piperidines and Atrial-Fibrillation

Ibrutinib is a potent Bruton tyrosine kinase inhibitor and is an effective and well-tolerated treatment for a variety of lymphoid diseases. However, its use is associated with an increased incidence of atrial fibrillation ranging from 4% to 16%. New onset atrial fibrillation in cancer patients is associated with a significantly higher risk of heart failure and thromboembolism, even after adjusting for known risk factors. Ibrutinib also inhibits platelet activation and decisions regarding anticoagulation must be carefully weighed against this increased risk of bleeding. It is well-known that the anti-arrhythmic and antithrombotic strategy for atrial fibrillation related to ibrutinib has its own characteristics. Physicians should be familiar with the special management considerations imposed by this drug. Indeed, the co-prescription of therapy in combination with ibrutinib must be carefully weighed in view of its numerous drug interactions. We review the potential mechanisms and incidence of ibrutinib-associated atrial fibrillation.

Topics: Anticoagulants; Atrial Fibrillation; Humans; Piperidines; Pyrazoles; Pyrimidines

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; 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The use of ibrutinib is hampered by major bleeding events and atrial fibrillation. Speculating whether randomized controlled trials might underestimate the risk of adverse events in clinical practice, we conducted a systematic review and meta-analysis studying patients treated in any setting and indication. We systematically searched the literature using MEDLINE and EMBASE databases for case series, cohort studies, or randomized controlled trials and retrieved all data in parallel. Proportions of patients with adverse events were pooled in relevant subgroups using the binominal distribution and Freeman-Tukey double arcsine transformation. Among 2'537 records screened, 85 were finally included, comprising 7'317 patients. Methodological quality according to the Newcastle-Ottawa Scale was rated as moderate to poor with regard to bleeding events and atrial fibrillation; 106 studies were excluded because of missing data at all. Reported events varied substantially between 0 % and 78 % (any bleedings), 0 % and 25 % (major bleedings), and 0 % and 38 % (new-onset atrial fibrillation). Pooled estimates were 28 % (95 % confidence interval 22 %, 34 %), 3 % (2 %, 4 %), and 8 % respectively (7 %, 10 %). The risk of events was higher in studies with an older population, high ibrutinib dosage, thrombocytopenia, antithrombotic treatment, and retrospective studies. In conclusions, reporting of bleeding events and atrial fibrillation varied substantially among studies. These observations, in combination with the estimates obtained, suggest a relevant risk in clinical practice.

Topics: Adenine; Atrial Fibrillation; Humans; Piperidines; Pyrazoles; Pyrimidines; Retrospective Studies

The purpose of this review is to summarize the epidemiology, mechanisms, and management of cardiovascular complications of Bruton's Tyrosine Kinase inhibitors (BTKIs).. Ibrutinib increases the risk of atrial fibrillation, bleeding, and hypertension compared with non-BTKI therapies. The evidence to support an association between ibrutinib and other cardiovascular complications including ventricular tachyarrhythmias or cardiomyopathy is limited. Ibrutinib metabolism can be inhibited by some medications used to treat cardiovascular complications. The cardiovascular effects of more selective BTKIs, such as acalabrutinib, remain to be determined. Future research should address the mechanisms underlying the cardiovascular complications of BTKIs and how best to manage them. The risks and benefits of more selective BTKIs as compared with ibrutinib require further evaluation.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Atrial Fibrillation; Cardiotoxicity; Heart Failure; Hemorrhage; Humans; Hypertension; Piperidines; Protein Kinase Inhibitors; Tachycardia, Ventricular

Ibrutinib is a new first-line drug for treating chronic lymphocytic leukemia (CLL), and could change frontline treatment of CLL from traditional IV chemotherapy to oral targeted therapy. Lymphocytosis often worsens with initiation of ibrutinib, but typically resolves over 6 to 18 months. Though patients generally tolerate ibrutinib well, the drug can cause adverse reactions including hypertension, atrial fibrillation, bleeding, and infections such as fungal pneumonia.

