Orthostatic Dysregulation and Associated Gastrointestinal Dysfunction in Parkinson's Disease -Treatment
Condition: Autonomic Disturbances in Parkinson's Disease
MeSH terms: Parkinson Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      Disabling symptoms of blood pressure dysregulation, impaired swallowing and digestion are
      common amongst Parkinson's patients. So far the exact pathophysiology for this is not fully
      understood. There are results from pathological analyses that the autonomic nervous system is
      also affected by the accumulation of alpha-Synuclein and that this might even happen in very
      early stages of the disease process (Qualman et al., 1984; Wakabayashi et al., 1989;
      Wakabayashi et al., 1990; Bloch et al., 2006).

      Blood pressure dysregulation is a common autonomic symptom in Parkinson's patients and
      treatment - currently most often achieved with Fludrocortisone - often leads to supine
      hypertension (Plaschke et al., 1998; Braune et al., 1999; Magerkurth et al., 2005).

      There are studies in patients with autonomic failure that indicate that Pyridostigmine
      bromide might be an alternative treatment option without causing disabling supine
      hypertension (Singer et al., 2003; Sandroni et al., 2005; Singer et al., 2006; Yamamoto et
      al., 2006).

      Delayed gastric emptying is also an autonomic symptom associated with Parkinson's disease. By
      the elevation of the cholinergic tone with Pyridostigmine bromide the investigators also
      expect to alleviate symptoms of delayed gastric emptying and obstipation, possibly even
      facilitating the uptake of dopaminergic medication through the gut (Sadjadpour, 1983;
      Bharucha et al., 2008).

      Therefore the investigators designed a monocentric randomized, controlled, double blind,
      crossover phase II trial to show non-inferiority of the effect of pyridostigmine bromide vs.
      fludrocortisone on symptoms of autonomic dysregulation in Parkinson's disease.
    

Detailed description: 
      In summary, investigators in recent years became more and more aware of the non-motor
      symptoms of PD and their impact on affected individuals. Therefore therapeutic strategies to
      ameliorate these symptoms are ever more needed. Sufficient clinical data for the treatment of
      symptoms of blood pressure dysregulation is still lacking. This study is aiming at closing
      this knowledge gap by comparing the efficacy and tolerability of a promising new agent,
      pyridostigmine bromide with the standard treatment, fludrocortisone.

      The proposed target of pyridostigmine in this respect is at the autonomic ganglion in the
      efferent limb of the baroreflex. Via a reduction of acetylcholine breakdown the sympathetic
      ganglionic transmission increases upon orthostatic stress (Singer et al., 2006).

      Via the same mechanism we aim to facilitate gastrooesophageal motility and gastric emptying:
      Both relaxation and contractibility of the oesophagus are known to be affected in PD patients
      as shown in a manometric study (Sung et al., 2010). Both relaxation and contractability are
      mainly influenced by nicotinergic and muscarinergic, cholinergic vagal efferents to the
      oesophagus (Chang et al., 2003). Via a reduction of acetylcholine breakdown we aim to
      increase the cholinergic tone and thereby normalize the reduced relaxation and
      contractibility.

      We also intent to show that this faster gastric transit results in a faster absorption of
      Madopar into the bloodstream - we therefore will measure Levodopa and its metabolites during
      the first 60mins after ingestion of 125mg fast-release Madopar in serial venous blood samples
      via high-pressure liquid chromatography.
    

Intervention name(s): Pyridostigmine bromide; fludrocortisone
Intervention type(s): Drug; Drug
Intervention description(s): Drug doses during the trial:
Pyridostigmine bromide: 30mg p.o. 1-1-1 to 2-2-2 given for 14 days; drug dose during the trial Fludrocortisone: 0,1mg p.o. 1-0-0 to 2-0-0 given for 14 days
Other intervention name(s): Mestinon; florinef
Intervention MeSH terms: Fludrocortisone; Bromides; Pyridostigmine Bromide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment