Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nicotine in tobacco brings illness and death to millions of people. Yet nicotine in its pure form has the potential to be a valuable pharmaceutical agent. Nicotine fairly specifically binds to the cholinergic nicotinic gating site on cationic ion channels in receptors throughout the body. This action stimulates the release of a variety of neurotransmitters including especially catecholamines and serotonin. When chronically taken, nicotine may result in: (1) positive reinforcement, (2) negative reinforcement, (3) reduction of body weight, (4) enhancement of performance, and protection against; (5) Parkinson's disease (6) Tourette's disease (7) Alzheimers disease, (8) ulcerative colitis and (9) sleep apnea. The reliability of these effects varies greatly but justifies the search for more therapeutic applications for this interesting compound.
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PMID:Beneficial effects of nicotine. 185 21

The association between suicide and medical disorder has not received as much attention as the association between suicide and psychiatric disorder. We identified by statistical overview medical disorders with an altered suicide risk. We found reports on the mortality of 63 medical disorders (ICD9 001-289, 320-999) said to have an altered suicide risk. English-language reports were located on MEDLINE with the search terms "disease name with mortality and follow-up"; and from the reference lists of these reports. We abstracted 235 reports of mortality studies of medical disorders with 2 years or more of follow-up, less than 10% loss of subjects, observed numbers of suicides given, and either the expected number or the facts from which to derive this. The ratio of the sum of the observed to the sum of the expected suicides, for each disorder, tested by the Poisson distribution gave an assessment of altered risk of death from suicide. Increased risk (p < 0.05) was seen for HIV/AIDS, malignant neoplasms as a group, head and neck cancers, Huntington disease, multiple sclerosis, peptic ulcer, renal disease, spinal cord injury, and systemic lupus erythematosus. Inconclusive evidence for increased risk was observed for amputation, heart valve replacement and surgery, disorders of the intestine (Crohn disease, ileostomy, ulcerative colitis), hormone replacement therapy, alcoholic liver disease, neurofibromatosis, systemic sclerosis, and Parkinson disease. Pregnancy and the puerperium had decreased risks (p < 0.05). There was no evidence of either increased or decreased risk for any of the other disorders studied.
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PMID:Suicide as an outcome for medical disorders. 798 80

To clarify the prognosis of patients with intractable diseases, a baseline survey of patients who received financial aid for intractable disease treatment between April 1984 and March 1985 was performed in Wakayama Prefecture, followed by a follow-up survey over a period of 8 years. Based on public welfare-subsidized system in Wakayama Prefecture, all patients with intractable diseases were checked up annually their certificates of financial aid for treatment. The results obtained were as follows: Parkinson's disease had the highest rate of discontinuation of medical care at 65%, followed by idiopathic thrombocytopenic purpura (ITP) at 64%, aplastic anemia at 55%, ulcerative colitis (UC) at 54%, and Behcet's disease at 50%. Systemic lupus erythematosus (SLE) had the lowest rate of discontinuation of medical care at 32%. Discontinuation was due to death in approximately 50% of the patients with SLE, scleroderma, dermatomyositis and polymyositis, and aplastic anemia. Of these, the causes of death in more than 50% were directly related to the primary diseases. However, in patients with SLE and aplastic anemia, 25% discontinued care because of cure or alleviation. Some patients remained in remission even though the prognosis for these diseases is not generally considered to be favorable. Transfer of jurisdiction to the Disabled Persons Welfare Act was seen in 28% of patients with Parkinson's disease, 24% with Behcet's disease, and 23% with ossification of posterior longitudinal ligament, diseases which are believed to cause restriction in daily activities of patients in some cases. On the other hand, cure or alleviation was the reason for discontinuation in 60-70% of patients with Buerger's disease, UC and ITP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Prognosis of patient with intractable diseases in Wakayama Prefecture--a follow-up study based on medical care certificates]. 802 9

Nicotine maintains tobacco addiction and has therapeutic utility to aid smoking cessation and possibly to treat other medical diseases. Nicotine acts on nicotinic cholinergic receptors, which demonstrate diversity in subunit structure, function, and distribution within the nervous system, presumably mediating the complex actions of nicotine described in tobacco users. The effects of nicotine in people are influenced by the rate and route of dosing and by the development of tolerance. The metabolism of nicotine is now well characterized in humans. A few individuals with deficient C-oxidation of nicotine, unusually slow metabolism of nicotine, and little generation of cotinine have been described. Nicotine affects most organ systems in the body, although its contribution to smoking-related disease is still unclear. Nicotine as a medication is currently available as a gum, a transdermal delivery device, and a nasal spray, all of which are used for smoking cessation. Nicotine is also being investigated for therapy of ulcerative colitis, Alzheimer's disease, Parkinson's disease, Tourette's syndrome, sleep apnea, and attention deficit disorder.
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PMID:Pharmacology of nicotine: addiction and therapeutics. 872 3