Topics: Adenine; Administration, Oral; Antineoplastic Agents; Atrial Fibrillation; Hemorrhage; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Lung Diseases, Fungal; Lymphocytosis; Piperidines; Warfarin

Advances in the molecular biology of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and development of molecularly targeted therapies have resulted in treatment innovations. Therapeutic approaches for previously untreated CLL/SLL patients are changing from chemoimmunotherapy (CIT) to molecularly targeted drugs. The aim of therapy for CLL patients has been to control the disease; however, FCR (fludarabine, cyclophosphamide, rituximab) has improved outcomes and reduced the high incidence of undetectable minimum/measurable residual disease (MRD) in previously untreated CLL patients with no 17p deletion/TP53 disruption and mutated immunoglobulin heavy chain gene (IGHV). Patients achieving undetectable MRD in the bone marrow are expected to be cured. BTK inhibitors and BCL-2 inhibitors are effective for CLL/SLL patients. However, atrial fibrillation and bleeding are associated with the BTK inhibitor, ibrutinib, while tumor lysis syndrome is an adverse event (AE) of the BCL-2 inhibitor, venetoclax. Although these novel targeted drugs are very useful, they are also expensive. Emergence of resistant clones of CLL cells must also be addressed. Therefore, treatments of indefinite duration until progression have been replaced by fixed-duration treatments. This review introduces advances in the treatment of previously untreated CLL/SLL patients in Europe and the United States.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Bridged Bicyclo Compounds, Heterocyclic; Cyclophosphamide; Humans; Immunotherapy; Japan; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Neoplasm, Residual; Piperidines; Pyrazoles; Pyrimidines; Rituximab; Sulfonamides; Vidarabine

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Atrial Fibrillation; Benzamides; Central Nervous System Diseases; Clinical Trials as Topic; Febrile Neutropenia; Gastrointestinal Diseases; Gene Expression Regulation, Neoplastic; Humans; Multicenter Studies as Topic; Myeloid Differentiation Factor 88; Neoplasm Proteins; NF-kappa B; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Quality of Life; Receptors, CXCR4; Recurrence; Salvage Therapy; Signal Transduction; Treatment Outcome; Waldenstrom Macroglobulinemia

Chronic lymphocytic leukemia (CLL) therapy has changed dramatically with the introduction of several targeted therapeutics. Ibrutinib was the first approved for use in 2014 and now is used for initial and salvage therapy of CLL patients. With its widespread use in clinical practice, ibrutinib's common and uncommon adverse events reported less frequently in earlier clinical trials have been experienced more frequently in real-world practice. In particular, atrial fibrillation, bleeding, infections, and arthralgias have been reported. The management of ibrutinib's adverse events often cannot be generalized but must be individualized to the patient and their long-term risk of additional complications. When ibrutinib was initially developed, there were limited therapeutic alternatives for CLL, which often resulted in treating through the adverse events. At the present time, there are several effective alternative agents available, so transition to an alternative CLL directed therapy may be considered. Given the continued expansion of ibrutinib across many therapeutic areas, investigation of the pathogenesis of adverse events with this agent and also clinical trials examining therapeutic approaches for complications arising during therapy are needed. Herein, we provide strategies we use in real-world CLL clinical practice to address common adverse events associated with ibrutinib.

Topics: Adenine; Aged; Anti-Infective Agents; Anticoagulants; Arthralgia; Atrial Fibrillation; Drug Resistance, Neoplasm; Female; Hemorrhage; Humans; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Prognosis; Pyrazoles; Pyrimidines

Ibrutinib is an oral covalent inhibitor of Bruton's tyrosine kinase approved for the treatment of patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma and Waldenstrӧm's macroglobulinemia. Ibrutinib has an increased risk of atrial fibrillation but the mechanism is unknown, and hypertension may play a role in the pathogenesis of this adverse drug reaction.. We aimed to review the risk of hypertension and atrial fibrillation as adverse events associated with ibrutinib through a systematic review with meta-analysis of randomized controlled trials (RCTs) retrieved in December 2018 on MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov. The data were pooled using random-effects meta-analyses using the risk ratio (RR) with the 95% confidence interval (95%CI). The confidence on the pooled estimates was ascertained through the grading of recommendations assessment, development, and evaluation (GRADE) approach.. There were 8 eligible RCTs (2580 patients), all reporting safety data of interest. Ibrutinib was associated with a significant increase in the risk of hypertension with a RR of 2.82 (95%CI 1.52-5.23) with moderate quality evidence. Ibrutinib increased significantly the risk of atrial fibrillation with a RR of 4.69 (95%CI 2.17-7.64) with high quality evidence.. Ibrutinib was associated with significantly increased risks of both hypertension and atrial fibrillation.

