Biomedical subjects
Publications and source records attributed to N S Miller.
Although often used in the medical management of anxiety, insomnia, seizures and muscle spasm, benzodiazepines lead to significant complications after continuous use. These complications include tolerance, addiction, dependence and abuse. Knowledge of the diagnostic criteria and treatment of side effects improves the physician's use of these commonly prescribed drugs.
The quest for an ideal sedative-hypnotic drug has been fraught with failure. The goals of the perfect sedative-hypnotic drug are to: (1) produce a transient reduction in the level of consciousness for the purpose of sedation, calmness, and tranquility without lingering aftereffects; (2) produce sleep without the potential to arrest respirations and without aftereffects on sensorium and mood; and (3) produce no abuse, addiction, tolerance, or dependence. Nonetheless, clinical conditions have required the use of sedative-hypnotic drugs in spite of the inherent difficulties with them. The history of sedative-hypnotic drugs is replete with attempts to produce a safe and effective drug. The introduction of one sedative-hypnotic drug for another has been heralded by unguarded optimism and misguided claims. History has repeated itself with each new drug. Toxicities, abuse, addiction, and development of tolerance and dependence have remained in force for each drug that has appeared on the market. Only minor variations on a theme have differentiated one drug from another as the essential features have remained in force.
Abnormal alcohol consumption commonly leads to medical, psychiatric, neurologic, traumatic, neoplastic and sociologic sequelae. Adequate prevention or treatment of these conditions requires recognition of alcohol as a primary etiological or precipitating agent. The consequences of alcohol addiction must be separated from the alcoholic's actual motivation or drive to use alcohol. Alcohol reinforces and perpetuates its own use with psychosocial stressors not required to produce addiction in the biologically vulnerable. Psychosocial stressors may stimulate alcohol consumption, but not necessarily addiction in the nonvulnerable. The consequences of drinking do not produce the abnormal drinking. A major life problem associated with alcohol use may lead to a presumptive diagnosis of alcohol addiction, but definitive diagnosis is based upon the presence of a preoccupation with the acquisition, compulsive use of and relapse or recurrent use of alcohol.
The effects of alcohol and drugs on sexual function are important to consider in clinical histories and medication prescribing practices. Virtually all aspects of the human sexual response are affected by alcohol and drugs: 1. Desire (libido) is reduced. 2. Performance. Impotency as defined by lack of erection and ejaculation occurs. 3. Dissatisfaction ensues. These effects of alcohol and drugs can be understood and illustrated by examining the phases of excitement, plateau, orgasm, and resolution in the human sexual response. The important first step in the treatment of sexual dysfunction is to identify the alcohol/drug/medication use. The next is to recognize the profound effect it can have on the human sexual response. Furthermore, knowledge of the mechanism of action of the drugs and a basic conception of the physiology and psychology of sexual performance are necessary to predict the course of the sexual dysfunction. In many instances, the sexual dysfunction is reversible even after chronic alcohol/drug/medication use.
The so-called Oriental flushing reaction associated with ingestion of small amounts of alcohol was antagonized by combined antihistamine administration. In stage one of the study, the flushing reaction to low doses of alcohol was produced in Orientals. Most subjects experienced a cutaneous flush, an increase in skin temperature, a decrease in blood pressure, an increase in pulse rate and subjective symptoms such as dizziness, sleepiness, anxiety, headache, generalized weakness and nausea. Before the administration of alcohol, one-half of the subjects were given 50 mg of diphenhydramine (H1 receptor antagonist) and 300 mg of cimetidine (H2 receptor antagonist). The second half received placebo tablets. The clearest difference between the antihistamine group and placebo group was in the skin flushing reaction. The antihistamine group showed a significant reduction in the skin flush. The antihistamine also neutralized the systolic hypotension induced by the administration of alcohol. The possible importance of histamine in the expression of sensitivity to alcohol is considered. The relevance to genetic susceptibility for development of alcoholism is discussed.
Sexual dysfunction is not uncommon in alcoholics and in cocaine addicts. Alcohol abuse frequently develops along with cocaine dependence and the reverse is also common. We examined the sexual history of this common dually-addicted population. Sexual dysfunction was found in 62% (N = 50) of male cocaine and alcohol abusers consecutively admitted to a substance disorder treatment unit. The influence of cocaine and alcohol on commonly studied neurotransmitters and hormones along with their influence on sexual function are discussed.
