22 results on '"Clarke, Carl"'
Search Results
2. Initiation of pharmacological therapy in Parkinson's disease: when, why, and how.
- Author
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de Bie RMA, Clarke CE, Espay AJ, Fox SH, and Lang AE
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- Humans, Quality of Life, Time Factors, Treatment Outcome, Antiparkinson Agents therapeutic use, Dopamine Agents therapeutic use, Levodopa therapeutic use, Parkinson Disease drug therapy
- Abstract
Debate is ongoing regarding when, why, and how to initiate pharmacotherapy for Parkinson's disease. Early initiation of dopaminergic therapies does not convey disease-modifying effects but does reduce disability. Concerns about the development of motor complications arising from the early initiation of levodopa, which led to misconceived levodopa-sparing strategies, have been largely mitigated by the outcomes of the PD MED and Levodopa in Early Parkinson's Disease (LEAP) studies. The LEAP study also showed the potential for early improvement in quality of life, even when disability is negligible. Until more effective methods of providing stable dopamine concentrations are developed, current evidence supports the use of levodopa as initial symptomatic treatment in most patients with Parkinson's disease, starting with low doses and titrating to therapeutic threshold. Monoamine oxidase-B inhibitors and dopamine agonists can be reserved as potential adjunct treatments later in the disease course. Future research will need to establish effective disease-modifying treatments, address whether patients' quality of life is substantially improved with early initiation of treatment rather than a wait and watch strategy, and establish whether new levodopa formulations will delay onset of dyskinesia., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
- Full Text
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3. Authors' reply to Braithwaite and Elrington.
- Author
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Muzerengi S and Clarke CE
- Subjects
- Humans, Antiparkinson Agents administration & dosage, Dopamine Agonists administration & dosage, Levodopa administration & dosage, Monoamine Oxidase Inhibitors administration & dosage, Neuroprotective Agents administration & dosage, Parkinson Disease drug therapy
- Published
- 2015
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4. Initial drug treatment in Parkinson's disease.
- Author
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Muzerengi S and Clarke CE
- Subjects
- Cost-Benefit Analysis, Dose-Response Relationship, Drug, Drug Administration Schedule, Humans, Parkinson Disease diagnosis, Parkinson Disease physiopathology, Treatment Outcome, Antiparkinson Agents administration & dosage, Dopamine Agonists administration & dosage, Levodopa administration & dosage, Monoamine Oxidase Inhibitors administration & dosage, Neuroprotective Agents administration & dosage, Parkinson Disease drug therapy
- Published
- 2015
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5. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open-label, pragmatic randomised trial.
- Author
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Gray R, Ives N, Rick C, Patel S, Gray A, Jenkinson C, McIntosh E, Wheatley K, Williams A, and Clarke CE
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- Aged, Aged, 80 and over, Animals, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Monoamine Oxidase drug effects, Treatment Outcome, Antiparkinson Agents therapeutic use, Dopamine Agonists therapeutic use, Levodopa therapeutic use, Monoamine Oxidase Inhibitors therapeutic use, Parkinson Disease drug therapy
- Abstract
Background: Whether initial treatment for Parkinson's disease should consist of levodopa, dopamine agonists, or monoamine oxidase type B inhibitors (MAOBI) is uncertain. We aimed to establish which of these three classes of drug, as initial treatment, provides the most effective long-term control of symptoms and best quality of life for people with early Parkinson's disease., Methods: In this pragmatic, open-label randomised trial, patients newly diagnosed with Parkinson's disease were randomly assigned (by telephone call to a central office; 1:1:1) between levodopa-sparing therapy (dopamine agonists or MAOBI) and levodopa alone. Patients and investigators were not masked to group assignment. Primary outcomes were the mobility dimension on the 39-item patient-rated Parkinson's disease questionnaire (PDQ-39) quality-of-life scale (range 0-100 with six points defined as the minimally important difference) and cost-effectiveness. Analysis was intention to treat. This trial is registered, number ISRCTN69812316., Findings: Between Nov 9, 2000, and Dec 22, 2009, 1620 patients were assigned to study groups (528 to levodopa, 632 to dopamine agonist, 460 to MAOBI). With 3-year median follow-up, PDQ-39 mobility scores averaged 1·8 points (95% CI 0·5-3·0, p=0·005) better in patients randomly assigned to levodopa than those assigned to levodopa-sparing therapy, with no increase or attrition of benefit during 7 years' observation. PDQ-39 mobility scores were 1·4 points (95% CI 0·0-2·9, p=0·05) better in patients allocated MAOBI than in those allocated dopamine agonists. EQ-5D utility scores averaged 0·03 (95% CI 0·01-0·05; p=0·0002) better with levodopa than with levodopa-sparing therapy; rates of dementia (hazard ratio [HR] 0·81, 95% CI 0·61-1·08, p=0·14), admissions to institutions (0·86, 0·63-1·18; p=0·4), and death (0·85, 0·69-1·06, p=0·17) were not significantly different, but the upper CIs precluded any substantial increase with levodopa compared with levodopa-sparing therapy. 179 (28%) of 632 patients allocated dopamine agonists and 104 (23%) of 460 patients allocated MAOBI discontinued allocated treatment because of side-effects compared with 11 (2%) of 528 patients allocated levodopa (p<0·0001)., Interpretation: Very small but persistent benefits are shown for patient-rated mobility scores when treatment is initiated with levodopa compared with levodopa-sparing therapy. MAOBI as initial levodopa-sparing therapy was at least as effective as dopamine agonists., Funding: UK National Institute for Health Research Health Technology Assessment Programme and UK Department of Health., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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6. Selecting deep brain stimulation or infusion therapies in advanced Parkinson's disease: an evidence-based review.
