Norepinephrine Transporter Blockade, Autonomic Failure
Norepinephrine Transporter Blockade, Autonomic Failure
Atomoxetine, a selective norepinephrine transporter (NET) blocker, increases standing blood
 pressure and improves neurogenic orthostatic hypotension (NOH)-related symptoms to a greater
 extent than midodrine, the current standard of care. Atomoxetine could be a new therapeutic
 alternative for the treatment of NOH in patients with autonomic failure, particularly those
 with multiple system atrophy (MSA).

 The proposed study consists of an open-label, dose-optimization phase followed by a
 randomized, double-blind, placebo-controlled, 2x2 crossover phase.
Inclusion Criteria:

 -  Neurogenic Orthostatic Hypotension (defined by a reduction of ≥30 mmHg drop in SBP
 within 3 minutes of standing, associated with impaired autonomic reflexes as assessed
 by autonomic function tests.

 Exclusion Criteria:

 -  Pregnancy or breastfeeding

 -  Hypersensitivity to atomoxetine (severe allergic reaction, rash, urticaria,
 anaphylaxis)

 -  Use of other norepinephrine transporter inhibitors such as Wellbutrin (Bupropion),
 Cymbalta (Duloxetine), Effexor (venlafaxine), Pristiq (desvenlafaxine), Savella
 (milnacipran)

 -  Previous history (within 14 days prior to enrollment) and current use of monoamine
 oxidase inhibitors

 -  Concomitant use of strong CYP2D6 inhibitors such as delavirdine, paroxetine,
 fluoxetine, quinidine

 -  Pre-existing sustained severe hypertension (BP 140/80 mmhg in the sitting position)

 -  Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino
 transaminase [ALT] >2 x upper limit of normal range)

 -  Impaired renal function (serum creatinine equal or more than 1.6 mg/dl)

 -  Myocardial infarction within 6 months prior to enrollment

 -  Congestive heart failure (LV hypertrophy acceptable)

 -  History of serious neurologic disease such as cerebral hemorrhage, or stroke

 -  Inability to comply with the protocol, e.g., uncooperative attitude, inability to
 return for follow-up visits, unlikelihood of completing the study, and mental
 conditions rendering the subject unable to understand the nature, scope, and possible
 consequences of the study

 -  Patients with narrow angle glaucoma

 -  Patients with or a history of pheochromocytoma