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)

The etiology of Parkinson's disease remains unknown, and a search for environmental agents continues. In 1985, Fishman induced infection of the basal ganglia by a coronavirus in mice. Although coronavirus is recognized primarily as a respiratory pathogen in humans, its affinity for the basal ganglia led us to investigate its possible role in human Parkinson's disease. The cerebrospinal fluid of normal controls (CTL) (n = 18), and patients with Parkinson's disease (PD (n = 20) and other neurological disease (OND) (n = 29) was analyzed in a blinded manner by enzyme-linked immunosorbent assay [measurements in optical density (OD) units] for antibody response to four coronavirus antigens: mouse hepatitis virus JHM (J) and A59 (A), and human coronavirus 229E (E) and OC43 (O). When compared with CTL, PD patients had an elevated (p less than 0.05) mean OD response to J (0.0856 vs. 0.0207) and A (0.1722 vs. 0.0636). Response (p greater than 0.05) to O (0.0839 vs. 0.0071) was greater than that to E (0.1261 vs. 0.0743). When compared to OND, PD patients had an elevated mean OD response to J (0.0856 vs. 0.0267, p less than 0.05). Responses (p greater than 0.05) to A (0.1722 vs. 0.0929) and O (0.0839 vs. 0.0446) were greater than that to E (0.1261 vs. 0.0946). These results suggest that there may be an association between coronavirus and PD.
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PMID:Cerebrospinal fluid antibodies to coronavirus in patients with Parkinson's disease. 131 52

Nonhuman primates are excellent animal models for human diseases because of their close relationship to humans. Indeed, comparisons of the chromosomes and DNA homologies between primates and humans testify to the commonality of the genetic material between these phylogenetically related species. Not surprisingly, this close relationship at the genotypic level extends to the phenotypic level. Thus, the patho-physiological responses of humans and nonhuman primates to internal and external insults are remarkably similar. Two types of human diseases for which nonhuman primates are paramount animal models are discussed. One type includes diseases with defined, single agent etiologies and to which all members of the species are genetically susceptible. Examples of these are leprosy, AIDS, hepatitis and Parkinson's disease. A second type represents diseases that have a substantial genetic component, but are multifactorial and are greatly influenced by the environment. Examples of these are diabetes, lymphoma, atherosclerosis, alcoholic cirrhosis and anxiety disorders. Nonhuman primates are also ideally suited to the role of animal models in the new area of human gene therapy. In the future, biomedical research will focus increasingly on genetic manipulations such as the transfer of genes from one individual to another to correct genetic diseases, particularly those diseases caused by single recessive gene defects. Before gene transfers are attempted in humans, they should be done in nonhuman primates. In a real sense, nonhuman primates, as animal models, represent the "step to man."
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PMID:Genetic significance of some common primate models in biomedical research. 360 96

A polymorphic CYP2C19 gene was analyzed in 233 Japanese subjects, including 63 with Parkinson's disease, 92 with chronic liver diseases (35 chronic hepatitis, 19 liver cirrhosis, 16 hepatocellular carcinoma, 10 primary biliary cirrhosis and 12 autoimmune hepatitis), 14 with lung cancer (squamous cell carcinoma) and 64 healthy subjects to determine the genotype distributions of the CYP2C19 gene and to investigate its involvement in the diseases. Among Japanese healthy subjects 14.1% are predicted to be poor metabolizers (PM) of mephenytoin. The frequencies of the m1 and the m2 mutations of the CYP2C19 gene in the healthy subjects were 21.9% and 11.7%, respectively. Though the number of patients was small, patients with lung cancer (squamous cell carcinoma) are believed to have reduced enzyme activities of CYP2C19.
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PMID:Genotype analysis of the CYP2C19 gene in the Japanese population. 889 Sep 45