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Volkmann J, Albanese A, Antonini A, Chaudhuri KR, Clarke CE, de Bie RM, Deuschl G, Eggert K, Houeto JL, Kulisevsky J, Nyholm D, Odin P, Østergaard K, Poewe W, Pollak P, Rabey JM, Rascol O, Ruzicka E, Samuel M, Speelman H, Sydow O, Valldeoriola F, van der Linden C, and Oertel W
- Subjects
- Apomorphine administration & dosage, Carbidopa administration & dosage, Drug Administration Routes, Evidence-Based Practice, Humans, Levodopa administration & dosage, Antiparkinson Agents administration & dosage, Deep Brain Stimulation, Parkinson Disease therapy
- Abstract
Motor complications in Parkinson's disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more continuous dopaminergic stimulation by adjusting oral medication fail, patients may be candidates for one of three device-aided therapies: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or continuous duodenal/jejunal levodopa/carbidopa pump infusion (DLI). These therapies differ in their invasiveness, side-effect profile, and the need for nursing care. So far, very few comparative studies have evaluated the efficacy of the three device-aided therapies for specific motor problems in advanced PD. As a result, neurologists currently lack guidance as to which therapy could be most appropriate for a particular PD patient. A group of experts knowledgeable in all three therapies reviewed the currently available literature for each treatment and identified variables of clinical relevance for choosing one of the three options such as type of motor problems, age, and cognitive and psychiatric status. For each scenario, pragmatic and (if available) evidence-based recommendations are provided as to which patients could be candidates for either DBS, DLI, or subcutaneous apomorphine.
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- 2013
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7. Helicobacter pylori eradication for Parkinson's disease.
- Author
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Rees K, Stowe R, Patel S, Ives N, Breen K, Clarke CE, and Ben-Shlomo Y
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- Antiparkinson Agents pharmacokinetics, Helicobacter Infections epidemiology, Humans, Levodopa pharmacokinetics, Parkinson Disease metabolism, Randomized Controlled Trials as Topic, Anti-Bacterial Agents therapeutic use, Antiparkinson Agents therapeutic use, Helicobacter Infections drug therapy, Helicobacter pylori, Levodopa therapeutic use, Parkinson Disease drug therapy
- Abstract
Background: Levodopa is the mainstay of treatment for alleviating the motor symptoms associated with Parkinson's disease. However, patients often experience fluctuations in their symptoms over time and 'wearing off' which may be partly related to variable absorption of the drug. There is some evidence that treatment of the common gastrointestinal infection Helicobacter pylori (H pylori) with antibiotics may improve levodopa absorption in the gut and hence improve symptoms., Objectives: 1) What is the prevalence of H pylori in Parkinson's disease patients? 2) Does treatment of H pylori infection with antibiotics improve symptoms in Parkinson's disease patients? Is this effect dependent on improvements in the absorption of levodopa?, Search Methods: We searched electronic databases (including CENTRAL, MEDLINE, EMBASE, PsycINFO and CINAHL) and trial registers, handsearched conference proceedings and carried out citation searching on key articles. All searching was updated in August 2009. We contacted authors to provide additional information where necessary., Selection Criteria: Clinical trials in patients with a well-defined definition of Parkinson's disease and who were H pylori-positive. Two people independently selected studies for inclusion using predetermined criteria. We used recruitment figures from clinical trials and other studies identified from the searching to determine the prevalence of H pylori in Parkinson's disease., Data Collection and Analysis: Two authors abstracted data from the source papers and assessed methodological quality independently. We presented results descriptively., Main Results: Two completed and one ongoing clinical trial met the inclusion criteria. One trial (34 patients randomised) examined the effects of H pylori eradication on levodopa absorption and motor symptoms and found significant improvements in both. The ongoing trial has similar objectives and aims to recruit 100 patients. The other completed trial (20 patients analysed) sought to find a causal link between infection with H pylori and Parkinsonism and was non-contributory. A worsening of symptoms was noted with eradication failure.The prevalence of H pylori in Parkinson's disease was reported in four studies and ranged from 37% to 59% which is similar to that of the general population., Authors' Conclusions: There is currently a lack of evidence on the effects of screening and treating H pylori in patients with Parkinson's disease. There is limited evidence to suggest that H Pylori eradication improves the absorption of levodopa and improves motor symptoms. Results from an ongoing trial will inform the evidence base and will be incorporated in an update of this review. There is a need for well-conducted randomised controlled trials with standard outcome measures for motor symptoms and incorporating the costs of screening and treatment.
