina, arrhythmia, and febrile diseases in general (Quanguo Zhongcaoyao Huibian editing group, pp. 829-830, Quanguo Zhongcaoyao Huibian People's Health Publisher, Beijing, 1983). It has been applied also to treat symptoms of febrile illness including chills, and is administered as a root decoction, whose principal use was based on its diaphoretic, antipyretic and spasmolytic effects, according to Niiho et al., 1989, Yakugaku Zasshi 109: 424-431 (English translation). According to Niiho et al., 1989, supra, FP is prescribed as a flower decoction to "activate the stomach, stop the thirst and relieve alcohol intoxication," and is believed to have an effect on alcohol elimination.
Although RP has been a part of Chinese medical practice for more than 2000 years, only in the past several decades have attempts been made to purify and classify its active ingredients (see, for example, Fang, 1980, J. Ethnopharmacol. 2: 57-63 and references cited therein, including Fang et al., 1974, Zhong HuaYiXueZaZhi(Chinese Medical Journal) 5: 271-274; Chen and Zhang, 1985, Zhong Yao Tong Bao 10: 34-36; Shibata, 1979, Amer. J. Chin. Med. 1: 103-141).
RP is a complex mixture with a multiplicity of components, only some few of which have been identified. Besides starch major constituents include daidzein, daidzin, puerarin, genistein, 6,7-dimethoxycoumarin, formononetin, .beta.-sitosterol, allantoin and 5-methylhydantoin. The only pharmacological activities of crude RP which have been studied are its effects on smooth muscle and cerebrovascular and cardiovascular systems. In this regard puerarin is the primary active constituent examined for this purpose (for a review, see Lai and Tang, 1989, Zhong Guo Zhong Yao Za Zhi14: 308-311; see also, Fang, 1980, supra).
Daidzein has been examined regarding its metabolic fate, but not with regard to any human pharmacological effectiveness, disease state or body system. It is metabolized rapidly, with a half-life on the order of one hour, after intravenous administration to mice (Yueh and Chu, 1977, Scientia Sinica 20: 513-521; Su and Zhu, 1979, Acta Pharmaceutical Sinica 14: 134 (Abstract)); an experiment in which daidzein was administered to two human volunteers revealed only that little daidzein had appeared in urine and feces after 60 hours. With this exception, the metabolic fate of daidzein in humans remains unknown. Similarly there is very little knowledge about the effects of crude RP or its constituents on acute or chronic alcohol intoxication.
With respect to daidzin, the only reported pharmacological activity is its estrogenic activity at high doses (Farmakalidis and Murphy, 1984, Fd. Chem. Toxic. 22: 237-239; Price and Fenwick, 1985, Food Add. Contam. 2: 73-106); daidzin administered subcutaneously in propylene glycol showed no antifebrile (hypothermic) effect in rats and showed no spasmolytic effect in mice (Nakamoto et al., 1977, Yakugaku Zasshi 97: 103-105). Thus, the art has not yet identified any components of RP or their activities in the metabolism of ethanol and/or the mediation of the behavioral effects of ethanol. Further, to increase ethanol elimination, RP has been employed in Traditional Chinese medicine in order to relieve or remedy excess alcohol consumption. With respect to ethanol metabolism via ADH and ALDH, this would suggest that components of RP would activate, not inhibit, ADH and ALDH to eliminate consumed ethanol more rapidly. Unexpectedly, we have found ADH-inhibitory compounds in RP. Such compounds, and methods for their use in the treatment of drug-alcohol reactions, have been described and claimed by us in co-pending and co-assigned U.S. applications Ser. Nos. 07/724,213 and 07/723,945 filed Jul. 1, 1991, hereby incorporated by reference in their entirety.
In the present invention, a hitherto completely unknown inhibitor of ALDH has been unexpectedly identified and purified from RP. This inhibitor is daidzin, a compound which selectively inhibits the activity of ALDH-I. Daidzin is a potent, yet reversible, inhibitor of ALDH-I, the enzyme whose mutation and resultant inactivation in about 50% of all Chinese, Japanese, Vietnamese and yet other Orientals results in their avoidance of ethanol and correlates with the virtual non-existence of alcoholism in this group (Ohmori et al., 1986, supra). Hence it is useful in the treatment and prevention of alcoholism and alcohol abuse. Daidzin's activity mimics the effect of the naturally occurring ALDH-I genetic variant found among the Chinese. Daidzin selectively inhibits the low Km ALDH isozyme, hence in its presence high levels of acetaldehyde are likely oxidized via the high K.sub.m, isozyme (ALDH-II). This suggests that in the presence of daidzin the accumulation of acetaldehyde will be limited to non-toxic levels by ALDH-II, in contrast to the high levels of acetaldehyde that accumulate with disulf iram which inhibits both ALDH-I and ALDH-II. RP, from which daidzin was isolated, has been used safely and effectively in Traditional Chinese Medicine for two thousand years in a number of medical conditions. Jointly these facts suggest that daidzin would be a direct, safe, effective and reversible agent to induce alcohol intolerance, but without significant toxic side effects which have been consistently observed in the treatment of alcohol abuse with the chemically-reactive and toxic disulfiram and cyanamide. Daidzin's properties as a selective, reversible and potent inhibitor of ALDH-I, while unexpected, are virtually ideal for a compound intended to promote alcohol intolerance and avoidance of its abuse, as is observed in the genetic condition which its use mimics. Even structurally closely related chemical compounds failed to mimic daidzin's selectivity for ALDH-I and remarkable potency as an ALDH inhibitor (see Tables IV and V). Prunetin and genistin were the only other naturally-occurring compounds of those tested which selectively inhibited ALDH-I but was nearly an order of magnitude less potent as an inhibitor than daidzin. In fact, daidzin is the first reversible inhibitor of any ALDH described so far with such high effectiveness and selectivity. Identification of other compounds that may act in concert with daidzin or modify daidzin such that its bioavailability is increased in vivo would be particularly advantageous. Bioavailability refers to the in vivo availability of a compound (e.g., to effect its intended function, for example, as an inhibitor or suppressor of drinking behavior) and can be measured in a variety of ways, for example, by quantitating the amount of compound circulating in the blood relative to the amount administered. For daidzin, the bioavailability has been unexpectedly found to be increased by a factor in RP. The bioavailability of an ALDH-inhibitory analog of daidzin by such factor may be similarly increased.
Daidzein, the aglycone of daidzin which is also present in RP, not only does not inhibit ALDH but instead selectively inhibits certain ADH isozymes. Hence, daidzein inhibits the first but not the second step in human ethanol metabolism, while daidzin inhibits the second but not the first step in human ethanol metabolism as described above. It cannot be predicted so far on strict structural or other grounds which flavone/isoflavone compound present in RP, or any closely related compound, will inhibit ADH or a selective isozyme of ADH, ALDH or a selective isozyme of ALDH, both ADH and ALDH, or neither ADH or ALDH. For example, improved inhibitory compounds may be obtained by synthetic derivatives (i.e., analogs) of daidzin, wherein the glucose is replaced with a different sugar moiety. For example, L and D aldo- or keto-tetroses, pentoses, hexoses, heptoses or the amino, alcohol and/or acid derivatives of such tetroses, pentoses, hexoses or heptoses; or wherein the glucose is replaced by the deoxy analogs of such tetroses, pentoses, hexoses or heptoses. Alternatively, the glucose (GlcO) moiety of daidzin may be replaced by alkoxy or acyloxy groups at the 7-position bearing various chain lengths, for example, up to 11 or more, comprising any of straight chain alkyl, peptidic, polyether, etc. backbones, and the backbones may be substituted with various neutral (e.g., hydroxyl, sugar, etc.) or charged (e.g., carboxylate, phosphate, phosphonate, sulfate, sulfonate, etc.) moieties. Additionally suitable moieties (e.g., carboxylate, hydroxyl, etc.) may be esterified.
These examples are not exhaustive in scope but suggest to those skilled in the art routes to the identification of daidzin derivatives (i.e., analogs) having increased bioavailability and improved potency, selectivity, controlled release, solubility, absorbability and/or stability.

