Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Subcutaneous application of interferon-beta1b (IFN-beta1b) is an established therapy for patients with relapsing-remitting multiple sclerosis (RRMS), but early side effects are still a major concern. In vitro studies with myelin basic protein (MBP)-specific T-cell lines revealed a synergistic suppressive effect of IFN-beta1b and the phosphodiesterase inhibitor pentoxifylline (PTX) on proliferation and the production of tumor necrosis factor-alpha (TNF-alpha), lymphotoxin (LT), and interferon-gamma (IFN-gamma). In an initial, open labeled prospective trial, the cytokine messenger RNA (mRNA) expression of blood mononuclear cells from MS patients, receiving either IFN-beta1b alone or in combination with oral PTX, was determined by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Patients treated with IFN-beta1b alone reported more side effects during the first 3 months of treatment and had upregulated TNF-alpha as well as IFN-gamma mRNA expression during the first month, which was not detected in patients receiving both drugs. A synergistic effect of both drugs was observed on the upregulation of interleukin (IL)-10 mRNA, which was accompanied by an increase in IL-10 serum levels. Both in vitro and in vivo data suggest that co-treatment of IFN-beta1b with PTX is a promising approach to correct the disturbed cytokine balance in MS patients.
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PMID:Synergistic immunomodulatory effects of interferon-beta1b and the phosphodiesterase inhibitor pentoxifylline in patients with relapsing-remitting multiple sclerosis. 966 87

The inflammatory nature of multiple sclerosis (MS) implicates the participation of cytokines as immune response mediators. Targeting the cytokine balance by downregulating proinflammatory cytokines and/or upregulating immunosuppressive cytokines could benefit patients with MS. This article reports on the in vitro effects of the phosphodiesterase i.v. inhibitor Rolipram on the production of pro- and anti-inflammatory cytokines in MS and, for reference, in myasthenia gravis (MG). Blood mononuclear cells (MNC) were cultured in the presence of the organ-specific autoantigens myelin basic protein (MBP) or acetylcholine receptor (AChR), and in the absence of antigens, with and without Rolipram. In situ hybridization with synthetic oligonucleotide probes was used to detect and enumerate blood MNC expressing IFN-gamma, TNF-alpha, LT, TGF-beta, IL-4, and IL-10 mRNA. Numbers of MNC-secreting IFN-gamma and IL-4 in blood blood were examined by ELISPOT assays. Rolipram reduced the numbers of MBP-reactive IFN-gamma- and TNF-alpha mRNA-expressing blood MNC in MS, and numbers of AChR-reactive IFN-gamma-, TNF-alpha-, and LT mRNA-positive cells in MG. In contrast, expression of the Th2 cell related IL-4 and the anti-inflammatory IL-10, and TGF-beta was not affected. These data support a role for Rolipram in the treatment of diseases such as MS.
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PMID:The phosphodiesterase i.v. inhibitor rolipram in vitro reduces the numbers of MBP-reactive IFN-gamma and TNF-alpha mRNA expressing blood mononuclear cells in patients with multiple sclerosis. 970 65

A phosphodiesterase inhibitor (PDEI), Ibudilast, which has been in wide use for the management of bronchial asthma and cerebrovascular disease in Japan, was tested for its clinical efficacy on experimental autoimmune encephalomyelitis (EAE) in Dark August rats. The severity of acute EAE was significantly ameliorated by prophylactic oral treatment with Ibudilast (10 mg/kg per day) starting on the day of immunization, although it did not modify the course of the disease when it was given after the onset of the first clinical sign of EAE. Histologically, inflammatory cell infiltration in the lumbar spinal cord was significantly reduced in Ibudilast-treated animals as compared to control animals. Ibudilast mildly suppressed MBP-induced proliferation of T cells in regional lymph nodes, the secretion of interferon-gamma from T cells activated by MBP in CFA, and the secretion of tumor necrosis factor-alpha from macrophages. While the in vitro studies did not suggest difference between Ibudilast and other PDEIs such as rolipram, the clinical dose of Ibudilast is approximately 200-fold higher than that of rolipram and the effective dose of Ibudilast was relatively close to what has been therapeutically used in patients. Thus, Ibudilast may be a candidate for clinical use for patients with multiple sclerosis. 1999 Elsevier Science B.V. All rights reserved.
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PMID:Ibudilast, a phosphodiesterase inhibitor, ameliorates experimental autoimmune encephalomyelitis in Dark August rats. 1022 13

