3,4 Diaminopyridine - A Promising Novel Treatment Approach to Orthostatic Hypotension (P05.204)

Abstract

Objective: To prove the hypothesis that 3,4-diaminopyridine (3,4-DAP) effectively improves blood pressure (BP) and symptoms in orthostatic hypotension (OH) with predominant effects in the upright position. Background Treatment options for OH are limited and often associated with aggravation of supine hypertension. We could recently demonstrate that acetylcholinesterase inhibition is efficacious in OH without worsening of supine hypertension, but with modest efficacy. We now hypothesized that the potassium channel blocker 3,4-DAP has similar but greater beneficial effects in patients with OH, as it should not only enhance adrenergic ganglionic neurotransmission but also neurotransmission at the adrenergic endorgan synapse, resulting in serially linked and therefore potentiated effects. Design/Methods: We studied 11 patients with neurogenic OH in a placebo-controlled patient-blinded protocol. Following a 20 minute period of supine rest, BP and heart rate (HR) were continuously monitored for 10 minutes in the supine position, followed by 5 minutes of 70 degree head-up tilt, 1 hour following administration of placebo and 1 hour after 20mg of 3,4-DAP. Cardiovascular parameters, orthostatic symptoms, QTc interval, and side effects were compared between treatment status in this pilot trial. Results: Orthostatic BP was significantly improved after administration of 3,4-DAP compared to placebo (systolic BP 111.9±6.2 vs. 88.7±6.3mmHg, diastolic BP 77.9±3.8 vs. 63.3±3.8, both p Conclusions: 3,4-DAP is safe and well tolerated, and dramatically improves OH and orthostatic symptoms. The improvement is much more pronounced than that seen with pyridostigmine, consistent with the hypothesis of potentiated, serially linked effects. A large double-blind, placebo-controlled trial is now planned to further confirm these findings. Supported by: Ronald F. Kinney Executive Dean for Research Career Development Award, NIH (BIRCWH 5K12HD065987-02 and NS 44233), and Mayo CTSA (RR00585). Disclosure: Dr. Singer has nothing to disclose. Dr. Gehrking has nothing to disclose. Dr. Gehrking has nothing to disclose. Dr. Sletten has nothing to disclose. Dr. Figueroa has nothing to disclose. Dr. Sandroni has nothing to disclose. Dr. Low has received personal compensation for activities with Chelsea, Pfizer, and WR Medical Inc. as a consultant.Dr. Low has received personal compensation in an editorial capacity for Autonomic Neuroscience.