Drug therapy for Parkinson's disease: An update

Parkinson's disease(PD) is the most common neurodegenerative movement disorder, affecting about 1% of the population above the age of 65. PD is characterized by a selective degeneration of the dopaminergic neurons of the substantia nigra pars compacta. This results in a marked loss of striatal dopamine and the development of the characteristic features of the disease, i.e., bradykinesia, rest tremor, rigidity, gait abnormalities and postural instability. Other types of neurons/neurotransmitters are also involved in PD, including cholinergic, serotonergic, glutamatergic, adenosine, and GABAergic neurotransmission which might have relevance to the motor, non-motor, neuro-psychiatric and cognitive disturbances that occur in the course of the disease. The treatment of PD relies on replacement therapy with levodopa(L-dopa), the precursor of dopamine, in combination with a peripheral decarboxylase inhibitor(carbidopa or benserazide). The effect of L-dopa, however, declines over time together with the development of motor complications especially dyskinesia in a significant proportion of patients within 5 years of therapy. Other drugs include dopaminereceptor-agonists, catechol-O-methyltransferase inhibitors, monoamine oxidase type B(MAO-B) inhibitors, anticholinergics and adjuvant therapy with the antiviral drug and the N-methyl-D-aspartate glutamate receptor antagonist amantadine. Although, these medications can result in substantial improvements in parkinsonian symptoms, especially during the early stages of the disease, they are often not successful in advanced disease. Moreover, dopaminergic cell death continues over time, emphasizing the need for neuroprotective or neuroregenerative therapies. In recent years, research has focused on non-dopaminergic approach such as the use of A2 A receptor antagonists: istradefylline and preladenant or the calcium channel antagonist isradipine. Safinamide is a selective and reversible inhibitor of MAO-B, a glutamate receptor inhibitor as well as sodium and calcium channel blocker. Minocycline and pioglitazone are other agents which have been shown to prevent dopaminergic nigral cell loss in animal models of PD. There is also an evidence to suggest a benefit from iron chelation therapy with deferiprone and from the use of antioxidants or mitochondrial function enhancers such as creatine, alpha-lipoic acid, l-carnitine, and coenzyme Q10.

Clinical characteristics of fatigued Parkinson’s patients and the response to dopaminergic treatment

Background:Fatigue,which is commonly observed in Parkinson’s disease(PD),can greatly reduce quality of life and is difficult to treat.We here aimed to investigate the prevalence and characteristics of fatigue among PD patients and to explore an effective strategy to treat PD fatigue.Method:This was an observational cross-sectional study conducted in northeastern China.We examined fatigue in 222 PD patients from northeastern China using the Parkinson Fatigue Scale-16(PFS-16).The disease severity,depression,sleep and cognitive functioning were assessed with the Hoehn&Yahr staging(H-Y stage),Unified Parkinson’s Disease Rating Scale(UPDRS),Hamilton Depression Scale(HAMD),Parkinson’s Disease Sleep Scale(PDSS)and Montreal Cognitive Assessment(MoCA)by interview.Results:The frequency of fatigue in PD patients was 59.46%.Fatigued patients had longer disease durations and greater disease severity than nonfatigued patients.Additionally,fatigued PD patients scored significantly higher for all motor symptoms,except for tremor,and had more serious depressive symptoms and sleep disturbances than nonfatigued PD patients did.The sleep disturbance severity was an independent factor for fatigue.Furthermore,43.04% of fatigued patients taking dopaminergic drugs had fatigue remission.Depression severity was identified as an independent factor for dopaminergic drug non-responsive fatigue.Conclusions:PD patients with severe sleep disturbances tend to suffer from fatigue.Levodopa improved fatigue only in PD patients with mild depression or no depression,implying that dopaminergic medication is required,but not sufficient,for fatigue suppression in PD patients with moderate or severe depression.Thus,restoring serotonergic neurotransmission as a combination therapy may offer a better strategy for the treatment of fatigue in these patients.