Method for the inhibition of ALDH-I useful in the treatment of alcohol dependence or alcohol abuse

The Endowment for Research in Human Biology, Inc.


A method is disclosed for growing high-quality low-defect crystal films heteroepitaxially on substrates that are different than the crystal films. The growth of the first two heteroepitaxial bilayers is performed on a first two-dimensional nucleate island before a second growth of two-dimensional nucleation is allowed to start. The method is particularly suited for the growth of 3C-SiC, 2H-AlN, or 2H-GaN on 6H-SiC, 4H-SiC, or silicon substrates.

The invention described herein was made by employees of the United States Government and may be used by or for the Government for governmental purposes without payment of any royalties thereon or therefor.
The invention relates to the growth of semiconductor device crystal films, and more particularly, to a method for producing high quality films of silicon carbide (SiC), aluminum nitride (AlN), gallium nitride (GaN), and other materials or compounds on atomically flat crystalline surfaces. Specifically, the invention enables the growth of low defect heteroepitaxial single crystal films on atomically flat crystal surfaces. The semiconductor devices find application in high power, high frequency, high temperature and high radiation environments, as well as use in optoelectronic devices such as lasers and light-emitting diodes.
This invention relates to the controlled growth of crystal films for application to the fabrication of semiconductor devices. The invention is particularly applicable to the production of crystals (herein used to include crystal films) of silicon carbide, aluminum nitride, gallium nitride, diamond, and other materials. A primary aspect of the invention is related to silicon carbide (SiC) and the nitrides (e.g., AlN and GaN) of the Group III elements; however, the invention has much broader applications and can be used for other elemental crystals and compounds. For example, films of ternary and quaternary compounds (and higher order compounds) of the III-V elements (e.g., GaAlN) could be grown. Also, elemental single crystal films, such as silicon and diamond could also be grown.
The term xe2x80x9catomically-flatxe2x80x9d is known in the art and is generally referred to herein as meaning a surface that is totally without any atomic-scale or macro-scale steps over an area defined by selected boundaries that may be created by grooves in a manner to be further described herein with reference to FIG. 4. Many of the methodologies of the present invention are shared with that of U.S. Pat. No. 5,915,194, as well as U.S. Pat. No. 6,165,874, both of which are herein incorporated by reference.
Semiconductor devices, including MISFETs and other device structures all related to the present invention, are used in a wide variety of electronic applications. Semiconductor devices include diodes, transistors, integrated circuits, sensors, and opto-electronic devices, such as light-emitting diodes and diode lasers. Various semiconductor devices using silicon or compound semiconductors, such as gallium arsenide (GaAs) and gallium phosphide (GaP) are commonly used. In order to fabricate semiconductor devices, it is necessary to be able to grow high-quality, low-defect-density single-crystal films with controlled impurity incorporation while possessing good surface morphology. The substrate upon which the film is grown should also be a high-quality, low-defect-density single crystal. In recent years, there has been an increasing interest in research on wide-bandgap semiconductors for use in high temperature, high power, high frequency, and/or high radiation operating conditions under which silicon and conventional III-V semiconductors cannot adequately function. Particular research emphasis has been placed on SiC, and III-nitride alloys, including AlN, GaN, InGaN, AlGaN, and others.
Conventional semiconductors are unable to meet some of the increasing demands of the automobile and aerospace industries as they move to smarter and more electronic systems. New wide bandgap materials are being developed to meet the diverse demands for more power at higher operating temperatures. Two of the most promising emerging wide bandgap semiconductors are silicon carbide (SiC) and gallium nitride (GaN). At over three electron volts, the bandgap of these materials is nearly three times as large as that of silicon. This advantage theoretically translates into very large improvements in power handling capabilities and higher operating temperatures that will enable revolutionary product improvements. Once material-related technology obstacles are overcome, SiC""s properties are expected to dominate high power switching and harsh-environment electronics for manufacturing and engine control applications, while GaN will enable high power high frequency microwave systems at frequencies beyond 10 GHz. To date the best SiC devices to our knowledge are homojunction (i.e., wafer and device layers are all hexagonal SiC), while GaN devices are heterojunction (i.e., SiC or sapphire wafers with device layers of GaN, AlGaN, AlN, etc.) because production of bulk GaN wafers is not practical at the present time.
Silicon carbide crystals exist in hexagonal, rhombohedral and cubic crystal structures. Generally, the cubic structure, in particular, the zincblende structure is referred to as xcex2-SiC or 3C-SiC, whereas numerous polytypes of the hexagonal and rhombohedral structures are collectively referred to as xcex1-SiC. To our knowledge, only bulk (i.e., large) crystals of the a polytypes have been grown to date with reasonable quality and size acceptable for device applications. The xcex2 (or 3C) polytype can only be obtained as small (less than 1 cm2) blocky crystals or thick epitaxial films on small 3C substrates or crystal films of poor quality grown heteropitaxially on some other substrate. The most commonly available xcex1-SiC polytypes are 4H-SiC and 6H-SiC; these are commercially available as polished wafers, presently up to 75 mm in diameter. Each of the SiC polytypes has its own specific advantages over the others. For example, (1) 4H-SiC has a significantly higher electron mobility compared to 6H-SiC; (2) 6H-SiC is used as a substrate for the commercial fabrication of GaN blue light-emitting diodes (LED""s); and (3) 3C-SiC has a high electron mobility similar to that of 4H-SiC and may function over wider temperature ranges, compared to the xcex1 polytypes, but crystals of sufficient quality and size have not been readily obtainable.
