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  • br Discussion Previous studies have reported conflicting ass


    Discussion Previous studies have reported conflicting association results between the functional variant DBH −1021C>T and PD [8], [9]. Our findings would suggest that DBH −1021C>T does not dramatically decrease the risk of disease although it may marginally affect symptomatic AAO. However, whether AAO is relevant to the majority of patients is still debatable. The vast majority of patients have an AAO that falls within the 55–75 years of age category; therefore, to truly assess AAO as a disease trait requires a large series of patients aged <40 years and >80 years. Evidence from studies of familial and apparent monogenic forms of PD have also shown that AAO can greatly vary between affected family members with the same mutation. The DBH gene is located on chromosome 9q34.2, a region which has not been previously implicated in PD, neither by linkage nor association, see[11]. A combined analysis (n=6984) of our results with the data of Healy et al. and Chun et al. do not support a role for DBH −1021C>T in susceptibility to PD. These studies, however, have only examined this one SNP in the DBH gene and, therefore, we cannot rule out the possibility of other variants at this locus affecting susceptibility to PD. To date, identification and consistent association of risk factors in PD have been revealed through linkage studies of familial forms of autosomal dominantly inherited parkinsonism (SNCA and LRRK2). Therefore, further pedigree-based linkage studies may be the best approach to identifying variants which affect susceptibility to sporadic PD and related neurodegenerative disorders.
    Introduction The activation of the sympathetic nervous system, which involves increased spillover of noradrenaline in specific organs such as the keap1 nrf2 and kidney, plays a major role in hypertension1, 2, 3 and congestive heart failure physiopathology,4, 5 and is associated with increased mortality.6, 7, 8 The use of adrenoceptor blockers to inhibit the sympathetic drive has been shown to be a valuable therapeutic approach in such diseases, but can cause hemodynamic deterioration in some patients, especially in heart failure. Alternative strategies include inhibition of dopamine β-hydroxylase (DβH), which has the merit to cause gradual sympathetic slowdown instead of acute inhibition.10, 11 It also increases the availability of dopamine12, 13 and improves renal function by causing renal vasodilatation and inducing diuresis and natriuresis.14, 15, 16 Etamicastat (also known as BIA 5-453) is a new-generation DβH inhibitor in development as a new putative drug therapy for cardiovascular disorders. Etamicastat is a reversible DβH, has limited access to the brain, and acts mainly at the periphery by decreasing noradrenaline levels in sympathetically innervated tissues.17, 18 Etamicastat has been shown to reduce both systolic blood pressure (SBP) and diastolic BP (DBP), alone or in combination with other antihypertensive drugs, and to reduce noradrenaline urinary excretion in spontaneously hypertensive rats, while no changes in blood pressure were reported in normotensive Wistar-Kyoto rats.19, 20, 21 No significant changes in heart rate (HR) were found following etamicastat administration in spontaneously hypertensive rats and Wistar-Kyoto rats. In male cardiomyopathic hamsters (Bio TO-2 dilated strain) with advanced congestive heart failure, etamicastat increased survival rates. The safety and pharmacokinetic profiles of etamicastat have been investigated in healthy subjects. Etamicastat was well tolerated and showed approximate linear pharmacokinetics following single oral doses in the range 2 to 1200 mg and multiple once-daily oral doses in the range 25 to 600 mg. The presence of food caused a 28% decrease in etamicastat Cmax and a 4% decrease in AUC0–∞. The delay in absorption and decrease in peak exposure of etamicastat was considered not clinically significant; therefore, etamicastat can be administered without regard to meals. Following single and repeated 100-mg keap1 nrf2 once-daily dosing of etamicastat, no significant differences were observed in elderly versus young healthy subjects.