The authors present a case of confusion and mood disturbance caused by a focal cerebral fungal (phycomycosis) infection in an otherwise healthy intravenous drug addict. A review of the literature found only 9 cases of phycomycosis with localized cerebral involvement. This report describes the sixth occurrence of phycomycosis in an intravenous drug addict (the fifth to localize in the basal ganglia). In addition to the human immunodeficiency virus, unusual infectious causes of confusion and mood disturbance may be increasing as the intravenous drug-using population expands. Recognition of the clinical features of a fungal infection in a high-risk population may lead to earlier diagnosis and more effective treatment of this uniformly fatal disease. The clinician should consider localized cerebral phycomycosis as a cause of confusion and mood disturbance in intravenous drug addicts, especially when there is evidence of basal ganglia involvement.
PCP is again becoming a popular drug of abuse in the United States, particularly among the young. A variety of medical, psychiatric and pathologic effects make PCP both appealing and profoundly dangerous to naive and chronic drug users. Pharmacologic intervention is helpful in PCP-induced acute intoxication and psychosis. Effective long-term treatment is available in addiction programs.
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The treatment of alcoholism may be delayed because of the difficulty in confirming a diagnosis. There are currently no direct blood tests to objectively determine the presence of pharmacodynamic tolerance to alcohol. The state of the membrane fluidity of the peripheral blood erythrocyte may provide a biophysical measurement of the pharmacodynamic tolerance to alcohol. This discussion proposes methods that potentially may be applied to the clinical purpose of diagnosing alcoholism in humans. The methods have been used to successfully measure pharmacodynamic tolerance in animals and humans. The development of the physiologic state of acquired tolerance and dependence is related to alcohol intake. Chronic alcohol consumption that leads to pharmacodynamic tolerance may be assessed by measuring the membrane fluidity of the peripheral blood erythrocyte. Physiologic recovery from tolerance and dependence to alcohol may also be assessed during withdrawal in which the reversal of changes in membrane fluidity is measured in the abstinent state. Relapse to drinking may be detected in the state of the membrane fluidity of the peripheral blood erythrocytes that reflect the return of tolerance and dependence. Tolerance to alcohol may be a manifestation of the inheritability to alcoholism. Alcoholics and high risk individuals appear to have an increased, innate (genetic) tolerance to alcohol. High risk individuals are nonalcoholic, blood relatives of alcoholics. Animal studies suggest that innate (genetic) tolerance and dependence to alcohol may be related to the biophysical state of erythrocyte membrane fluidity. The assessment of these changes in membrane fluidity of the erythrocyte may be performed in the peripheral blood in humans. A trait marker (in the genetically predisposed) for high risk individuals and a state (in the actively drinking) marker for pharmacodynamic tolerance in the erythrocyte might be developed. In this way, a blood test may be used to detect the inheritability for alcoholism and the development of pharmacodynamic tolerance to alcohol. No blood test for pharmacodynamic tolerance is currently available. This article represents an extrapolation from animal and human research data. The proposals contained therein may not be considered readily, clinically applicable.
Alcohol and drug addiction are defined in behavioral terms as the preoccupation with, compulsive use of, and relapse to drugs that are descriptive and confirmatory. The basis of addiction may involve neurochemical changes in the brain that distort and redirect the drive states (instincts). Tolerance and dependence may only be incidentally associated with addiction as a result of a nonspecific adaptation by the body to the presence of a drug. The cellular adaptation may be the same in all organs. Addiction to alcohol and drugs may have no specific relationship to tolerance and dependence. Addiction occurs in the absence of observable tolerance and dependence to alcohol and drugs. Alcohol and drug addiction is probably more complex than tolerance and dependence. Addiction is difficult to study because of the variability of behavioral phenomena and the underlying intricacies of the neurosubstrates. Tolerance and dependence are still useful as they are indicators of drug use. It is a misconception that long term chronic use is necessary for tolerance and dependence to develop. Some studies have shown that tolerance can develop within hours and days to a single dose of alcohol or other drugs. Anxiety, depression and insomnia can occur after a single dose of ethanol in humans. These symptoms of withdrawal from the alcohol or drug constitute dependence. Redefining the criteria for addiction tolerance and dependence to alcohol and other drugs may be in order. A neurochemical model may provide a more definitive and uniform basis for considering addiction, tolerance, and dependence to alcohol and drugs.