Silicon carbide polytypes are formed by the stacking of double layers, also referred to as bilayers, of covalently bonded Si and C atoms. As will be more fully described later, each double layer may be situated in one of three atomic stacking positions known as A, B, and C. The sequence of stacking determines the particular polytype; for example, the repeat sequence for 3C-SiC is ABCABC . . . (or ACBACB . . . ) the repeat sequence for 4H-SiC is ABACABAC . . . and the repeat sequence for 6H is ABCACBABCACB . . . From this it can be seen that the number in the polytype designation gives the number of double layers in the repeat sequence and the letter denotes the structure type (cubic, hexagonal, or rhombohedral). The stacking direction is designated as the crystal c-axis and is in the crystal  less than 0001 greater than  direction; it is perpendicular to the basal plane which is the crystal (0001) plane. The SiC polytypes are polar in the  less than 0001 greater than  directions; in one direction, the crystal face is terminated with silicon (Si) atoms; in the other direction, the crystal face is terminated with carbon (C) atoms. These two faces of the (0001) plane are known as the silicon face (Si-face) and carbon face (C-face), respectively. As will be more fully described later with respect to FIG. 15(A), the 3C-SiC (i.e., cubic) polytype has four equivalent stacking directions, and thus there are four equivalent planes, the (111) planes, that are basal planes. As used herein, xe2x80x9cbasal planexe2x80x9d shall refer to either the (0001) plane for a xcex1-SiC, or the (111) plane of 3C-SiC. The term xe2x80x9cvicinal (0001) waferxe2x80x9d shall be used herein for wafers whose polished surface (the growth surface) is misoriented less than 10xc2x0 from the basal plane. The angle of misorientation shall be referred to herein as the tilt angle. The term xe2x80x9chomoepitaxialxe2x80x9d shall be referred to herein as epitaxial growth, whereby the film and the substrate (wafer) are of the same polytype and material, and the term xe2x80x9cheteroepitaxialxe2x80x9d shall be referred to herein as epitaxial growth whereby the film is of a different polytype or material than the substrate. The term xe2x80x9cmesaxe2x80x9d is meant to represent an isolated growth region to be further described herein. The term xe2x80x9cbilayerxe2x80x9d shall be referred to herein as a layer along the basal plane consisting of two-tightly bonded monolayers of atoms, such as Si and C atoms tightly bonded in bilayers of SiC to be further described. The term xe2x80x9cdefect freexe2x80x9d shall be referred to herein as a single crystal that is free of extended structural defects, such as dislocations and stacking faults that propagate over numerous atoms in at least one direction. The term xe2x80x9cdefect freexe2x80x9d is not meant to describe isolated point defects that involve at most 1 or 2 atoms at an isolated 3D point in the crystal, such as atomic vacancy point defects, interstitial point defects, and impurity point defects.
Theories explaining epitaxial single-crystal growth are well known. Crystal growth can take place by several mechanisms. Two of these are: (1) growth can take place by the lateral growth of existing atomic-scale steps on the surface of a substrate and (2) growth can take place by the formation of two-dimensional atomic-scale nuclei on the surface followed by lateral growth from the steps formed by the nuclei. The lateral growth from steps is sometimes referred to as xe2x80x9cstep-flow growth.xe2x80x9d In the first mechanism, growth proceeds by step-flow from existing steps without the formation of any two-dimensional nuclei (i.e., without 2D nucleation). In the nucleation mechanism, the nucleus must reach a critical size in order to be stable: in other words, a potential energy barrier must be overcome in order for a stable nucleus to be formed. Contamination or defects on the substrate surface can lower the required potential energy barrier at a nucleation site. In the processes described in U.S. Pat. No. 5,915,194, having certain drawbacks related to lattice mismatch giving rise to undesired crystal defects, crystal growth proceeds by (1) step flow without 2D nucleation or by (2) step-flow with 2D nucleation. Step-flow growth with 2D nucleation allows the growth of epitaxial films of any desired thickness. In the processes described in the present invention, optimum growth (i.e., defect free) occurs when a first bilayer and a second bilayer are completed from lateral step-flow expansion of single nucleation islands of heteroepitaxial film on an atomically flat surface.
As discussed above, as well as in U.S. Pat. No. 5,915,194, 3C-SiC, to our knowledge, is not available in high quality single-crystal large wafer form. Hence, 3C-SiC device structures must be grown heteroepitaxially on some other substrate material. The present invention overcomes the problems of prior art, including recently discovered deficiencies of U.S. Pat. No. 5,915,194 to be further described, to realize the growth of high quality low-defect 3C-SiC films on 6H-SiC and 4H-SiC substrates.
In addition to non-availability of high quality 3C-SiC single crystal wafers or epilayers, other wide-bandgap semiconductor compounds that are not available in single-crystal wafer form and which have great commercial potential are the nitrides of aluminum, gallium, and indium. Gallium nitride (GaN) in particular, has great potential as an optoelectronic material. Currently, commercial light-emitting diodes are being fabricated by growing GaN or InGaN films on 6H-SiC or sapphire substrates. Even though these films have extremely high defect densities (typically around 108 cmxe2x88x922), very bright and efficient LED""s can be fabricated. Pulsed blue lasers have been fabricated from III-N, as well as continuous blue lasers that operate for a period of time before failure related to crystal defects. The present invention provides a means for reducing defects in the GaN and InGaN films and hence makes a more durable continuous duty III-N laser possible.
Although U.S. Pat. No. 5,915,194, as well as U.S. Pat. No. 6,165,874, provides many benefits, it has certain limitations. In our practice of the teachings of U.S. Pat. No. 5,915,194, it has been determined that other defects, not related to surface steps, form when practicing heteroepitaxial growth on atomically flat surfaces as taught by U.S. Pat. No. 5,915,194. As pointed out in U.S. Pat. No. 5,915,194, heteroepitaxial growth on an atomically flat basal plane starts by the nucleation of a growth island that consists of a bilayer of tightly bonded Si and C atoms. In U.S. Pat. No. 5,915,194, as illustrated in FIGS. 7 and 8 thereof, it is described that multiple growth islands (Reference #46 in FIG. 7 thereof) nucleated on the flat surfaces would coalesce without defects because the atoms of the expanding islands would remain coherent with the substrate crystal lattice. However, recent experimental observations in growing heteroepitaxial 3C-SiC films on atomically flat 6H and 4H-SiC substrates indicate this is not the case. In reality, numerous stacking faults are experimentally observed when nucleation of multiple islands takes place within a given atomically flat mesa surface.
