The inhibitory effects of a positive inotropic quinolinone derivative, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone (OPC-8212), on bone-marrow progenitor cells and peripheral lymphocytes

Busch, Friedrich W.; Tillmann, A.; Becker, E. W.; Owsianowski, M; Berg, Peter A.

doi:10.1007/bf00265927

Cited by 23 publications

(6 citation statements)

References 23 publications

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“…The lower dose of vesnarinone probably reduces mortality through specific dose-dependent pharmacological properties, and these may not be the same as those responsible for the inotropic effects, and may even be independent of the phosphodiesterase inhibition. One possible clue is provided by a recent report that vesnarinone inhibits the production of cytokines, some of which may play a key part in the pathogenesis of heart failure [52].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the effect of phosphodiesterase inhibitors on mortality in chronic heart failure patients

Nony

Boissel

Lièvre

et al. 1994

Eur J Clin Pharmacol

114

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We examined the influence of phosphodiesterase inhibitors (PDIs) on mortality in patients with overt chronic heart failure. A total of 13 randomised, placebo-controlled trials of PDIs involving 2808 patients were selected. Meta-analysis, using data for all patients, showed that there was a non-significant (P = 0.16) increase of about 17% in the mortality rate of patients receiving a PDI [odds ratio (OR) 1.17, 95% confidence interval (CI) 0.94-1.46]. However, the observed treatment effects were found to be heterogeneous due to the results from the trials on vesnarinone. The heterogeneity became non-significant (P = 0.77) when these trials were removed, and a significant increase in the mortality rate was observed under treatment with the other PDIs (OR 1.41, 95% CI 1.11-1.79). In the subgroups of patients with or without additional vasodilator (VD) treatment, similar results were observed (PDI with VD: OR 1.3, 95% CI 1.03-1.7; PDI without VD: OR 2.04, 95% CI 1.1-3.8). These results indicate that PDIs (with the exception of vesnarinone) should not be prescribed for long-term use in patients with overt chronic heart failure. Additional vasodilator treatment in patients receiving PDIs for chronic heart failure does not explain the increased mortality seen with PDIs. This toxicity must, therefore, arise by other mechanisms. Further experimental and clinical evaluation is needed to confirm the beneficial influence of vesnarinone on survival in chronic heart failure patients and to identify the mechanism(s) differentiating this agent's therapeutic effect from that of other PDIs.

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Section: Discussionmentioning

confidence: 99%

Evaluation of the effect of phosphodiesterase inhibitors on mortality in chronic heart failure patients

Nony

Boissel

Lièvre

et al. 1994

Eur J Clin Pharmacol

114

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“…It exhibits immunomodulatory activities, such as suppression of TNF-induce activation of NF-κB [37], the suppression of NK cell activity [38,39], endotoxin-induced production of inflammatory cytokines [40][41][42][43][44][45], nitric oxide synthetase from macrophage and cardiac myocytes [46,47], and abrogation of E-selectin expression in endothelial cells [41]. Vesnarinone also causes agranulocytosis by impairing stromal functions and cytokine inhibition [48,49], and in- Nerve growth factor (NGF) [15] Retinoic acid (RA) [10,13,18,22,25,[27][28][29][30] Dimethyl sulfoxide (DMSO) [23] Active form vitamin D3 [11,21] Peroxisome proliferator-activated receptorγ (PPARγ) [26,32] 12-0-tetradecanoylphorbol 13-acetate (TPA) [13] Hexamethylene-bis-acetamide (HMBA) [23] Transforming growth factor-β (TGF-β) [24] Interferon-α (INF-α) [23] Interferon-β (INF-β) [13] Butyric acid (BA) [20,21,23] Cyclic-AMP (cAMP) [14,16] Histone deacetylase inhibitor [19] Vesnarinone [1, 2, 33, 53-56, 64-73, 79-81] hibits immune-mediated hepatic injury [50]. In addition, ...…”

