pyrimidinones and Heart-Failure

The MEK inhibitor trametinib was approved in 2013 for the treatment of unresectable or metastatic melanoma with a BRAF V600E mutation, the most common pathogenic mutation in melanoma. Trametinib blocks activation of ERK1/2, inhibiting cell proliferation in melanoma. ERK1/2 also protects against multiple types of cardiac insult in mouse models. Trametinib improves survival in melanoma patients, but evidence of unanticipated cardiotoxicity is emerging. Here we describe the case of a patient with metastatic melanoma who developed acute systolic heart failure after trametinib treatment and present the results of the literature review prompted by this case. A patient with no cardiac history presented with a 6.5-mm skin lesion and was found to have metastatic BRAF V600E melanoma. Combination treatment with trametinib and the BRAF inhibitor, dabrafenib, was initiated. The patient's pre-treatment ejection fraction was 55-60%. His EF declined after 13 days and that was 40% 1 month after treatment. Two months after initiating trametinib, he developed dyspnea and fatigue. We conducted a chart review in the electronic medical record. We conducted a PubMed search using trametinib/adverse effects AND ("heart failure" OR "left ventricular dysfunction" OR hypertension OR cardiotoxicity OR mortality). We also queried the FDA Adverse Events Reporting System for reports of cardiomyopathy, ejection fraction decrease, and left ventricular dysfunction associated with trametinib between January 1, 2013, and July 20, 2017. The literature search retrieved 19 articles, including clinical trials and case reports. Early clinical experience with the MEK inhibitor trametinib suggests that its clinical efficacy may be compromised by cardiotoxicity. Further studies in humans and animals are required to determine the extent of this adverse effect, as well as its underlying mechanisms.

Topics: Aged; Heart Failure; Humans; Male; Melanoma; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Stroke Volume

About 50% of patients with meta- static or inoperable melanoma carry a tumour with BRAF V600 mutation.The drug of first choice for these patients is vemurafenib, a BRAF inhibitor, which appears to prolong survival by a few months. Dabrafenib is a vemurafenib me-too with a slightly different known profile of adverse effects. Trametinib, a MEK inhibitor, is now authorised in the European Union for use in this setting, either as monotherapy or in combination with dabrafenib (marketed by the same company). Trametinib monotherapy has not been compared to BRAF inhibitor monotherapy. In a randomised, unblinded trial versus cytotoxic drugs in 322 patients, the median survival time did not differ statistically between the groups (15.6 versus 11.3 months; p = 0.09), but 65% of patients in the chemotherapy group received trametinib after disease pro- gression, making it more difficult to detect a difference between the groups. In an unblinded randomised controlled trial in 704 patients who had never received treatment for metastatic or inoperable disease, the trametinib + dabrafenib combination prolonged median survival by about 8 months more than vemurafenib. In another double-blind randomised controlled trial in 423 patients, median survival was about 6 months longer with trametinib + dabrafenib than with placebo + dabrafenib. The trametinib+ dabrafenibcombination was poorly effective after BRAF inhibitor failure in non-comparative trials including a few dozen patients in which the only endpoint was tumour response. Trametinib has many adverse effects, some of which can be life-threatening, such as heart failure, deep vein thrombosis, bleeding (including intracranial haemorrhage), neutropenia, and gastrointestinal perforation. Trametinib also causes retinal disorders and pneumonitis. Combining trametinib with dabrafenib reduces the risk of hyperkeratosis and skin cancer associated with dabrafenib, but increases the frequency of fever (including very high fever). Trametinib interactions mainly involve additive effects or antagonism. In practice, when a patient with metastatic or inoperable BRAF V600-positive melanoma is willing to accept the significant toxicity of trametinib in the hope of gaining several extra months of life, the trametinib + dabrafenib combination is a first-line option.

Topics: Heart Failure; Hemorrhage; Humans; Imidazoles; Intestinal Perforation; Intracranial Hemorrhages; MAP Kinase Kinase 1; Melanoma; Neutropenia; Oximes; Pneumonia; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retinal Diseases; Skin Neoplasms; Survival Rate; Venous Thrombosis

This paper describes our continued efforts in the area of small-molecule apelin receptor agonists. Recently disclosed compound

Topics: Animals; Apelin Receptors; Dogs; Drug Discovery; Heart Failure; Humans; Pyrimidinones; Rats; Structure-Activity Relationship

