piperidines and Myocarditis

Unstable coronary artery disease (CAD) is a multifactorial disease involving both thrombotic and inflammatory processes. We have assessed the time-course and the influence of thrombin inhibitors on changes in fibrinogen and C-reactive protein levels, and their relation to myocardial ischaemia in unstable CAD.. Three hundred and twenty patients were randomized to 72 h infusion with three different doses of inogatran, a direct thrombin inhibitor, or unfractionated heparin. There were no significant differences between the treatment groups in fibrinogen or C-reactive protein levels. Overall, the fibrinogen levels were significantly increased in the first 24-96 h and still elevated at 30 days. The C-reactive protein levels showed a more pronounced increase during the first 24-96 h, but then markedly decreased over 30 days. Troponin-positive compared to troponin-negative patients had higher fibrinogen and C-reactive protein levels up to 96 h, although there was an increase compared to pre-treatment levels in both groups. A high fibrinogen level (pre-treatment top tertile) was associated with an increased rate of death or myocardial (re-)infarction at 30 days, 13% vs 5.6%, P=0.03, and increased long-term mortality. A high C-reactive protein level was related to increased 30-day mortality, 4% vs 0%, P=0.01.. Myocardial cell injury was related to a high degree of inflammation, only some of which is an acutephase response due to tissue damage. The rise in fibrinogen was sustained, which might reflect low grade inflammation with long-term risk of thrombosis. The transient elevation of C-reactive protein levels might indicate a propensity to a pronounced inflammatory response and is associated with increased mortality.

Topics: Adult; Aged; Aged, 80 and over; Antithrombins; C-Reactive Protein; Coronary Disease; Female; Fibrinogen; Follow-Up Studies; Glycine; Humans; Male; Middle Aged; Myocardial Infarction; Myocarditis; Piperidines; Survival Analysis; Troponin T

We assessed the antiarrhythmic effectiveness, therapeutic plasma concentrations and adverse effects of pirmenol in 16 patients with frequent (mean 933 h-1) premature ventricular complexes (PVC). Progressive increase in dose to a maximum of 200 mg twice daily suppressed PVC in a majority of patients. By preset criteria 11 patients (69%) exhibited an effective suppression of PVCs whereas in 5 patients (31%) the suppression was inadequate despite therapeutic plasma concentrations. The responders exhibited an 87% mean reduction of PVCs and a 97% reduction in repetitive PVC. This therapeutic effectiveness was verified against placebo by repetitive 24-hour ECG monitorings recorded in a double-blind cross-over fashion. The plasma trough concentration during the effective dose averaged 1.31 +/- 0.67 mg-1 (SD). The efficacy was maintained with the twice daily regimen despite an elimination half life of 6.3 +/- 1.7 h (SD) but a slight decrease in PVC suppression was observed towards the end of the administration interval. Pirmenol was well tolerated but aggravation of the arrhythmia occurred in one patient who shared an associated excessive prolongation of the Q-T interval, a feature observed with quinidine-like class I agents.

Topics: Anti-Arrhythmia Agents; Cardiac Complexes, Premature; Coronary Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Evaluation; Electrocardiography; Female; Humans; Kinetics; Male; Myocarditis; Piperidines; Tachycardia

Immune therapy has ushered in a new era of tumor treatment, at the expense of immune-related adverse events, including rare but fatal adverse cardiovascular events, such as myocarditis. Steroids remain the cornerstone of therapy for immune-related myocarditis, with no clear consensus on additional immunosuppressive treatment for steroid-refractory cases yet.. Here, we report a patient with stage IV nasopharyngeal carcinoma who developed immune-related myocarditis in the fourth course of therapy with immune checkpoint inhibitors. The patient presented with precordial discomfort with elevation of cardiac enzymes and interleukin-6, atypical electrocardiographic abnormalities, and reduced left ventricular ejection fraction. Coronary computed tomography angiography excluded the possibility of acute coronary syndrome. The therapy with tofacitinib targeting the Janus kinase-signal transducer and activator of transcription signal pathway was successfully conducted, since there was no significant improvement in troponin under high-dose steroid and intravenous immunoglobulin treatment. The patient recovered without major adverse cardiac events during hospitalization.. The safety and efficacy of tofacitinib in a patient with steroid-refractory immune-related myocarditis were investigated, hoping to provide a basis for prospective therapeutic strategies. Tofacitinib led to remarkable remissions in primary autoimmune disease by blocking the inflammatory cascade, indicating its potential therapeutic use in immune-related adverse events.