- Published
- 2011
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8. Should treatment for Parkinson's disease start immediately on diagnosis or delayed until functional disability develops?
- Author
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Clarke CE, Patel S, Ives N, Rick C, Wheatley K, and Gray R
- Subjects
- Early Diagnosis, Humans, Parkinson Disease physiopathology, Antiparkinson Agents therapeutic use, Disability Evaluation, Parkinson Disease diagnosis, Parkinson Disease drug therapy, Watchful Waiting methods
- Abstract
Background: Evidence from clinical trials with monoamine oxidase type B inhibitors (TEMPO, ADAGIO and DATATOP) and levodopa (ELLDOPA) suggests that Parkinson's disease patients may benefit from treatment being commenced immediately on diagnosis rather than waiting for functional disability to develop, as is traditional clinical practice., Methods: We performed a narrative literature review and meta-analysis of delayed-start design trials in Parkinson's disease., Results: There was inconsistency in the results of the two rasagiline delayed-start design trials, with early treatment with a 2 mg dose significantly superior in the TEMPO trial, but the 1 mg dose significantly better in the ADAGIO trial, making interpretation difficult. Further, the benefits of immediate treatment were small in terms of total unified Parkinson's disease rating scale scores, with a mean difference of 0.91 units (95% confidence interval 0.01, 1.80; P = 0.05) in a meta-analysis of the TEMPO and ADAGIO delayed-start design trials. Such small differences are unlikely to be of clinical relevance. There is also little information on whether immediate treatment has a beneficial effect on patient quality of life with an acceptable adverse reaction profile, and we have no data on whether immediate treatment is cost-effective., Discussion: Based on the evidence available, changing clinical practice to immediate therapy on diagnosis is not warranted and further trials are needed., (Copyright © 2010 Movement Disorder Society.)
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- 2011
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9. Meta-analysis of the comparative efficacy and safety of adjuvant treatment to levodopa in later Parkinson's disease.
- Author
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Stowe R, Ives N, Clarke CE, Handley K, Furmston A, Deane K, van Hilten JJ, Wheatley K, and Gray R
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- Clinical Trials as Topic, Disability Evaluation, Enzyme Inhibitors therapeutic use, Humans, Treatment Outcome, Adjuvants, Pharmaceutic therapeutic use, Antiparkinson Agents therapeutic use, Levodopa therapeutic use, Parkinson Disease drug therapy
- Abstract
Background: Levodopa initially provides good symptomatic control of the symptoms of Parkinson's disease, but motor complications often develop after long-term use. Other classes of antiparkinsonian drugs including dopamine agonists, catechol-O-methyl transferase inhibitors, or monoamine oxidase type B inhibitors are then added as adjuvant therapy. It is unclear whether one class of drug is more effective than another. This meta-analysis evaluates the comparative benefits and risks of these agents as adjuvant treatment in Parkinson's disease patients with motor complications., Methods: A systematic review of the literature from 1966 to the end of June 2010 was conducted to identify randomized trials involving a dopamine agonist, catechol-O-methyl transferase inhibitor, or monoamine oxidase type B inhibitor versus placebo, as adjuvant to levodopa therapy., Results: Forty-five trials involving nearly 9,000 participants were included. The meta-analysis confirms reports from individual trials that compared with placebo, adjuvant therapy significantly reduces patient off-time and levodopa dose, with improved symptom severity scores (e.g., Unified Parkinson's Disease Rating Scale). However, dyskinesia and numerous other side effects are increased with adjuvant therapy. Few randomized comparisons between drugs have been undertaken, but indirect comparisons suggest that dopamine agonist therapy may be more effective than catechol-O-methyl transferase inhibitor and monoamine oxidase type B inhibitor therapy, which have comparable efficacy. No differences between drugs within each class were observed other than the catechol-O-methyl transferase inhibitor tolcapone appearing more efficacious than entacapone., Discussion: This meta-analysis highlights the need for direct head-to-head randomized trials to assess the impact of adjuvant therapy on patient-rated quality of life and health economic outcomes., (Copyright © 2011 Movement Disorder Society.)
