project 2 - Autonomic Rare Diseases Clinical Research Consortium

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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.