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)

Selegiline is used as an adjunct to levodopa in the symptomatic treatment of Parkinson's disease (PD). The normal daily dose of selegiline is 10 mg administered orally. This study, based on monoamine oxidase-B (MAO-B) inhibition, investigates whether a reduction in selegiline dose can provide the same beneficial effects seen with a 10-mg dose. The inhibition of platelet MAO-B activity against multiple dosing of selegiline (2.5, 5, and 7.5 mg) was predicted from the data obtained from literature (0.5, 1.0, 1.5, and 10 mg). A pharmacokinetic-pharmacodynamic model for selegiline was also developed. The data suggested that by 96 hours (four doses) the inhibition of platelet MAO-B activity is approximately 95% after a daily dose of 2.5 mg selegiline, whereas it takes only 48 hours (two doses) for doses of 5 mg and 7.5 mg to achieve this degree of inhibition. The pharmacokinetic-pharmacodynamic model was best described by a sigmoidal Emax model with an effect compartment. Based on the inhibition of MAO-B activity, a reduction in daily oral dose of selegiline appears possible without compromising the therapeutic effect. Therefore, lower doses of selegiline should be tested in clinical trials.
Ther Drug Monit 1998 Dec
PMID:Is 10 milligrams selegiline essential as an adjunct therapy for the symptomatic treatment of Parkinson's disease? 985 94

A symposium on 'Neurodegenerative disorders: from management to disease modification', organized by Athena Neurosciences (a division of Elan Pharma Ltd) was held at the Royal College of Physicians in London. Speakers outlined recent clinical advances in understanding of the underlying mechanisms of conditions such as multiple sclerosis, Alzheimer's disease and Parkinson's disease.
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PMID:Management of neurodegenerative disorders. 1060 44

The authors assessed differences in both therapeutic and dyskinesia-matched concentrations of levodopa by kinetic-dynamic modeling in a large cohort of patients with Parkinson disease grouped by severity of symptoms. The goal was to provide a kinetic-dynamic approach to levodopa therapy monitoring to assist treating physicians in rationalizing patients' drug schedules in line with disease progression. Eighty-six patients, grouped according to Hoehn & Yahr (H&Y) clinical stage (H&Y I, n = 23; II, n = 25; III; n = 25; IV, n = 13) enrolled in the study. After a 12-hour levodopa washout each patient was examined using a standard oral levodopa test, based on simultaneous serial measurements of plasma levodopa concentrations, finger-tapping motor effects, and dyskinesia ratings. The kinetic-dynamic modeling for both effects was carried out according to the "link" effect compartment model and sigmoidal pharmacodynamic model. Levodopa plasma kinetics did not differ among patient groups. Duration of motor response was significantly (p < 0.001) curtailed in patients in advanced clinical stages whereas dyskinesia duration showed minor changes among the three affected groups (H&Y II, III, and IV). Median effective concentrations (EC 50 ) were increased at the more advanced clinical stage (p < 0.001), from a median 0.2 microg/mL in patients at H&Y stage I to 0.9 microg/mL in patients at H&Y stage IV, whereas the maximum effect showed less consistent changes among the four groups. Intrasubject levodopa therapeutic concentrations were lower than values for dyskinesias in patients at the moderate stage of the disease, equaling dyskinesia-matched drug concentrations in the more affected patients. These findings are in line with previous observations of major changes in levodopa concentration-effects relationship with disease progression and support a stratification of patients with Parkinson disease according to kinetic-dynamic modeling. From a practical point of view, knowledge of individual patients' kinetic-dynamic variables can help the physician assess patients' clinical needs objectively and optimize levodopa dosing according to disease progression.
Ther Drug Monit 2001 Dec
PMID:Levodopa therapy monitoring in patients with Parkinson disease: a kinetic-dynamic approach. 1180 94

It has been known for many years that immune system alterations occur in Parkinson's disease (PD). Changes in lymphocyte populations in cerebrospinal fluid and blood, immunoglobulin synthesis, and cytokine and acute phase protein production have been observed in patients with PD. In this regard, PD patients exhibit a lower frequency of infections and cancer, suggesting that immune system stimulation may occur. This hypothesis is further supported by the observation of T-cell activation leading to the production of interferon gamma in PD. As in other CNS degenerative diseases, in damaged regions in the brains of PD patients, there is evidence of inflammation, characterized by glial reaction (especially microglia), as well as increased expression of HLA-DR antigens, cytokines, and components of complement. These observations suggest that immune system mechanisms are involved in the pathogenesis of neuronal damage in PD. The cellular mechanisms of primary injury in PD have not been clarified, however, but it is likely that mitochondrial mutations, oxidative stress and apoptosis play a role. Furthermore, inflammation initiated by neuronal damage in the striatum and the substantia nigra in PD may aggravate the course of the disease. These observations suggest that treatment with anti-inflammatory drugs may act to slow progression of PD.
Med Sci Monit 2002 Aug
PMID:Immune processes in the pathogenesis of Parkinson's disease - a potential role for microglia and nitric oxide. 1216 54