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- 2011
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10. Evaluation of the efficacy and safety of adjuvant treatment to levodopa therapy in Parkinson s disease patients with motor complications.
- Author
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Stowe R, Ives N, Clarke CE, Deane K, Wheatley K, Gray R, Handley K, and Furmston A
- Subjects
- Antiparkinson Agents adverse effects, Chemotherapy, Adjuvant, Dopamine Agonists adverse effects, Dyskinesias etiology, Humans, Levodopa therapeutic use, Monoamine Oxidase Inhibitors adverse effects, Parkinson Disease complications, Randomized Controlled Trials as Topic, Antiparkinson Agents therapeutic use, Catechol O-Methyltransferase Inhibitors, Dopamine Agonists therapeutic use, Dyskinesias drug therapy, Monoamine Oxidase Inhibitors therapeutic use, Parkinson Disease drug therapy
- Abstract
Background: One of the complications of long-term treatment of Parkinson's disease (PD) with levodopa is the development of motor complications. Generally, when motor complications develop, clinicians add in an additional drug (to the levodopa regimen) from one of three other classes of anti-Parkinsonian treatments (dopamine agonists, catechol-O-methyl transferase inhibitors (COMTIs) or monoamine oxidase type B inhibitors (MAOBIs)). However, despite trials having shown that these drugs are beneficial compared to placebo, it remains unclear as to the best way to treat patients experiencing motor complications and whether one class of drug is more effective than another., Objectives: This meta-analysis aims to assess more reliably the benefits and risks of the three classes of drugs (dopamine agonists, COMTIs and MAOBIs) currently used as adjuvant treatment to levodopa in PD patients suffering from motor complications. The three drug classes were compared with the aim of determining whether one class of drug provides better symptomatic control than another., Search Strategy: We searched CENTRAL (The Cochrane Library), MEDLINE, EMBASE, PubMed, LILACS and Web of Science, plus major journals in the field, abstract books, conference proceedings and reference lists of retrieved publications., Selection Criteria: Randomised trials comparing an orally administered dopamine agonist, COMTI or MAOBI versus placebo, both on a background of levodopa therapy, in PD patients experiencing motor complications., Data Collection and Analysis: Two authors independently extracted data on off-time, levodopa dose, motor complications, side-effects, treatment concordance, clinician-rated disability, mortality, quality of life and health economic data., Main Results: Forty-four eligible trials, involving 8436 participants were identified. Compared to placebo, adjuvant therapy significantly reduced off-time (-1.05 hours/day, 95% confidence interval (CI) -1.19 to -0.90; P<0.00001), the required levodopa dose (-55.65 mg/day, CI -62.67 to -48.62; P<0.00001) and improved UPDRS scores (UPDRS ADL score: -1.31 points, CI -1.62 to -0.99; P<0.00001; UPDRS motor score: -2.84 points, CI -3.36 to -2.32; P<0.00001; UPDRS total score: -3.26 points, CI -4.52 to -2.00; P<0.00001). However, dyskinesia (odds ratio (OR) 2.50, CI 2.21 to 2.84; P<0.00001) and side-effects including constipation (OR 3.19, CI 2.17 to 4.68; P<0.00001), dizziness (OR 1.57, CI 1.30 to 1.90; P<0.00001), dry mouth (OR 2.33, CI 1.22 to 4.47; P=0.01), hallucinations (OR 2.16, CI 1.70 to 2.74; P<0.00001), hypotension (OR 1.47, CI 1.18 to 1.83; P=0.0007), insomnia (OR 1.38, CI 1.09 to 1.74; P=0.007), nausea (OR 1.78, CI 1.53 to 2.07; P<0.00001), somnolence (OR 1.87, CI 1.40 to 2.51; P<0.0001) and vomiting (OR 2.56, CI 1.67 to 3.93; P<0.0001) were all increased with adjuvant therapy.Indirect comparisons of the three drug classes suggested that dopamine agonists were more efficacious in reducing off-time (dopamine agonist: -1.54 hours/day; COMTI: -0.83 hours/day; MAOBI: -0.93 hours/day; test for heterogeneity between drug classes P=0.0003) and levodopa dose (dopamine agonist: -116 mg/day; COMTI: -52 mg/day; MAOBI: -29 mg/day; test for heterogeneity between drug classes P<0.00001). UPDRS scores also improved more with dopamine agonists than with COMTI or MAOBI (UPDRS total scores - dopamine agonist: -10.01 points versus COMTI: -1.46 points versus MAOBI: -2.20 points; test for heterogeneity between drug classes P<0.00001), although more dyskinesia were seen with dopamine agonists (OR 2.70) and COMTI (OR 2.50) than with MAOBI (OR 0.94) (test for heterogeneity between drug classes P=0.009). Although the increase in the overall incidence of side-effects was generally more marked with dopamine agonists (OR 1.52) and COMTI (OR 2.0) than with MAOBI (OR 1.32), heterogeneity between drug classes was only of borderline significance (P=0.07)., Authors' Conclusions: Compared to placebo, adjuvant therapy reduces off-time, levodopa dose, and improves UPDRS scores in PD patients who develop motor complications on levodopa therapy. However, this is at the expense of increased dyskinesia and numerous other side-effects. Indirect comparisons suggest that dopamine agonist therapy may be more effective than COMTI and MAOBI therapy, which have comparable efficacy. However, as indirect comparisons should be interpreted with caution, direct head-to-head randomised trials assessing the impact of these different drug classes on overall patient-rated quality of life are needed.
