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

Limited information is available regarding the relationship between elderly individuals and depression; but the clinician can anticipate problems in those who have had depression in the past, in those who are bereaved, in caretakers, and in patients with a number of other illnesses, including Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, alcoholism, and severe medical illness. Treatment may shorten the duration of the depression, limit long-term sequelae, and reduce the likelihood of suicide. More research with careful methodology would be helpful in clarifying directions for primary, secondary, and tertiary prevention.
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PMID:The prevention of major depression in the elderly. 157 73

L-Deprenyl, the selective inhibitor of monoamine oxidase type B (MAO-B), has gained wide acceptance as a useful form of adjunct therapeutic drug in the treatment of Parkinson's disease. This review summarizes the molecular pharmacology of L-deprenyl, and the advances in our understanding of its possible mode of action in Parkinson's disease. L-Deprenyl belongs to the class of enzyme-activated irreversible inhibitors also described as 'suicide' inhibitors, because the compound acts as a substrate for the target enzyme, whose action on the compound results in irreversible inhibition. L-Deprenyl first of all forms a noncovalent complex with MAO as an initial, reversible step. The subsequent interaction of L-deprenyl with MAO leads to a reduction of the enzyme-bound flavin-adenine dinucleotide (FAD), and concomitant oxidation of the inhibitor. This oxidized inhibitor then reacts with FAD at the N-5-position in a covalent manner. The observed in vitro selectivity of L-deprenyl for MAO-B may be accounted for by differences in the affinities of the two MAO subtypes for reversible interaction with L-deprenyl, differences in the rates of reaction within the noncovalent complexes to form the irreversibly inhibited adduct, or a combination of both these factors. However, if selective inhibition is to be maintained in vivo, correct dosage schedules are critically important, since all selective MAO inhibitors described up to now lack selectivity at high doses. In experimental animals L-deprenyl is protective against the damaging effects of several neurotoxins, including the dopaminergic agents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) and the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). Beside MAO-B inhibition, which above all explains the prevention of neurotoxic action of MPTP by preventing its metabolism, L-deprenyl appears to exhibit other mechanisms of action which are independent of its action on MAO-B.
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PMID:The molecular pharmacology of L-deprenyl. 163 15

Primary care physicians have a vital role to play in identifying depression in their elderly patients. Diagnosis may be difficult, because symptoms are atypical and frequently include psychomotor agitation, somatic symptoms, and complaints of memory loss. Patients with medical illnesses, such as cancer, postmyocardial infarction, stroke, Parkinson's disease, and early Alzheimer's disease are particularly vulnerable to depression. Drugs that may cause depressive symptoms are digitalis at toxic levels, beta-blockers, centrally acting antihypertensives, immunosuppressants, and nonsteroidal anti-inflammatory agents. Cyclic antidepressants are the drugs of first choice. Selection depends on the patient's physical health and current medications and the side effect profile of the drug. Side effects are more pronounced in old age because of drug accumulation owing to slowed clearance. Troublesome side effects are anticholinergic effects, orthostatic hypotension, sedation, cardiotoxicity, and weight gain. The most useful antidepressants for geriatric patients are the secondary amines, desipramine and nortriptyline. The second-generation drug trazodone has the advantage of causing the least anticholinergic effects, but it is very sedating. Before treatment, the patient should have an electrocardiogram, liver function tests, tonometry, sitting and standing blood pressures, evaluation of urinary symptoms for outflow obstruction, review of current medications, and estimation of suicide risk. Cyclic antidepressants are contraindicated during recovery from myocardial infarction, in heart disease when there is severe impairment of myocardial performance, in seizure disorders, and in the presence of glaucoma or a large prostate. Drug interactions that may cause trouble can occur with epinephrine, MAO inhibitors, thyroid hormone, cimetidine, and centrally acting antihypertensives. Dosage should start low, increasing usually by 25 mg every 4 to 5 days until a therapeutic level is reached. Failure of a noradrenergic antidepressant after 4 to 5 weeks can be followed by a trial of a serotonergic drug. Drug serum level monitoring is useful for imipramine, desipramine, and nortriptyline. Monoamine oxidase inhibitors are effective in many elderly patients who are resistant to TCAs. Sympathomimetic drugs must be avoided with MAOIs. Elderly patients are at high risk of toxicity and drug interactions with lithium. Electroconvulsive therapy is useful for patients who do not respond to drug treatment, but medical complications, particularly cardiovascular, often occur in patients 75 or older. Many patients relapse after ECT. Psychotherapy together with pharmacotherapy may be the optimal treatment for elderly depressives. Older patients are more likely to become chronically depressed than younger patients. The risk of suicide in depressed elderly males is high, particularly in those with psychosocial problems, and depression rises with age.
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PMID:Management of depression in the elderly. 266 41

Depression and suicide are significant problems in the elderly, both in terms of their severity and their prevalence. It is particularly difficult to distinguish depression from early dementia, since elderly depressed patients often deny mood disorder and focus on their memory problems. This differential diagnostic dilemma is further complicated by the fact that 20 percent of Alzheimer-type dementia patients have moderate to severe depression. An even higher prevalence of depression can be seen in elderly patients with stroke or Parkinson's disease. Most all of the depressive disorders of the elderly are amenable to one form or combination of therapies: pharmacologic, electro-convulsive, or psychotherapy. Tricyclic antidepressants are often associated with adverse drug reactions in the elderly, so alternatives such as MAO inhibitors, alprazolam, bupropion and psychostimulants are currently being explored in this patient population.
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PMID:Diagnosis and treatment of depression in the elderly. 306 74

