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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
Pathologies of the basal ganglia, such as Parkinson’s and Huntington’s diseases
Published in Jacques Corcos, David Ginsberg, Gilles Karsenty, Textbook of the Neurogenic Bladder, 2015
Teruyuki Ogawa, Satoshi Seki, Naoki Yoshimura, Osamu Nishizawa
It is well known that dopamine replacement therapy is the most effective for the motor dysfunction in patients with PD, but the treatment is less effective with time. Therefore, there is a demand for developing an alternative therapy that would allow the possibility of giving an equal efficacy with fewer side effects. In this regard, adenosine A2A receptor antagonists are under investigation, and preclinical and clinical studies have provided promising results.69,70 Kitta et al.71 recently reported a study to examine the effect of ZM241385, an adenosine A2A receptor antagonist, on the micturition reflex in a rat model of PD. Supraspinal administration of ZM241385 increased the intercontraction intervals (ICIs) in rats with PD induced by 6-OHDA injection into the SNpc. The increased effects of this adenosine A2A receptor antagonist were not affected by administration of a D2 dopamine receptor agonist. In addition, administration of a D1 receptor agonist increased ICIs and this effect was further increased with a subsequent administration of ZM241385; however, when administered in the reverse order, a further increase in ICI was not seen. These data indicate that D1 dopamine receptor activation can induce the partial suppression of adenosine A2A receptor-mediated excitatory mechanisms in the rat model of PD. In addition, since the loss of D1 receptor activation after dopaminergic neuronal degeneration is one of the major causes inducing bladder overactivity in PD as discussed earlier, it is possible that the reduction in D1 receptor-mediated inhibition of adenosine A2A receptor activation following degeneration of nigrostriatal dopaminergic nerves contributes at least in part to the enhancement of adenosine A2A receptor-mediated excitatory mechanisms at the brain level, resulting in bladder overactivity in the rat model of PD. Taken together, adenosine A2A receptor antagonists could be useful, as a new pharmacologic treatment for bladder overactivity in PD.
A case study of foliglurax, the first clinical mGluR4 PAM for symptomatic treatment of Parkinson’s disease: translational gaps or a failing industry innovation model?
Published in Expert Opinion on Investigational Drugs, 2020
Dario Doller, Anton Bespalov, Rob Miller, Malgorzata Pietraszek, Mikhail Kalinichev
In a press release on 27 March 2020, Lundbeck announced that the AMBLED study did not meet the primary study endpoint (reduction in OFF time) or secondary endpoint (dyskinesia). For the OFF time, the observed difference in change from baseline versus placebo was 0.27 h and 0.44 h for the 10 and 30 mg doses of foliglurax, respectively. Albeit the changes in the OFF time appear dose-dependent, the magnitude of the effect and therefore clinical significance are rather small. Indeed, the effect size observed in clinical studies with other mechanisms of action such as adenosine A2A receptor antagonist istradefylline or the NMDA receptor open channel blocker Gocovri (amantadine) was larger [86,87]. Disappointment with these results led Lundbeck to announce termination of the development program of foliglurax (https://investor.lundbeck.com/news-releases/news-release-details/lundbeck-reports-headline-results-phase-iia-ambled-study).
Therapeutic innovation in Parkinson’s disease: a 2020 update on disease-modifying approaches
Published in Expert Review of Neurotherapeutics, 2020
Daniele Colombo, Paraskevi Pnevmatikou, Elsa Melloni, Charlotte Keywood
Levodopa remains the mainstay of disease management as motor symptoms improve, by enhancing dopaminergic transmission [8,9]. Few New Chemical Entities for the treatment of PD have been launched in the last decade with the notable exceptions of Safinamide, an α-aminoamide with a double mechanism of action: inhibition of monoamino-oxidase-B (MAO-B) and inhibition of voltage-gated sodium channels in a frequency and use-dependent manner [10] and Istradefylline, an adenosine A2A receptor antagonist [11]. All treatments available on the market such as dopamine agonists, catechol-O-methyltransferase (COMT) inhibitors and MAO-B inhibitors and surgical treatments have a symptomatic effect only and a major medical need still exists, as none of them acts on the progressive neurodegeneration [12].
Chemical management of levodopa-induced dyskinesia in Parkinson’s disease patients
Published in Expert Opinion on Pharmacotherapy, 2019
Nataša Dragašević-Mišković, Igor Petrović, Iva Stanković, Vladimir S. Kostić
The theory of continuous DA stimulation has fallen out of favor for a variety of reasons and the incidence of dyskinesias has not been proven to be directly correlated with drug half-life [32]. The new concept of developing treatment should be based on the fact that changing the profile of the same drug, even with shorter half-life, can induce less motor complications. Developing treatments that can provide continuous DA delivery throughout the day in noninvasive manner will probably be one of the solutions. l-DOPA patch would be ideal since transdermal drug delivery is a patients-compliant method for delivering drugs in a continuous manner. However, l-DOPA is poorly soluble and has low permeability through the skin. Although the development of transdermal patch has to overcome these technical difficulties, there are some results in experimental animal models and recently a new transdermal formulation for l-DOPA/carbidopa combination, based on a self-assembling nano-micellar system, was presented [126]. The second line of future strategy for the development of new drugs could be based on the fact that the key molecular elements implicated in LID include interaction between DA, glutamatergic, and serotonergic receptors. Recent studies showed that combination of 5-HT1 agonist and metabotropic glutamate type 5 antagonist or adenosine A2A receptor antagonist reduced dyskinesias in the rat model and MPTP monkeys [127,128]. The synthesis of similar combinations of positive and negative modulations of different receptors could provide better antidyskinetic effect without impairment of antiparkinsonian effect.