- Published
- 2010
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11. Systematic review of apomorphine infusion, levodopa infusion and deep brain stimulation in advanced Parkinson's disease.
- Author
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Clarke CE, Worth P, Grosset D, and Stewart D
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- Humans, Parkinson Disease drug therapy, Antiparkinson Agents therapeutic use, Apomorphine therapeutic use, Deep Brain Stimulation methods, Levodopa therapeutic use, Parkinson Disease therapy
- Abstract
The effectiveness of oral levodopa in complex Parkinson's disease (PD) is limited by its short half-life, and the resulting pulsatile dopaminergic stimulation leads to complex motor fluctuations and dyskinesia. Several treatments provide more continuous/less pulsatile dopaminergic stimulation by modifying the pharmacokinetics of levodopa or dopamine; however, patients with advanced disease can be refractory to these treatments. In such cases infusion therapies (apomorphine and intraduodenal levodopa) and neurosurgery (deep brain stimulation [DBS]) may be used. The purpose of this systematic review is to assess, as far as possible, the relative effectiveness of these therapies. There were no randomised controlled trials comparing the three treatment modalities or any directly comparable studies, therefore a descriptive analysis of the data was performed. Studies identified for levodopa infusion and DBS supported a significant benefit compared with best medical management in terms of improvements in the proportion of the waking day in a functional "on" state, activities of daily living and motor score. This finding was supported in observational studies for all three therapies. Adverse events were not adequately reported in the majority of included studies and it was therefore not possible to obtain a reliable tolerability profile of the different treatment options. The absence of direct comparative data means that, for the immediate future at least, treatment choices for advanced PD will be determined by clinical judgement and patient preference. There is an urgent need for well-designed clinical trials to generate reliable data to inform the clinical management of this difficult-to-treat subgroup of PD patients.
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- 2009
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12. Rotigotine transdermal patch in early Parkinson's disease: a randomized, double-blind, controlled study versus placebo and ropinirole.
- Author
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Giladi N, Boroojerdi B, Korczyn AD, Burn DJ, Clarke CE, and Schapira AH
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- Administration, Cutaneous, Antiparkinson Agents adverse effects, Dose-Response Relationship, Drug, Double-Blind Method, Endpoint Determination, Female, Humans, Male, Middle Aged, Parkinson Disease psychology, Patient Selection, Tetrahydronaphthalenes adverse effects, Thiophenes adverse effects, Antiparkinson Agents administration & dosage, Antiparkinson Agents therapeutic use, Indoles therapeutic use, Parkinson Disease drug therapy, Tetrahydronaphthalenes administration & dosage, Tetrahydronaphthalenes therapeutic use, Thiophenes administration & dosage, Thiophenes therapeutic use
- Abstract
Rotigotine is a new, non-ergot dopamine agonist formulated in a transdermal delivery system. The present study was to investigate the efficacy and safety of the rotigotine transdermal patch in the treatment of early Parkinson's disease. Patients (n = 561) were randomized to rotigotine, ropinirole, or placebo. The titration period was up to 13 weeks, and there was a minimum dose-maintenance period of 24 weeks for ropinirole and 33 weeks for rotigotine. The primary endpoint was the proportion of patients with a minimum of 20% decrease in the combined Unified Parkinson's Disease Rating Scale Part II and Part III scores. The responder rate in the rotigotine group was significantly higher than in the placebo group (52% vs. 30%, P < 0.0001). Transdermal rotigotine at doses < or =8 mg/24 h did not show noninferiority to ropinirole at doses < or =24 mg/day. In a post-hoc subgroup analysis, rotigotine < or =8 mg/24 hours had a similar efficacy to ropinirole at doses < or =12 mg/day. The rotigotine transdermal patch was well tolerated. The most common adverse events were application-site reactions, nausea, and somnolence. Application-site reactions were predominantly mild or moderate in intensity. In conclusion, the rotigotine transdermal patch represents an effective and safe option for the treatment of patients with early Parkinson's disease.
