Selegiline delays the onset of disability in de novo parkinsonian patients

Pålhagen, Sven; Heinonen, Esa; Hägglund, Jarl V.; Kaugesaar, T; Kontants, H; Mäki-Ikola, O; Palm, R.; Turunen, J.

doi:10.1212/wnl.51.2.520

Cited by 137 publications

(83 citation statements)

References 7 publications

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“…9 In early PD, treatment with MAO-B inhibitors such as (R)-depenyl allows for a reduction in levodopa and dopamine agonist doses and delays the emergence of disabilities that require the initiation of levodopa therapy (Table 2). 79,80 It should be noted that both MAO-A and MAO-B contribute to oxidation of dopamine in the primate brain. Even though MAO-A activity is much lower than MAO-B activity in the striatum, the extent by which the MAO-A selective inactivator (i.e., clorgyline) enhances the elevation of dopamine levels in the striatum of primates treated with levodopa, it is similar to that obtained with (R)-deprenyl.…”

Section: Mao-b Inhibitors In the Symptomatic Treatment Of Pdmentioning

confidence: 99%

“…89 Furthermore, the expression of ADH was found to be reduced in the 2. Allow for the reduction of levodopa and dopamine agonist dose 79,80 3. Delay the emergence of disability that require levodopa treatment 79,80 4.…”

Section: Mao-b Inhibitors and Neuroprotectionmentioning

confidence: 99%

“…Allow for the reduction of levodopa and dopamine agonist dose 79,80 3. Delay the emergence of disability that require levodopa treatment 79,80 4. Enhance the motor restorative effects of dopamine agonists substantia nigra of PD patients.…”

Section: Mao-b Inhibitors and Neuroprotectionmentioning

confidence: 99%

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Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

et al. 2009

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Summary:Inadequacies of the current pharmacotherapies to treat Parkinson's disease (PD) have prompted efforts to identify novel drug targets. The adenosine A 2A receptor is one such target. Antagonists of this receptor (A 2A antagonists) are considered promising agents for the symptomatic treatment of PD. Evidence suggests that A 2A antagonists may also have neuroprotective properties that may prevent the development of the dyskinesia that often complicates levodopa treatment. Because the therapeutic benefits of A 2A antagonists are additive to that of dopamine replacement therapy, it may be possible to reduce the dose of the dopaminergic drugs and therefore the occurrence of side effects. Inhibitors of monoamine oxidase (MAO)-B also are considered useful tools for the treatment of PD. When used in combination with levodopa, inhibitors of MAO-B may enhance the elevation of dopamine levels after levodopa treatment, particularly when used in early stages of the disease when dopamine production may not be so severely compromised. Furthermore, MAO-B inhibitors may also possess neuroprotective properties in part by reducing the damaging effect of dopamine turnover in the brain. These effects of MAO-B inhibitors are especially relevant when considering that the brain shows an age-related increase in MAO-B activity. Based on these observations, dual-target-directed drugs, compounds that inhibit MAO-B and antagonize A 2A receptors, may have value in the management of PD. This review summarizes recent efforts to develop such dual-acting drugs using caffeine as the lead compound.

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Section: Mao-b Inhibitors In the Symptomatic Treatment Of Pdmentioning

confidence: 99%

Section: Mao-b Inhibitors and Neuroprotectionmentioning

confidence: 99%

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Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

et al. 2009

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“…Previous studies29, 30, 41 support a standard deviation of 12.0 units for the change in the primary outcome, total UPDRS from baseline to 36 months. The same data suggest an average change in total UPDRS of around 4.0 points over this same time period.…”

Section: Methodsmentioning

confidence: 87%

A novel design of a Phase III trial of isradipine in early Parkinson disease (STEADY‐PD III)

Biglan

Oakes

Lang

et al. 2017

Ann Clin Transl Neurol

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ObjectiveTo describe the rationale for a novel study design and baseline characteristics of a disease‐modifying trial of isradipine 10 mg daily in early Parkinson disease (PD).Methods STEADY‐PDIII is a 36‐month, Phase 3, parallel group, placebo‐controlled study of the efficacy of isradipine 10 mg daily in 336 participants with early PD as measured by the change in the Unified Parkinson Disease Rating Scale (UPDRS) Part I‐III score in the practically defined ON state. Secondary outcome measures include clinically meaningful measures of disability progression in early PD: (1) Time to initiation and utilization of dopaminergic therapy; (2) Time to onset of motor complications; (3) Change in nonmotor disability. Exploratory measures include global measures of functional disability, quality of life, change in the ambulatory capacity, cognitive function, and pharmacokinetic analysis. Rationale for the current design and alternative design approaches are discussed.ResultsThe entire cohort of 336 participants was enrolled at 55 Parkinson Study Group sites in North America. The percentage of male participants were 68.5% with a mean age of 61.9 years (sd 9.0), mean Hoehn and Yahr stage of 1.7 (sd 0.5), mean UPDRS total of 23.1 (sd 8.6), and MoCA of 28.1 (sd 1.4).Interpretation STEADY‐PD III has a novel and innovative design allowing for the determination of longer duration benefits on clinically relevant outcomes in a relatively small cohort on top of the benefit derived from symptomatic therapy. Baseline characteristics are similar to those in previously enrolled de novo PD trials. This study represents a unique opportunity to evaluate the potential impact of a novel therapy to slow progression of PD disability and provide clinically meaningful benefits.

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“…38 This study randomized 157 de novo PD subjects between treatment arms of selegiline monotherapy (10 mg/day) or placebo in a double-blind manner. Follow-up at 5 years revealed that selegiline significantly delayed the need for starting dopaminergic treatment.…”

Section: Selegiline (Deprenyl)mentioning

confidence: 99%

Protection Against Parkinson’s Disease Progression: Clinical Experience

LeWitt

Taylor

2008

Neurotherapeutics

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Summary:Treatments with potential neuroprotective capability for Parkinson's disease (PD) have been investigated in randomized, controlled, clinical trials and other studies since the mid-1980s. Although promising leads have arisen, no therapy has been proven to halt or slow disease progression. Several large-scale studies have highlighted progress in methodology, as well as the frustrations of translating laboratory science to practical applications. This review summarizes findings from clinical trials with several classes of compounds, including monoamine oxidase-B inhibitors (selegiline, lazabemide, rasagiline), dopaminergic drugs (ropinirole, pramipexole, levodopa), antioxidant strategies (␣-tocopherol), mitochondrial energy enhancers (coenzyme Q 10 , creatine), antiapoptotic agents (TCH346, minocycline, CEP-1347), and antiglutamatergic compounds (riluzole). Beyond small-molecule pharmacology, gene therapy approaches, such as delivering neurotrophic substances (e.g., neurturin) by viral vector, are the next generation of treatment options.

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Selegiline delays the onset of disability in de novo parkinsonian patients

Cited by 137 publications

References 7 publications

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

A novel design of a Phase III trial of isradipine in early Parkinson disease (STEADY‐PD III)

Protection Against Parkinson’s Disease Progression: Clinical Experience

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