TZD AND SPMS
Posted: Tue Oct 12, 2004 11:13 am
Well, well............after mentioning TZDs on another thread here with BioDoc, I thought......hey, I'll check and see what, if anything, IS coming down the pike regarding TZDs and MS. (I mentioned in the other thread where a few months ago, actually I think it was more like a year ago, I had run across a quick mention buried in a diabetes publication about TZDs and MS.)
Here's what I found today. This is anecdotal, at best, but talk about "doo doo doo doo".........(I live in the twilight zone.)
Deb
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.
Here's an excerpt regarding the application of a TZD in MS. The full article can be found at: http://www.pubmedcentral.nih.gov/articl ... tid=483056
Copyright © 2004 Pershadsingh et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
J Neuroinflammation. 2004; 1: 3.
doi: 10.1186/1742-2094-1-3. Published online 2004 April 20.
Effect of pioglitazone treatment in a patient with secondary multiple sclerosis
Harrihar A Pershadsingh,1,2 Michael T Heneka,2 Rashmi Saini,1 Navin M Amin,1 Daniel J Broeske,3 and Douglas L Feinstein4
1Departments of Family Medicine, Kern Medical Center, Bakersfield, and University of California, Irvine, California, USA 2Department of Neurology, University of Bonn, Bonn, Germany 3Department of Internal Medicine, Kern Medical Center, Bakersfield, California, USA 4Department of Anesthesiology, University of Illinois, Chicago, Illinois, USA
Corresponding author.
Harrihar A Pershadsingh: pershadh@kernmedctr.com; Michael T Heneka: Michael.Heneka@ukb.uni-bonn.de; Rashmi Saini: pershadh@kernmedctr.com; Navin M Amin: aminn@kernmedctr.com; Daniel J Broeske: broeske1@juno.com; Douglas L Feinstein: dlfeins@Uic.edu
Received March 24, 2004; Accepted April 20, 2004.
ABSTRACT
Background
Ligands of the peroxisome proliferator-activated receptor-gamma (PPARγ) induce apoptosis in activated T-lymphocytes and exert anti-inflammatory effects in glial cells. Preclinical studies have shown that the thiazolidinedione pioglitazone, an FDA-approved PPARγ agonist used to treat type 2 diabetes, delays the onset and reduces the severity of clinical symptoms in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). We therefore tested the safety and therapeutic potential of oral pioglitazone in a patient with secondary MS.
Case presentation
The rationale and risks of taking pioglitazone were carefully explained to the patient, consent was obtained, and treatment was initiated at 15 mg per day p.o. and then increased by 15 mg biweekly to 45 mg per day p.o. for the duration of the treatment. Safety was assessed by measurements of metabolic profiles, blood pressure, and edema; effects on clinical symptoms were assessed by measurement of cognition, motor function and strength, and MRI. Within 4 weeks the patient exhibited increased appetite, cognition and attention span. After 12 months treatment, body weight increased from 27.3 to 35.9 kg (32%) and maintained throughout the duration of the study. Upper extremity strength and coordination improved, and increased fine coordination was noted unilaterally after 8 months and bilaterally after 15 months. After 8 months therapy, the patient demonstrated improvement in orientation, short-term memory, and attention span. MRIs carried out after 10 and 18 months of treatment showed no perceptible change in overall brain atrophy, extent of demyelination, or in Gd-enhancement. After 3.0 years on pioglitazone, the patient continues to be clinically stable, with no adverse events.
Conclusions
In a patient with secondary progressive MS, daily treatment with 45 mg p.o. pioglitazone for 3 years induced apparent clinical improvement without adverse events. Pioglitazone should therefore be considered for further testing of therapeutic potential in MS patients.
Keywords: Multiple sclerosis, thiazolidinedione, PPARγ, pioglitazone, inflammation
Background
Current therapies for MS are limited in efficacy and can have adverse effects. Although immuno-modulating type-1β interferons and glatiramer acetate reduce active CNS inflammatory lesions, clinical severity and attack frequency in relapsing remitting MS, they are less efficacious in progressive disease [1]. The immunosuppressive agent, mitoxantrone is presently approved for treating progressive MS but is limited because of severe adverse side-effects especially cardiotoxicity [1]. The insulin-sensitizing anti-diabetic thiazolidinediones (TZDs) are high affinity activators of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPARγ). 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]. In view of these effects and the established safety profile of TZDs, we investigated the therapeutic potential of the FDA-approved anti-diabetic TZD pioglitazone in a patient with secondary progressive MS.