Section: Molecular Structure and Biological Activity Of Vesnarinonementioning

confidence: 99%

Differentiation-Inducing Therapy for Solid Tumors

Kawamata

Tachibana²,

Fujimori³

et al. 2006

CPD

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Treating malignant tumor through the induction of cell differentiation has been an attractive concept, but clinical development of differentiation-inducing agents to treat malignant tumor, especially for solid tumors has been limited to date. Nerve growth factor, all trans retinoic acid, dimethyl sulfoxide, active form vitamin D(3), peroxisome proliferator-activated receptorgamma, 12-0-tetradecanoylphorbol 13-acetate, hexamethylene-bis-acetamide, transforming growth factor-beta, butyric acid, cAMP, and vesnarinone are known to have a differentiation-inducing capability on solid tumors in vitro and/or in vivo. Moreover some of the differentiation-inducing agents have been used for treating patients with solid tumor, but the therapeutic effect of the differentiation-inducing agents on solid tumor is not strong when compared with that of conventional chemotherapeutic agents. However, because most of the differentiation-inducing agents can potentiate the effect of conventional chemotherapy or radiation therapy, combination of differentiation-inducing therapy with conventional chemotherapy or radiation therapy might be used as a second- or third-line therapy in patients with advanced cancer. Furthermore, analysis of the molecular mechanisms of the tumor differentiation therapy might provide selective and targeted molecules for novel cancer therapy.

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“…The concentration of LPS was determined in accordance with a previous study. 10,11) The OPC-8212 cultures were performed with OPC-8212 at a concentration of 30 µg / ml, which was comparable to the serum concentration obtained when 60 mg / day OPC-8212 is administered to humans, 12) in the above-described LPS culture medium. After 24-hour cultures under each of the 3 culture conditions, we measured the α1(III) mRNA expression, and TNFα and TGF-β1 concentrations.…”

Section: Methodsmentioning

confidence: 74%

OPC-8212, a Quinoline Derivative, Counteracts the Reduction in Type III Collagen mRNA due to Lipopolysaccharides in Cultured Rat Cardiac Fibroblasts.

et al. 2001

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SUMMARYFibrillar collagen plays an essential role in ventricular remodeling, which is a major prognostic factor in various heart diseases. Inflammatory cytokines, including tumor necrosis factor α (TNFα), have been reported to play a role in various heart diseases and OPC-8212, a quinolinone derivative, has been demonstrated to reduce TNFα production. No studies have examined the effects of OPC-8212 on collagen metabolism in connection with inflammatory cytokine and growth factors. Using lipopolysaccharides as a tool to enhance TNFα, we examined the effects of OPC-8212 on the expression of type III collagen mRNA [α1(III)] in cultured neonatal rat cardiac fibroblasts. We also measured the concentration of TNFα and transforming growth factor β (TGFβ) in the cultured medium. Northern blot analysis revealed that LPS reduced the expression of α1(III) mRNA, and OPC-8212 counteracted this reduction (on average 25% above the reduced level by LPS stimulation). LPS enhanced the TNFα concentration in the medium, and OPC-8212 inhibited this enhancement. LPS increased the TGF-β1 concentration in the cultured medium, while OPC-8212 did not affect this increase. In summary, OPC-8212 counteracted the reduction in type III collagen mRNA expression by LPS accompanied by suppression of the increase in TNFα. (Jpn Heart J 2001; 42: 125-134)

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The inhibitory effects of a positive inotropic quinolinone derivative, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone (OPC-8212), on bone-marrow progenitor cells and peripheral lymphocytes

Cited by 23 publications

References 23 publications

Evaluation of the effect of phosphodiesterase inhibitors on mortality in chronic heart failure patients

Evaluation of the effect of phosphodiesterase inhibitors on mortality in chronic heart failure patients

Differentiation-Inducing Therapy for Solid Tumors

OPC-8212, a Quinoline Derivative, Counteracts the Reduction in Type III Collagen mRNA due to Lipopolysaccharides in Cultured Rat Cardiac Fibroblasts.

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