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- 2007
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13. Parkinson's disease.
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Clarke CE and Moore AP
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- Aged, Aged, 80 and over, Evidence-Based Medicine, Female, Humans, Male, Parkinson Disease physiopathology, Parkinson Disease therapy, Randomized Controlled Trials as Topic, Antiparkinson Agents therapeutic use, Levodopa therapeutic use, Parkinson Disease drug therapy
- Published
- 2007
14. Development of dyskinesias in a 5-year trial of ropinirole and L-dopa.
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Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE, and Abdalla M
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- Confidence Intervals, Drug Therapy, Combination, Dyskinesia, Drug-Induced mortality, Humans, Longitudinal Studies, Parkinson Disease drug therapy, Parkinson Disease epidemiology, Parkinson Disease mortality, Predictive Value of Tests, Proportional Hazards Models, Risk Factors, Survival Analysis, Antiparkinson Agents adverse effects, Dyskinesia, Drug-Induced etiology, Indoles adverse effects, Levodopa adverse effects
- Abstract
A 5-year trial of ropinirole and levodopa in early Parkinson's disease showed that ropinirole is associated with reduced incidence of dyskinesias. This post hoc analysis investigated whether the dyskinesia-sparing benefit of ropinirole is lost when levodopa is added to the regimen and evaluated other risk factors for developing dyskinesias. Patients receiving levodopa had a significantly higher risk of dyskinesias than those taking ropinirole monotherapy (hazard ratio [HR], 6.67; 95% confidence interval [CI], 3.23-14.29; P < 0.001). When patients randomized to ropinirole were treated with supplementary levodopa, the development of dyskinesias was not significantly different from that in those receiving levodopa from the start (HR, 0.80; 95% CI, 0.48-1.33; P = 0.39). However, the onset of dyskinesias was delayed by around 3 years compared with levodopa monotherapy. Adjusted analyses taking into account baseline and on-treatment factors that influenced use of supplementary levodopa or the development of dyskinesias produced similar results. In conclusion, the risk of developing dyskinesias during maintained initial ropinirole monotherapy is very low. Only once levodopa is added does the risk substantially change. Early use of ropinirole postpones the onset of dyskinesias, but these benefits decline when levodopa therapy is started, with no evidence of a subsequent rapid "catch-up" or a persisting preventive effect.
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- 2006
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15. Rasagiline for motor complications in Parkinson's disease.
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Clarke CE
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- Aged, Antiparkinson Agents adverse effects, Catechol O-Methyltransferase Inhibitors, Catechols administration & dosage, Catechols adverse effects, Drug Therapy, Combination, Dyskinesia, Drug-Induced etiology, Enzyme Inhibitors therapeutic use, Humans, Levodopa adverse effects, Middle Aged, Nitriles, Antiparkinson Agents administration & dosage, Dyskinesia, Drug-Induced prevention & control, Indans administration & dosage, Levodopa administration & dosage, Monoamine Oxidase Inhibitors administration & dosage, Parkinson Disease drug therapy
- Published
- 2005
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16. Monoamine oxidase type B inhibitors in early Parkinson's disease: meta-analysis of 17 randomised trials involving 3525 patients.
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Ives NJ, Stowe RL, Marro J, Counsell C, Macleod A, Clarke CE, Gray R, and Wheatley K
- Subjects
- Antiparkinson Agents adverse effects, Humans, Levodopa therapeutic use, Monoamine Oxidase Inhibitors adverse effects, Psychomotor Disorders chemically induced, Randomized Controlled Trials as Topic, Antiparkinson Agents therapeutic use, Monoamine Oxidase Inhibitors therapeutic use, Parkinson Disease drug therapy
- Abstract
Objective: To quantify more reliably the benefits and risks of monoamine oxidase type B inhibitors (MAOBIs) in early Parkinson's disease., Data Sources: Searches of the Cochrane Library, Medline, Embase, PubMed, and Web of Science for years 1966-2003, plus major journals in the field, abstract books, and proceedings of meetings, for randomised trials comparing MAOBIs with placebo or levodopa., Data Extraction: Available data on mortality, motor complications, side effects, treatment compliance, and clinician rated disability (for example, unified Parkinson's disease rating scale) were extracted from 17 trials and combined using standard meta-analytic methods., Results: No significant difference in mortality existed between patients on MAOBIs and control patients (odds ratio 1.13, 95% confidence interval 0.94 to 1.34; P = 0.2). Patients randomised to MAOBIs had significantly better total scores, motor scores, and activities of daily living scores on the unified Parkinson's disease rating scale at three months compared with patients taking placebo; they were also less likely to need additional levodopa (0.57, 0.48 to 0.67; P < 0.00001) or to develop motor fluctuations (0.75, 0.59 to 0.95; P = 0.02). No difference existed between the two groups in the incidence of side effects or withdrawal of patients., Conclusions: MAOBIs reduce disability, the need for levodopa, and the incidence of motor fluctuations, without substantial side effects or increased mortality. However, because few trials have compared MAOBIs with other antiparkinsonian drugs, uncertainty remains about the relative benefits and risks of MAOBIs. Further large, long term comparative trials that include patient rated quality of life measures are needed.
