Disabling orthostatic hypotension dominates the clinical picture of autonomic failure and is the cause of substantial morbidity. Most patients require pressor agents to maintain upright blood pressure above the lower threshold that overcomes cerebral blood flow autoregulation. The alpha agonist midodrine, the only agent approved for orthostatic hypotension, is not effective in a significant proportion of patients because of lack of efficacy, or intolerable side effects. It would be useful, therefore, to develop alternative pressor agents for the treatment of orthostatic hypotension. Recent findings by participants of this Rare Disease Network, revealed that patients with multiple system atrophy (Shy-Drager syndrome) have impaired central autonomic pathways crucial for autonomic cardiovascular control, but intact peripheral postganglionic noradrenergic fibers, as evidenced by the near normal levels of plasma norepinephrine and the presence of uptake of catecholamine in the heart. This latter observation implies the presence of both intact noradrenergic nerve terminals and catecholamine reuptake mechanisms. Thus, patients with multiple system atrophy have peripheral residual sympathetic tone that is unregulated by central autonomic centers or baroreflex control, but could be harnessed to improve orthostatic hypotension. Pharmacological inhibition of the norepinephrine reuptake could be used to potentiate the effects of synaptic norepinephrine present in multiple system atrophy patients and increase their blood pressure. Indeed, our proof-of-concept studies indicate that the norepinephrine transporter atomoxetine is an effective pressor agent in these patients, and acutely improves orthostatic tolerance. We now propose a two phase Clinical Trial to determine the efficacy and safety of atomoxetine in the treatment of orthostatic hypotension. Atomoxetine responders will be identified in Protocol #1 after an acute dose of atomoxetine, placebo (control) or midodrine (standard of care). In Protocol #2 atomoxetine responders will be treated with atomoxetine for 1 month in an open-label study and will then be randomized in an inpatient CRC setting to continue on atomoxetine or be given placebo, using a randomized double blind withdrawal design.
Research from members of this Consortium has shown that patients with multiple system atrophy have residual sympathetic tone, but that does not increase when they stand up and, therefore, their blood press-ure drops and they suffer from disabling fainting on standing. Our pilot studies show that we can harness this residual sympathetic tone with atomoxetine, which potentiates the effects of the body's on noradrenaline, and now propose a clinical trial to show the effectiveness of this novel treatment.
|Arnold, Amy C; Okamoto, Luis E; Gamboa, Alfredo et al. (2016) Mineralocorticoid Receptor Activation Contributes to the Supine Hypertension of Autonomic Failure. Hypertension 67:424-9|
|Palma, Jose-Alberto (2016) Not all dysautonomias are created equal. Clin Auton Res 26:83|
|Loavenbruck, Adam J; Singer, Wolfgang; Mauermann, Michelle L et al. (2016) Transthyretin amyloid neuropathy has earlier neural involvement but better prognosis than primary amyloid counterpart: an answer to the paradox? Ann Neurol 80:401-11|
|Okamoto, Luis E; Diedrich, AndrÃ©; Baudenbacher, Franz J et al. (2016) Efficacy of Servo-Controlled Splanchnic Venous Compression in the Treatment of Orthostatic Hypotension: A Randomized Comparison With Midodrine. Hypertension 68:418-26|
|GutiÃ©rrez, Joel V; Norcliffe-Kaufmann, Lucy; Kaufmann, Horacio (2016) Brainstem reflexes in familial dysautonomia. Reply to ""Evidence of brainstem dysfunction in patients with familial dysautonomia and carriers of the IKBKAP mutation"". Clin Neurophysiol 127:1749-50|
|LabbÃ©, Catherine; Heckman, Michael G; Lorenzo-Betancor, Oswaldo et al. (2016) MAPT haplotype diversity in multiple system atrophy. Parkinsonism Relat Disord 30:40-5|
|Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto; Kaufmann, Horacio (2016) Mother-induced hypertension in familial dysautonomia. Clin Auton Res 26:79-81|
|Merkel, Peter A; Manion, Michele; Gopal-Srivastava, Rashmi et al. (2016) The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis 11:66|
|Palma, Jose-Alberto; Norcliffe-Kaufmann, Lucy; Kaufmann, Horacio (2016) An orthostatic hypotension mimic: The inebriation-like syndrome in Parkinson disease. Mov Disord 31:598-600|
|Norcliffe-Kaufmann, Lucy; Kaufmann, Horacio; Martinez, Jose et al. (2016) Autonomic Findings in Takotsubo Cardiomyopathy. Am J Cardiol 117:206-13|
Showing the most recent 10 out of 114 publications