The present invention prevents the occurrence of these stacking faults while enabling the growth of low-defect heteroepitaxial single crystal films on atomically flat single crystal surfaces. The present invention overcomes deficiencies in prior art, including those of U.S. Pat. Nos. 5,915,194 and 5,363,800 (herein incorporated by reference), as well as those of U.S. Pat. No. 6,165,874, while initiating growth of heteroepitaxial single crystal films on device-size regions of atomically flat substrate surfaces.
It is a primary object of the present invention to provide a method of growing high quality low-defect crystal films of semiconductors on substrates that are different than the crystal film. The method is particularly suited for the growth of 3C-SiC, 2H-AlN, and 2H-GaN or InGaN on 6H/4H-SiC substrates.
It is another object of the present invention to provide a method of growing III-N heteroepitaxial films on atomically flat surfaces of 6H/4H-SiC substrates.
It is still a further object of the present invention to provide high quality heteroepitaxial growth of materials with relatively large lattice mismatch to the substrate, yielding heterojunctions.
It is still another object of the present invention to eliminate the need for buffer layers that are required by prior art to overcome lattice mismatch in single-crystal heteroepitaxial films.
Moreover, it is an object of the present invention to provide a method that produces devices that are comprised of reduced defect material having an extended operational life, reduced power consumption, and reduced size thereby decreasing production costs.
The practice of the present invention particularly related to atomically-flat crystalline surfaces and crystal films is partially based on our discovery of that by selecting a particular set of growth conditions intended to greatly reduce the rate of two-dimensional (2D) nucleation, we reproducibly achieve the growth of 3C-SiC heterofilms entirely free of stacking faults. We also discovered that after initial 3C-SiC nucleation was carried out on a step-free surface at a low nucleation rate, that we could then change the growth conditions to greatly increase the nucleation rate without any detriment to the quality of the heteroepitaxial film. These discoveries strongly indicate that optimum growth (i.e., defect-free) occurs when a first bilayer and a subsequent second layer is completed from the lateral step-flow expansion of single nucleation islands (one island for each bilayer) of the heteroepitaxial film on the atomically-flat surface.
In general, the invention is a method of producing low-defect crystal film structures of materials that are not presently available in the form of large area single-crystal substrates. This method is accomplished by utilizing particular heteroepitaxial growth processes on an atomically-flat basal plane surface of a substrate of different material and/or structure other than the desired crystal film.
The method is primarily concerned with depositing a heteroepitaxial single-crystal film on a plurality of step-free surfaces of a basal plane surface orientation of a selected single-crystal substrate material serving as a wafer. The method comprises the steps of:
(a) preparing more than one step-free planar surface on the selected substrate, wherein each of the plurality of step-free surfaces has a boundary of selected size and shape;
(b) selecting a heteroepitaxial film material whose chemical bonding structure is tetrahedral and exhibits a property that under predetermined growth conditions that growth of the heteroepitaxial film material grows in bilayers on the selected step-free planar surface;
(c) carrying out a selected deposition process under selected growth conditions that produce (1) a single nucleus of the heteroepitaxial film material at least one bilayer thick on the step-free surface with the selected boundary, followed by (2) lateral expansion of the single nucleus over an entire surface defined by the selected boundary of the plurality of step-free basal plane surfaces before a second nucleus can form elsewhere on the selected step-free planar surface, and (3) a single nucleus of the second bilayer of heteroepitaxial film, followed by (4) lateral expansion of the single nucleus over the entire surface defined by the selected boundary before a second nucleus can form elsewhere on the first bilayer of heteroepitaxial film on the selected step-free planar surface, and
(d) providing growth of subsequent additional bilayers of the said heteroepitaxial film by providing a suitable set of growth conditions until a desired thickness of said heteroepitaxial film is achieved.
Further, the present invention relates to a method of growing high-quality low-defect single crystal films of silicon and diamond materials on substrates that are different than the film. As an example, the growth of 3C-SiC, 2H-AlN, and/or 2H-GaN on 6H-SiC substrates is related to the present invention.
A specific application of this invention is the growth of 3C-SiC on a 6H-SiC substrate. Another application is the growth of 2H-GaN on a 6H-SiC substrate. Other SiC polytypes, such as 4H-SiC could also be used as substrates in the practice of this invention.
In the practice of our invention, important considerations to achieve growth with little or no two-dimensional nucleation are the following: contamination and surface defects must be minimized because the contamination""s can reduce the energy barrier that hinders two-dimensional nucleation. Also line defects (dislocations) that intersect the growth surface must be minimized because some dislocations act as localized step sources that can dominate growth on the substrate mesas preventing the achievement of atomically-flat or nearly atomically-flat mesas necessary for the practice of the present invention.
A further consideration related to the invention is that multiple rotational orientations of the polytypic stacking sequence can occur on surfaces with steps when a 3C sequence is grown on a higher order polytypic substrate, such as a 4H or a 6H polytypic sequence. When crystal film islands, that have different rotational orientations, coalesce, then defects such as double positioning boundaries (DPB""s) form at a boundary between the two domains. It is expected that this same behavior holds for the 2H sequence grown on the 4H or 6H sequence.