Cardiovascular adverse events (CVAEs) associated with BRAF inhibitors alone versus combination BRAF/MEK inhibitors are not fully understood.. This study included all adult patients who received BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) or combinations BRAF/MEK inhibitors (vemurafenib/cobimetinib; dabrafenib/trametinib; encorafenib/binimetinib). We utilized the cross-sectional FDA's Adverse Events Reporting System (FAERS) and longitudinal Truven Health Analytics/IBM MarketScan database from 2011 to 2018. Various CVAEs, including arterial hypertension, heart failure (HF), and venous thromboembolism (VTE), were studied using adjusted regression techniques.. In FAERS, 7752 AEs were reported (40% BRAF and 60% BRAF/MEK). Median age was 60 (IQR 49-69) years with 45% females and 97% with melanoma. Among these, 567 (7.4%) were cardiovascular adverse events (mortality rate 19%). Compared with monotherapy, combination therapy was associated with increased risk for HF (reporting odds ratio [ROR] = 1.62 (CI = 1.14-2.30); p = 0.007), arterial hypertension (ROR = 1.75 (CI = 1.12-2.89); p = 0.02) and VTE (ROR = 1.80 (CI = 1.12-2.89); p = 0.02). Marketscan had 657 patients with median age of 53 years (IQR 46-60), 39.3% female, and 88.7% with melanoma. There were 26.2% CVAEs (CI: 14.8%-36%) within 6 months of medication start in those receiving combination therapy versus 16.7% CVAEs (CI: 13.1%-20.2%) among those receiving monotherapy. Combination therapy was associated with CVAEs compared to monotherapy (adjusted HR: 1.56 (CI: 1.01-2.42); p = 0.045).. In two independent real-world cohorts, combination BRAF/MEK inhibitors were associated with increased CVAEs compared to monotherapy, especially HF, and hypertension.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Carbamates; Carcinoma, Non-Small-Cell Lung; Cardiotoxicity; Cardiovascular Diseases; Colonic Neoplasms; Cross-Sectional Studies; Female; Heart Failure; Humans; Hypertension; Imidazoles; Lung Neoplasms; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Registries; Regression Analysis; Skin Neoplasms; Sulfonamides; Vemurafenib; Venous Thromboembolism; Young Adult

In heart failure (HF) caused by hypertension, the myocyte size increases, and the cardiac wall thickens. A low-molecular-weight compound called ICG001 impedes β-catenin-mediated gene transcription, thereby protecting both the heart and kidney. However, the HF-preventive mechanisms of ICG001 remain unclear. Hence, we investigated how ICG001 can prevent cardiac hypertrophy and fibrosis induced by transverse aortic constriction (TAC). Four weeks after TAC, ICG001 attenuated cardiac hypertrophy and fibrosis in the left ventricular wall. The TAC mice treated with ICG001 showed a decrease in the following: mRNA expression of brain natriuretic peptide (Bnp), Klf5, fibronectin, β-MHC, and β-catenin, number of cells expressing the macrophage marker CD68 shown in immunohistochemistry, and macrophage accumulation shown in flow cytometry. Moreover, ICG001 may mediate the substrates in the glycolysis pathway and the distinct alteration of oxidative stress during cardiac hypertrophy and HF. In conclusion, ICG001 is a potential drug that may prevent cardiac hypertrophy and fibrosis by regulating KLF5, immune activation, and the Wnt/β-catenin signaling pathway and inhibiting the inflammatory response involving macrophages.

Topics: Animals; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Cardiomegaly; Cardiomyopathies; Fibrosis; Glycolysis; Heart Failure; Inflammation; Kruppel-Like Transcription Factors; Macrophages; Membrane Proteins; Mice; Myocardium; Oxidative Stress; Phosphoproteins; Pyrimidinones; Wnt Signaling Pathway

Topics: Acute Disease; Adult; Antineoplastic Agents; Granuloma; Heart Failure; Humans; Imidazoles; Lymphatic Metastasis; Male; Melanoma; Myocarditis; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

The clinical use of HIV protease inhibitors is associated with insulin resistance and other metabolic changes that increase long-term cardiovascular risk. Since the failing heart has increased reliance on glucose, the influence of drug exposure on glucose homeostasis, myocardial glucose uptake, cardiac function, and survival was determined in TG9 mice, an established transgenic model of dilated cardiomyopathy generated by cardiac-specific overexpression of Cre-recombinase, as these animals progressed to overt heart failure. Beginning on day of life 75, TG9 mice and nontransgenic littermate controls were given a daily 10 mg/kg intraperitoneal injection of HIV protease inhibitors (ritonavir, lopinavir/ritonavir 4:1, atazanavir, atazanavir/ritonavir 4:1) or vehicle. Glucose tolerance testing, measurement of in vivo myocardial 2-deoxyglucose uptake, and echocardiography were performed before and 30 min following drug administration. The progression of dilated cardiomyopathy in TG9 animals was accompanied by impaired glucose tolerance, which was acutely exacerbated by exposure to ritonavir. Ritonavir and lopinavir precipitated acute, decompensated heart failure and death from pulmonary edema in TG9 mice. However, atazanavir, which does not inhibit glucose transport, had no effect. These studies demonstrate that, in the presence of dilated cardiomyopathy, HIV protease inhibitors that impair glucose transport induce acute, decompensated heart failure. The potential for HIV protease inhibitors to contribute to or exacerbate cardiomyopathy in human patients warrants further investigation.

