This Is MS Multiple Sclerosis Knowledge & Support Community

I was wondering, how on earth do you grasp all this medical crap so easily - is it your profession, or do you read lots and lots? im just being nosey... so tell me to bugger off if you like!!

First, here's a very brief explanation of a TZD:

Normal cells tightly control cell growth and ACTH secretion by what genes are tuned on or off and how much of a gene product is present (expressed). Some gene products are often over-expressed in tumor cells when compared to normal cells. PPAR-g is a member of the nuclear receptor superfamily, like the better-known estrogen receptor, and regulates expression of other genes. Compounds that bind to PPAR-g and mediate its actions (called ligands) include the thiazolidinedione compounds (TZDs) that are commonly employed in the treatment of type II diabetes. The PPAR-g is expressed at high levels in several cancers including breast, prostate and colon cancer, and treatment of cancer cells with PPAR-g ligands, such as TZDs, inhibits prostate and colon tumor cell growth.

"TZDs inhibit T lymphocyte proliferation and activation, reduce expression and production of inflammatory molecules including interleukin-1β, tumor necrosis factor-α and inducible nitric oxide synthase, increase astrocyte metabolism and resistance to cytotoxicity [11], and reduce clinical symptoms in experimental autoimmune encephalomyelitis (EAE), an autoimmune-mediated, demyelinating disease which provides a model for MS [2,3]. "

Douglas Feinstein, PhD
University of Illinois at Chicago
The School of Medicine
Chicago, IL
Region: Greater Illinois Chapter
Award: Research Grant
Term/Amount: 10/1/04-9/30/07 $360,113

“Therapeutic potential of PPAR delta agonists in demyelinating disease” Determining whether a natural brain chemical can stop MS-like disease and stimulate myelin repair by replacement cells.

MS is thought to result from an immune attack on nerve-insulating myelin and nerve fibers, with immune cells migrating into the brain and increasing production of inflammatory immune proteins. Recent evidence suggests that certain medications approved by the FDA to treat diabetes, known as PPAR-gamma agonists, can reduce the activity of genes that regulate such immune responses in the brain.
Douglas Feinstein, PhD, has found that treatment with PPAR-gamma agonists reduced the incidence and the severity of EAE, an MS-like disease, in mice by reducing inflammation and blocking immune T cells. His team also has shown that treatment with a slightly different drug – a PPAR-delta agonist – results in the growth and development of myelin-making cells. Together, these two agonists might control immune responses early in disease, and stimulate myelin repair later on.

Dr. Feinstein is exploring the mechanisms by which PPAR-delta can stimulate myelin growth, focusing on the effects of this agent on mice with EAE and in laboratory experiments using isolated mouse and human nervous system cells. This project should provide vital information necessary to determine whether PPAR-delta agonist will be a useful treatment for people with MS.

Hey...........there's a common denominator here! Between epilepsy, multiple sclerosis, and diabetes. PPAR: "peroxisome proliferator-activated receptor-alpha (PPAR), a transcription factor that regulates the use of fatty acids within cells."

bromley wrote:OddDuck wrote: (I can't work out the quote option)

author wrote: followed by the end quote.

NHE

OddDuck wrote: (I can't work out the quote option)

EDIT: OH!!!!! I'm dying laughing at myself!!! THAT was BROMLEY talking, saying HE couldn't work out the quote option!!!! I wondered what the heck? I guess I was hallucinating! HAH! No wonder I was confused!

http://www.nationalmssociety.org/pdf/re ... trials.pdf

Agent: Actos® (pioglitazone)
Purpose of study: To test safety and tolerability
Possible mechanism: Reduces proinflammatory gene expression and T cell activation
Study description: Pilot, double blinding
Dose/route: Actos 30 mg/d po vs. PBO
Outcome parameters: Frequency of relapse, MSFC, EDSS, MRI, liver function
Type of MS: RR
Number of Subjects: 15
Start date: April 2004
Observation period: 2 years
Investigators: D. Skias, D. Hier, D. Feinstein
Sites: University of Illinois at Chicago
Results/Publications: Not Available
Funding: Takeda Pharmaceuticals North America, Inc.
Last update: Summer/Fall 2004

Drug commonly used for diabetes might be effective in treating multiple sclerosis

Pharmaceutical News
Published: Thursday, 10-Jun-2004

Researchers at the University of Illinois at Chicago are launching a clinical trial to determine whether a drug commonly used for diabetes might be effective in treating multiple sclerosis, an autoimmune disease that affects 350,000 Americans.

In an animal model of the disease, the researchers found that the drug reduced the inflammation of nervous tissue that occurs with multiple sclerosis and prevented the aberrant immune response that ends up destroying the body's own brain and spinal cord.