Type III and IV phosphodiesterase inhibitors (PDEIs) have recently been shown to suppress the production of TNF-alpha in several types of cells. In the present study, we have shown that all the types of PDEIs, from type I- to V-specific and non-specific, suppress the production of TNF-alpha by mouse microglia stimulated with lipopolysaccharide (LPS) in a dose-dependent manner. Certain combinations of three different types of PDEIs synergistically suppressed TNF-alpha production by microglia at a very low concentration (1 microM). Since some PDEIs reportedly pass through the blood-brain barrier (BBB), the combination of three PDEIs may be worth trying in neurological diseases, such as multiple sclerosis and HIV-related neurological diseases in which TNF-alpha may play a critical role. Some PDEIs also suppressed interleukin-I (IL-I) and IL-6 production by mouse microglia stimulated with LPS. In contrast, the production of IL-10, which is known to be an inhibitory cytokine, was upregulated by certain PDEIs. The suppression of TNF-alpha and induction of IL-10 were confirmed at the mRNA level by RT-PCR. PDEIs may be useful anti-inflammatory agents by downregulating inflammatory cytokines and upregulating inhibitory cytokines in the central nervous system. (CNS).
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PMID:Effects of phosphodiesterase inhibitors on cytokine production by microglia. 1033 22

Vesnarinone (OPC-8212) is a synthetic quinolinone derivative with inotropic and immunomodulatory effects. Vesnarinone has been shown to inhibit tumor necrosis factor-alpha (TNF alpha) produced by mitogen stimulated macrophages, and to inhibit phosphodiesterase (PDE) type III in cardiac muscle. TNF alpha and interferon-gamma (IFNgamma) have been implicated in the pathogenesis of autoimmune diseases, and both cytokines are targets for therapeutic intervention. IFNgamma can enhance autoimmune disease through direct effects, and indirectly by priming macrophages to produce TNF alpha. In this study, we demonstrate that while vesnarinone enhances basal TNF alpha levels, it inhibits TNF alpha production in peripheral blood mononuclear cells from multiple sclerosis (MS) patients and healthy donors stimulated with lipopolysaccharide (LPS) or primed with IFNgamma and stimulated with suboptimal doses of LPS. In addition, vesnarinone inhibited TNF alpha production in primary adult human microglial cultures. However, in contrast to rolipram, another TNF alpha inhibiting agent, vesnarinone failed to inhibit TNF alpha production by myelin basic protein specific T-cell lines. As oral TNF inhibitors are currently being considered in the USA for clinical application in MS, the implications of our findings on the development of vesnarinone for treatment of MS are discussed.
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PMID:The effect of vesnarinone on TNF alpha production in human peripheral blood mononuclear cells and microglia: a preclinical study for the treatment of multiple sclerosis. 1040 67

Preclinical and clinical studies of phosphodiesterase 4 inhibitors have shown that these agents may find utility in a wide range of inflammatory disorders, including asthma, chronic obstructive pulmonary disease, atopic dermatitis, rheumatoid arthritis, multiple sclerosis and various neurological disorders. The future of this class of drugs will depend upon the ability to demonstrate a reasonable safety margin against emesis and other typical phosphodieserase (PDE4) side effects, as well as in identification of the inflammatory disorder(s) most relevant to PDE4 inhibition.
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PMID:Phosphodiesterase 4 inhibitors as novel anti-inflammatory agents. 1041 56

Proinflammatory cytokines, secreted by autoreactive CD4+ T lymphocytes may contribute to the pathogenesis of several human autoimmune diseases, including multiple sclerosis (MS). Since the antigen specificities of these T cells are not known at present, therapeutic strategies aiming at common effector pathways, in particular cytokine secretion, may be more feasible in the near future. We have studied the influence of the isoenzyme-specific phosphodiesterase inhibitor rolipram on the proliferation and cytokine secretion of human myelin basic protein-specific T cell clones. The inhibition of proliferation correlated with interference with the IL-2/IL-2 receptor system, while the effects of rolipram on several T helper 1-(TNF-alpha, TNF-beta, IFN-gamma) and T helper 2-like cytokines (IL-4, IL-13) as well as IL-10 revealed an interesting drug profile, with preferential inhibition of TNF-beta, TNF-alpha and IL-10. This profile suggest that rolipram differs from other currently used immunomodulatory drugs.
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PMID:Differential effects of phosphodiesterase type 4-specific inhibition on human autoreactive myelin-specific T cell clones. 1043 48