Method for growing low-defect single crystal heteroepitaxial films

The United States of America as represented by the Administrator of the National Aeronautics and Space Administration


A target lens shape measuring device for measuring a target lens shape for processing an eyeglass lens includes: amount on which at least one of a template and a base of a fixing cup to which a dummy lens is attached is to be mounted; a fixing portion for pressing and fixing the template or the dummy lens mounted on the mount during measurement; a moving mechanism for moving the fixing portion between a pressing position, at which the fixing portion presses the template or the dummy lens, and a non-pressing position; a measuring pin to be brought into contact with a periphery of the template or the dummy lens mounted on the mount; a movement detecting mechanism for detecting an amount of movement of the measuring pin to obtain a target lens shape; and a linking mechanism for moving the measuring pin from a retracted position to a measuring position in linking with movement of the fixing portion to the pressing position by the moving mechanism.

The present invention relates to a target lens shape measuring device for measuring a target lens shape of a template or a dummy lens obtained by tracing the shape of a lens frame of an eyeglass frame, and an eyeglass-lens processing apparatus having the same.
An eyeglass-lens processing apparatus using a target lens shape of a template has been designed to process an eyeglass lens while tracing the template attached to a lens rotating shaft of the processing apparatus. However, recent, popular eyeglass-lens processing apparatuses are designed to measure the target lens shape of the template in the same way as the eyeglass frame, and then process a lens on the basis of data on the target lens shape.
A target lens shape measuring device for measuring the target lens shape of the template includes a measuring pin which is brought into contact with an end face of a fixed template; a moving mechanism for moving the measuring pin; and a detecting mechanism for detecting the amount of movement of the measuring pin. Although some target lens shape measuring devices are configured as dedicated devices, most of the devices are designed to commonly use mechanisms provided in an eyeglass frame shape measuring device, such as a moving mechanism for moving a feeler (that is to be inserted into a frame groove) and a detecting mechanism for detecting the amount of movement of the feeler.
Besides, the eyeglass frame shape measuring device requires a relatively large space since it has a mechanism for rotating the feeler for obtaining information on the radius vector of the frame, and other components such as a slider for holding the frame in a measurable state (i.e., a slider for moving a pair of abutment members respectively coming into contact with upper and lower portions of the lens frame to clamp and hold the frame by the movement of the abutment members).
In the case of the frame shape measuring device that is also designed as the measuring mechanism for the template, it is necessary to separately prepare a fixing jig for fixing the template. For the measurement of the template, it is required to fix the template to the fixing jig by screws or the like, and attach the fixing jig to a template measuring position in the frame shape measuring device. Hence, time and trouble are involved in the measurement, and the operational efficiency is not satisfactory.
On the other hand, in the case of the device dedicated for the measurement of the template, it is unnecessary to prepare the fixing jig. However, after fixing the template, the measuring pin must be moved so as to be set in a measuring state in which the measuring pin is brought into contact with the end face of the template, and if this movement is effected by a motor, the cost becomes high correspondingly, hindering the provision of the inexpensive device. If this movement is effected manually, the operation is troublesome.
In addition, there has been no target lens shape measuring device provided with a measuring mechanism for the template measurement and a measuring mechanism for the frame measurement independently. In providing the device with both measuring mechanisms, it is desirable to make the device as compact as possible.
In view of the drawbacks mentioned above, it is an object of the invention to provide a target lens shape measuring device which is superior in operational efficiency and is capable of saving the space for installing the mechanisms while improving the operational efficiency, and an eyeglass-lens processing apparatus having the same.
The present invention provides the followings:
(1) A target lens shape measuring device for measuring a target lens shape for processing an eyeglass lens, said device comprising:
a mount on which at least one of a template and a base of a fixing cup to which a dummy lens is attached is to be mounted;
a fixing portion for pressing and fixing the template or the dummy lens mounted on the mount during measurement;
moving means for moving the fixing portion between a pressing position, at which the fixing portion presses the template or the dummy lens, and a non-pressing position;
a measuring pin to be brought into contact with a periphery of the template or the dummy lens mounted on the mount;
movement detecting means for detecting an amount of movement of the measuring pin to obtain a target lens shape; and
linking means for moving the measuring pin from a retracted position to a measuring position in linking with movement of the fixing portion to the pressing position by the moving means.
(2) The target lens shape measuring device of (1), wherein the mount includes a side wall portion on which positioning pins for insertion into small holes of the template are projectingly provided, and an insertion hole surrounded by the side wall portion for receiving the base of the fixing cup.
(3) The target lens shape measuring device of (1), further comprising:
rotating means for rotating the mount,
wherein the fixing portion includes a rotatable contact portion to be brought into contact with the template or the dummy lens mounted on the mount.
(4) The target lens shape measuring device of (1), further comprising:
rotating means for rotating the mount;
rotation detecting means for detecting a rotational angle of the rotating means or a rotational angle of the mount by the rotating means;
arithmetic means for obtaining the target lens shape based on the amount of movement of the measuring pin detected by the movement detecting means and the rotational angle detected by the rotation detecting means.
(5) The target lens shape measuring device of (1), further comprising:
arithmetic means for obtaining the target lens shape based on the amount of movement of the measuring pin detected by the movement detecting means.
(6) The target lens shape measuring device of (1), further comprising:
an eyeglass frame holding unit including:
a pair of sliders to be respectively brought into contact with upper and lower end surfaces of an eyeglass frame;
clamping pins for clamping the eyeglass frame; and
urging means for moving the sliders to a position at which the sliders do not interfere with the template or the dummy lens mounted on the mount,
wherein measurement of the template or the dummy lens is carried out using a space obtained as a consequence of moving the sliders by the urging means.
(7) The target lens shape measuring device of (6), further comprising:
position detecting means for detecting whether or not the sliders are located at the position at which the sliders do not interfere with the template or the dummy lens on the mount;
mode determining means for determining a template measurement mode, in which the template or the dummy lens is measured, based on result of detection of the position detecting means.
(8) An eyeglass-lens processing apparatus, having the target lens shape measuring device of (1), for processing the eyeglass lens based on the obtained target lens shape, comprising:
lens processing means having a rotatable abrasive wheel and a lens rotating shaft for holding and rotating the lens; and
control means for controlling the lens processing means based on an obtained target lens shape.
The present disclosure relates to the subject matter contained in Japanese patent application No. Hei. 11-151231 (filed on May 31, 1999), which is expressly incorporated herein by reference in its entirety.

