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)

In the past 10 years, significant progress on the development of new brain-imaging agents for single-photon emission computed tomography has been made. Most of the new radiopharmaceuticals are designed to bind specific neurotransmitter receptor or transporter sites in the central nervous system. Most of the site-specific brain radiopharmaceuticals are labeled with (123)I. Results from imaging of benzodiazepine (gamma-aminobutyric acid) receptors by [(123)I]iomazenil are useful in identifying epileptic seizure foci and changes of this receptor in psychiatric disorders. Imaging of dopamine D2/D3 receptors ([(123)I]iodobenzamide and [(123)I]epidepride) and transporters [(123)I]CIT (2-beta-carboxymethoxy-3-beta(4-iodophenyl)tropane) and [(123)I]FP-beta-CIT (N-propyl-2-beta-carboxymethoxy-3-beta(4-iodophenyl)-nortropane has proven to be a simple but powerful tool for differential diagnosis of Parkinson's and other neurodegenerative diseases. A (99m)Tc-labeled agent, [(99m)Tc]TRODAT (technetium, 2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo [3,2,1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino] ethanethiolato(3-)]oxo-[1R-(exo-exo)]-), for imaging dopamine transporters in the brain has been successfully applied in the diagnosis of Parkinson's disease. Despite the fact that (123)I radiopharmaceuticals have been widely used in Japan and in Europe, clinical application of (123)I-labeled brain radiopharmaceuticals in the United States is limited because of the difficulties in supplying such agents. Development of (99m)Tc agents will likely extend the application of site-specific brain radiopharmaceuticals for routine applications in aiding the diagnosis and monitoring treatments of various neurologic and psychiatric disorders.
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PMID:Radiopharmaceuticals for single-photon emission computed tomography brain imaging. 1260 53

Imaging of dopaminergic function is useful in the investigation of patients with Parkinson disease (iPD) and other extrapyramidal diseases. Using agents that bind to dopamine transporters ([123I]beta-CIT) and receptors ([123I]IBF SPECT), we investigated SPECT in 9 healthy volunteers and 24 patients for dopamine transporters as well as 15 patients for dopamine receptors. In beta-CIT SPECT studies, we examined 17 iPD patients (63.3 +/- 9.9 y/o), 3 multiple system atrophy (MSA) patients (OPCA type) (64.0 +/- 8.0 y/o), 2 vascular parkinsonism (VP) patients (71.0 +/- 0.0 y/o), 1 progressive supranuclear palsy (PSP) patient (69 y/o), 1 cortico-basal degeneration (CBD) patient (50 y/o) and nine healthy controls (39.1 +/- 9.3 y/o). For IBF SPECT studies 11 iPD patients (60.6 +/- 10.9 y/o), 3 MSA patients (2 OPCA type (50.5 +/- 3.5 y/o) and 1 SND type (65 y/o)) and 1 PSP patient (60 y/o) underwent SPECT scans after the injection of [123I]IBF. The specific to nonspecific striatal uptake ratio(St/Oc-1), ratio of putaminal uptake to caudatal uptake (Pu/Ca), and asymmetry indices (AI) were estimated. beta-CIT studies showed St/Oc-1 as follows; iPD: 2.66 +/- 1.09 (n = 17), VP: 5.73 and 7.39, MSA: 1.84 +/- 0.46 (n = 3), PSP: 2.34, CBD: 2.16. In all extrapyramidal diseases except VP, St/Oc-1 ratios were significantly lower than those in normal volunteers (6.46 +/- 1.08) (p < 0.01). Also in early-phase iPD patients (Yahr I-II), St/Oc-1 (3.16 +/- 1.49: n = 4) was significantly lower than those in normal volunteers (p < 0.01). In IBF studies, St/Oc-1 ratios were significantly higher in early-phase (Yahr I-II) iPD patients (1.82 +/- 0.25: n = 5) than those in late-phase (Yahr III-IV) iPD patients (1.38 +/- 0.32: n = 6) (p < 0.05). The Pu/Ca ratios in iPD patients (1.12 +/- 0.13) and MSA (OPCA type) patients (0.95 +/- 0.05) were higher than that in MSA (SND type) patient (0.78) and were lower than that in PSP patient (1.55). In conclusion, beta-CIT-SPECT is useful for the diagnosis of early-phase iPD patients and for differentiating VP from other extrapyramidal diseases. IBF-SPECT is useful for the diagnosis of the severity of iPD and has the possibility for ruling out MSA (SND type) or PSP from iPD. Both tracers are useful for investigating the pathophysiology of patients with iPD and other extrapyramidal diseases.
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PMID:[SPECT imaging using [123I]beta-CIT and [123I]IBF in extrapyramidal diseases]. 1264