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease with pathological features reminiscent of those seen in multiple sclerosis and thus serves as an animal model for this disease. Inhibition of type IV phosphodiesterase (PDE IV) in animals with this disease has been shown to result in amelioration of disease symptoms. Here we describe the immunomodulatory activity of the novel potent and selective PDE IV inhibitor mesopram. In vitro, mesopram selectively inhibits the activity of type 1 helper T (Th1) cells without affecting cytokine production or proliferation of type 2 helper T (Th2) cells. Administration of mesopram to rodents inhibits EAE in various models. Clinically, EAE is completely suppressed by mesopram in Lewis rats. This is accompanied by a reduction of inflammatory lesions in spinal cord and brain. RT-PCR analysis revealed a marked reduction in the expression of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the brains of these animals. Furthermore, the ex vivo production of Th1 cytokines by activated spleen cells derived from mesopram-treated animals is significantly reduced compared to vehicle-treated controls. Amelioration of the clinical symptoms is also observed during chronic EAE in mesopram-treated SJL mice as well as in relapsing-remitting EAE in SWXJ mice using a therapeutic treatment regimen. These data demonstrate the anti-inflammatory activity of mesopram and provide a rationale for its clinical development.
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PMID:The type IV phosphodiesterase specific inhibitor mesopram inhibits experimental autoimmune encephalomyelitis in rodents. 1090 Mar 47

Phosphodiesterase (PDE) enzymes are responsible for the inactiviation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Phosphodiesterase 4 (PDE4) is a cAMP specific phosphodiesterase expressed in inflammatory cells such as eosinophils. Inhibition of PDE4 results in an elevation of cAMP in these cells, which in turn downregulates the inflammatory response. The anti-inflammatory effects of PDE4 inhibitors have been well documented both in vitro and in vivo in a range of animal models. The potential use of PDE4 inhibitors as anti-inflammatory agents for the treatment of diseases such as asthma, chronic obstructive pulmonary disease (COPD) and multiple sclerosis (MS), has received considerable attention from the pharmaceutical industry but to date, there are no selective PDE4 inhibitors on the market. Early PDE4 inhibitors, such as rolipram suffered from dose limiting side effects, including nausea and emesis, which severely restricted their therapeutic utility. Second generation compounds such as cilomilast have been identified with reduced side effect liability. Indeed, cilomilast is showing good therapeutic effects in clinical trials for asthma and COPD and represents the most advanced selective PDE4 inhibitor for any indication. The utility of this class of inhibitor in other inflammatory diseases is less well advanced. However, data in animal models of rheumatoid arthritis (RA) and MS suggests that there is also significant potential for PDE4 inhibitors as treatments for these diseases and the results of clinical trials in these disease areas are eagerly awaited.
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PMID:Update on the therapeutic potential of PDE4 inhibitors. 1177 17

Nitric oxide (NO) is considered to play a crucial role in the development of various pathological processes in the CNS, such as neuronal degeneration, inflammation and demyelination. In order to search for the agents which suppress NO production in the CNS, we examined the effects of one of the agents which elevate cyclic AMP production, phosphodiesterase inhibitors (PDEIs), on NO production by glial cells in vitro. All the types of PDEIs, from type I- to V-specific and non-specific, suppressed the production of NO by mouse microglia and astrocytes stimulated with lipopolysaccharide, in a dose-dependent manner. Suppression of inducible NO synthase by PDEIs was confirmed by the expression of mRNA by RT-PCR. Although it required 10 microM or higher concentration to effectively suppress NO production in vitro, certain combinations of three different PDEIs synergistically suppressed NO production by astrocytes at 1 microM which could be obtained in vivo at usual therapeutic doses. Similary, combinations of three PDEIs at 1 microM synergistically increased intracellular cAMP in astrocytes. The suppressive effects of PDEIs on NO production were abolished by addition of tumor necrosis factor alpha (TNFalpha). Thus, the main suppression mechanism of NO might be indirect through suppression of TNFalpha. Since some PDEIs are reported to pass through the blood-brain-barrier, the combination of three PDEIs may be worth trying in neurological diseases, such as multiple sclerosis, human immunodeficiency virus-related neurological diseases and other neurodegenerative disorders in which NO may play a crucial role.
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PMID:Effect of phosphodiesterase inhibitors on nitric oxide production by glial cells. 1200 73


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