"At present, few medications have been approved by the Food and Drug Administration for the treatment of multiple sclerosis," said Douglas Feinstein, associate professor of anesthesiology in the UIC College of Medicine. "These drugs are only partially effective, and none helps significantly in the later, progressive forms of the disease. The drugs also have undesirable side effects, and they need to be injected, making them difficult to administer."

The drug being tested, called pioglitazone, is prescribed for the treatment of type 2 diabetes. Marketed by Takeda Pharmaceuticals North America, pioglitazone "sensitizes" the body's cells to insulin, a hormone produced by the pancreas that lets sugar into cells so that it can be converted into energy. People with type 2 diabetes are unable to use insulin efficiently, leading to elevated blood sugar levels (hyperglycemia) and tissue damage.

Research has shown that drugs like pioglitazone not only raise the levels of certain proteins involved in the uptake and metabolism of glucose but also lower the levels of other molecules involved in the immune response and inflammation.

"It is amazing that this drug, at least in animal tests, has shown a dramatic effect on two different targets of multiple sclerosis, namely the immune system and the inflammation process," Feinstein said.

Feinstein also noted that the drug is available as a tablet, simplifying its administration.

The clinical trial will enroll about 30 patients with relapsing remitting multiple sclerosis, the most common form of the disease. People with this type of multiple sclerosis experience episodes of acute worsening of neurological function, followed by partial or complete recovery. In most patients, the disease will eventually change into a chronic, persistent form, with symptoms worsening throughout life.

Participants in the trial will take a 30-milligram dose of pioglitazone daily for a period of 18 months, during which they will be monitored for any side effects or changes in their symptoms.

"At this stage in the drug trial, we are simply trying to determine whether the drug is safe and can be tolerated by people with multiple sclerosis," Feinstein said. "But we'll also be doing neurological examinations and biochemical analyses of blood samples, looking for signs of inflammation and immune cell activation to determine whether the drug is having any effect on symptoms of the disease."

Employing UIC's state-of-the-art magnetic resonance imaging technology, the researchers will do a series of three brain scans over the course of the trial to look for changes in the cerebral lesions associated with multiple sclerosis.

In multiple sclerosis, the T cells of the immune system go awry, attacking proteins in the myelin sheath that insulates the nerve fibers. When the sheath is destroyed, electrical signals that are normally transmitted throughout the brain and spinal cord are disrupted, and the brain is no longer able to correctly send or receive the messages that help control muscle movements.

Patients with multiple sclerosis suffer a range of symptoms, including tingling and numbness, loss of balance, blurry vision, weakness in the limbs, difficulty walking, impaired thinking and even paralysis. The disease affects women about twice as often as men.

In the United States, health care costs for multiple sclerosis are second only to those for Alzheimer's disease.

Co-directors of the UIC study are Drs. Daniel Hier and Demetrios Skias, in the department of neurology at UIC, and Dr. Dusan Stefoskil, director of the multiple sclerosis clinic at Rush University Medical Center.

Ann Neurol. 2002 Jun;51(6):694-702.

Peroxisome proliferator-activated receptor-gamma agonists prevent experimental autoimmune encephalomyelitis.

Feinstein DL, Galea E, Gavrilyuk V, Brosnan CF, Whitacre CC, Dumitrescu-Ozimek L, Landreth GE, Pershadsingh HA, Weinberg G, Heneka MT.

Department of Anesthesiology, University of Illinois, 11819 West Polk Street, MC519, Chicago, IL 60612, USA. dlfeins@uic.edu

The development of clinical symptoms in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) involves T-cell activation and migration into the central nervous system, production of glial-derived inflammatory molecules, and demyelination and axonal damage. Ligands of the peroxisome proliferator-activated receptor (PPAR) exert anti-inflammatory effects on glial cells, reduce proliferation and activation of T cells, and induce myelin gene expression. We demonstrate in two models of EAE that orally administered PPARgamma ligand pioglitazone reduced the incidence and severity of monophasic, chronic disease in C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide and of relapsing disease in B10.Pl mice immunized with myelin basic protein. Pioglitazone also reduced clinical signs when it was provided after disease onset. Clinical symptoms were reduced by two other PPARgamma agonists, suggesting a role for PPARgamma activation in protective effects. The suppression of clinical signs was paralleled by decreased lymphocyte infiltration, lessened demyelination, reduced chemokine and cytokine expression, and increased inhibitor of kappa B (IkB) expression in the brain. Pioglitazone also reduced the antigen-dependent interferon-gamma production from EAE-derived T cells. These results suggest that orally administered PPARgamma agonists could provide therapeutic benefit in demyelinating disease.

PMID: 12112074 [PubMed - indexed for MEDLINE]