During the period from July 1995 to June 1996 we performed transurethral resection of the prostate (TURP) on 824 patients with benign prostatic hyperplasia (BPH). Among them, 13 were dementia patients between 74 and 96 years old; they presented with urinary hesitancy in 6, retention in 4, frequency in 2 and incontinence in 1 patient. Past history included stroke in 7, hypertension in 6, pulmonary tuberculosis in 4, diabetes in 3, asthma in 2, angina pectoris in 1, Parkinson's disease in 1, pneumonia in 1, and hepatitis in 1. Careful preoperative examination revealed that they were proper candidates for TURP. They underwent TURP under spinal anesthesia. The mean operative time was 34 min, ranging from 20 to 60 min. The adenoma resected weighed 24 g on the average, ranging from 7.5 to 48 g. During surgery, although hypotension was noted in 2 patients, there was no serious morbidity. Their mental condition was well controlled with ketamine and diazepam during and after surgery. Postoperative complications included acute myocardial infarction in 1, multiple gastric ulcer in 1, and decubitus in 1. None died within 3 months after TURP, 3 died there after, and 10 patients were alive at the mean follow-up period of 26 months. Six patients reported good urination, 3 reported some improvement in urination after surgery, although requiring intermittent catheterization and 1 developed mild incontinence. In conclusion, TURP appears to provide some benefit in selected patients with dementia and should not be considered to be a contraindication for such patients.
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PMID:[Transurethral resection of the prostate for patients with dementia]. 1036 42

Glial cell line-derived neurotrophic factor (GDNF) is able to protect dopaminergic neurons against various insults and constitutes therefore a promising candidate for the treatment of Parkinson's disease. Lentiviral vectors that infect quiescent neuronal cells may allow the localized delivery of GDNF, thus avoiding potential side effects related to the activation of other brain structures. To test this hypothesis in a setting ensuring both maximal biosafety and optimal transgene expression, a self-inactivating (SIN) lentiviral vector was modified by insertion of the posttranscriptional regulatory element of the woodchuck hepatitis virus, and particles were produced with a multiply attenuated packaging system. After a single injection of 2 microl of a lacZ-expressing vector (SIN-W-LacZ) in the substantia nigra of adult rats, an average of 40.1 +/- 6.0% of the tyrosine hydroxylase (TH)-positive neurons were transduced as compared with 5.0 +/- 2.1% with the first-generation lentiviral vector. Moreover, the SIN-W vector expressing GDNF under the control of the mouse phosphoglycerate kinase 1 (PGK) promoter was able to protect nigral dopaminergic neurons after medial forebrain bundle axotomy. Expression of hGDNF in the nanogram range was detected in extracts of mesencephalon of animals injected with an SIN-W-PGK-GDNF vector, whereas it was undetectable in animals injected with a control vector. Lentiviral vectors with enhanced expression and safety features further establish the potential use of these vectors for the local delivery of bioactive molecules into defined structures of the central nervous system.
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PMID:Self-inactivating lentiviral vectors with enhanced transgene expression as potential gene transfer system in Parkinson's disease. 1064 49

