Pentoxifylline Abstracts

  1. Pentoxifylline: is it useful in Multiple Sclerosis?
    Rev Neurol 2001 Apr 1;32(6):529-531

  2. Prevention of Experimental Allergic EncephaloMyelitis via inhibition of IL-12 signaling and IL-12-mediated Th1 differentiation
    J Immunol 1998 Dec 15;161(12):7015-22

  3. Pentoxifylline is not a promising treatment for Multiple Sclerosis in Progression phase
    Neurology 1998 Nov;51(5):1483-6

  4. Controlled therapeutic trials of Pentoxifylline in Relapsing Experimental AutoImmune EncephaloMyelitis
    Acta Neurol Scand 1998 Jun;97(6):404-8

  5. Effective treatment of models of Multiple Sclerosis by Matrix MetalloProteinase Inhibitors
    Ann Neurol 1998 Jul;44(1):35-46

  6. Pentoxifylline delays the onset of Experimental Allergic EncephaloMyelitis in mice by modulating Cytokine production in Peripheral Blood MonoNuclear Cells
    ImmunoPharmacology 1996 Nov;35(2):141-8

  7. A pilot study investigating the effects of orally administered Pentoxifylline on selected Immune variables in Multiple Sclerosis
    J NeuroImmunol 1996 May;66(1-2):49-55

  8. Volumetric measurement of multifocal Brain lesions. Implications for treatment trials of Vascular Dementia and Multiple Sclerosis
    J NeuroImaging 1996 Jan;6(1):36-43


Is It Useful In Multiple Sclerosis?

Prieto Gonzalez JM, Lema Bouzas M, Cacabelos Perez P, Dapena Bolano D, Noya Garcia M, Ares Pensado B
Rev Neurol 2001 Apr 1;32(6):529-531
Hospital Clinico Universitario de Santiago de Compostela, Servicio de Neurologia, Santiago de Compostela, 15705, Espana
PMID# 11353990

Pentoxifylline (PTX) is a PhosphoDiesterase Inhibitor which has been found in studies in vitro to inhibit the production of Th1 Cytokines.

It has been postulated that it might be used as a possible coadjuvant treatment for Interferon in patients with Multiple Sclerosis. This would also reduce the potential side effects of Interferon.

To show the efficacy of PTX in reducing the side effects of Interferon, and in the functional improvement of these patients.

Patients And Methods
We studied 18 patients with Remitting/Relapsing Multiple Sclerosis over a period of 18?months; nine patients were given PTX and Interferon 800 mg/day simultaneously, and nine patients were treated with Interferon alone.

The clinical condition was evaluated every three months using the Expanded Disability Status Scale (EDSS) and the Neurological Score (NRS) scales.

We found no statistical improvement in the clinical course of EDSS and NRS in either group of patients after treatment for 18 months.

The patients treated with PTX have fewer secondary effects due to Interferon (Fever and Myalgia) during the first three months, but these differences between the groups subsequently disappear. In two patients PTX caused transient gastralgias and nauseas.

PTX may be useful as a coadjuvant drug with Interferon during the first three months of treatment since some of the side effects of Interferon may thus be reduced.

However, there seems no justification for using PTX for a longer period since there is no functional improvement.


Prevention Of EAE Via Inhibition Of IL-12 Signaling And IL-12-Mediated Th1 Differentiation: Effect Of The Anti-Inflammatory Drug Lisofylline

Bright JJ, Du C, Coon M, Sriram S, Klaus SJ
J Immunol 1998 Dec 15;161(12):7015-22
Vanderbilt Univ, Medical Center, Dept of Neurology, Nashville, TN 37212, USA
UI# 99077574

Experimental Allergic EncephaloMyelitis (EAE) is an Inflammatory, CD4+ Th1-mediated AutoImmune Disease, which serves as a model for Multiple Sclerosis.

We examined the effect of a novel Anti-Inflammatory drug, Lisofylline (LSF), on EAE induced either by injection of mouse Spinal Cord homogenate or following transfer of Myelin Basic Protein-reactive T-Cells.

Orally administered LSF significantly inhibited EAE in both cases, decreasing peak clinical scores by >70% and >80%, respectively.

In addition, analysis of representative Spinal Cord sections from LSF-treated mice showed complete lack of DeMyelination and Lymphocyte infiltration.

The reduction in EAE correlated with the inhibition of Th1 differentiation by LSF in vivo, as indicated by a reduction in T-Cell IFN-gamma production ex vivo after Ag restimulation.