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- 2004
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17. Neuroprotection and pharmacotherapy for motor symptoms in Parkinson's disease.
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Clarke CE
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- Algorithms, Animals, Clinical Trials as Topic, Dopamine metabolism, Humans, Motor Neuron Disease etiology, Motor Neuron Disease pathology, Parkinson Disease complications, Parkinson Disease pathology, Antiparkinson Agents therapeutic use, Motor Neuron Disease prevention & control, Neuroprotective Agents therapeutic use, Parkinson Disease prevention & control
- Abstract
Parkinson's disease leads to major disability that impairs the quality of life of patients and leads to increased health-care costs. While there is no proven neuroprotective treatment, more basic-science research and clinical trials are needed to identify drugs that slow or halt the progression of the disorder. The mainstay of symptomatic treatment is levodopa. With long-term use, levodopa causes motor complications including involuntary movements and response fluctuations. These have lead to more cautious prescribing of levodopa. Dopamine agonists can be used as an alternative initial therapy to delay the onset of motor complications but at the expense of more dopaminergic adverse events, poorer control of motor symptoms, and increased cost. Once motor complications have developed, adjuvant therapy with dopamine agonists or entacapone can reduce off time and levodopa dose. Severe fluctuations that are not controlled by oral combination therapy can be controlled with subcutaneous apomorphine injections or infusions.
- Published
- 2004
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18. Cabergoline versus levodopa monotherapy.
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Wheatley K, Clarke CE, Ives N, and Gray R
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- Antiparkinson Agents economics, Cabergoline, Cost-Benefit Analysis, Ergolines economics, Humans, Levodopa economics, Middle Aged, Parkinson Disease economics, Antiparkinson Agents therapeutic use, Ergolines therapeutic use, Levodopa therapeutic use, Parkinson Disease drug therapy
- Published
- 2004
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19. A "cure" for Parkinson's disease: can neuroprotection be proven with current trial designs?
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Clarke CE
- Subjects
- Brain blood supply, Brain metabolism, Cost-Benefit Analysis, Humans, Parkinson Disease diagnosis, Parkinson Disease economics, Quality of Life, Randomized Controlled Trials as Topic, Tomography, Emission-Computed, Tomography, Emission-Computed, Single-Photon, Antiparkinson Agents therapeutic use, Dopamine Agonists therapeutic use, Levodopa therapeutic use, Neuroprotective Agents therapeutic use, Parkinson Disease drug therapy, Selegiline therapeutic use
- Abstract
Current medical and surgical therapies for Parkinson's disease provide symptomatic control of motor impairments rather than slowing or halting the progression of the disease. Previous clinical trials examining drugs such as dopamine agonists and selegiline for neuroprotective effects used "surrogate" outcomes, including clinical measures (rating scales, time to require levodopa), neuroimaging techniques (beta-CIT single photon emission computed tomography; fluorodopa positron emission tomography), and mortality tracking. These studies failed to provide conclusive results because of design faults such as failing to control for symptomatic effects, small sample size, and not accounting for the possible effects of drugs on radionuclide tracer handling. Lessons must be learned from these failed neuroprotection trials. This review summarises the problems with previous neuroprotection studies and makes recommendations for future trial design. It is concluded that the primary outcome of explanatory trials should continue to be clinical measures such as the Unified Parkinson's Disease Rating Scale (UPDRS). It should be assumed that all agents have a symptomatic effect, which necessitates evaluation after a prolonged drug washout period. To achieve the evaluation after a prolonged drug washout period more effectively, trials must be performed in early disease and over a short period (6-12 months) so that symptomatic therapy is not required. To achieve adequate statistical power, these trials will need to include thousands of patients. Radionuclide imaging can only be used in such trials after considerable methodological work has been performed to establish its validity and reliability. To be affordable, such large explanatory trials need more streamlined designs with fewer hospital visits, fewer outcome measures, and rationalised safety monitoring. The clinical effectiveness of promising compounds from explanatory trials will need to be established in large long-term pragmatic trials using outcome measures such as quality of life, cost-effectiveness, and mortality. Such pragmatic trials could be continuations of the explanatory trials: after the primary outcome of the explanatory study (e.g., UPDRS) has been reported in an interim analysis, the trial could be continued for a further 5 to 10 years to report on quality of life and health economics outcomes., (Copyright 2004 Movement Disorder Society)
