Effects of L-DOPS in Patients with Low- and Normal- Blood Pressure Variants of Orthostatic Intolerance.

Difficulty in maintaining the upright posture is called Orthostatic Intolerance. Orthostatic Intolerance may result in fainting or symptoms such as light-headedness, blurred vision, nausea and palpitations. These symptoms come on when standing or sitting, particularly for prolonged periods or time or in warm weather, and are relieved by lying down. They are often associated with an abnormal blood pressure or heart rate response to sitting or standing. Our research to date has looked in detail at two clinical groups with these symptoms. Both of these groups have overall normal nervous system function, but with intermittent difficulty in maintaining the upright posture. One group always has very low blood pressure (Low Supine Blood Pressure Orthostatic Intolerance) and the other normal blood pressure (Normal Supine Blood Pressure Orthostatic Intolerance). Our studies have particularly looked for differences in the way a part of the nervous system called the sympathetic nervous system responds to the upright posture in these two groups when compared to healthy control participants. The sympathetic nervous system, the stimulant arm of the nervous system is responsible for our “flight and fight” response to a threatening situation. The sympathetic nervous system is also crucial in the control of blood pressure and allows us to stand upright and supply blood to our vital organs, including the brain, in the face of gravity that pulls blood towards our legs. We have found that people with these two forms of Orthostatic Intolerance do not release as much of the main chemical messenger of the sympathetic nervous system – called noradrenaline - into their circulation in response to upright posture when compared with healthy control participants. We have found distinct differences between these two groups and between each group and healthy control participants in the processing pathways for noradrenaline. Current medical treatments for these forms of Orthostatic Intolerance have focused on increasing blood volume by increasing dietary salt or by the use of a medication (Fludrocortisone) that make the body retain salt and fluid. In addition medications that act to tighten blood vessels with standing (Midodrine or Dihydroergotamine) may also be used. These medications can be very helpful for some patients but are often not tolerated due to side effects and many patients continue to experience symptoms even with these medications. None of these medications has been proven to be of benefit in randomised trials to date. This trial will be comparing a new treatment – L-DOPS (Droxidopa) – with placebo (a tablet that appears the same as the L-DOPS tablets but contains no active ingredients) in patients with the two forms of Orthostatic Intolerance described above. L-DOPS is a nerve transmitter precursor that is converted by the body to noradrenaline, the main nerve messenger of the sympathetic nervous system. L-DOPS is an experimental treatment. This means it is not approved for patients with Low- or Normal- supine blood pressure Orthostatic Intolerance in Australia or other parts of the world. L-DOPS has been marketed in Japan since 1989 for use in patients with Parkinson Disease and Orthostatic Intolerance. L-DOPS remains an investigational drug in the United States and Australia. Current trials in the United States and Canada are studying its benefit in blood pressure regulation disorders in Parkinson disease and in symptoms in patients with Chronic Fatigue syndrome and Fibromyalgia (a condition associated with painful muscles). This study will include: 20 Healthy control Participants 28 Participants with Low supine Blood Pressure Orthostatic Intolerance 28 Participants with Normal Supine Blood Pressure Orthostatic Intolerance All participants will be studied through the Alfred Baker Medical Unit at the Alfred Hospital The purpose of this research is twofold: 1. The baseline assessment will compare the way the sympathetic nervous system responds to the ‘stress’ of the upright posture in healthy control participants and participants with the two different clinical presentations of Orthostatic Intolerance described above. These responses will be correlated with the individual pattern of nerve proteins and nerve transmitter levels - obtained from a forearm vein biopsy- in the participants. This part of the study is to being performed to confirm our previous findings in a larger group of participants and to provide baseline measurements for the participants with Orthostatic Intolerance who will participate in the second phase of the study. 2. The second phase of the study is to assess whether the nerve transmitter replacement L-DOPS(Droxidopa) is able to improve symptoms and normalise the sympathetic nervous system response to upright posture in participants with the low- and normal- supine blood pressure variants of Orthostatic Intolerance.