Topics: Animals; Atazanavir Sulfate; Blood Glucose; Cardiomyopathy, Dilated; Deoxyglucose; Disease Models, Animal; Echocardiography; Glucose Tolerance Test; Glucose Transporter Type 4; Heart Failure; HIV Protease Inhibitors; Humans; Insulin Resistance; Lopinavir; Mice; Myocardium; Oligopeptides; Pulmonary Edema; Pyridines; Pyrimidinones

Class III antiarrhythmic agents have been widely used to suppress ventricular tachyarrhythmias in patients with heart failure because they have been shown to have positive inotropic effects as well. However, it remains to be examined whether those agents also exert positive inotropic effects in failing hearts. We addressed this important issue in a rat model of heart failure. We used Nifekalant as a representative class III antiarrhythmic agent. Four weeks after a s.c. injection of 60 mg/kg monocrotaline (MCT) or vehicle (Ctr) into rats, we obtained trabeculae from right ventricles and measured the developed force and intracellular Ca(2+) ([Ca(2+)](i)) by the fura-2 microinjection method. The sarcoplasmic reticulum (SR) Ca(2+) content was assessed by the rapid-cooling contracture (RCC) technique. MCT rats exhibited right ventricular hypertrophy induced by pressure overload. The protein expression of SR Ca(2+) ATPase type 2 (SERCA2) and the SERCA2/phospholamban ratio in MCT rats was lower with a slower decline of Ca(2+) transients and a reduced amplitude of RCCs. Nifekalant concentration-dependently increased the force, peak [Ca(2+)](i), and the amplitude of RCCs in Ctr rats but not in MCT rats with identical prolongation of the action potential. Under the SR inhibited with cyclopiazonic acid and ryanodine, Nifekalant increased the force in Ctr rats but not in MCT rats. These results indicate that the positive inotropic effects of Nifekalant is reduced in failing hearts, probably due to the depressed SR Ca(2+) uptake and reduced reserve of the trans-sarcolemmal Ca(2+) transport, warranting a caution in the antiarrhythmic therapy with a class III antiarrhythmic agent in heart failure.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Calcium; Cardiotonic Agents; Disease Models, Animal; Heart Failure; Monocrotaline; Myocardial Contraction; Pyrimidinones; Rats; Rats, Sprague-Dawley; Sarcoplasmic Reticulum

Nifekalant is a class III antiarrhythmic drug, which prolongs the refractory period of the atrial and ventricular myocardium, without negative inotropic action. Intravenous nifekalant was administered in four patients with atrial tachyarrhythmia and severe heart failure to terminate or prevent atrial tachyarrhythmia.. Two of three episodes of atrial tachyarrhythmia were terminated by intravenous nifekalant (0.22 to 0.30 mg/kg) administration. Continuous intravenous infusion of nifekalant (0.15 to 0.40 mg/kg/hr) during six episodes to maintain the sinus rhythm, prevented recurrence of atrial tachyarrhythmia in five episodes in which prolongation of the QTc interval was observed to more than 450 msec. None of the patients showed worsening of the hemodynamics during treatment. One patient developed polymorphic ventricular tachycardia, which deteriorated into ventricular fibrillation.. Nifekalant may be effective for treating atrial tachyarrhythmia in patients with severe heart failure. Further clinical studies are needed to confirm these findings.

Topics: Adult; Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Female; Heart Failure; Humans; Infusions, Intravenous; Male; Middle Aged; Pyrimidinones; Tachycardia

The effects of FK664, a novel positive inotropic agent, and enoximone on pentobarbital-induced heart failure were compared in dog heart-lung preparations. Both FK664 and enoximone improved the cardiac function curve in a dose-dependent manner and restored it to the control level at drug concentrations of 1 microgram/ml and 10 micrograms/ml, respectively. Therefore, the cardiotonic potency of FK664 appears to be 10 times that of enoximone. These agents were almost equal in force-rate separation of cardiac effect. Neither of the agents produced arrhythmia at any dose tested. These results suggest that FK664 may be a potent cardiotonic agent for the treatment of heart failure.

Topics: Animals; Cardiotonic Agents; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Enoximone; Extracorporeal Circulation; Heart; Heart Failure; Imidazoles; Lung; Pyrimidinones