Reactive oxygen species, such as superoxide radicals, are thought to underlie the pathogenesis of various diseases. Almost 3 to 10% of the oxygen utilized by tissues is converted to its reactive intermediates, which impair the functioning of cells and tissues. Superoxide dismutase (SOD) catalyzes the conversion of single electron reduced species of molecular oxygen to hydrogen peroxide and oxygen. There are several classes of SOD that differ in their metal binding ability, distribution in different cell compartments, and sensitivity to various reagents. Among these, Cu, Zn superoxide dismutase (SOD1) is widely distributed and comprises 90% of the total SOD. This ubiquitous enzyme, which requires Cu and Zn for its activity, has great physiological significance and therapeutic potential. The present review describes the role of SODs, especially Cu, Zn SOD, in several diseases, such as familial amyotrophic lateral sclerosis (FALS), Parkinson's disease, Alzheimer's disease, dengue fever, cancer, Down's syndrome, cataract, and several neurological disorders. Mutations in the SOD1 gene cause a familial form of amyotrophic lateral sclerosis. The mechanism by which mutant SOD1 causes the degeneration of motor neurons is not well understood. Transgenic mice expressing multiple copies of FALS-mutant SOD1s develop an ALS-like motor neuron disease. Vacuolar degeneration of mitochondria has been identified as the main pathological feature associated with motor neuron death and paralysis in several lines of FALS-SOD1 mice. Various observations and conclusions linking mutant SOD1 and FALS are discussed in this review in detail.
Med Sci Monit 2002 Sep
PMID:Superoxide dismutase--applications and relevance to human diseases. 1221 58

Evidence is presented to demonstrate neurodegenerative processes in Parkinson's disease which are interconnected and may be synergistic in a way that they self-perpetuate progression. Free iron plays a predominant role, because it may be continuously and unlimitedly taken up through a disturbed blood-brain-barrier. Iron's toxic action is at both neuronal and glial sites. Loss of tyrosine hydroxylase protein and activity and fibrillation of alpha-synuclein connected with disturbed proteasomal protein breakdown contribute to cell death, as are changes in neuromelanin concentration and binding affinity, e.g. for iron. The interplay of genetic disturbances and neuronal and glial pathological processes involving the functioning of the blood-brain barrier, eventually initiated via an ascending toxic process, is the key for attacking vulnerable catecholaminergic neurons such as those in the substantia nigra and locus coeruleus. Neuroprotective therapeutic strategies are difficult to achieve because of the immanent complexity of cell death cascades.
Med Sci Monit 2004 Dec
PMID:Views on neurodegeneration as a basis for neuroprotective strategies. 1556 92

Parkinson's disease is one of the major neurodegenerative disorders. This disease is mainly characterized by tremor, bradykinesia, rigidity and postural instability that results primarily from a loss of dopaminergic neurons of nigrostriatal pathway. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is well known to damage the nigrostriatal dopaminergic pathway as seen in Parkinson's disease. Recent evidence shows that glial-related response plays a key role in the MPTP neurotoxic process and the blockade of glial activation may be a new therapeutic approach, which has applicability for Parkinson's disease. On the other hand, dopamine transporters (DAT) are important to the appearance of MPTP neurotoxicity because to be neurotoxin, an MPTP metabolite must first gain access to the dopaminergic neurons via DAT. Several studies suggest that DAT is a mandatory factor for expression of MPTP neurotoxicity and may explain the selective neuronal damage in the substantia nigra in MPTP toxicity. Therefore, DAT is thought to play an important role in the MPTP neurotoxic process and specific blockade of DAT with high-affinity inhibitors in neurodegenerative diseases such as Parkinson's disease, where the effective levels of dopamine are markedly reduced, may have beneficial consequences. In view of these new insights, this article suggests that the overexpression of S100beta protein secreted by glial cells may be an exacerbating factor in the neurodegeneration of dopaminergic cells. In this review, we also demonstrate the possible role of DAT in the brain cells in MPTP neurotoxicity. Thus this review provides valuable information for progressive neurodegeneration of the nigrostriatal dopaminergic neuronal pathway.
Med Sci Monit 2005 Jan
PMID:Mechanisms of MPTP toxicity and their implications for therapy of Parkinson's disease. 1561 2

