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PARACTIN^® useful for the treatment of autoimmune diseases,
and Alzheimer disease by activation of PPAR-g Receptor. 
Juan L. Hancke.  Instituto de Farmacologia, Universidad Austral de Chile, Valdivia Chile.  

Autoimmune disorders develop when the immune destroys normal body tissues or inflammatory flares refuse to die down.  Autoimmune disorders may occur when the normal body tissue is altered so that it is no longer recognized as "self."  Various microorganisms and drugs may trigger some of these changes, particularly in people with a genetic predisposition to an autoimmune disorder.  Autoimmune disorders result in destruction of one or more types of body tissues, abnormal growth of an organ, or changes in organ function.  There are over 80 autoimmune diseases, which include multiple sclerosis, rheumatoid arthritis, type 1 diabetes, lupus, fibromyalgia, etc.  About 75% of autoimmune diseases are found in women.  These diseases are often chronic, requiring lifelong care and monitoring.  Currently few autoimmune diseases can be cured.  Corticosteroids and immunosuppressant medications are used to reduce the immune response.  However, side effects of medications can be severe.

Alzheimer’s disease is a disorder that destroys cells in the brain. The disease is the leading cause of dementia, a condition that involves gradual memory loss, decline in the ability to perform routine tasks, disorientation, difficulty in learning, loss of language skills, impairment of judgment, and personality changes. Alzheimer’s disease (AD) is characterized by the extra cellular deposition of b-amyloid fibrils within the brain and the activation of microglial cells associated with the amyloid plaque.  The activated microglia subsequently secretes a diverse range of inflammatory products.  Kitamura et al. assessed the occurrence of COX-1, COX-2, and PPARgin normal and AD brains using specific antibodies and found increased expression of these moieties in AD brains. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be efficacious in reducing the incidence and risk of AD and in delaying disease progression.  Researcher showed epidemiological evidence that long-term treatment of patients suffering from rheumatoid arthritis with NSAIDs results in reduced risk and delayed onset of Alzheimer's disease (AD).  NSAIDs is also a cyclooxygenase (COX)-1 and COX-2 inhibitor as well as a peroxisome proliferator-activated receptor (PPARg) agonist, decreases the production of nitric oxide (NO), protects neurons against glutamate toxicity and decreases the production of proinflammatory cytokines. NSAID crosses the blood brain barrier and suppresses neuritic plaque pathology and inflammation in AD brain.

Combs et al. demonstrated that NSAIDs, thiazolidinediones, and PGJ2, all of which are PPARg agonists, inhibited the b-amyloid-stimulated secretion of inflammatory products by microglia and monocytes.  PPARg agonists were shown to inhibit the b-amyloid-stimulated expression of the genes for IL-6 and TNF-a and the expression of COX-2. Finally, Heneka et al. demonstrated that microinjection of LPS and IFN-ginto rat cerebellum induced iNOS expression in cerebellar granule cells and subsequent cell death. Co injection of PPARg agonists (including troglitazone and 15d-PGJ2) reduced iNOS expression and cell death, whereas co injection of a selective COX inhibitor had no effect. Overall, work in AD seems to suggest that PPARgagonists can modulate inflammatory responses in the brain and that NSAIDs may be helpful in AD as a result of their effect on PPARg.  

A recently appreciated target of AD is the ligand-activated nuclear receptor peroxisome proliferatoractivated receptor g (PPARg).  PPARgis a DNA-binding transcription factor whose transcriptional regulatory actions are activated after agonist binding.  PPARg agonists were shown to inhibit the b-amyloid-stimulated expression of the cytokine genes interleukin-6 and tumor necrosis factor a. Furthermore, PPARg agonists inhibited the expression of cyclooxygenase-2 (COX-2). Various researches have provided direct evidence that PPARg plays a critical role in regulating the inflammatory responses of microglia and monocytes to b-amyloid.

250mg of PARACTIN^® is administered to patients who have manifested an early stage of Alzheimer's disease (AD), as diagnosed by their practitioner and confirmed by an independent board-certified neurologist. Two weeks before the clinical trial, the patients undergo appropriate psycho neurological tests such as the Mini Mental Status Exam (MMSE), the Alzheimer Disease Assessment Scale (ADAS), the Boston Naming Test (BNT), and the Token Test (TT).  Neuropsychological tests are repeated on Day 0, 6 weeks and 3 months of the clinical trial. The tests are performed by neurophysiologists who are not aware of the patient's treatment regimen.

Patients are randomly assigned to PARACTIN^® or placebo at the start of the study. The PARACTIN^® and placebo are taken orally one or two times per day. Treatment for conditions such as diabetes, hypertension, etc. is allowed during the study. Scores are statistically compared between the test formulation and the placebo for each of the three observational periods. Without treatment, the natural course of AD is significant deterioration in the test scores during the course of the clinical trial. Patients treated with the composition as described in the formulation are considered improved if the patients' scores remain the same or improve during the course of the clinical trial.

The PARACTIN^® and placebo results are statistically compared for all the study periods. Patients using placebo show a significant cognitive deterioration. The patients treated with PARACTIN^® ameliorate in a considerable way the test scores.  This research shows that PARACTIN^® activates the PPAR-g Receptor like NSAIDs and may have application for early stage Alzheimer Disease.  Specifically, PARACTIN^® stimulates the PPAR-g receptor, thereby inhibits the NF kappaB factor, which reduces the synthesis and expression of cytokines and COX-2.