Advances in our understanding of the cause and pathogenesis of Parkinson's disease (PD) have permitted the rational selection of putative neuroprotective agents for study in PD. However, the list of agents that might provide neuroprotective effects derived from laboratory studies is daunting, and we face the challenge of determining which agents to bring to the clinic and how to find the resources (patients and funds) to properly study so many promising therapeutic opportunities.1 Appropriate outcome variables that are not confounded by any symptomatic effect of the drug and are acceptable to clinicians and regulatory authorities also remain to be defined. The first clinical trials designed to test the capacity of putative neuroprotective agents to alter the natural history of PD have now been performed and illustrate some of these problems. The DATATOP (Deprenyl and Tocopherol Antioxidant Therapy of PD) study used the time to reach a disease milestone in untreated PD patients (ie, need for levodopa) as the primary end point. However, interpretation of results was confounded by the drug's symptomatic effect. The SINDEPAR (Sinemet-Deprenyl-Parlodel) study used the change in motor score between initial visit and final visit after washout of all study medications as the primary end point. However, here too there were concerns about confounding symptomatic effects, because antiparkinsonian medications have now been shown to have a long duration response that can persist for weeks and perhaps even months after withdrawal. More recent studies have used surrogate markers of the integrity of nigrostriatal function such as striatal uptake of fluorodopa on positron emission tomography (PET) or beta-CIT-on single-photon emission computerized tomography (SPECT) as primary outcome measures. However, it has not yet been confirmed that striatal uptake of these isotopes does in fact correlate with the remaining number of dopamine neurons or terminals, and the possibility of a confounding pharmacological effect has not yet been completely excluded. To date, no drug has been established to have a neuroprotective effect in PD, and none has been approved for a neuroprotective indication. Furthermore, regulatory agencies have not yet agreed that any of the outcome measures currently used will be acceptable for approval of a new drug. Resolution of these issues is of critical importance to convince pharmaceutical companies to expend the hundreds of millions of dollars necessary to bring a new drug to market. Drugs that already have been approved in PD for their symptomatic effects, such as dopamine agonists or propargylamines (eg, selegiline), offer the best opportunity for establishing that a drug is neuroprotective in PD in the immediate future, but herein also lies the difficulty of establishing that any benefits observed are not solely because of the drug's symptomatic properties. Currently, this will most likely entail demonstrating that the drug provides benefit for PD patients for both imaging and clinical markers of disease progression.
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PMID:Neuroprotection in Parkinson's disease: clinical trials. 1266 1

There is increasing evidence of a potential role of the dopaminergic system in orthostatic tremor (OT): Association with parkinsonism and treatment effects of L-dopa and dopamine agonists have been reported. Eleven patients with isolated OT had single-photon emission computed tomography (SPECT) using (123)I-FP-CIT ([(123)I]-2 beta-carbomethoxy-3beta-(-4-iodophenyl)-N-(3-fluoropropyl)-nortropane) as dopamine transporter tracer. Results were compared with 12 age-matched normal controls and 12 patients with Parkinson's disease (PD). A marked reduction in striatal tracer binding was found in OT compared to normal controls (p < 0.001). Tracer uptake was significantly higher and more symmetrical than in PD, and caudate and putamen were equally affected. L-dopa challenges, performed in seven patients, showed a small but non-significant improvement on EMG and a small but significant improvement in clinical parameters on blinded video rating. Two-month open-label L-dopa treatment (600 mg/day) led to a small improvement in two of five patients but no significant overall change. Olfactory function on University of Pennsylvania Smell Identification Test was normal. Our finding of a marked tracer uptake reduction on dopamine transporter SPECT supports a role of the dopaminergic system in OT. Lack of evidence of a clinically relevant therapeutic response to L-dopa suggests that other mechanisms must also be involved in the pathogenesis.
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PMID:[123I]-FP-CIT-SPECT demonstrates dopaminergic deficit in orthostatic tremor. 1266 16

