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)

Patients on chronic carbidopa-levodopa (Sinemet) therapy underwent thyroid function testing that included measurement of serum thyroxine (T4), triiodothyronine (t3), thyrotropin (TSH), T3 uptake (T3U), free T4 index (FT4I), and free T3 index (FT3I). The subjects were studied both in a random sampling and in a controlled manner, fasting and 2 hours after receiving the drug. All subjects were euthyroid by testing, and there was no significant difference in thyroid hormone levels of patients and controls or in fasting values and values 2 hours after the drug. However, there was a small but significant reduction in serum TSH levels after Sinemet. Therapeutic doses of Sinemet have no significant effect on thyroid function in euthyroid patients with Parkinson disease.
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PMID:Sinemet and thyroid function in Parkinson disease. 57 39

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

It has been believed that patients with neurogenic orthostatic hypotension (NOH) usually develop denervation supersensitivity of cardiovascular alpha-, beta 1- and beta 2-adrenoceptors, because the majority studies have shown augmented cardiovascular responses to intravenously given noradrenaline (NA) or isoprenaline (IP) in these patients. This view, however, leaves room for discussion. First, drugs were administered by means of drip infusion method in most of the previous studies. Since this method necessarily provokes baroreflex, which is buffering fluctuations in blood pressure and heart rate, the results may reflect diminished baroreflex rather than denervation supersensitivity. Second, adrenoceptor functions are modulated by multiple factors, such as ageing, thyroid hormone and chronic inflammation. It is, thus, inappropriate to explain the whole picture of functional change in adrenoceptors by the denervation mechanism only. In order to look over the cardiovascular adrenoceptor functions in NOH, we performed bolus infusion tests of NA and IP on the patients. The subjects comprised 7 cases of NOH with pre-ganglionic sympathetic deficit (NOH-I), 6 cases with post-ganglionic deficit (NOH-II) and 15 healthy controls. NOH-I group included 6 patients with multiple system atrophy and one with Parkinson disease, while NOH-II group consisted of 3 patients with idiopathic orthostatic hypotension (pure autonomic failure) and 3 with diabetic autonomic neuropathy. Both NA and IP infusion tests were carried out under the continuous measurement of blood pressure and heart rate. In NA test, different bolus doses (0.01, 0.02, 0.05 and 0.1 microgram/kg) of NA were intravenously administered, and a degree of subsequent rise in mean blood pressure was used as an index for alpha-adrenoceptor function. IP test was performed in the same manner, and an increase in heart rate and a fall in mean blood pressure in response to the drug (0.001, 0.002 and 0.005 microgram/kg) were measured as indices for beta 1- and beta 2-functions, respectively. A rise in blood pressure following the administration of any dose of NA did not statistically differ among three groups. An increase in heart rate in IP test was generally lower in both NOH groups, and a significant difference was obtained between NOH-I and control when a given dose was 0.005 microgram/kg) (p < 0.02). A fall in blood pressure in IP test was significantly greater in NOH-I compared to control when doses were 0.002 and 0.005 microgram/kg (p < 0.02 and 0.01, respectively). It was also greater in NOH-II than in control when a dose was 0.002 microgram/kg (p < 0.01). In disagreement with most of the previous studies, the present results suggest that alpha-adrenoceptor function is hardly altered, beta 1-function is suppressed, and beta 2-function is augmented in NOH.
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PMID:[Cardiovascular alpha-, beta 1- and beta 2-adrenoceptor functions in neurogenic orthostatic hypotension]. 882 96

Recent reports have revealed that Nurr1 (also known as NOT/TINUR/RNR-1/HZF-3), a member of the steroid/thyroid hormone nuclear receptor superfamily, is predominantly expressed in the midbrain; substantia nigra (SN) and ventral tegmental area (VTA). Nurr1 null mice are born lethal, lacking the midbrain dopamine (DA) neurons, suggesting that Nurr1 is essential for the development and differentiation of midbrain DA neurons. Human Nurr1 gene has been mapped on chromosome 2q22-23, which is reported to associate weakly with schizophrenia. We cloned and sequenced the human Nurr1 gene, which is approximately 8.3kb long, consisting of eight exons and seven introns. Comparisons of the human Nurr1 with the mouse Nurr1, mouse Nur77 and human NOR-1 revealed that their genomic structures were highly conserved. The 5'-flanking region of the human Nurr1 included three transcriptional regulatory elements, cAMP-response element (CRE), CArG-like element and Sp-1 site, which were surrounded by CpG island, and showed a strong homology with the mouse Nurr1. We performed a primer extension analysis using mRNA from HeLa S3 cells stimulated with phorbol 12-myristate 13-acetate (PMA), Ca2+ ionophore A23187 and cycloheximide (CHX) in order to induce the Nurr1 mRNA expression, and determined one transcription initiation site within CRE. The transient transfection assay indicates that the regulatory elements in the 5'-flanking region are robust for mitogen-induced expression of the human Nurr1. Further analysis of the polymorphism of the human Nurr1 gene may reveal the association with diseases characterized by changes of the DA system, such as Parkinson's disease and schizophrenia.
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PMID:Organization of the human orphan nuclear receptor Nurr1 gene. 1021 61

