Disease relevance of vesnarinone

• Six months of therapy with 60 mg of vesnarinone per day resulted in lower morbidity and mortality and improved the quality of life of patients with congestive heart failure [1].
• Agranulocytosis occurred in 1.2 percent of the patients given 60 mg of vesnarinone per day and 0.2 percent of those given 30 mg of vesnarinone [2].
• CONCLUSIONS: Vesnarinone is associated with a dose-dependent increase in mortality among patients with severe heart failure, an increase that is probably related to an increase in deaths due to arrhythmia [2].
• The principal side effect associated with vesnarinone was reversible neutropenia, which occurred in 2.5 percent of the patients [1].
• In this study, using a murine model of acute viral myocarditis resulting from encephalomyocarditis virus infection, survival and myocardial damage were markedly improved by treatment with vesnarinone [3].

Psychiatry related information on vesnarinone

• We conclude, therefore, that inhibition of NK cell activity and suppression of cytokine production appear to be important immunological defense mechanisms which could contribute to the observed salutary effects of vesnarinone in the treatment of chronic heart failure [4].
• However, the improvement in patient self-assessment scores and the trend for improvement in ventricular arrhythmia profiles suggest that OPC-8212 may have some benefit for patients with congestive heart failure, but additional placebo-controlled, double-blind studies are necessary [5].

High impact information on vesnarinone

• The increase in mortality with vesnarinone was attributed to an increase in sudden death, presumed to be due to arrhythmia [2].
• Treatment of virus-induced myocardial injury with a novel immunomodulating agent, vesnarinone. Suppression of natural killer cell activity and tumor necrosis factor-alpha production [3].
• Therefore, we postulate that vesnarinone exerted its beneficial effects through an inhibition of natural killer cell activity, and that it serves as an immunomodulator providing new therapeutic possibilities for the treatment of viral myocarditis and/or immunological disorders [3].
• Effects of tumor necrosis factor gene polymorphisms on patients with congestive heart failure. VEST Investigators for TNF Genotype Analysis. Vesnarinone Survival Trial [6].
• Vesnarinone prolongs action potential duration without reverse frequency dependence in rabbit ventricular muscle by blocking the delayed rectifier K+ current [7].

Chemical compound and disease context of vesnarinone

• Estrogen is associated with improved survival in aging women with congestive heart failure: analysis of the vesnarinone studies [8].
• In this study, we used immunochemical techniques to compare the covalent binding of clozapine, vesnarinone, and procainamide (three drugs associated with agranulocytosis) to phorbol-12,13-myristate acetate (PMA)-activated human neutrophils in vitro and rat tissues in vivo [9].
• 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 [10].
• These results indicate that NKH477, unlike other new positive inotropic agents such as amrinone, milrinone, sulmazole and vesnarinone, did not worsen these arrhythmias; thus, NKH477 may be a useful positive inotropic agent with little arrhythmogenic effect [11].
• Effects of OPC-8212, a new positive inotropic agent, and dobutamine on left ventricular global and ischemic regional functions and coronary hemodynamics under coronary artery stenosis [12].

Biological context of vesnarinone

• The present study investigated the effect of vesnarinone as a novel immunomodulating agent on CD4XL-induced T-cell apoptosis [13].
• This apoptosis-inhibitory effect of vesnarinone was associated with the blocking of CD4XL-induced TNF-alpha IFN-gamma secretion and of Fas antigen upregulation [13].
• There was no impact of vesnarinone on gemcitabine concentrations, and the vesnarinone pharmacokinetics did not change with gemcitabine between weeks 1 and 2 [14].
• Vesnarinone, a synthetic quinolinone derivative used in the treatment of cardiac failure, exhibits immunomodulatory, anti-inflammatory, and cell growth regulatory properties [15].
• TNF-induced cytotoxicity, caspase activation, and lipid peroxidation were also abolished by vesnarinone [15].

Anatomical context of vesnarinone

• In rabbit papillary muscles, vesnarinone (10 micromol/L) prolonged APD at stimulation frequencies >0.2 Hz, whereas E-4031 (0.3 micromol/L) prolonged that in a reverse frequency-dependent manner [7].
• CONCLUSIONS: Vesnarinone may prolong the repolarization of human cardiac muscle without reverse frequency dependence, because I(Kr) is expressed in humans as well as in the rabbit [7].
• The addition of vesnarinone to peripheral blood mononuclear cells (PBMC) significantly inhibited CD4XL-induced lymphocyte apoptosis [13].
• This suggests that vesnarinone indirectly activates tyrosine phosphorylation of membrane proteins related to cell adhesion, which influences a signaling pathway linked to the stress fiber assembly in certain cell lines [16].
• C2-ceramide enhanced vesnarinone-induced inhibition of the ROI-scavenging enzyme catalase at the levels of protein and activity in HL-60 cells; in contrast, however, vesnarinone did not induce ceramide generation, oxidative damage, or catalase depletion in HL-60/ves cells, where vesnarinone could not induce apoptosis [17].

Associations of vesnarinone with other chemical compounds

• In vivo, the area under the concentration-time curve extrapolated to infinity (AUC[infinity]) of vesnarinone after pretreatment with erythromycin increased from 133 +/- 26 micrograms.hr/ml to 202 +/- 47 micrograms.hr/ml (p < 0.001), and the half-life increased from 36.5 +/- 9.6 hours to 46.2 +/- 9.2 hours (p < 0.01) [18].
• Taken together, the results suggest that vesnarinone induces myeloid cell apoptosis by increasing oxidative damage via ceramide-induced inhibition of catalase function [17].
• Amino acids important for the binding of vesnarinone were identified using alanine-scanning mutagenesis of residues believed to line the inner cavity of the HERG channel [19].
• The pharmacokinetics of vesnarinone and OPC-18692 were defined for 12 health white men after oral administration of 60 mg vesnarinone before and after CYP3A inhibition, which was produced by pretreatment with erythromycin [18].
• Here we investigate the molecular mechanisms of voltage-dependent block of human ether-a-go-go-related gene (HERG) delayed rectifier K(+) channels expressed in Xenopus laevis oocytes by quinidine, an antiarrhythmic drug, and vesnarinone, a cardiotonic drug [20].

Gene context of vesnarinone

• Effect of CYP3A inhibition on vesnarinone metabolism in humans [18].
• Whether CYP3A induction and altered CYP2E1 activity may also change the in vivo disposition of vesnarinone remains to be determined [18].
• These findings suggest that vesnarinone can suppress the angiogenesis and growth of oral squamous cell carcinoma cells by inhibiting the expression of VEGF and IL-8 involved in blockade of NF-kappaB activity [21].
• Induction of cyclin-dependent kinase inhibitor p21 in vesnarinone-induced differentiation of squamous cell carcinoma cells [22].
• Overall these results indicate that vesnarinone inhibits the growth of gastric cancer cells by down-regulating G1 cyclins and CDK2 to induce G0-G1 arrest through a pathway different from that of cyclin inactivation by p21(Waf1/Cip1) or p27Kip1 [23].

Analytical, diagnostic and therapeutic context of vesnarinone

• Effects of vesnarinone, a novel orally active inotropic agent with an immunosuppressive action, on experimental cardiac transplantation in rats [24].
• Prolongation of murine cardiac allograft survival with vesnarinone [25].
• The best of times, the worst of times: the wealth and poverty of heart failure pharmacotherapies: is there a role for vesnarinone [26]?
• Northern blot analysis showed a reduction of c-myc mRNA expression in HL60 cells by vesnarinone [27].
• However, OPC-8212 did not at any time induce ventricular fibrillation in dogs subjected to coronary ligation [28].

References