Nitric oxide (NO), in excess, behaves as a cytotoxic substance mediating the pathological processes that cause neurodegeneration. The NO-induced dopaminergic cell loss causing Parkinson's disease (PD) has been postulated to include the following: an inhibition of cytochrome oxidase, ribonucleotide reductase, mitochondrial complexes I, II, and IV in the respiratory chain, superoxide dismutase, glyceraldehyde-3-phosphate dehydrogenase; activation or initiation of DNA strand breakage, poly(ADP-ribose) synthase, lipid peroxidation, and protein oxidation; release of iron; and increased generation of toxic radicals such as hydroxyl radicals and peroxynitrite. NO is formed by the conversion of L-arginine to L-citrulline by NO synthase (NOS). At least three NOS isoforms have been identified by molecular cloning and biochemical studies: a neuronal NOS or type 1 NOS (nNOS), an immunologic NOS or type 2 NOS (iNOS), and an endothelial NOS or type 3 NOS (eNOS). The enzymatic activities of eNOS or nNOS are induced by phosphorylation triggered by Ca(2+) entering cells and binding to calmodulin. In contrast, the regulation of iNOS seems to depend on de novo synthesis of the enzyme in response to a variety of cytokines, such as interferon-gamma and lipopolysaccharide. The evidence that NO is associated with neurotoxic processes underlying PD comes from studies using experimental models of this disease NOS inhibitors can prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Furthermore, NO fosters dopamine depletion, and the said neurotoxicity is averted by nNOS inhibitors such as 7-nitroindazole working on tyrosine hydroxylase-immunoreactive neurons in substantia nigra pars compacta. Moreover, mutant mice lacking the nNOS gene are more resistant to MPTP neurotoxicity when compared with wild-type littermates. Selegiline, an irreversible inhibitor of monoamine oxidase B, is used in PD as a dopaminergic function-enhancing substance. Selegiline and its metabolite, desmethylselegiline, reduce apoptosis by altering the expression of a number of genes, for instance, superoxide dismutase, Bcl-2, Bcl-xl, NOS, c-Jun, and nicotinamide adenine nucleotide dehydrogenase. The selegiline-induced antiapoptotic activity is associated with prevention of a progressive reduction of mitochondrial membrane potential in preapoptotic neurons. As apoptosis is critical to the progression of neurodegenerative disease, including PD, selegiline or selegiline-like compounds to be discovered in the future may be efficacious in treating PD.
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PMID:Peroxynitrite and mitochondrial dysfunction in the pathogenesis of Parkinson's disease. 1288 Apr 86

Iometopane [(123)I beta-CIT, GPI 200, RTI 55], a tropane derivative labelled with iodine-123, is a dopamine imaging agent that was under development with Guilford Pharmaceuticals (as Dopascan Injection) for the early diagnosis of Parkinson's disease. Neurochemical imaging with iometopane using conventional single photon emission computerised tomography (SPECT) provided images of the brain for the distinguished diagnosis of Parkinson's disease. The ability of iometopane to bind to the dopamine transporter on presynaptic dopaminergic nerve terminal in the striatum (caudate nucleus and putamen) has been used to differentiate the uptake of the agent by the neurons in the striatum in patients with a Parkinsonian disorder (Parkinson's disease and progressive supranuclear palsy) from patients without a Parkinsonian disorder (essential tremor and healthy controls) with high sensitivity and specificity. The diminished uptake of iometopane in the striatum on the SPECT images of patients with a Parkinsonian disorder can be applied to assess both disease trait and disease state (severity) reflected by the severity of the brain dopamine neuron loss. The rate of clinical progression of Parkinson's disease varies greatly and is currently unpredictable. Imaging with iometopane provides the opportunity to evaluate patients longitudinally from early to late disease using an objective biomarker for dopamine nerve cell degeneration. Diagnostic imaging with Dopascan Injection is thought to differentiate Parkinson's disease from other forms of tremor, eliminate tests such as MRI and CT scans, unnecessary and inappropriate medications (psychotropics), and significantly reduce the number of people remaining on Parkinson's disease medications for life, despite not having Parkinson's disease. Guilford Pharmaceuticals acquired the licence for iometopane from the Research Triangle Institute, US, and sub-licensed it to Daiichi Radioisotope Laboratories for marketing, sales and distribution in Japan, Korea and Taiwan. In July 2003, Daiichi Radioisotope Laboratories paid a milestone payment of $0.55 million to Guilford after filing an application for approval in Japan. In January 2002, Guilford signed an exclusive European development, marketing and sales and distribution agreement for iometopane with MAP Medical Technologies of Finland. Under the terms of the agreement, MAP Medical Technologies will assume responsibility for regulatory approvals, manufacturing, marketing and selling the agent in all member states of the EU and other selected markets. In return, Guilford will receive an upfront payment, milestone payments and royalties on future sales in these territories. In July 2002, MAP Medical Technologies become a subsidiary of Schering AG. In March 2002, Guilford Pharmaceuticals sublicensed iometopane to Molecular Neuroimaging LLC (MNI) of Connecticut, USA. Under the terms of the agreement, MNI will pay a royalty for each administration of iometopane, and also provide Guilford Pharmaceuticals with favourable pricing for the services (including administration of iometopane) for any clinical trials of Guilford's product candidates. This agreement will be terminated upon the US FDA's approval of the product candidate for marketing and sale in the US. Guilford has retained commercial rights to Dopascan Injection in the US. MAP Medical Technologies (Schering AG) submitted a Marketing Authorisation Application (MAA) in Finland for European approval of iometopane for the diagnosis of Parkinson's disease in April 2002. Daiichi Radioisotope Laboratories filed an application for approval of iometopane (Dopascan Injection) for the diagnosis of Parkinson's disease in Japan in July 2003. Guilford Pharmaceuticals is conducting a phase II clinical trial in 200 patients with Parkinson's disease where iometopane imaging is used to assess the effectiveness of GPI 1485, an investigational drug candidate, at baseline and at one year and two years after treatment with either GPI 1485 or placebo. The enrolment is expected to be completed in Q3 of 2003. Guint with either GPI 1485 or placebo. The enrolment is expected to be completed in Q3 of 2003. Guilford Pharmaceuticals decided not to proceed with phase III clinical trials and further development of iometopane due to its inability to contract a suitable manufacturer for the clinical and commercial supply of iometopane on acceptable conditions in the US. Guilford Pharmaceuticals obtained the patent coverage for iometopane in the US, Australia and Europe (Austria, Belgium, Switzerland, Liechtenstein, Germany, Denmark, Spain, France, the United Kingdom, Italy, Luxembourg, the Netherlands, Sweden and Greece). Separate filings were made in Finland, Norway, Japan, Canada and Korea. The manufacturing methods of Dopascan are protected by patents in the US and Europe. Dopascan is a registered trademark in the US, Canada, Europe and Asia.
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PMID:Iometopane: (123)I beta-CIT, dopascan injection, GPI 200, RTI 55. 1295 3