Topics: Humans; Immune Checkpoint Inhibitors; Immunoglobulins, Intravenous; Interleukin-6; Janus Kinases; Myocarditis; Neoplasms; Piperidines; Pyrimidines; Steroids; Stroke Volume; Troponin; Ventricular Function, Left

Viral myocarditis (VMC) is an inflammation of heart muscle in infants and young adolescents. This study explored the function of halofuginone (HF) in Coxsackievirus B3 (CVB3) -treated suckling mice. HF-treated animal exhibited higher survival rate, lower heart/body weight, and more decreased blood sugar concentration than CVB3 group. HF also reduced the expressions of interleukin(IL)-17 and IL-23 and the numbers of Th17 cells. Moreover, HF downregulated pro-inflammatory cytokine levels and increased anti-inflammatory cytokine levels. The expressions of transforming growth factor(TGF-β1) and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) p65/ tumor necrosis factor-α (TNF-α) proteins were decreased by HF as well. Finally, the overexpression of TGF-β1 counteracted the protection effect of HF in CVB3-treated suckling mice. In summary, our study suggests HF increases the survival of CVB3 suckling mice, reduces the Th17 cells and pro-inflammatory cytokine levels, and may through downregulation of the TGF-β1-mediated expression of NF-κB p65/TNF-α pathway proteins. These results offer a potential therapeutic strategy for the treatment of VMC.

Topics: Animals; Anti-Inflammatory Agents; Coxsackievirus Infections; Enterovirus B, Human; Mice; Mice, Inbred BALB C; Myocarditis; NF-kappa B; Piperidines; Quinazolinones; Signal Transduction; Th17 Cells; Transforming Growth Factor beta1

The study aimed to investigate the variance of myocardial and serum Nampt levels and the role of Nampt inhibition by FK866 in relatively mild endotoxemia- and severe endotoxemia-induced myocardial injury. Different doses of LPS were injected intraperitoneally to establish relatively mild endotoxemia (4mg/kg) and severe endotoxemia (20mg/kg). FK866 (10mg/kg b.w.) was injected intraperitoneally at hour one after LPS injection. The hearts were isolated from rats at hour six after LPS treatment and mounted in a Langendorff setup to measure cardiac function. Myocardial expression of Nampt was determined with immunohistochemistry assay and western blot. Serum Nampt level and myocardial TNF-α level were determined with ELISA. The myocardial level of TNF-α mRNA was detected with RT-PCR. The degree of myocardial oxidative injury was reflected by measuring lipid peroxidation and GSH/GSSG ratio. The apoptosis of cardiomyocytes was determined with detecting caspase-3 activity and with TUNEL assay. Myocardial expression of Nampt was markedly increased in 4mg/kg LPS-induced endotoxemia but decreased in 20mg/kg LPS-induced endotoxemia. Serum Nampt level was consistently up-regulated in both severities of endotoxemia. Inhibition of Nampt by FK866 reduced myocardial inflammation, oxidative injury and apoptosis of cardiomyocytes and improved cardiac function in 4mg/kg LPS-induced endotoxemia. In 20mg/kg LPS-induced endotoxemia, FK866 reduced myocardial inflammation, exacerbated apoptosis of cardiomyocytes, and failed to attenuate myocardial oxidative injury and cardiac dysfunction. In conclusion, the variance of myocardial Nampt expression may be associated with severities of endotoxemia. Nampt may play complicated roles and consequently application of Nampt inhibition should be critically evaluated in endotoxemia-induced myocardial impairment.

Topics: Acrylamides; Animals; Apoptosis; Caspase 3; Cells, Cultured; Disease Models, Animal; Disease Progression; Endotoxemia; Gene Expression Regulation; Lipid Peroxidation; Lipopolysaccharides; Male; Myocarditis; Myocardium; Myocytes, Cardiac; Nicotinamide Phosphoribosyltransferase; Oxidative Stress; Piperidines; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Nuclear factor kappa B (NF-kappaB) is activated by several factors, which increase the inflammatory response, and this activation, in turn, leads to the expression of several genes such as cytokines, and may play an important role in cardiovascular diseases.. The aim of the study is to examine the effect of SUN C8079, a newly synthesized NF-kappaB inhibitor in vitro and in vivo.. We examined the effects of SUN C8079 on the transcriptional responses of NF-kappaB, on activation of NF-kappaB in electrophoretic mobility shift assay, and on the gene expressions of tumor necrosis factor (TNF)-alpha and iNOS. We also studied effects of SUN C8079 on lethal endotoxemia and viral myocarditis in mice.. SUN C8079 inhibited the lipopolysaccharide (LPS)-induced expression of the genes of TNF-alpha and iNOS by inhibiting the activation of NF-kappaB in vitro. SUN C8079 inhibited the systemic release of TNF-alpha and improved mortality in LPS-treated mice. In addition to protecting mice against lethal endotoxemia, SUN C8079 prevented the development of myocarditis due to the encephalomyocarditis virus (EMCV), and inhibited the expressions of proinflammatory cytokines and the iNOS gene in cardiac tissues.. These findings suggest that the activation of NF-kappaB plays an important role in the pathogenesis of endotoxemia and viral myocarditis, and that the NF-kappaB inhibitor, SUN C8079, may be therapeutic in these disorders.

Topics: Animals; Cardiovirus Infections; Cell Nucleus; Cells, Cultured; DNA, Complementary; Encephalomyocarditis virus; Endotoxemia; Female; Gene Expression Regulation; Humans; In Vitro Techniques; Interleukin-1; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Myocarditis; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Piperidines; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Topics: Acute Disease; Adult; Aminopyrine; Benzophenones; Dipyrone; Drug Combinations; Drug Hypersensitivity; Humans; Male; Myocarditis; Piperidines; Pulmonary Edema