A 59-year-old man, who was diagnosed as having Parkinson's disease and depression seven years ago and was on oral antiparkinsonian agents, antianxiety agents, and antidepressants, developed a high fever, disturbed consciousness, and marked muscle rigidity after discontinuation of etizolam and amitriptyline. He was admitted to a nearby hospital. Hypothyroidism had been noted two months before admission. Marked muscle rigidity and increased serum CK were observed. Since discontinuation of benzodiazepine has been known to rarely trigger a neuroleptic malignant syndrome (NMS), he was diagnosed as having NMS. After receiving dantrolene and bromocriptine, these symptoms temporarily improved but he again developed consciousness disturbance, and convulsive seizures associated with an elevated serum CK. He was transferred to our hospital. On admission, the CK level was normal at 168 IU/l, while free T4 was 0.6 ng/dl (normal range, 0.9-2.3) and TSH was 108.7 mU/ml (normal range, 0.2-4.2) in serum, indicating the presence of primary hypothyroidism. As an increase in thyroid hormone dosage improved the thyroid function to normal level, his disturbed consciousness and muscle rigidity gradually improved. Convulsive seizure and recurrence of NMS in a short interval are unusual in neuroleptic malignant syndrome. In this patient, hypothyroidism may have contributed to the development of malignant syndrome through metabolic changes of the central dopaminergic system, and discontinuation of etizolam, a kind of benzodiazepine, may have triggered NMS, since there has not been reported that discontinuation of antidepressants including amitriptyline triggers NMS.
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PMID:[A patient with Parkinson's disease complicated by hypothyroidism who developed malignant syndrome after discontinuation of etizolam]. 1242 63

Age-related depletion of testosterone may increase the brain's vulnerability to parkinsonian- or Alzheimer's-like neurodegenerative disorders. In rats, rotenone, a mitochondrial complex I inhibitor, causes specific nigral dopaminergic neurodegeneration producing parkinsonian symptoms. In this study, rotenone was administered on a daily basis (2 mg/kg i.p.) to two groups of rats, over a period of 30 and 60 days, respectively. In order to contribute towards the validation of the rotenone rat model, the changing level of the peripheral sex steroid hormone, testosterone, which would also mimic those found in Parkinson's disease (PD) patients, was evaluated. Parallel to this, prolactin, luteinizing hormone (LH), the nonsexual steroid thyroid-stimulating hormone, and the corticosterone hormone levels in the peripheral blood plasma were measured to show whether other hormones have also been affected by complex I inhibition. The rotenone treatment caused a decrease of testosterone level in the peripheral blood plasma. There were no differences in the thyroid hormone and prolactin but increases in leutinizing hormone and corticosterone were observed. Data from this study indicate that rotenone depleted the sex steroid hormone which is preferentially produced in the periphery, e.g., adrenal gland and testis. In conclusion, because a decrease in testosterone levels is also one of the comorbidities which are found in male PD patients, our results indicate that the rotenone model mimics PD symptoms not only on a neuronal and behavioral level, but also on the testosterone levels.
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PMID:Mitochondrial complex I inhibition depletes plasma testosterone in the rotenone model of Parkinson's disease. 1558 61

Both of environmental and genetic factors confer vulnerability to Parkinson's disease (PD). NR4A2 (Nurr1), a member of the steroid/thyroid hormone nuclear receptor superfamily, is essential for the neurogenesis and differentiation of dopaminergic neurons in the midbrain. Brain derived neurotrophic factor (BDNF) deficiency may play a role in the pathogenesis of PD, as the surviving dopaminergic nigrostriatal neurons have reduced levels of BDNF. This study examines whether BDNF V66M (c.196 G --> A) or NR4A2 IVS6 +18insG polymorphism is associated with the risk of Taiwanese PD and the age of onset using a case-control study. The genotype or allele frequency distribution of both BDNF V66M and NR4A2 IVS6 +18insG polymorphisms was not significantly different between the cases and the controls. Neither BDNF nor NR4A2 polymorphism influences PD onset age. Notably, after stratification by sex, female individuals carrying the NR4A2 2G/2G genotype demonstrated a trend toward significant decrease in risk of developing PD (OR = 0.49, 95% CI = 0.25-0.96, P = 0.039). These results suggest that the NR4A2 IVS6 +18insG polymorphism may play a minor role in PD susceptibility among Taiwanese women.
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PMID:Nuclear receptor NR4A2 IVS6 +18insG and brain derived neurotrophic factor (BDNF) V66M polymorphisms and risk of Taiwanese Parkinson's disease. 1742 85

