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)

Symptoms or signs of abnormal autonomic nervous system function occur commonly in several neurological disorders. Clinical evaluations have depended on physiological, pharmacological, and neurochemical approaches. Recently, imaging of sympathetic noradrenergic innervation has been introduced and applied especially in the heart. Most studies have used the radiolabeled sympathomimetic amine, (123)I-metaiodobenzylguanidine. Decreased uptake or increased "washout" of (123)I-metaiodobenzylguanidine-derived radioactivity is associated with worse prognosis or more severe disease in hypertension, congestive heart failure, arrhythmias, and diabetes mellitus. This pattern may reflect a high rate of postganglionic sympathetic nerve traffic to the heart. Many recent studies have agreed on the remarkable finding that all patients with Parkinson's disease and orthostatic hypotension have a loss of cardiac sympathetic innervation, whereas all patients with multiple system atrophy, often difficult to distinguish clinically from Parkinson's disease, have intact cardiac sympathetic innervation. Because Parkinson's disease entails a postganglionic sympathetic noradrenergic lesion, the disease appears to be not only a movement disorder, with dopamine loss in the nigrostriatal system of the brain, but also a dysautonomia, with noradrenaline loss in the sympathetic nervous system of the heart. As new ligands are developed, one may predict further discoveries of involvement of components of the autonomic nervous system in neurological diseases.
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PMID:Imaging of the autonomic nervous system: focus on cardiac sympathetic innervation. 1508 63

Orthostatic hypotension is the most incapacitating symptom of autonomic failure. This disorder occurs with both central autonomic neurodegenerative disorders, such as multiple system atrophy and Parkinson's disease, and peripheral autonomic disorders, such as the autonomic peripheral neuropathies and pure autonomic failure. The hallmark of both central and peripheral causes of neurogenic orthostatic hypotension is the failure to release norepinephrine appropriately upon standing. Patient education is the cornerstone of management. There are several measures that can be implemented to improve orthostatic tolerance prior to pharmacological intervention. Plasma volume expansion is essential to improve orthostatic tolerance, and fluid and sodium chloride intake should be increased. Most patients can be treated successfully with volume expansion or fludrocortisone or both in combination with a sympathomimetic agent. Desmopressin acetate and erythropoietin are useful supplementary agents in patients with more refractory symptoms. There are rare patients who will require additional agents to treat their symptoms. A small group of patients remain refractory to all therapeutic modalities.
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PMID:Treatment of orthostatic hypotension. 1508 64

Mitochondria are involved directly in cell survival and death. The assumption has been made that drugs that protect mitochondrial viability and prevent apoptotic cascade-induced mitochondrial permeability transition pore (MPTp) opening will be cytoprotective. Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO) B inhibitor anti-Parkinson drug. Unlike selegiline, it is not derived from amphetamine, and is not metabolized to neurotoxic L-methamphetamine derivative. In addition, it does not have sympathomimetic activity. Rasagiline is effective as monotherapy or adjunct to levodopa for patients with early and late Parkinson's disease (PD) and adverse events do not occur with greater frequency in subjects receiving rasagiline than in those on placebo. Phase III controlled studies indicate that it might have a disease-modifying effect in PD that may be related to its neuroprotective activity. Its S isomer, TVP1022, is more than 1,000 times less potent as an MAO inhibitor. Both drugs, however, have neuroprotective activity in neuronal cell cultures in response to various neurotoxins, and in vivo in response to global ischemia, neurotrauma, head injury, anoxia, etc., indicating that MAO inhibition is not a prerequisite for neuroprotection. Their neuroprotective effect has been demonstrated to be associated directly with the propargylamine moiety, which protects mitochondrial viability and MTPp by activating Bcl-2 and protein kinase C (PKC) and by downregulating the proapoptotic FAS and Bax protein families. Rasagiline and its derivatives also process amyloid precursor protein (APP) to the neuroprotective, neurotrophic, soluble APP alpha (sAPPalpha) by PKC- and MAP kinase-dependent activation of alpha-secretase. The identification of the propargylamine moiety as the neuroprotective component of rasagiline has led us to development of novel bifunctional anti-Alzheimer drugs (ladostigil) possessing cholinesterase and brain-selective MAO inhibitory activity and a similar neuroprotective mechanism of action.
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PMID:Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition. 1557 6