Target lens shape measuring device and eyeglass-lens processing apparatus having the same


In a liquid filling machine having a metering cylinder, a piston accommodated in the cylinder with a clearance formed therebetween, and a membrane closing each open end of the clearance to form a closed space, a device for detecting a leak in the metering cylinder comprising a vacuum pipe connected to the metering cylinder in communication with the closed space, an orifice plate inserted in the vacuum pipe for maintaining the interior portion of the pipe upstream from the orifice plate at a pressure lower than a predetermined value when the membrane has no leak with a standard quantity of leakage fluid flowing through the pipe and maintaining the interior portion at a pressure not lower than the predetermined value when the membrane has a leak, and a pressure sensor for detecting the pressure of the upstream interior portion of the pipe and producing a leak detection signal when the detected pressure is not lower than the predetermined pressure.

The present invention relates to a device for detecting a leak in the membrane sealing of a metering cylinder, for use in machines having the metering cylinder and adapted to fill containers with a specified quantity of liquid such as fluid food.
Filling machines of this type are known which comprise a metering cylinder for charging a filling nozzle with a specified quantity of liquid at a time, a piston accommodated in the metering cylinder and having a skirt opposed to the peripheral wall of the cylinder with a clearance formed therebetween, and a membrane closing each open end of the clearance to form a closed space in the clearance.
The membrane has a limit of durability and is periodically replaced when exceeding the limit. However, some membranes develop a leak, such as a pinhole, before the lapse of the period. Thus, there arises a need to discontinue the operation of the machine upon detecting such a leak. The following device is used for detecting leaks.
The metering cylinder has connected thereto a vacuum pipe in communication with the closed space between the cylinder and the piston. The vacuum pipe is provided at an intermediate portion thereof with a tank equipped with a pressure gauge and an electrode rod. When air leaks, the pressure gauge as observed with the eye indicates a variation in the internal pressure of the tank, notifying the operator of the leak. If the leakage fluid is liquid, the electrode rod detects the liquid collected in the tank, indicating the leak.
When leaks are as small as pinholes, the pressure gauge fails to detect the leak accurately since the resulting variation in pressure is small. This drawback is attributable further to the fact that the piping system including the vacuum pipe inevitably permits leakage in its entirety. The electrode rod requires a considerable period of time for an amount of liquid to collect in the tank.

Device for detecting leak in metering cylinder of liquid filling machine


A liquid-jet head is provided. In the liquid-jet head, a lower electrode, as a common electrode common to a plurality of piezoelectric elements, is continuously formed as far as an outer region opposite the piezoelectric elements, an auxiliary electrode layer is provided which comprises the same layers as layers constituting a lead-out electrode, and which is electrically connected to the lower electrode located outwardly of the region opposite the piezoelectric elements, a first insulation film at least in the vicinity of an end portion of a passage-forming substrate in a direction parallel to the arrangement of the piezoelectric elements is provided with a penetrated portion in a region opposite the auxiliary electrode layer, and the auxiliary electrode layer is in contact with the lower electrode via the penetrated portion provided in the first insulation film.