Manganese (Mn) is an essential trace nutrient that is potentially toxic at high levels of exposure. As a constituent of numerous enzymes and a cofactor, manganese plays an important role in a number of physiologic processes in mammals. The manganese-containing enzyme, manganese superoxide dismutase (Mn-SOD), is the principal antioxidant enzyme which neutralizes the toxic effects of reactive oxygen species. Other manganese-containing enzymes include oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases and glutamine synthetase. Environmental or occupational exposure to high levels of manganese can cause a neuropathy resembling idiopathic Parkinson's disease, commonly referred to as manganism. Manganism and Parkinson's disease are both characterized by motor deficits and damage to nuclei of the basal ganglia, particularly the substantia nigra, with altered dopamine (and its metabolites) contributing to these disorders. Dopamine, a major neurotransmitter plays a crucial role in the modulation of the cognitive function, working memory and/or attention of the prefrontal cortex and the hippocampus. Dopamine is also a known inhibitory modulator of thyroid stimulating hormone (TSH) secretion. The involvement of dopamine and dopaminergic receptors in neurodevelopment, as well as TSH modulation, led us to hypothesize that excessive manganese exposure may lead to adverse neurodevelopmental outcomes due to the disruption of thyroid homeostasis via the loss of dopaminergic control of TSH regulation of thyroid hormones. This disruption may alter thyroid hormone levels, resulting in some of the deficits associated with gestational exposure to manganese. While the effects of manganese in adult populations are relatively well documented, comprehensive data on its neurodevelopmental effects are sparse. Given the importance of this topic, we review the potential participation of thyroid hormone dyshomeostasis in the neurodevelopmental effects of manganese positing the hypotheses that manganese may directly or indirectly affect thyroid function by injuring the thyroid gland or dysregulating dopaminergic modulation of thyroid hormone synthesis.
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PMID:Effects of manganese on thyroid hormone homeostasis: potential links. 1757 15

The members of the NOX/DUOX family of NADPH oxidases mediate such physiologic functions as host defense, cell signaling, and thyroid hormone biosynthesis through the generation of reactive oxygen species (ROS), including superoxide anion and hydrogen peroxide. Moreover, ROS are involved in a broad range of fundamental biochemical and cellular processes, and data accumulated in recent years indicate that the NOX enzymes comprise one of the most important biological sources of ROS. Given the high biochemical reactivity of ROS, it is not surprising that they have been implicated in a wide variety of pathologies and diseases. Prominent among the settings that feature ROS-mediated tissue injury are disorders associated with inflammation, aging, and progressive degenerative changes in cells and organ systems, and it appears that essentially no organ system is exempt. Among the disorders currently believed to be mediated at least in part by NOX-derived ROS are hypertension, aortic aneurysm, myocardial infarction (and other ischemia-reperfusion disorders), pulmonary fibrosis and hypertension, amyotropic lateral sclerosis, Alzheimer's disease, Parkinson's disease, ischemic stroke, diabetic nephropathy, and renal cell carcinoma. Several small-molecule and peptide inhibitors of the NOX enzymes have been useful in experimental studies, but issues of specificity, potency, and toxicity militate against any of the existing published compounds as candidates for drug development. Given the broad array of disease targets documented in recent work, the time is here for vigorous efforts to develop clinically useful inhibitors of the NOX enzymes. As most (though not all) NOX-related diseases appear to be mediated by a single member of the NOX family, agents with isoform specificity will be preferred, although broadly active NOX inhibitors may prove to be useful in some settings.
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PMID:NOX enzymes as novel targets for drug development. 1850 46

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in newborn premature infants. Clinical studies show increased incidence of NEC in premature infants with enteral formula feeding; however, pathogenesis remains unclear. To identify the NEC-related proteins for molecular mechanisms, we applied proteomics analysis to characterize changes in the protein expression profile of newborn premature piglet intestines with NEC developed after enteral formula feeding for 24 h. Changes in protein expression were identified using 2-dimensional gel electrophoresis and peptide mass fingerprinting with MS as well as western blotting analysis. Nineteen differentially expressed proteins were identified and these have roles in oxidative stress, chaperone, signal transduction, protein folding and degradation, oxygen transport, signal transduction, and energy metabolism. Proteins with increased levels include manganese-containing superoxide dismutase and hemoglobin subunit and proteins with decreased expression include sorbitol dehydrogenase, mitochondrial aldehyde dehydrogenase 2, glucose-regulated protein 75, CRY protein, snail homolog 3, thyroid hormone-binding protein precursor, and DJ1 (Parkinson's disease 7) etc. The data provided novel mechanistic insights into the pathogenesis of NEC and the insults of a formulated diet to the premature gut.
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PMID:The small intestine proteome is changed in preterm pigs developing necrotizing enterocolitis in response to formula feeding. 1880 98


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