Cigarette smoking is an established risk factor for cancer and cardiovascular disease, and is the leading cause of avoidable disease in most industrialized countries. Less well-known are possible beneficial effects, which are briefly considered in this survey. Preliminary data suggest that there may be inverse associations of smoking with uterine fibroids and endometriosis, and protective effects on hypertensive disorders and vomiting of pregnancy are likely. Smoking has consistently been found to be inversely related to the risk of endometrial cancer, but cancers of the breast and colon seem unrelated to smoking. Inverse associations with venous thrombosis and fatality after myocardial infarction are probably not causal, but indications of benefits with regard to recurrent aphthous ulcers, ulcerative colitis, and control of body weight may well reflect a genuine benefit. Evidence is growing that cigarette smoking and nicotine may prevent or ameliorate Parkinson's disease, and could do so in Alzheimer's dementia. A variety of mechanisms for potentially beneficial effects of smoking have been proposed, but three predominate: the 'anti-estrogenic effect' of smoking; alterations in prostaglandin production; and stimulation of nicotinic cholinergic receptors in the central nervous system. Even established inverse associations cannot be used as a rationale for cigarette smoking. These data can be used, however, to clarify mechanisms of disease, and point to productive treatment or preventive options with more narrowly-acting interventions.
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PMID:Beneficial effects of nicotine and cigarette smoking: the real, the possible and the spurious. 874 97

The proceedings of the inaugural scientific meeting of the Society for Research on Nicotine and Tobacco (SRNT) are summarized. The primary objective of the meeting was to foster the exchange of information on the effects of nicotine and tobacco use, as well as factors which influence their use, drawing from biological, behavioral and social sciences. Much of this research can be viewed as a tale of "two" drugs--nicotine as a key to an important public health problem, and nicotine as a classical tool of physiological and pharmacological research. A historical overview of research on "both" drugs is provided first. Public policy alternatives for reducing the prevalence of tobacco use have been derived in part from basic and clinical research results and are briefly outlined. Evidence for genetic determinants on nicotine use and effects is presented using data from twin studies and from molecular genetic research with humans and animals. Consistent with this research, there is evidence of individual differences in pharmacokinetics and effects of nicotine, which could account for differences in smoking behavior and nicotine dependence. Finally, recent developments in the therapeutic uses of nicotine and novel nicotinic agonists with schizophrenia, Alzheimer's disease, Parkinson's disease, Tourette's syndrome and ulcerative colitis are presented. Overall, the research presented at the meeting demonstrated the vast diversity of areas of study involving nicotine and tobacco, as well as the rich opportunities for cross-communication among researchers from different disciplines.
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PMID:Society for Research on Nicotine and Tobacco. 882 21

Although tobacco smoking has long been associated with diseases of the lungs and cardiovascular system, numerous studies have demonstrated a negative association between tobacco smoking and ulcerative colitis, and the neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD). The evidence suggests that nicotine--the main pharmacologically active ingredient of tobacco--appears to be responsible for this effect. Pure nicotine has no known carcinogenic properties and can be administered in numerous ways including transdermal patches and tablets. As a therapeutic agent, its association with tobacco can be likened to morphine and opium smoking. There is ample clinical evidence to suggest that nicotine could be beneficial in the treatment of some patients with diseases. Pharmacologically, nicotine acts on cholinergic (nicotinic-specific) receptors which are depleted in AD and PD. Nicotinic receptors also interact closely with several neurotransmitters including dopamine, which is implicated in both PD and Gilles de la Tourettes's syndrome. There is no doubt that tobacco smoking can be harmful and no-one should be encouraged to smoke. However, although nicotine has many harmful side-effects, it may have therapeutic value or at the very least be a useful tool for future drug development.
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PMID:Does nicotine have beneficial effects in the treatment of certain diseases? 900 84