All suicides occurring among the inhabitants of the County of Uppsala in Sweden between 1977 and 1984 were analyzed on the basis of information from autopsy reports and from somatic and psychiatric medical records. Among the 416 persons who committed suicide, 70 (17%) had a somatic disease of probable importance for the suicidal act. No somatic diagnosis appeared to stand out as being especially associated with a very high risk of suicide. Some diagnoses (e.g. malignant neoplasm, Parkinson's disease, multiple sclerosis) were, however, associated with a suicidal rate above that in the general population. Further knowledge about the relation between suicide and specific somatic diagnoses would be of value, since a high suicide rate in association with a particular illness might indicate insufficient medical care and rehabilitation.
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PMID:Physical disease and disability among 416 suicide cases in Sweden. 319 26

Until recently little was known concerning the chemical details of the mechanism of interaction of flavin-linked mitochondrial membrane bound monoamine oxidase (MAO) with its substrates and inhibitors. Substrates which have enzymes as their targets have been valuable in elucidating active site residues and structural features. Acetylenic amines as exemplified by clorgyline, deprenyl and pargyline are called 'suicide inhibitors' because an irreversible inhibitor is formed by the action of MAO from a relatively innocuous compound which acts as a substrate. These inhibitors can selectively inactivate MAO 'type A' and/or 'type B'. MAO isolated in homogeneous form from liver or kidney contains 1 mole of covalently bound coenzyme, cysteinyl-flavin, per mole enzyme. The flavin is bound to a pentapeptide via the thio-ether of cysteine at the 8 alpha-position of the isoalloxazine. A comparison of the inhibitory effects of clorgyline, deprenyl and pargyline on liver enzyme preparations from bovine or rat have confirmed our expectation that these irreversible inactivators form the same type of adduct with the cysteinyl-flavin active site of MAO 'type A' and 'type B', and that binding is stoichiometric at the N-5 of the covalently bound flavin in a flavocyanine linkage. Substrates protect from inhibition. In contrast to the reported observation of Tipton (39), pig brain mitochondrial MAO purified by two alternative methods contains cysteinyl-flavin in substantial amounts. The turnover number of enzyme from brain per mole of cysterinyl-flavin in apparently homogeneous samples is nearly the same as that of highly purified kidney and liver enzyme. Thus it is apparent that brain MAO also contains cysteinyl-flavin at the active center and therefore it is expected that acetylenic as well as hydrazine inhibitors form the same linkage with the flavin moiety as that formed with enzyme from peripheral tissues. A specific inhibitor for the deamination and potentiation of dopamine formed in the brain of Parkinsonian patients after treatment with L-Dopa has been regarded desirable. Deprenyl, a selective MAO 'type B inhibitor without the 'cheese effect', is the most potent inactivator of human brain MAO, and clinical results show that the drug is very useful in the treatment of Parkinson's disease and depression.
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PMID:Biochemical characterization of the active site of brain monoamine oxidase. 678 74

The purpose of this study was to estimate the risk of suicide for patients with Parkinson's disease (PD) in Denmark compared with that in the background population. The study involved 458 patients with a PD diagnosis, 226 men and 232 women. The follow-up period to either death or end of follow-up on December 31, 1990 was 0 to 17 years, mean 5.7 years. Deaths in the follow-up period amounted to 254, 135 men and 119 women. Two women committed suicide. The number of expected suicides was 1.06 for men and 0.55 for women, a total of 1.62. Neither for men nor for women was the difference between expected and observed suicides statistically significant.
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PMID:Suicide in patients with Parkinson's disease. An epidemiological study. 797 53

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

The acetylenic selective monoamine oxidase (MAO) type B suicide inhibitor, l-deprenyl (l-selegiline), has proved to be a useful adjuvant to L-dopa therapy and monotherapy of Parkinson's disease. Although not all features of its antiParkinson action are known, studies that used brains obtained at autopsy from patients who took l-deprenyl show that the selective inhibition of MAO-B with a concomitant increase of phenylethylamine and dopamine, but not of serotonin or noradrenaline, in the basal ganglia may be responsible for its mode of action. The increased life expectancy noted in patients with Parkinson's disease who received long-term therapy (9 years in an uncontrolled study) is another unexpected feature of the drug. These exciting data, if confirmed in other long-term clinical trials, may herald a neuroprotective approach to the treatment of this degenerative disease. More recent studies indicate that Parkinson's disease may eventually turn out to be a neurotoxic event resulting from oxidative stress-induced free radical species in the substantia nigra. Thus selective MAO-B inhibitors could represent a unique class of drugs, having symptomatic actions with possible neuroprotective and neurorescue actions in one.
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PMID:Pharmacological actions of l-deprenyl (selegiline) and other selective monoamine oxidase B inhibitors. 799 14

An analytical solution to the differential equations describing the kinetics of the suicide inhibition of a two-enzyme system has been derived and the modelling of suicide inhibition of the monoamine oxidases A and B (MAO A and B, EC 1.4.3.4) by a quasi-selective agent, (-)-deprenyl, is presented as an example. A new parameter, the specificity index is defined and used in a model which describes the specific and non-specific binding of (-)-deprenyl to MAO B and MAO A, respectively. This type of analysis may be of therapeutic value by indicating optimal dosage of quasi-selective MAO B inhibitors for the treatment of Parkinson's disease.
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PMID:Suicide inhibition of monoamine oxidases A and B by (-)-deprenyl. A computer-aided solution for determining inhibition specificity. 836 32


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