1. Field of the Invention
This invention relates to a liquid-jet head and a liquid-jet apparatus in which a part of a pressure generating chamber communicating with a nozzle orifice for ejection of liquid droplets is composed of a vibration plate, a piezoelectric element is formed on the vibration plate, and liquid droplets are ejected by displacement of the piezoelectric element. More particularly, the invention relates to an ink-jet recording head and an ink-jet recording apparatus for ejecting ink as a liquid.
2. Description of the Related Art
In an ink-jet recording head, a part of a pressure generating chamber communicating with a nozzle orifice for ejection of ink droplets is composed of a vibration plate, and the vibration plate is deformed by a piezoelectric element to pressurize ink in the pressure generating chamber, thereby ejecting ink droplets from the nozzle orifice. Two types of the ink-jet recording heads are put into practical use. One of them uses a piezoelectric actuator of a longitudinal vibration mode which expands and contracts in the axial direction of the piezoelectric element. The other uses a piezoelectric actuator of a flexural vibration mode.
The former type can change the volume of the pressure generating chamber by abutting the end surface of the piezoelectric element against the vibration plate, thus making it possible to manufacture a head suitable for high density printing. However, this necessitates a difficult process in which the piezoelectric element is cut and divided in a comb tooth shape coincident with the array pitch of the nozzle orifice, and an operation for aligning and fixing the cut and divided piezoelectric element to the pressure generating chamber. Thus, the problem arises that the manufacturing process is complicated. With the latter type, on the other hand, the piezoelectric element can be fabricated and installed on the vibration plate by a relatively simple process in which a green sheet, as a piezoelectric material, is affixed to the vibration plate in agreement with the shape of the pressure generating chamber, and is then sintered. However, a certain size of vibration plate is required due to the usage of flexural vibration, thus posing the problem that a high density array of the piezoelectric elements is difficult.
In order to solve the disadvantage of the latter recording head, a proposal has been made for a recording head in which a uniform piezoelectric material layer is formed across the entire surface of the vibration plate by a deposition technology, the piezoelectric material layer is cut and divided into a shape corresponding to the pressure generating chamber by a lithography method, and the piezoelectric element is formed so as to be independent of one another piezoelectric element for each pressure generating chamber. According to this process, the operation for affixing the piezoelectric element to the vibration plate is unnecessary. Moreover, the advantage is obtained that not only the piezoelectric element can be fabricated and installed in high density by the lithography method which is an accurate and simple method, but also the thickness of the piezoelectric element can be rendered small and a high speed drive can be accomplished.
With the ink-jet recording head having the piezoelectric elements arranged in a high density as described above, one of electrodes (i.e., a common electrode) of each piezoelectric element is formed to be common to the plurality of piezoelectric elements. Thus, when many of the piezoelectric elements are driven at the same time to eject many ink droplets at one time, the problem is presented that a drop in voltage occurs, leading to an unstable amount of displacement of the piezoelectric element and deteriorated ink ejection characteristics. To solve such a problem, a multi-layered electrode layer, a connecting wiring layer, etc., which comprise a conductive material, are provided on a lower electrode film which is the common electrode of the piezoelectric element. By so doing, it is attempted to lower the resistance value of the lower electrode film substantially, thereby preventing the occurrence of a drop in voltage (see, for example, Japanese Patent Application Laid-Open No. 2004-1431).
However, if the multi-layered electrode layer is directly formed on the lower electrode film, as in the structure described in the above patent document, there may be a problem such that stray current corrosion occurs between the lower electrode film and the multi-layered electrode layer in forming the multi-layered electrode layer.
Such a problem is not limited to the ink-jet recording head for ejecting ink, but also holds true of other liquid-jet heads for ejecting liquid droplets other than ink.

Liquid-jet head and liquid-jet apparatus


Production of sodium bicarbonate from natural soda deposits that may occur as natural brines or solid soda salts is disclosed. The alkalinity in these natural soda deposits consists of carbonates and bicarbonates. The carbonates are converted to bicarbonates by reacting sodium carbonate with ammonium bicarbonate which acts as a carbon dioxide carrier until all the sodium carbonate is exhausted. The solubility of the sodium bicarbonate is lowered by the presence of non-alkaline sodium salts, e.g., sodium chloride. The regeneration of the cyclic reagent (NH.sub.3) is done using the sodium bicarbonate formed by the double decomposition of sodium chloride and ammonium bicarbonate giving a final soda free brine exempt of contaminants foreign to its original components.

The present invention relates generally to the field of carbonation processes; more specifically, the present invention relates to the use of ammonia in a carbonation process to obtain sodium bicarbonate (NaHCO.sub.3) and/or sodium carbonate (Na.sub.2 CO.sub.3) from natural soda deposits.
The Solvay process is a well-known and efficient process for the production of sodium bicarbonate from sodium chloride (NaCl). However, economical operation of this process requires recycling of ammonia gas (NH.sub.3). This recycling is accomplished through the addition of calcium hydroxide Ca(OH).sub.2, resulting in the formation of calcium chloride (CaCl.sub.2). There are no known cost-effective methods for the environmentally safe disposal of this calcium chloride. Thus, in most parts of the world, including the United States, the storage and disposal of calcium chloride is regulated, thereby curtailing the use of the Solvay process in countries having natural soda deposits.
Accordingly, in the United States and other countries that have soda deposits, sodium bicarbonate is produced from natural soda deposits. These deposits are wide-spread throughout the southwestern United States, in Mexico and in other parts of the world and consist of a mixture of sodium chloride, sodium carbonate, sodium bicarbonate, sodium sulfate, along with other soluble salts. However, in some parts of the world, including the United States, deposits containing solid trona are found. Trona is sodium sesquicarbonate (Na.sub.2 CO3.NaHCO.sub.3.2H.sub.2 O). Trona deposits are often found substantially free of other soluble salts.
The technique generally used for the production of sodium bicarbonate from natural soda deposits is to bubble carbon dioxide gas through the soda brine solution. The introduction of carbon dioxide gas to a solution is known as carbonation.

Process for producing sodium bicarbonate from natural soda salts


The present invention provides methods and apparatus for controlling light-induced tissue treatment. In accordance with various aspects of the present invention, the invention provides for improved, real-time control of the light beam operational parameters which enables greater safety, efficiency, uniformity and continuity of the treatment process.