The inhibition of Th1 differentiation in vivo is consistent with a block in IL-12 receptor signaling, because LSF blocked IL-12-driven Th1 differentiation and T-Cell proliferation in vitro, yet had no effect on IL-12 secretion from APCs ex vivo or in vitro.


Pentoxifylline Is Not A Promising Treatment For Multiple Sclerosis In Progression Phase

Myers LW, Ellison GW, Merrill JE, El Hajjar A, St Pierre B, Hijazin M, Leake BD, Bentson JR, Nuwer MR, Tourtellotte WW, Davis P, Granger D, Fahey JL
Neurology 1998 Nov;51(5):1483-6
UCLA School of Medicine, Dept of Neurology, Los Angeles, CA 90095-1769, USA
UI# 99034200

Fourteen MS patients took Pentoxifylline at varying doses for up to 24 months. In vitro production of Tumor Necrosis Factor-alpha was reduced in patients taking 2,400 to 3,200 mg/day of Pentoxifylline for 12 weeks or more.

Twelve of the 14 patients experienced worsening of the disease during the study according to clinical, MRI, or Visual Evoked Potential criteria. These results provide no hint of efficacy for Pentoxifylline as a treatment for MS in Progression phase.


Controlled Therapeutic Trials Of Pentoxifylline In Relapsing-Experimental AutoImmune EncephaloMyelitis

Grassin M, Brochet B, Coussemacq M, Brochet H
Acta Neurol Scand 1998 Jun;97(6):404-8
Experimental NeuroBiology and Neuroimagery Laboratory, JE 480, BP 78, Universite Bordeaux II, France
UI# 98332138

This study was designed to assess the capacity of several doses of Pentoxifylline to prevent or treat Chronic-Relapsing-EAE (CR-EAE) exacerbations induced in the Lewis rat.

Pentoxifylline (PTX) is a Methylxanthine derivative that inhibits the production of TNF-alpha, a Cytokine involved in EAE and Multiple Sclerosis PhysioPathology.

Three blind placebo-controlled randomized studies were performed in respectively 40, 30 and 18 rats: a trial of different (PTX) dosages (8, 30, 50, 100 and 200 mg/kg) versus placebo to prevent EAE onset.

A trial of PTX (8, 30 or 50 mg/kg) versus placebo to prevent 2 attacks of EAE and a trial of PTX (100 mg/kg) versus placebo to abrogate ongoing clinical EAE.

No statistically significant difference was observed between groups in any trial. PTX was ineffective to prevent or treat CR-EAE in these studies.


Effective Treatment Of Models Of Multiple Sclerosis By Matrix MetalloProteinase Inhibitors

Liedtke W, Cannella B, Mazzaccaro RJ, Clements JM, Miller KM, Wucherpfennig KW, Gearing AJ, Raine CS
Ann Neurol 1998 Jul;44(1):35-46
Albert Einstein College of Medicine, Dept of Pathology, Bronx, NY, USA
UI# 98330165

The ProInflammatory Th1 Cytokine, Tumor Necrosis Factor-alpha (TNF-alpha), the cell death signaling molecule FasL, and several ExtraCellular Matrix degrading MetalloProteinases have been implicated in the PathoGenesis of Multiple Sclerosis (MS).

The latter enzymes, as well as TNF-alpha converting enzyme and FasL-converting enzyme, can be blocked by Matrix MetalloProteinase Inhibitors (MMPIs).

In this study, we show that a potent MMPI was clinically effective in an animal model for MS, Experimental AutoImmune EncephaloMyelitis (EAE) in the SJL/J mouse.

Efficacy was remarkable, as indicated by blocking and reversal of acute disease and reduced number of relapses and diminished mean cumulative disease score in Chronic Relapsing animals.

Also, DeMyelination and Glial scarring were significantly decreased in MMPI-treated mice with chronic Relapsing EAE, as was Central Nervous System Gene expression for TNF-alpha and fasL.

It is interesting that expression of the beneficial Cytokine InterLeukin-4 (IL-4) was increased, and IL-4 was expressed on Glial Cells.

The relevance of these compounds for MS was underscored by their ability to specifically inhibit TNF-alpha shedding and CytoToxicity of Myelin-AutoReactive human Cytotoxic CD4+ T-Cell clones.

This is the first report to show a positive effect by MMPIs on Chronic Relapsing EAE, its Central Nervous System Cytokine profile, and on TNF-alpha shedding by human Myelin-AutoReactive T-Cells.