To record prospectively, from early presentation, the clinical features of parkinsonism and tremor disorders, in relation to evidence of dopaminergic deficit shown with [(123)I]-FP-CIT (DaTSCAN, Amersham Health) single photon emission computerised tomography (SPECT). Clinical signs were recorded in 62 patients, of whom 24 failed standard Parkinson's disease (PD) and essential tremor criteria, and 38 fulfilled UK Brain Bank step 1 PD criteria. Striatal radioligand uptake was graded visually as normal or abnormal, and specific:nonspecific ratios were calculated. Bradykinesia and rigidity showed significant overall association with abnormal scans (P < or = 0.003), but rest tremor did not (P = NS). In the 24 patients not fulfilling specific criteria (mean age 63 [SD 9] years, disease duration 3 [SD 4] years), 10 (42%) had abnormal visual SPECT assessment and 14 (58%) had normal scans. Of 38 patients with early PD by clinical criteria (mean age 60 [SD 9] years, disease duration 3 [SD 1.7] years), 33 (87%) were visually abnormal. Baseline clinical diagnosis corresponded with SPECT imaging results in 51 of 62 cases (82%), which increased to 56 of 62 cases (90%) with amendment of seven clinical diagnoses at 3 months (blind to SPECT results). Akinetic-rigid cardinal diagnostic features of parkinsonism associate well with dopaminergic deficit in patients with early and mild clinical features. When these clinical features are uncertain, or the patient fails clinical diagnostic criteria, testing for dopaminergic deficit with [(123)I]-FP-CIT SPECT may assist the diagnostic process.
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PMID:Prospective study of presynaptic dopaminergic imaging in patients with mild parkinsonism and tremor disorders: part 1. Baseline and 3-month observations. 1450 64

During the past decade, dopamine transporter (DAT) imaging with single photon emission computerized tomography (SPECT) or positron emission tomography (PET) has evolved as an objective in vivo marker of nigrostriatal neuron loss in Parkinson's disease (PD). We investigate the relationship between striatal DAT binding, measured with [(123)I]beta-CIT SPECT, and parkinsonian motor handicap in a sample of 59 PD patients with minimal to severe disability, and review published cross-sectional studies on the correlation between DAT imaging and motor symptoms in PD. Earlier studies as well as the present results show a good correlation between overall striatal DAT binding and global measures of disease severity such as the Hoehn and Yahr scale, the total score on the Unified Parkinson's Disease Rating Scale (UPDRS), and UPDRS activities of daily living, with a progressive decline of DAT binding with increasing disability. A number of studies found a significant inverse correlation of striatal DAT binding with UPDRS motor score. Bradykinesia, posture, gait, and other midline symptoms, such as speech and facial expression, compared with rigidity, seem to be more closely related to striatal DAT binding. By contrast, neither the severity of parkinsonian rest nor of action tremor is related to the degree of dopaminergic denervation as measured by DAT imaging. Motor symptoms in the clinically less affected body side show a closer correlation with striatal DAT binding than do symptoms occurring in the dominantly affected body side. The correlation of putamen and caudate DAT binding with parkinsonian motor handicap seems to be similar. Although there have been limited comparative studies applying [(18)F]fluorodopa PET and DAT imaging in the same group of PD patients, available data suggest that putamen [(18)F]fluorodopa uptake, when compared with striatal DAT binding, may be more closely related to parkinsonian motor handicap.
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PMID:Correlation of dopamine transporter imaging with parkinsonian motor handicap: how close is it? 1453 Oct 46

