Brasofensine Sulfate

Pharmacological treatment of Parkinson's disease (PD) is entering a new and exciting era. Real promise now exists for the clinical application of a large range of molecules in development that will combat different aspects and stages of the condition. These include methyl- and ethyl-esterified forms of L-dopa (etilevodopa and melevodopa), inhibitors of enzymes such as monoamine oxidase type-B (eg, rasagiline), catechol-O-methyl transferase (eg, BIA-3202) and the monoamine re-uptake mechanism (eg, brasofensine). In addition, a range of full and partial dopamine agonists (eg, sumanirole, piribedil and BP-897) and their new formulations, for example, patch delivery systems (eg, rotigotine) are being developed. We also highlight non-dopaminergic treatments that will have wide ranging applications in the treatment of PD and L-dopa-induced dyskinesia. These include alpha2 adrenergic receptor antagonists (eg, fipamezole), adenosine A2A receptor antagonists (eg, istradefylline), AMPA receptor antagonists (eg, talampanel), neuronal synchronization modulators (eg, levetiracetam) and agents that interact with serotonergic systems such as 5-hydroxytryptamine (5-HT)1A agonists (eg, sarizotan) and 5-HT2A antagonists (eg, quetiapine). Lastly, we examine a growing number of neuroprotective agents that seek to halt or even reverse disease progression. These include anti-apoptotic kinase inhibitors (eg, CEP-1347), modulators of mitochondrial function (eg, creatine), growth factors (eg, leteprinim), neuroimmunophilins (eg, V-10367), estrogens (eg, MITO-4509), c-synuclein oligomerization inhibitors (eg, PAN-408) and sonic hedgehog ligands.

The common marmoset develops motor deficits after MPTP treatment and exhibits dyskinesia after chronic levodopa (L‐dopa) dosing and subsequent re‐challenge with L‐dopa and other dopaminergic agents. We report on the actions of the potent monoamine reuptake blocker brasofensine on motor disability, locomotor activity, and dyskinesia in the 1‐methyl‐4‐1, 2,3,6‐tetrahydropyridine (MPTP) ‐treated marmoset model of Parkinson's disease. Oral administration of brasofensine (0.25, 0.5, 1.0, or 2.5 mg/kg) to MPTP‐treated marmosets produced a long‐lasting, dose‐dependent increase in locomotor activity and reduction in disability scores. In addition, coadministration of the lowest dose of brasofensine (0.25 mg/kg orally) with a threshold oral dose of L‐dopa (2.5 mg/kg) caused a marked increase in locomotor activity, greater than that produced by either drug alone. In other MPTP‐treated marmosets previously primed to exhibit dyskinesia by repeated L‐dopa dosing, brasofensine effectively reversed akinesia with a naturalistic and prolonged motor response without the appearance of dyskinesia or stereotypy. This finding contrasts with the severe dyskinesia, stereotypy, and hyperkinesis produced by equivalent doses of L‐dopa. The ability of brasofensine to produce a prolonged and naturalistic antiparkinsonian response without eliciting dyskinesia after previous L‐dopa priming may relate to actions on D1 receptor‐linked pathways. These findings suggest that monoamine reuptake blockade may be of value in the treatment of Parkinson's disease, both early in the disease course and when L‐dopa–induced dyskinesias complicate treatment. © 2002 Movement Disorder Society