Study About Efficacy and Safety to Treat Multi-System-Atrophy

• Change in motor function: Difference between the UMSARS II baseline score and the UMSARS II score 48 weeks after start of therapy
  

• Difference between the UMSARS II baseline score and the UMSARS II score 24 weeks after start of therapy
  
• Difference between the UMSARS I, III, IV baseline score and the UMSARS I, III, IV score 24 and 48 weeks after start of therapy
  
• Difference between the UPDRS I–III baseline score and the UPDRS I–III score 24 and 48 weeks after start of therapy
  
• Difference between the SF-12 baseline score and the SF-12 score 24 and 48 weeks after start of therapy
  
• Difference between the EQ-5D baseline score and the EQ-5D score 24 and 48 weeks after start of therapy
  

Study Hypothesis:

• Does a treatment with Minocycline of 2 x daily 2 x 50 mg effect the progression of clinical symptoms and diagnosis in patients with MSA?
• Minocycline is an antibiotic belonging to the group of the Tetracyclines. It is applied in treating bacterial infections and skin disorders (acne), but there are studies that prove a good effect on the inflammatory changes with rheumatoid arthritis (O´Dell, 1999; O´Dell et al., 2001; Pillemar et. al., 1997). In a four-years-lasting double-blind-placebo-controlled study it could be demonstrated that Minocycline represents an effective therapy for the seropositive rheumatoid arthritis. Moreover, during the long term therapy only a low side effect rate was observed (O´Dell et al., 1999; Langevitz et al., 2000; Alarcon, 2000).
• Recently, it could be demonstrated that Minocycline has a neuroprotective impact besides the anti-inflammatory impact. In the focal and global animal stroke model there was a clearly reduced stroke volume during the treatment of Minocycline in comparison to an untreated group (Yrjanheikki, 1998; Yrjanheikki, 1999). These data were replicated by various groups, from our group as well (unpublished data). Furthermore, the neuroprotective impact of Minocycline was examined with a number of animal experiences (Chen et al., 2000; Zhu et al., 2002; Kriz et al. 2002, Sanchez et al., 2001; Van Den Bosch et al., 2002; Popovic et al., 2002): amyotrophic lateral sclerosis, M. Huntington, trauma, multiple sclerosis.In these trials it could be demonstrated that Minocycline slows down the neuronal cell death.
• Recently, in cooperation with American colleagues we were able to demonstrate that Minocycline possesses a high neuroprotective potency in the MPTP-Mouse model, (an animal-model of Parkinson’s disease, in which a degeneration of neuronal cells in the basal ganglia occurs (Lin et al., 2001; Du et al., 2001). Dependent on the applied dosage (30-120 mg/kg), a neuroprotection of up to 77% could be observed. In our results we could prove, that NO as well as Caspase-1 play an important role in the pathogenesis of cell death. Both, the expression of iNOS and the activation of Caspase-1 could be blocked in the presence of Minocycline in the animal-model and in further cell culture trials. In addition, there was a decrease of inflammatory microglia activation in the examined brain sections in the presence of Minocycline. Similar results could be presented from the study group Przedborski (Wu et al., 2002).
• In various studies it could be demonstrated that the regulation of iNOS as well as the activation of Microglia at the MSA play an important role. This activation of Microglia in persons can be proved by Positron-emission-tomography (PET) with the Benzodiazepine-Ligands PK11195. PK11195 (1-(2-chlorophenyl)–N-methyl-N-(1-methylpropyl)-3isoquinoline- carboxamide) is a highly specific Ligand for peripheral Benzodiazepine-binding sites (PBBS) (Leong et al., 1996). As in a normal brain only a few binding sites for PK11195 can be verified, a significant increase of the PBBS-Expression by activated microglia after neuronal cell death can be verified (Gerhard et al., 2001).
• The results of our examinations and the results out of literature suggest that Minocycline could also have an effect on neuro-degenerative diseases and particularly have an effect with MSA. In the USA a study already examining the impact of orally given Minocycline to patients with Chorea Huntington or amyotrophic lateral sclerosis is taking place. The National Institutes of Health (NIH) in the USA will perform a multicentre, double-blind study about the effect of Minocycline on Parkinson’s Disease (NIH website, www.nih.gov).
• In this study, the effectiveness of Minocycline on the progression of clinical symptoms of MSA shall be examined.