As a diagnostic test for patients with suspected Parkinson's disease (PD), single photon emission computed tomography (SPECT) using [(123)I]FP-CIT tracer has better sensitivity but is more expensive than regular clinical examination (CE). Our objective was to evaluate the clinical and economic impacts of different diagnostic strategies involving [(123)I]FP-CIT SPECT. We developed a decision tree model to predict adequate treatment-month equivalents (ATME), costs, and incremental cost-effectiveness ratio (ICER) during a 12-month time horizon in patients with suspected PD referred to a specialized movement disorder outpatient clinic. In our cost- effectiveness analysis, we adopted the perspective of the German health care system and used data from a German prospective health care utilization study (n = 142) and published diagnostic studies. Compared strategies were CE only (EXAM+), SPECT only (SPECT+), SPECT following negative CE (SINGLE+), and SPECT following positive CE (DOUBLE+). Costs of SPECT amounted to euro;789 per investigation. Based on our model, expected costs (and ATME) were euro;946 (52.85 ATME) for EXAM+, euro;1352 (53.40 ATME) for DOUBLE+, euro;1731 (32.82 ATME) for SINGLE+, and euro;2003 (32.96 ATME) for SPECT+; performance of SPECT was induced in 0%, 54%, 56%, and 100% of the patients, respectively. DOUBLE+ was more effective and less expensive than SINGLE+ or SPECT+; thus these two do not offer reasonable choices. The ICER of DOUBLE+ compared to EXAM+ was euro;733 per ATME gained. In sensitivity analyses, the ICER of DOUBLE+ versus EXAM+ ranged from euro;63 to euro;2411 per ATME gained. Whether the diagnostic work-up of patients referred to a specialized movement disorder clinic with a high prevalence of PD should include [(123)I]FP-CIT SPECT depends on patient preferences and the decision maker's willingness to pay for adequate early treatment. SPECT should be used as a confirmatory test before treatment initiation and limited to patients with a positive test result in the clinical examination. These results should be adjusted to the specific setting and individual patient preferences.
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PMID:Dopamine transporter imaging and SPECT in diagnostic work-up of Parkinson's disease: a decision-analytic approach. 1453 Oct 47

A major goal of research in Parkinson's disease (PD) has been the development of treatments to slow the progressive degeneration of the nigrostriatal dopaminergic system and to reduce the functional decline of patients. Because of the uncertainty in the ability of the clinical evaluation to reflect the status of the nigrostriatal dopaminergic system once dopaminergic therapy has commenced, investigators in PD have sought to develop alternative measures of disease. One approach, which has been extensively explored, is neuroimaging with radiotracers that interact with processes central to dopaminergic neurotransmission in the nigrostriatal dopaminergic axons-conversion of levodopa to dopamine through aromatic amino acid decarboxylase (AADC), [(18)F]fluorodopa PET, storage of dopamine in synaptic vesicles via the vesicular monoamine transporter 2 (VMAT2), (+)-[(11)C]dihydrotetrabenazine PET, and reuptake of dopamine into axons via the dopamine transporter (DAT), [(123)I]beta-CIT SPECT, and a number of other PET and SPECT ligands. During the 54(th) Annual Meeting of the American Academy of Neurology, a group of investigators active in the fields of biomakers, neuroimaging, and neuroprotection met to review the three techniques mentioned above. Prior to the meeting, the participants developed consensus on a set of 10 criteria for a neuroimaging technique to be considered adequate as a biomarker for progression of PD and levels at which the available data for each technique indicate that the criterion was met. The criteria and each of the three imaging techniques mentioned above were reviewed, and the results of that meeting are presented.
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PMID:Assessment of neuroimaging techniques as biomarkers of the progression of Parkinson's disease. 1459 29


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