The mitochondria are directly involved in cell survival and death. Drugs that protect mitochondria viability and prevent apoptotic cascade mechanisms involved in mitochondrial permeability transition pore (MPTp) will be cytoprotective. Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO) B inhibitor, anti-Parkinson drug. Unlike selegiline, rasagiline is not derived from amphetamine, is not metabolized to neurotoxic l-methamphetamine derivative, nor does it have sympathomimetic activity. Rasagiline is effective as monotherapy or adjunct to L-dopa for patients with early and late Parkinson's disease (PD), and adverse events do not occur with greater frequency in subjects receiving rasagiline than those on placebo. Controlled studies indicate that it might have a disease-modifying effect in PD that may be related to neuroprotection. Its S-isomer, TVP1022, is a relatively inactive MAO inhibitor. However, both drugs have similar neuroprotective activities in neuronal cell cultures in response to various neurotoxins and in vivo (global ischemia, neurotrauma, head injury, anoxia, etc.), indicating that MAO inhibition is not a pre-requisite for neuroprotection. Structure activity studies have shown that the neuroprotective activity is associated with the propargyl moiety of rasagiline which protects mitochondrial viability and MPTp by activating Bcl-2 and protein kinase C (PKC), and down regulating pro-apoptotic FAS and Bax. Rasagiline and its derivatives also process amyloid precursor protein (APP) to the neuroprotective-neurotrophic soluble APP alpha (sAPPalpha) by PKC and MAP kinase-dependent activation of alpha-secretase. The neuroprotective activity of propargylamine has led us to develop novel bifunctional neuroprotective iron-chelating MAO-inhibiting drugs possessing propargyl moiety for the treatment of other neurodegenerative diseases.
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PMID:Mechanism of neuroprotective action of the anti-Parkinson drug rasagiline and its derivatives. 1585 Jun 77

Neuronal death in Parkinson's disease (PD) may originate from the reciprocal interactions of a restricted number of conditions, such as mitochondrial defects, oxidative stress and protein mishandling, which would favor a state of apoptotic cell death in the nigrostriatal pathway. The search for pharmacological treatments able to counteract the nigrostriatal degeneration, possibly by interfering with these phenomena, has recently raised considerable interest in rasagiline [R(+)-N-propargyl-1-aminoindan], a potent, selective, and irreversible inhibitor of monoamine oxidase B (MAO-B). Rasagiline, like selegiline, is a propargylamine, but is approximately 10 times more potent. Unlike selegiline, rasagiline is not metabolized to amphetamine and/or methamphetamine and is devoid of sympathomimetic activity. Numerous experimental studies, conducted both in vitro and in vivo, have shown that rasagiline possesses significant protective properties on neuronal populations. The pro-survival effects of the drug appear to be linked to its propargyl moiety, rather than to the inhibitory effect on MAO-B. Rasagiline's major metabolite, aminoindan--which possesses intrinsic neuroprotective activity--may also contribute to the beneficial effects of the parent compound. Rasagiline has been recently evaluated in early PD patients, with results that are consistent with slowing the progression of the disease. Therefore, the neuroprotective activity shown by the drug under experimental conditions may be reflected in the clinic, thus providing new perspectives for the treatment of PD.
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PMID:Neuroprotection by rasagiline: a new therapeutic approach to Parkinson's disease? 1600 39

Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent, irreversible monoamine oxidase (MAO)-B inhibitor designed for use as an antiparkinsonian drug. Unlike selegiline, rasagiline is not derived from amphetamine or metabolized to neurotoxic l-methamphetamine derivative, and it does not have sympathomimetic activity. Moreover, at selective MAO-B inhibitory dosage, it does not induce a "cheese reaction." Rasagiline is effective as monotherapy or as an adjunct to L-dopa for patients with early and late Parkinson's disease. Adverse events do not occur with greater frequency in subjects receiving rasagiline than in those on placebo. Its S-isomer, TVP1022, is more than a thousand times less potent as an MAO inhibitor. However, both drugs have neuroprotective activities in neuronal cell cultures in response to various neurotoxins, as well as in vivo (e.g., in response to global ischemia, neurotrauma, head injury, anoxia, etc.), indicating that MAO inhibition is not a prerequisite for neuroprotection. The neuroprotective activity of these drugs has been demonstrated to be associated with the propargylamine moiety, which protects mitochondrial viability and mitochondrial permeability transition pore by activating Bcl-2 and downregulating the Bax family of proteins. Rasagiline processes amyloid precursor protein (APP) into the neuroprotective-neurotrophic soluble APPalpha (sAPPalpha) by protein kinase C- and mitogen-activated protein kinase-dependent activation of alpha-secretase, and increases nerve growth factor, glial cell- derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) expression and proteins. Thus, rasagiline may induce neuroprotection, neuroplasticity and long-term potentiation. Rasagiline has therefore been chosen by the National Institutes of Health (NIH) to study its neuroprotective effects in neurodegenerative diseases. Long-term studies are required to evaluate the drug's disease-modifying prospects in Parkinson's and Alzheimer's diseases.
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PMID:Neuropharmacological, neuroprotective and amyloid precursor processing properties of selective MAO-B inhibitor antiparkinsonian drug, rasagiline. 1611 Mar 45