The Oriental flushing reaction is an adverse response to alcohol that appears to be genetically determined. In this study, the Oriental flushing reaction that was produced with ingestion of small amounts of alcohol was antagonized by antihistamine administration. A group of 17 subjects was tested. Each subject received placebo, diphenhydramine 50 mg (H-1 receptor antagonist), and cimetidine 300 mg (H-2 receptor antagonist) singularly and in combination. Alcohol was then administered orally. Most subjects given placebo experienced the typical flushing reaction that included a cutaneous flush, increase in skin temperature, decrease in blood pressure, increase in pulse rate and subjective symptoms such as dizziness, sleepiness, anxiety, headache, generalized weakness, and nausea. The flush, temperature and systolic hypotension were significantly blocked by the combined antihistamine administration. Cimetidine given alone blocked the flush, temperature increase, and systolic hypotension significantly more than diphenhydramine but less than the combined antihistamines. Diphenhydramine was similar to placebo in its effect on the flushing reaction. The role of histamine in the expression of tolerance to alcohol is not known. Antihistamine antagonism of the adverse flushing reaction suggests that histamine receptors may participate in the intolerance to ethanol in Orientals. Histamine may be an important protective factor in the low prevalence of alcoholism in Orientals.
In a large multicenter study of 568 male alcoholics, structured interviews were used to compare the clinical characteristics of patients with a positive (65%) or negative (35%) family history of abusive drinking among first degree relatives. Alcoholics with a positive family history were found to have: an earlier onset of alcoholism, greater alcoholic severity, more medical and legal problems, a broader range of treatments, an increased lifetime prevalence of additional psychiatric disorders and a greater diversity of psychiatric disturbance among biological relatives. The degree of psychiatric heterogeneity in the patients roughly corresponded to the degree of psychiatric heterogeneity in their families. Assortative mating was proposed as a possible mechanism to account for clinical differences between the familial and nonfamilial alcoholic.
The so-called Oriental flushing reaction associated with ingestion of small amounts of alcohol was antagonized by combined antihistamine administration. In stage one of the study, the flushing reaction to low doses of alcohol was produced in Orientals. Most subjects experienced a cutaneous flush, increase in skin temperature, decrease in blood pressure, increase in pulse rate and subjective symptoms such as dizziness, sleepiness, anxiety, headache, generalized weakness and nausea. One half of the group of subjects was then given diphenhydramine, 50 mg (H1 receptor antagonist) and cimetidine, 300 mg (H2 receptor antagonist) and the second half received placebo tablets before the administration of alcohol. The clearest difference between the antihistamine group and placebo group was in the skin flushing reaction. The antihistamine group showed a statistically significant reduction in the skin flush. The antihistamines also neutralized the systolic hypotension induced by the administration of alcohol.
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The primary-secondary depression distinction was investigated in male alcoholic patients from five Veterans Administration Medical Centers. The Psychiatric Diagnostic Interview, a DSM-III-compatible, criterion-referenced, structured interview, was administered to 565 patients admitted to the Alcoholism and Drug Treatment Units. Seventy-eight patients (13.8%) who exhibited only alcoholism and depression were divided into three subgroups based on the temporal onset of depression relative to the onset of alcoholism. Although few statistical differences were found, observed trends suggested more impairment in alcoholic patients with primary depression than in those with concurrent or secondary depression. The findings indicate that the primary-secondary depression distinction may have important clinical relevance and should be made whenever possible.
The ability of a nucleic acid helix-destabilizing protein from calf thymus, UP1, to facilitate renaturation of yeast tRNALeu3 and Escherichia coli 5S RNA is shown to be a consequence of the protein's ability to bind stoichiometrically to single-stranded polynucleotide regions. A comparison of the inhibitory effect of different homopolymers on UP1-induced renaturation of tRNALeu3 does not indicate significant base specificity in UP1 binding, and a 3'-5' ribose phosphate polymer devoid of heterocyclic bases inhibits as well as the homopolynucleotides. These inhibition studies also show that UP1 requires polynucleotide segments of at least three phosphate residues to bind. Mg2+ (which is required for the stabilization of native tRNALeu3) dissociates complexes of UP1 with inactive tRNA, and since the RNAs in those complexes lack a substantial amount of secondary structure, it can upon dissociation readily refold into the native structure. A semiquantitative treatment of UP1-RNA interaction is developed that suggests that only a small number (approximately six) of protein molecules are bound to tRNALeu3 in the complex while analysis of the inhibition studies suggests that these UP1 molecules are not bound in a highly cooperative manner.
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