CYP2E1 is an ethanol- and drug-metabolizing enzyme that can also activate procarcinogens and hepatotoxicants and generate reactive oxygen species; it has been implicated in the pathogenesis of liver diseases and cancer. Cigarette smoke increases CYP2E1 activity in rodents and in humans and we have shown that nicotine (0.1-1.0 mg/kg s.c. x 7 days) increases CYP2E1 protein and activity in the rat liver. In the current study, we have shown that the induction peaks at 4 h postnicotine (1 mg/kg s.c. x 7 days) treatment and recovers within 24 h. No induction was observed after a single injection, and 18 days of treatment did not increase the levels beyond that found at 7 days. We found that CYP2E1 is induced by very low doses of chronic (x 7 days) nicotine with an ED50 value of 0.01 mg/kg s.c.; 0.01 mg/kg in a rat model results in peak cotinine levels (nicotine metabolite) similar to those found in people exposed to environmental tobacco smoke (passive smokers; 2-7 ng/ml). Previously, we have shown no change in CYP2E1 mRNA, and our current mechanistic study indicates that nicotine does not regulate CYP2E1 expression by protein stabilization. We postulated that a nicotine metabolite could be causing the induction but found that cotinine (1 mg/kg x 7 days) did not increase CYP2E1. Our findings indicate that nicotine increases CYP2E1 at very low doses and may enhance CYP2E1-related toxicity in smokers, passive smokers, and people treated with nicotine (e.g., smokers, patients with Alzheimer's disease, ulcerative colitis or Parkinson's disease).
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PMID:Rat hepatic CYP2E1 is induced by very low nicotine doses: an investigation of induction, time course, dose response, and mechanism. 1275 Apr 30

Nicotine has roles in the addiction to smoking, replacement therapy for smoking cessation, as a potential medication for several diseases such as Parkinson's disease, Alzheimer's disease, and ulcerative colitis. The absorbed nicotine is rapidly and extensively metabolized and eliminated to urine. A major pathway of nicotine metabolism is C-oxidation to cotinine, which is catalyzed by CYP2A6 in human livers. Cotinine is subsequently metabolized to trans-3'-hydroxycotinine by CYP2A6. Nicotine and cotinine are glucuronidated to N-glucuronides mainly by UGT1A4 and partly by UGT1A9. Trans-3'-hydroxycotinine is glucuronidated to O-glucuronide mainly by UGT2B7 and partly by UGT1A9. Approximately 90% of the total nicotine uptake is eliminated as these metabolites and nicotine itself. The nicotine metabolism is an important determinant of the clearance of nicotine. Recently, advances in the understanding of the interindividual variability in nicotine metabolism have been made. There are substantial data suggesting that the large interindividual differences in cotinine formation are associated with genetic polymorphisms of the CYP2A6 gene. Interethnic differences have also been observed in the cotinine formation and the allele frequencies of the CYP2A6 alleles. Since the genetic polymorphisms of the CYP2A6 gene have a major impact on nicotine clearance, its relationships with smoking behavior or the risk of lung cancer have been suggested. The metabolic pathways of the glucuronidation of nicotine, cotinine, and trans-3'-hydroxycotinine in humans would be one of the causal factors for the interindividual differences in nicotine metabolism. This review mainly summarizes recent results from our studies.
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PMID:Interindividual variability in nicotine metabolism: C-oxidation and glucuronidation. 1614 2

CYP2E1, the primary ethanol-metabolizing cytochrome P450, metabolizes endogenous substrates (e.g., arachidonic acid) and drugs (e.g., acetaminophen, chlorzoxazone) and bioactivates procarcinogens (e.g., tobacco-specific nitrosamines) and toxins (e.g., carbon tetrachloride). Nicotine from tobacco smoke may contribute to the enhanced hepatic CYP2E1 activity in smokers. We have previously shown that chronic nicotine treatment can increase CYP2E1 in rat liver and brain. In this study, induction of brain CYP2E1 was assessed after a single acute or a 7-day chronic treatment with saline or nicotine (1 mg/kg s.c.), with sacrifice performed at various times after the last injection. Chronic 7-day nicotine treatment showed the highest levels of CYP2E1 12 h after the last injection in frontal cortex (1.4-fold, p < 0.05) versus 8 h in hippocampus (1.8-fold, p < 0.01) and cerebellum (1.4-fold, p < 0.05), returning to basal levels by 24 h. In contrast, acute nicotine treatment did not induce CYP2E1 in frontal cortex and hippocampus but increased CYP2E1 in cerebellum 8 h after treatment (1.6-fold, p < 0.01). Brain CYP2E1 mRNA levels did not increase after chronic nicotine treatment, suggesting nontranscriptional regulation. Thus, humans exposed to nicotine may have altered CYP2E1-mediated metabolism of centrally acting drugs and toxins as well as altered toxicity because of oxidative stress caused by CYP2E1. Those affected may include current and passive smokers and people that may be treated with nicotine such as smokers and, potentially, patients with Alzheimer's, Parkinson's disease, or ulcerative colitis.
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PMID:Induction and recovery time course of rat brain CYP2E1 after nicotine treatment. 1643 48


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