Here's what I found today. This is anecdotal, at best, but talk about "doo doo doo doo".........(I live in the twilight zone.)
Deb
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.
Here's an excerpt regarding the application of a TZD in MS. The full article can be found at: http://www.pubmedcentral.nih.gov/articl ... tid=483056
Copyright © 2004 Pershadsingh et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
J Neuroinflammation. 2004; 1: 3.
doi: 10.1186/1742-2094-1-3. Published online 2004 April 20.
Effect of pioglitazone treatment in a patient with secondary multiple sclerosis
Harrihar A Pershadsingh,1,2 Michael T Heneka,2 Rashmi Saini,1 Navin M Amin,1 Daniel J Broeske,3 and Douglas L Feinstein4
1Departments of Family Medicine, Kern Medical Center, Bakersfield, and University of California, Irvine, California, USA 2Department of Neurology, University of Bonn, Bonn, Germany 3Department of Internal Medicine, Kern Medical Center, Bakersfield, California, USA 4Department of Anesthesiology, University of Illinois, Chicago, Illinois, USA
Corresponding author.
Harrihar A Pershadsingh: pershadh@kernmedctr.com; Michael T Heneka: Michael.Heneka@ukb.uni-bonn.de; Rashmi Saini: pershadh@kernmedctr.com; Navin M Amin: aminn@kernmedctr.com; Daniel J Broeske: broeske1@juno.com; Douglas L Feinstein: dlfeins@Uic.edu
Received March 24, 2004; Accepted April 20, 2004.
ABSTRACT
Background
Ligands of the peroxisome proliferator-activated receptor-gamma (PPARγ) induce apoptosis in activated T-lymphocytes and exert anti-inflammatory effects in glial cells. Preclinical studies have shown that the thiazolidinedione pioglitazone, an FDA-approved PPARγ agonist used to treat type 2 diabetes, delays the onset and reduces the severity of clinical symptoms in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). We therefore tested the safety and therapeutic potential of oral pioglitazone in a patient with secondary MS.
Case presentation
The rationale and risks of taking pioglitazone were carefully explained to the patient, consent was obtained, and treatment was initiated at 15 mg per day p.o. and then increased by 15 mg biweekly to 45 mg per day p.o. for the duration of the treatment. Safety was assessed by measurements of metabolic profiles, blood pressure, and edema; effects on clinical symptoms were assessed by measurement of cognition, motor function and strength, and MRI. Within 4 weeks the patient exhibited increased appetite, cognition and attention span. After 12 months treatment, body weight increased from 27.3 to 35.9 kg (32%) and maintained throughout the duration of the study. Upper extremity strength and coordination improved, and increased fine coordination was noted unilaterally after 8 months and bilaterally after 15 months. After 8 months therapy, the patient demonstrated improvement in orientation, short-term memory, and attention span. MRIs carried out after 10 and 18 months of treatment showed no perceptible change in overall brain atrophy, extent of demyelination, or in Gd-enhancement. After 3.0 years on pioglitazone, the patient continues to be clinically stable, with no adverse events.
Conclusions
In a patient with secondary progressive MS, daily treatment with 45 mg p.o. pioglitazone for 3 years induced apparent clinical improvement without adverse events. Pioglitazone should therefore be considered for further testing of therapeutic potential in MS patients.
Keywords: Multiple sclerosis, thiazolidinedione, PPARγ, pioglitazone, inflammation
Background
Current therapies for MS are limited in efficacy and can have adverse effects. Although immuno-modulating type-1β interferons and glatiramer acetate reduce active CNS inflammatory lesions, clinical severity and attack frequency in relapsing remitting MS, they are less efficacious in progressive disease [1]. The immunosuppressive agent, mitoxantrone is presently approved for treating progressive MS but is limited because of severe adverse side-effects especially cardiotoxicity [1]. The insulin-sensitizing anti-diabetic thiazolidinediones (TZDs) are high affinity activators of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPARγ). 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]. In view of these effects and the established safety profile of TZDs, we investigated the therapeutic potential of the FDA-approved anti-diabetic TZD pioglitazone in a patient with secondary progressive MS.