When peripheral decarboxylation is blocked by carbidopa or benserazide, the main metabolic pathway of levodopa is O-methylation by catechol-O-methyltransferase (COMT). Entacapone and tolcapone are new potent, selective and reversible nitrocatechol-type COMT inhibitors. Animal studies have demonstrated that entacapone mainly has a peripheral effect whereas tolcapone also inhibits O-methylation in the brain. In human volunteers, both entacapone and tolcapone dose-dependently inhibit the COMT activity in erythrocytes, improve the bioavailability and decrease the elimination of levodopa, and inhibit the formation of 3-O-methyldopa (3-OMD). Entacapone is administered with every scheduled dose of levodopa whereas tolcapone is administered 3 times daily. The different administration regimens for these agents are based on their different pharmacokinetic and pharmacodynamic profiles. Both entacapone and tolcapone enhance and extend the therapeutic effect of levodopa in patients with advanced and fluctuating Parkinson's disease. They prolong the duration of levodopa effect. Clinical studies show that they increase the daily ON time by an average 1 to 3 hours, improve the activities of daily living and allow daily levodopa dosage to be decreased. Correspondingly, they significantly reduce the daily OFF time. No comparative studies between entacapone and tolcapone have been performed. Tolcapone also appears to have a beneficial effect in patients with nonfluctuating Parkinson's disease. The main adverse effects of the COMT inhibitors are related to their dopaminergic and gastrointestinal effects. Enhancement of dopaminergic activity may cause an initial worsening of levodopa-induced adverse effects, such as dyskinesia, nausea, vomiting, orthostatic hypotension, sleep disorders and hallucinations. Levodopa dose adjustment is recommended to avoid these events. Tolcapone is associated with diarrhoea in about 16 to 18% of patients and entacapone in less than 10% of patients. Diarrhoea has led to discontinuation in 5 to 6% of patients treated with tolcapone and in 2.5% of those treated with entacapone. Urine discoloration to dark yellow or orange is related to the colour of COMT inhibitors and their metabolites. Elevated liver transaminase levels are reported in 1 to 3% of patients treated with tolcapone but very rarely, if at all, in patients treated with entacapone. The descriptions of acute, fatal fulminant hepatitis and potentially fatal neurological reactions, such as neuroleptic malignant syndrome and rhabdomyolysis, in association with tolcapone led to the suspension of its marketing authorisation in the European Community and Canada. In many other countries, the use of tolcapone is restricted to patients who are not responding satisfactorily to other therapies. Regular monitoring of liver enzymes is required if tolcapone is used. No such adverse reactions have so far been described for entacapone and no laboratory monitoring has been proposed. COMT inhibitors added to levodopa therapy are beneficial, particularly in patients with fluctuating disease. They may be combined with other antiparkinsonian drugs, such as dopamine agonists, selegiline and anticholinergics without adverse interactions. They provide a new treatment possibility in patients with Parkinson's disease who have problems with their present levodopa therapy.
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PMID:Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson's disease. 1088 60

A public health network involves several and different health professionals who work in synergy to achieve a common objective: to improve the management of a given disease. Per se, this objective could not be achieved by each of these professionals if working separately. In practice, existing public health networks ensue from very different legal frameworks and come up against various impediments. They have been developed mainly for the management of chronic and serious diseases (e.g. asthma, diabetes, virus C hepatitis, Parkinson's disease, drug abuse). Public health networks can be a very valuable source of data for clinical and epidemiological research, mainly because patients are followed up over a very long period and information coming from various health professionals (general practitioners, specialists, nurses, etc.) is centralized and recorded in a common database. It can also be useful for pharmacovigilance purposes (assessment of Type A and delayed reactions). In any case, the relative interest of such networks should be regularly assessed by an ad hoc methodology, e.g. an experimental or pseudo-experimental design vs. a reference. Despite the fact that there are relatively few operational networks, they can be of great interest for clinical research.
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PMID:[Public health networks: practical aspects and contribution to clinical research. Round table no. 2. XV]. 1109 33

Parkinson's disease patients treated with a combination of levodopa and an aromatic L-amino acid decarboxylase inhibitor usually develop motor complications after some years. To minimise this problem, selective catechol-O-methyltransferase (COMT) inhibitors were developed in order to improve the poor pharmacokinetic profile of levodopa. Tolcapone and entacapone are the two marketed drugs in this class, and both increase the half-life of levodopa and improve clinical parameters, such as the increase in the duration of 'on' and decrease of 'off' time. Soon after its release, tolcapone was suspended in the EU due to it's implication in the deaths of three Parkinsonian patients. The cause of death in these patients was fulminant hepatitis. The mechanism by which tolcapone induces liver damage has been studied. Results show that this drug induces uncoupling of oxidative phosphorylation in mitochondria, thus significantly reducing the cell's capacity to generate ATP. This toxic effect was demonstrated both in vitro and in vivo in several models but the concentrations required to induce it are significantly higher than those needed to inhibit COMT. Inter-individual differences in the capacity to metabolise tolcapone may yield higher plasma levels and may explain its toxic effects in a small sample of patients. Recently, the suspension on tolcapone was lifted, based on new clinical data and ongoing monitoring of its use in other countries. The European Agency for the Evaluation of Medicinal Products concluded that, in some situations, tolcapone has a clinical efficacy that is superior to entacapone and that an adequate level of safety could be achieved with appropriate liver function monitoring and other measures. It is concluded that tolcapone can be safely used in Parkinsonian patients who do not respond or cannot, for other reasons, be prescribed with other COMT inhibitors.
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PMID:Tolcapone in Parkinson's disease: liver toxicity and clinical efficacy. 1570 99