Monoamine oxidase (MAO, EC 1.4.3.4), a flavine-containing enzyme catalyzing the oxidative deamination of monoamines, is located in the outer mitochondrial membrane and exhibited in virtually all tissues of mammals. As the family of MAO substrates includes both important neurotransmitters and hormones (i.e. serotonin, dopamine, adrenaline, noradrenaline) as well as biologically active dietary amines, such as tyramine (an indirectly acting sympathomimetic amine) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP a Parkinsonian producing exogenous neurotoxin), it is commonly accepted that MAO may play a critical role in the regulation of central nervous system activity and contribute to the pathogenesis of human neurodegenerative and depressive disorders. Fifty years ago the first generation of MAO inhibitors was developed and applied in therapy as anti-depressive compounds. However, for many years MAO inhibitors were considered useless in therapy due to the serious side effects induced by these drugs. Recently, MAO and its inhibitors are again in the center of scientific and pharmacological interest, providing new drugs for the therapy of Parkinson's disease, Alzheimer's disease, and various types of depression. Moreover, a beneficial pharmacological action of currently available MAO inhibitors, extending far beyond the MAO-B inhibitory properties, encourages investigators to search for new compounds exhibiting no side effects.This article gives a brief overview of the physiological importance of MAO and the biochemical and pharmacological potential of its inhibitors, with a consideration of their importance in the therapy of various disorders in humans.
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PMID:[Monoamine oxidase as a target for drug action]. 1706 Aug 92

This study evaluated pupillary postganglionic autonomic dysfunction and its relationship to visual disturbance in idiopathic Parkinson's disease (PD). Pupillary sensitivity was examined in relation to a parasympathomimetic agent [0.05% pilocarpine hydrochloride (PL)] and to a sympathomimetic agent [0.02% dipivefrine hydrochloride (DPE)] using infrared pupillography in 40 PD patients and 17 age-matched controls. Visual disturbances were evaluated as well, including blurring, photophobia, night blindness and involuntary eyelid closure in response to light. Pupillary supersensitivity to PL and DPE and their relation to visual disturbances were found to be significantly greater in PD patients than in controls (22.3 +/- 15.1 vs. 10.4 +/- 11.4%, P < 0.005, and14.5 +/- 14.5 vs. 4.9 +/- 8.7%, P < 0.01, respectively). In addition, pupillary sympathetic supersensitivity did not correlate with a reduction of 123I-metaiodobenzylguanidine (MIBG) cardiac accumulation. Patients with PD reported more blurred vision (P < 0.001) and involuntary eyelid closure in response to light (P < 0.05) than controls. Patients with supersensitivity to both PL and DPE complained more often of blurred vision than patients without supersensitivity (P < 0.05). Pupillary sensitivity to PL correlated significantly with a summed score for visual disturbance (P < 0.05, r = 0.417), but DPE sensitivity did not. PD patients have both parasympathetic and sympathetic postganglionic impairments affecting the pupil. Our findings demonstrate that parasympathetic dysfunction contributes significantly to visual disturbance in PD.
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PMID:Pupillary supersensitivity and visual disturbance in Parkinson's disease. 1826 41

Rasagiline is an irreversible monoamine oxidase type B (MAO-B) inhibitor indicated for the treatment of the signs and symptoms of idiopathic Parkinson disease as initial monotherapy and as adjunct therapy to levodopa. Pharmacologic inhibition of monoamine oxidase type A (MAO-A), but not MAO-B, poses a risk of the "cheese effect," a hypertensive response to excess dietary tyramine, a biogenic sympathomimetic amine. Tyramine challenge studies, conducted to characterize rasagiline selectivity for the MAO-B enzyme and tyramine sensitivity, demonstrate that rasagiline, when used at the recommended dose, is selective for MAO-B and is not associated with heightened tyramine sensitivity. This conclusion is also supported by safety results from large clinical trials of rasagiline in Parkinson disease involving 2066 rasagiline-treated patients who did not require dietary tyramine restriction per protocol. In late 2009, US labeling for rasagiline was modified to state that dietary tyramine restrictions are not ordinarily required when rasagiline is administered at recommended doses. In addition, because rasagiline has been demonstrated to be selective for MAO-B at the approved dose of up to 1 mg/d, contraindications regarding concomitant use with sympathomimetic amines, use of sympathomimetic vasopressors in conjunction with general or local anesthesia, and use in patients with pheochromocytoma also were removed.
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PMID:The monoamine oxidase type B inhibitor rasagiline in the treatment of Parkinson disease: is tyramine a challenge? 2162

Non-motor aspects of Parkinson disease (PD) are now recognized to be important both clinically and scientifically. Among these facets are abnormalities in blood pressure regulation. As much as 40% of PD patients have orthostatic hypotension (OH), which is usually associated with supine hypertension (SH). Symptoms of OH range from light-headedness to falls with serious trauma. SH, while typically asymptomatic, poses a significant increased risk for cardiovascular morbidity and mortality. Neuroimaging, neurochemical, and neuropharmacological studies indicate cardiac and extra-cardiac sympathetic noradrenergic denervation and baroreflex failure in virtually all PD patients with OH, and cardiac sympathetic denervation has been confirmed histopathologically. Mechanisms of SH in PD+OH remain poorly understood. The diurnal blood pressure profile shows increased variability that is correlated with decreased baroreflex gain and with increased morbidity and mortality. Treatment should be individually tailored according to the timing of OH or SH, using primarily short-acting sympathomimetic medications in the daytime for OH and short-acting antihypertensive in the nighttime for SH. Future research is needed to understand better and attenuate blood pressure fluctuations through manipulations that improve baroreflex function.
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PMID:Mechanisms of orthostatic hypotension and supine hypertension in Parkinson disease. 2176 27


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