Evidence suggests that the placebo response is related to the tonic effects of constitutive nitric oxide in neural, vascular and immune tissues. Constitutive nitric oxide levels play a role in the modulation of dopamine outflow in the nigrostriatal movement and the mesolimbic and mesocortical reward and motivation circuitries. Endogenous morphine, which stimulates constitutive nitric oxide, may be an important signal molecule working at mu receptors on gamma aminobutyric acid B interneurons to disinhibit nigral and tegmental dopamine output. We surmise that placebo induced belief will activate the prefrontal cortex with downstream stimulatory effects on these dopamine systems as well as on periaqueductal grey opioid output neurons. Placebo responses in Parkinson's disease, depression and pain disorder may result. In addition, mesolimbic/mesocortical control of the stress response systems may provide a way for the placebo response to benefit other medical conditions.
Med Sci Monit 2005 May
PMID:Placebo neural systems: nitric oxide, morphine and the dopamine brain reward and motivation circuitries. 1587 1

Spasticity is a complex disorder characterized by a velocity-dependent increase in muscle tone associated with exaggerated deep tendon reflexes. It can be caused by numerous diffuse or focal cerebral and spinal pathologic conditions. Spasticity indicates upper motor neuron dysfunction and if severe, can lead to considerable motion restriction and eventually to more serious disability. The therapeutic interventions available to treat spasticity are often of limited benefit. In the last decade, many open-label and several double-blind, placebo-controlled, studies have demonstrated the effectiveness of intramuscular botulinum toxin (BTX) injections for the management of spasticity caused by multiple sclerosis, brain / spinal cord injury, cerebral palsy, and stroke. BTX can also be beneficial in the treatment of spasticity, or a mixture of spasticity and rigidity, in many neurodegenerative conditions; including Parkinson disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia and parkinsonism linked to chromosome 17, and in various sporadic and familial spinocerebellar ataxia syndromes. Currently, two BTX serotypes, which are serologically different but share a common subunit structure, are commercially available: type A (Botox(R), manufactured by Allergan, Inc, Irvine, California, USA; and Dysport(R), distributed by Beaufour-Ipsen Pharmaceuticals, Paris, France); and type B (manufactured by Elan Corporation, Dublin, Ireland, and available in the United States as MyoBloc(R) and in Europe as NeuroBloc(R)). BTX primarily affects the neuromuscular junction by inhibiting acetylcholine release. Dosages vary considerably depending on the particular preparation used, the muscle injected, the severity of the condition, and the duration of treatment.
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PMID:Treatment of spasticity with botulinum toxin. 1761 18

In the United States, more than 100,000 adults 50 years old and over are diagnosed with the Human Immunodeficiency Virus (HIV). The number of older adults living with HIV is increasing dramatically due primarily to Highly Active Antiretroviral Therapy (HAART) which is transforming this disease into a chronic condition for many who are responding well to treatment. This population is also growing due to later-life infections and reflects the overall aging of the larger population in general. Yet, despite the novelty of such developing demographic trends, the negative consequences of aging with HIV are largely unknown. Therefore, it is necessary to synthesize the gerontological and HIV/AIDS literatures to hypothesize possible areas that may be of concern to people as they age with this disease. One area of particular concern focuses on tell-tale signs of cognitive problems and the development of dementia. Separately, older adults and adults with HIV are more susceptible of experiencing cognitive declines and dementia. Thus, as people age with HIV, they may be particularly susceptible of such cognitive problems and therefore detecting such problems in the early stages may be vital in preventing further problems. Based on the literature, adults infected with HIV experience impairments in olfaction and psychomotor ability. Similar symptoms are exhibited in older adults with Parkinson's disease and other dementias. Thus, for older adults with HIV, declines in both olfaction and psychomotor skills may be early signs of a developing neurodegenerative disorder. Implications for those aging with HIV are posited.
Med Sci Monit 2007 Oct
PMID:Olfactory and psychomotor symptoms in HIV and aging: potential precursors to cognitive loss. 1790 63


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