Pentoxifylline Delays The Onset Of EAE In Mice By Modulating Cytokine Production
In Peripheral Blood MonoNuclear Cells

Okuda Y, Sakoda S, Fujimura H, Yanagihara T
Immunopharmacology 1996 Nov;35(2):141-8
Osaka Univ, Medical School, Dept of Neurology, Japan
UI# 97115607

The effect of Pentoxifylline (PTX) on Experimental Allergic EncephaloMyelitis (EAE) in mice, a known animal model of Multiple Sclerosis (MS), was investigated. PTX was orally administrated at 10, 40 and 100 mg/kg/day, respectively.

Although oral PTX at these doses had no significant effect on the incidence and severity of EAE, oral PTX (40 mg/kg/day) alone produced a significant delay in the onset of EAE.

Semiquantitative reverse transcriptase-polymerase chain reaction analysis revealed that PTX at this dose reduced the mRNA levels for Tumor Necrosis Factor-alpha (TNF)-alpha, InterLeukin-1ß (IL-1ß) and IL-6 in Peripheral Blood MonoNuclear Cells (PBMC) of mice with EAE.

A HistoPathological study showed that PTX treatment delayed infiltration of inflammatory cells in the Central Nervous System (CNS) of mice with EAE.

These results indicated that the tolerable dose of PTX had a suppressive effect on the induction phase of EAE by modulating Cytokine production in PBMC but had no effect on the severity of EAE.

The findings in the present study with animals suggested that a tolerable dose of PTX might prolong the intervals between relapses in MS, but might not improve the clinical sign and symptoms of MS.


A Pilot Study Investigating The Effects Of Orally Administered Pentoxifylline On Selected Immune Variables In Patients With Multiple Sclerosis

van Oosten BW, Rep MH, van Lier RA, Scholten PE, von Blomberg BM, Pflughaupt KW, Hartung HP, Ader HJ, Polman CH
J NeuroImmunol 1996 May;66(1-2):49-55
UI# 96265356

Multiple Sclerosis is probably mainly mediated by T-Helper 1 (Th1)-Lymphocytes. Th1-function can be down-regulated in vitro and in animal experiments by Pentoxifylline.

Therefore, we included 20 Multiple Sclerosis patients in an open label pilot trial of Pentoxifylline.

Outcome parameter was the effect of treatment on levels of various Cytokines and Adhesion Molecules in CerebroSpinal Fluid and Serum, on production of Th1- and Th2-Cytokines using cell stimulation assays, as well as on measures of T-Cell activation and proliferation.

Kurtzke's EDSS was a secondary efficacy parameter. A convincing and consistent effect of Pentoxifylline could not be demonstrated.


Volumetric Measurement Of Multifocal
Brain Lesions

Implications for treatment trials of Vascular Dementia & Multiple Sclerosis

Broderick JP, Narayan S, Gaskill M, Dhawan AP, Khoury J
J NeuroImaging 1996 Jan;6(1):36-43
Univ of Cincinnati, Dept of Neurology, OH 45267-0525, USA
UI# 96144175

This pilot study examined the reproducibility of serial Magnetic Resonance (MR) measurements of Brain, Ventricular, Sulcal, and lesion volumes in patients with Ischemic Brain Disease using an image analysis protocol designed at the Univ of Cincinnati.

Five patients with a clinical history of Brain Ischemia had two separate MR Brain imaging studies using the standard clinical MR imaging protocol at the Univ of Cincinnati Medical Center.

The MR images on both film and tape were digitized and then analyzed according to the standardized image analysis protocol.

Based on tape data, variability in volume measurements between the two MR studies, as measured by the coefficient of variation, ranged from 1% for IntraCranial volume to 8% for Ventricular volume.

Variability based on film data was slightly greater, ranging from 2% for IntraCranial volume to 12% for lesion volume.

As part of a multicenter treatment trial of Vascular Dementia, this method was then used to analyze MR films in 13 patients with Vascular Dementia who all had an MR study at baseline and at 1 year.

The mean annual change in lesion volume was 4 +/- 5 cm3 (a 24% increase from the baseline lesion volume); in Ventricular volume, 7 +/- 8 cm3 (a 10% increase from baseline); and in Sulcal volume, 13 +/- 25 cm3 (a 5% increase from baseline).

This method of image analysis, using MR film or tape-generated data, can provide reproducible serial measurements of Brain, Ventricular, Sulcal, and Ischemic lesion volumes.

This method, if applied in randomized treatment trials of Vascular Dementia or Multiple Sclerosis, can be used to monitor disease progression and to evaluate the effectiveness of a given therapy.

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