- Published
- 2004
- Full Text
- View/download PDF
20. Evaluating drug treatments for Parkinson's disease: how good are the trials?
- Author
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Wheatley K, Stowe RL, Clarke CE, Hills RK, Williams AC, and Gray R
- Subjects
- Catechol O-Methyltransferase therapeutic use, Dopamine Agonists therapeutic use, Follow-Up Studies, Humans, Monoamine Oxidase Inhibitors therapeutic use, Treatment Outcome, Antiparkinson Agents therapeutic use, Parkinson Disease drug therapy, Randomized Controlled Trials as Topic standards
- Published
- 2002
- Full Text
- View/download PDF
21. Parkinson's disease.
- Author
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Clarke C and Moore AP
- Subjects
- Antiparkinson Agents adverse effects, Dopamine Agonists adverse effects, Dopamine Agonists therapeutic use, Drug Therapy, Combination, Humans, Levodopa adverse effects, Levodopa therapeutic use, Neurologic Examination drug effects, Parkinson Disease diagnosis, Parkinson Disease etiology, Randomized Controlled Trials as Topic, Treatment Outcome, Antiparkinson Agents therapeutic use, Parkinson Disease drug therapy
- Published
- 2002
22. Cabergoline versus bromocriptine for levodopa-induced complications in Parkinson's disease
- Author
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Clarke, Carl E and Deane, Katherine HO
- Subjects
Antiparkinson Agents ,Levodopa ,Dyskinesia, Drug-Induced ,Cabergoline ,Dopamine Agonists ,Humans ,Parkinson Disease ,Pharmacology (medical) ,Ergolines ,Bromocriptine ,Randomized Controlled Trials as Topic - Abstract
BACKGROUND: Long term levodopa therapy in Parkinson's disease is associated with the development of motor complications including abnormal involuntary movements and a shortening response to each dose (wearing off phenomenon). It is thought that dopamine agonists can reduce the duration of immobile off periods and the need for levodopa therapy whilst maintaining or improving motor impairments and only minimally increasing dopaminergic adverse events. OBJECTIVES: To compare the efficacy and safety of adjuvant cabergoline therapy versus bromocriptine in patients with Parkinson's disease, already established on levodopa and suffering from motor complications. SEARCH METHODS: Electronic searches of MEDLINE, EMBASE and the Cochrane Controlled Trials Register. Handsearching of the neurology literature as part of the Cochrane Movement Disorders Group's strategy. Examination of the reference lists of identified studies and other reviews. Contact with Pharmacia Upjohn Limited. SELECTION CRITERIA: Randomised controlled trials of cabergoline versus bromocriptine in patients with a clinical diagnosis of idiopathic Parkinson's disease and long‐term complications of levodopa therapy. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by the authors and differences settled by discussion. The outcome measures used included Parkinson's disease rating scales, levodopa dosage, off time measurements and the frequency of withdrawals and adverse events. MAIN RESULTS: Cabergoline has been compared with bromocriptine in five randomised, double‐blind, parallel group studies including 1071 patients. Only one of the phase II studies was medium term (36 weeks), the others all being short term (12 ‐15 weeks). The non‐significant difference in off time reduction produced by cabergoline compared with bromocriptine was 0.29 hours/day in favour of the former (weighted mean difference; 95% CI ‐0.10, 0.68; p = 0.15). Dyskinesia reported as an adverse event was significantly increased with cabergoline compared with bromocriptine (Peto odds ratio 1.57; 95% CI 1.05, 2.35; p = 0.03). Motor impairment and disability were measured in four of the studies using the UPDRS rating scale but the small differences in UPDRS ADL (part II) and motor (part III) scores were not statistically significant in any study. Similarly, no significant difference in Schwab and England score was seen. The number of patients rated as much or very much improved on a clinician's global impression scale was similar with both agonists. Levodopa dose reduction was no different between cabergoline and bromocriptine. There was more confusion with cabergoline (Peto odds ratio 2.02; 95% CI 1.09, 3.76; p = 0.03). Otherwise, dopaminergic adverse events were comparable with these agonists and no significant difference in all cause withdrawal rate was found. AUTHORS' CONCLUSIONS: Cabergoline produces similar benefits to bromocriptine in off time reduction, motor impairment and disability ratings, and levodopa dose reduction over the first three months of therapy. Dyskinesia and confusion were increased with cabergoline but otherwise the frequency of adverse events and withdrawals from treatment were similar with the two agonists.
- Published
- 2001
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