(1) If patients with Parkinson's disease treated with levodopa develop end-of-dose motor fluctuations, the standard therapy is to add bromocriptine, a dopamine receptor agonist, to their ongoing treatment. (2) Evaluation data available in 1999 on entacapone, a catechol-o-methyltransferase (COMT) inhibitor, failed to show whether the balance of benefits versus harm was at least equivalent to that of bromocriptine. (3) Entacapone is now also available as a triple fixed-dose combination with levodopa + carbidopa. (4) Three double-blind trials have compared triple combinations of levodopa + carbidopa (or benserazide) + entacapone with levodopa + carbidopa (or benserazide) + placebo. Two of these trials showed an increase of about 1 hour in "on" phases during the day, together with a small reduction in the daily dose of levodopa. These results are consistent with earlier studies. (5) Entacapone has still not been compared with a dopamine agonist. (6) The fixed-dose combination of levodopa + carbidopa + entacapone has been compared with unfixed combinations in two unblinded trials only. (7) These two trials showed that efficacy was similar whether entacapone was used separately or included in a fixed-dose combination with levodopa + carbidopa. The only relevant trial (a non randomised cross-over trial) failed to show patient preference for the fixed-dose combination. (8) In France, a short-acting combination of levodopa and carbidopa is available, with a dose ratio of 10:1. This compares to a ratio of 4:1 for levodopa and carbidopa in the fixed-dose combination of levodopa + carbidopa + entacapone. The dose of carbidopa is therefore higher for a given dose of levodopa, provoking more dyskinesias and nausea. (9) Entacapone can cause drowsiness. Cases of cholestatic hepatitis have also been reported. Risks of liver toxicity, rhabdomyolysis and neuroleptic malignant syndrome remain to be determined. (10) In practice, bromocriptine remains the first-choice for adjunctive therapy when levodopa becomes ineffective.
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PMID:Levodopa + carbidopa + entacapone. Entacapone: a second look: new preparations. Parkinson's disease: a modest effect. 1587 40

(1) When patients with Parkinson's disease who are taking levodopa develop motor fluctuations that do not respond to dose adjustments, the standard treatment is the addition of bromocriptine, a dopaminergic agonist. Evaluation of entacapone fails to show whether the risk-benefit balance of this catechol-O-methyltransferase (COMT) inhibitor is at least as favourable as that of bromocriptine. (2) Tolcapone, another COMT inhibitor, is back on the French market after being withdrawn because of serious hepatic effects. The summary of product characteristics (SPC) specifies that tolcapone must only be used when entacapone treatment fails or is poorly tolerated. (3) Renewal of marketing authorisation was based on one clinical trial in which about half the patients were probably not resistant to entacapone. No difference in efficacy was found between tolcapone and entacapone. There is no firm evidence that tolcapone is effective in a significant number of patients in whom entacapone fails. (4) Placebo-controlled trials show that first-line treatment with tolcapone 100 mg to 200 mg 3 times a day reduces the duration of motor freezing ("off") periods, but the global impact of tolcapone on parkinsonism appears to be limited. (5) Unblinded randomised controlled trials have failed to show that tolcapone is more effective than bromocriptine or pergolide. There are no trials assessing the use of tolcapone in combination with dopamine agonists. (6) Adverse effects were frequent during clinical trials. They were mainly neurological and gastrointestinal, and differed from those associated with bromocriptine. In 1988, shortly after worldwide marketing of tolcapone, 3 cases of fatal fulminant hepatitis were reported among about 60 000 patients who had taken this drug. Some countries, including European Union member states, withdrew marketing authorisation. Other countries, including the United States, left tolcapone on the market but required stringent monitoring of liver function. Due to a lack of transparency on the part of both the manufacturer and the health authorities, we do not know if these measures reduced the risk of severe hepatitis. In the trial versus entacapone, one of the 75 patients treated with tolcapone 300 mg/day had an abnormal increase in serum transaminase activity. (7) In practice, tolcapone has a negative risk-benefit balance.
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PMID:Tolcapone: new drug. In Parkinson's disease: unacceptable risk of severe hepatitis. 1660 36


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