Effects of Midodrine and Droxidopa on Splanchnic Capacitance in Autonomic Failure

Patients with multiple system atrophy, pure autonomic failure or Parkinson disease, and orthostatic hypotension will be studied in a randomized?randomized Participants are assigned to the study groups by chance, like a coin toss, rather than chosen by the doctor or the participant. This is done so the groups are comparable., double-blind?double-blind Two types of people involved in the study do not know which intervention a participant is receiving. The ClinicalTrials.gov record specifies who is masked, for example participants, care providers, investigators or outcome assessors., 2-arm parallel design to compare the effects of droxidopa and midodrine on stoke volume during head up tilt. A total of 34 participants will be enrolled in the study (17 patients in each arm). Screening Procedures: Potential participants will be screened in the Vanderbilt Autonomic Dysfunction Center (ADC). Medications affecting blood pressure, blood volume and the autonomic nervous system such as pressor medications, fludrocortisone and carbidopa will be withdrawn for at least 5 half-lives?5 half-lives The time it takes for the amount of a drug in the body to fall by half. 'Five half-lives' is often used as the point at which a previous drug has essentially left the body. before studies. Patients will undergo a complete history and physical examination, ECG?ECG A recording of the heart's electrical activity. QTc is one measurement from it; some drugs are avoided if it is prolonged., routine clinical laboratory analyses and a blood pregnancy test for women with childbearing potential?childbearing potential Studies often ask participants who could become pregnant, or could father a child, to use contraception during the study and for a period afterwards, because the effect of the treatment on a pregnancy is unknown.. Autonomic testing including a tilt table testing and a posture study with plasma catecholamines is then performed to determine if they meet the inclusion/exclusion criteria?exclusion criteria The conditions that rule a person out even if they meet the inclusion criteria, for example other illnesses, certain medicines or pregnancy.. Eligible participants will then be randomized to the droxidopa or the midodrine treatment group. All patients will be studied on two separate days, two days apart: one day with the active drug (droxidopa 300mg PO or midodrine 10mg PO) and one day with placebo?placebo A treatment that looks like the study treatment but contains no active ingredient. Some participants receive it instead of the study treatment, usually without knowing which they got.. On each study day, two tilt table tests will be performed. Patients will be instrumented to measure blood pressure and heart rate (continuously and intermittently), segmental impedance, cardiac output (inert gas rebreathing technique and/or impedance cardiography), and venous capacitance. Baseline?Baseline Measurements taken at the start of the study, before any study treatment, so that later results can be compared with them. measurements will then be taken in the supine position for about 30 minutes, and during head-up tilt for ≤10 minutes at 60 degrees. Supine baseline measurements will include the estimation of splanchnic venous capacitance. At the end of the head up tilt (HUT), patients will be asked to rate severity of their orthostatic symptoms. Patients will then be placed in the seated position (time 0) and will receive a single oral dose of either droxidopa 300 mg or placebo, followed two hours later by a single oral dose of placebo or midodrine 10 mg. On the placebo day, both groups will receive a placebo pill at time 0 and at 2 hours. After ~3 hours of first drug administration, a second tilt table test will be performed, and outcome measurements will be repeated while supine and during HUT. The investigators may apply abdominal compression of 40 mmHg with an inflatable binder at the end of the second HUT. Outcome measurements will be repeated during 5 minutes of compression.