Lasers and other intense light sources are used for various types of tissue treatment, including dermatological tissue treatment. During dermatological tissue treatment utilizing light, a light beam irradiates the skin surface of a patient. Generally, lasers that are used for such treatment operate at a wavelength that is absorbed by one of the natural chromophores in the skin, such as water. In the case of water as the primary chromophore, cellular and interstitial water absorbs light energy and transforms the light energy into thermal energy. The transport of thermal energy in tissues during treatment is a complex process involving conduction, convection, radiation, metabolism, evaporation and phase change that vary with the operational parameters of the light beam. It is essential in such procedures not to damage tissue underlying or surrounding the target tissue area. If the light beam optical operational parameters, such as wavelength, power, the intensity of the light, pulse duration, rate of emission, etc. are properly selected, cellular and interstitial water in the patient's skin is heated causing temperature increases that produce a desired dermatological effect. Conversely, improper selection of the optical operational parameters can result in undertreatment or overtreatment of the tissue. Therefore, it is desirable to accurately control optical operational parameters used in the treatment so that the light is delivered to the tissue with the proper fluence and in a uniform, controllable manner. A variety of devices have been proposed that intelligently control laser beam power, intensity, duration, etc. However, as will be discussed in greater detail below, application of these devices have significant disadvantages.
Known devices for dermatological tissue treatment include a hand-held delivery apparatus, sometimes referred to as a handpiece. A handpiece is the preferred means by which physicians apply treatment to tissue. During treatment, the handpiece emitting light is moved by a physician's hand along the tissue to be treated. Treatment level from such a device is typically set in advance by manually selecting the light beam operational parameters. The operational parameters, which for example include power level, energy, pulsation rate, temperature, light intensity, and current, determine the degree of treatment of the entire treatment process.
One disadvantage of some of the existing handpiece apparatuses is that they require strict precision in positioning of the handpiece and application of controlled movement in order to stay within limits of safe, uniform and efficacious treatment. Theoretically, strict precision can be achieved with a high degree of skill, attention and dexterity from the treating physician. In a real procedure, however, manual application and control of the handpiece can easily result in non-uniformity of treatment due to imprecise or involuntary movements of the human hand and/or uneven tissue surfaces. This often results in either some areas of the targeted tissue being under-treated, or causes some areas to be over-treated.
A typical approach of known handpieces is to produce a macroscopic, pulsed treatment beam that is manually moved from one area of the skin to another in a patchwork like manner in order to treat a larger region of skin tissue. Such an approach has the disadvantage of producing artifacts and sharp boundaries associated with the inaccurate positioning of the individual treatments with respect to the treated skin surface.
Another disadvantage of known handpieces is that, as discussed- above, the laser operational parameters defining the selected level of treatment are typically pre-set once for the entire course of treatment. The individual tissue properties of each patient are factored-in based on a preliminary tissue assessment prior to the treatment and the treatment can proceed using the predetermined operational parameters.
For example, some existing handpiece apparatuses provide feedback indicating to the physician the rate of the handpiece movement which allows the physician to adjust the treatment speed. But this handpiece apparatus requires the physician to treat at a pre-selected rate of motion. The disadvantage of this apparatus is that it restricts the physician to a single treatment speed. In large flat areas, such as the cheek, it is desirable to treat at a high speed. In highly contoured areas, such as the lip, it is desirable to treat at a lower speed. Restricting the physician to a pre-selected rate of motion limits the flexibility of the physician when treating regions, such as the face, that include both large flat areas and highly contoured areas that are in close proximity. Additionally, if the speed of the handpiece changes during the treatment procedure, the apparatus does not provide for automatic adjustment of its operational parameters to compensate for the changed rate of movement, leading to uneven treatment.
The application of robotic means used in the field of dermatological or cosmetic surgery could overcome the limitation of human imprecision. However, one disadvantage of typical conventional robotic apparatuses is that they lack the necessary direction and judgment in treatment that a physician provides. Although robotics is precise, it is not typically intelligent enough to make complex choices or react to unforeseen circumstances during treatment. Additionally, robots deprive a physician of discretion in an aesthetic sense.
Another disadvantage of the typical conventional robotic apparatus is that the full treatment may require complete immobilization of the patient. Alternatively, a sophisticated image stabilization system must be employed to compensate for patient's movement. It is still another disadvantage of such robotic apparatuses that they are bulky and cannot be easily moved into treatment positions in relation to the areas allowing little room for movement. Rather, a tissue surface to be treated has to be brought into a specific position in relation to the apparatus before treatment can take place.
The present invention provides a method and apparatus which significantly reduce the problems associated with the existing laser-induced handpieces apparatuses and robotics.

This patent is subject to a terminal disclaimer.

Method and apparatus for monitoring and controlling laser-induced tissue treatment


The drilling apparatus according to the invention contains a body (1) to which rock-destroying organs--rollers (2) are attached. A subassembly for generating hydrodynamic waves is arranged in the body (1). This subassembly is designed in the form of a turbulence chamber (3) with tangentially arranged entry channels (4) and with a conically tapering outlet channel (5) the frontal surface of which is radially rounded off.

There is a familiar drilling apparatus that contains a hollow body with rock-destroying components --rollers --attached to it. A replaceable cylinder is arranged in the body and is fixed by pins to the body. A transition piece to the bit is attached to the body by a screw-coupling. Inside this transition piece and axially to the body is housed a sliding case with a subassembly for generating hydrodynamic waves, with lateral channels and a central channel. Fixtures that are resistant to wear are mounted in the channels. The transition piece to the bit has an inner flange that serves as support for a spring that embraces the case and works with the flared flange of the case.
After the drilling apparatus is inserted into a drill hole, flushing first takes place through the central channel of the sliding case. In the process, a force determined by a pressure difference at the fixture arranged in the central channel acts upon the flared flange of the case. The spring is compressed by the action of this force until the lateral channels come to rest under the frontal surface of the cylinder. The lateral channels open in the process and liquid pressure in the case drops enough for the spring to bring the case back upward until these channels are covered, and the cycle repeats itself. When the case moves downward the flushing liquid situated in the space between the case and the transition piece to the bit is expelled upward through overflow openings.
The frequency of the pendulum movements of the case can be adjusted by the pumping capacity and the cross-sectional surface of hydromonitor attachments.
Known drilling apparatuses are inadequate for current demands on drilling technology and do not ensure the sinking of a drill hole for the following reasons:
the generated hydrodynamic pulsations of the drill liquid do not contribute to destroying the rock due to their low frequency and slight amplitude and do not ensure an increase in drilling characteristics--mechanical speed and bit base length; PA1 the complexity of construction from the perspective of production and assembly increases production costs; PA1 the presence of movable subassemblies and elements in the construction does not guarantee the required service life and reliability, in particular in an abrasive medium of drill liquid. PA1 c.sub.1 is the acoustic velocity in the metal; PA1 n is the refractive index.