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Drug therapy
Published in Jeremy Playfer, John Hindle, Andrew Lees, Parkinson's Disease in the Older Patient, 2018
It is increasingly apparent that the key to reducing motor complications is continuous dopaminergic stimulation.85 The major advantage of dopamine agonists is their longer half-life and it is likely that this pharmacokinetic parameter is more important than any putative neuroprotection. The short half-life of levodopa and its erratic absorption leads to pulsatile stimulation of the dopaminergic receptors in the striatum, and in long-term use this causes compensatory dysregulation in the glutaminergic striatal medium spiny neurones. If this can be avoided from an early stage in management, the late motor complications are likely to be reduced. This is now established beyond reasonable doubt in animal studies.55 There is a variety of new systems of delivering continuous dopaminergic stimulus either based on levodopa or on dopamine agonists in development. Particularly exciting are the slower-release forms of dopamine agonists such as ropinirole.75 The STRIDE study using Stalevo™ will decide whether L-Dopa plus COMT-inhibition as initial therapy can achieve reduction in motor complications. Several smart dopamine agonists which have actions on other neurotransmitters are in development and offer promise of ameliorating non-motor complications. I suspect that most of the new drug developments in the next ten years will be drugs which modify non-dopaminergic pathways. Current active research areas include glutaminergic, serotonergic, adrenergic and adenosine A2A receptor modulation. Agents such as adenosine A2A receptor antagonists are already at a late stage of development. A2A receptors modulate the release of GABA.86 These drugs have downstream effects on both cholinergic and dopaminergic systems. The animal models show promise that this class of drug is useful in reducing motor complications. Istradefylline is a novel adenosine A2A receptor antagonist that has reached phase 3 clinical trials.87
Istradefylline, an adenosine A2a receptor antagonist, inhibits the CD4+ T-cell hypersecretion of IL-17A and IL-8 in humans
Published in Immunological Medicine, 2022
Mieko Tokano, Masaaki Kawano, Rie Takagi, Sho Matsushita
Adenosine binds to the adenosine receptors expressed on the cell surface. There are four subtypes of adenosine receptors (A1, A2a, A2b, and A3), all of which belong to the G protein-coupled receptor family. A2aR and A2bR signal the Gs protein, whereas A1R and A3R signal the Gi protein [1]. A1R, A2bR, and A3R are widely expressed in vivo, whereas A2aR is expressed at high levels in only a few regions of the body, such as the striatum, olfactory tubercle, nucleus accumbens, endothelial cells, vascular smooth muscle cells, platelets, and immune cells [2]. A1R and A2aR are high-affinity receptors, whereas A2bR and A3R are low-affinity receptors [3,4]. Adenosine also plays a role as a neurotransmitter [5], and istradefylline is a selective A2aR antagonist used for the treatment of Parkinson's disease [6]. Adenosine is also a potent endogenous regulator of inflammation and immune reactions [1]. However, the molecular mechanisms underlying these effects are largely unknown. In a previous study, adenosine was reported to induce T-helper (Th)17 differentiation by activating A2bR [7].
Istradefylline – a first generation adenosine A2A antagonist for the treatment of Parkinson’s disease
Published in Expert Review of Neurotherapeutics, 2021
Peter Jenner, Akihisa Mori, Stephen D. Aradi, Robert A. Hauser
The introduction of istradefylline as a first-in-class drug for use in PD has opened a new era in the pharmacological treatment of the illness. With this comes the promise of a change in expectations of the outcome of therapy and a lessening of side-effect potential that will be seen over the next 5 years – as a non-dopaminergic approach avoids the inevitability of the classic dopaminergic profile. In particular, it is evident that istradefylline has a favorable risk-benefit profile since the safety and adverse event profiles of the drug are unremarkable. The long and slow development of istradefylline has also yielded valuable lessons on how to develop a novel non-dopaminergic molecule for PD and shown that this should not necessarily follow the classic pathway used for dopaminergic therapies as these do not encompass the pharmacology and range of action specific to adenosine A2A antagonists. These experiences will guide the design of clinical trials for other novel molecules in PD and may of necessity lead to a change in the requirements and expectations of regulatory authorities.
Efficacy of istradefylline for gait disorders with freezing of gait in Parkinson’s disease: A single-arm, open-label, prospective, multicenter study
Published in Expert Opinion on Pharmacotherapy, 2019
Mutsumi Iijima, Satoshi Orimo, Hiroo Terashi, Masahiko Suzuki, Akito Hayashi, Hideki Shimura, Hiroshi Mitoma, Kazuo Kitagawa, Yasuyuki Okuma
Clinical studies have shown the benefit and tolerability of istradefylline in PD patients with motor complications on levodopa therapy. Patients administered once-daily 20 or 40 mg istradefylline showed a significant reduction in daily OFF time compared with placebo [16–20], with dyskinesia [16,17] or nausea [18] being the most common adverse events (AEs). More recently, a long-term phase 3 study of 308 PD patients with wearing-off symptoms on levodopa therapy reported that 20 mg/day istradefylline (with/without dose adjustment to 40 mg/day) promoted a significantly sustained reduction in OFF time and was well tolerated, although frequent AEs included nasopharyngitis and dyskinesia [19].