Topics: Adenine; Atrial Fibrillation; Databases, Factual; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Risk

Bruton tyrosine kinase signaling (BTK) is critical step for B-cell development and immunoglobulin synthesis. Ibrutinib is an orally bioavailable bruton tyrosine kinase inhibitor (BTKi) and forms an irreversible covalent bound to BTK at the Cysteine-481 residue. Ibrutinib has been approved by FDA for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, marginal zone lymphoma and chronic graft-versus-host disease in allogeneic stem cell transplantation. Ibrutinib is generally well tolerated drug with rapid and durable responses but has some side events. The most common side effects are diarrhea, upper respiratory tract infection, bleeding, fatigue and cardiac side effects. These events are generally mild (grade I-II). However atrial fibrillation (AF) and bleeding are important and may be grade III or higher side effects require strict monitoring. Here side effects of ibrutinib have been summarized and important considerations in the management of these adverse events have been reviewed.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Atrial Fibrillation; Drug-Related Side Effects and Adverse Reactions; Hemorrhage; Humans; Incidence; Leukemia; Lymphoma; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor finding increasingly widespread use in non-Hodgkin lymphoma. Evidence of an increased risk of atrial fibrillation (AF) emerged in Phase III studies with a median incidence of approximately 6%. The mechanism remains unknown, but inhibition of a cardioprotective pathway has been proposed. Ibrutinib induces a platelet function defect, increasing the bleeding risk of anticoagulation for AF stroke prophylaxis. Multiple potential drug interactions are an added complication. In this review we examine the characteristics and management of the reported cases of AF with ibrutinib and where possible make recommendations. The evidence suggests dose reduction or temporary suspension of drug, are feasible alternative to discontinuation. The optimum choice of thromboprophylaxis has not been determined, but we propose the use of novel anticoagulants (NOACs) and avoidance of anti-platelet agents where possible. Further research and consensus guidelines are required.

Topics: Adenine; Anticoagulants; Antineoplastic Agents; Atrial Fibrillation; Clinical Trials as Topic; Disease Management; Drug Interactions; Hemorrhage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Piperidines; Platelet Aggregation Inhibitors; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Risk Factors; Severity of Illness Index

The development of bruton tyrosine kinase inhibitors (BTKi) has been a significant advancement in the treatment of chronic lymphocytic leukemia and related B-cell malignancies. As experience in using ibrutinib increased, the first drug to be licensed in its class, atrial fibrillation (AF) emerged as an important side effect. The intersection between BTKi therapy for B-cell malignancies and AF represents a complex area of management with scant evidence for guidance. Consideration needs to be taken regarding the interplay of increased bleeding risk versus thromboembolic complications of AF, drug interactions between ibrutinib and anticoagulants and antiarrhythmic agents, and the potential for other, as yet seldom reported cardiac side effects. This review describes the current knowledge regarding BTKi and potential pathophysiologic mechanisms of AF and discusses the management of BTKi-associated AF. Finally, a review of the second generation BTKi is provided and gaps in knowledge in this evolving field are highlighted.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Anticoagulants; Antineoplastic Agents; Atrial Fibrillation; Cardiotoxicity; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Signal Transduction; Treatment Outcome

Ibrutinib is a transformative therapy for high-risk and relapsed refractory chronic lymphocytic leukemia (CLL) patients. In clinical trials in relatively healthy younger patients, ibrutinib has been well tolerated. As its use has become more widespread in the community, however, its full adverse event profile has emerged and proven more challenging than was initially anticipated. Reports of community-based use have estimated discontinuation rates as high as 40% in the first year of therapy. This article therefore reviews my approach to the evaluation and management of a CLL patient starting on ibrutinib, with the goal of minimizing and managing toxicity to maintain patients on ibrutinib. Key topics discussed include bleeding risk; cardiac complications, particularly atrial fibrillation; drug interactions; and infections.

Topics: Adenine; Aged; Aged, 80 and over; Atrial Fibrillation; Autoimmunity; Communicable Diseases; Disease Management; Drug Interactions; Exanthema; Female; Hemorrhage; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Ibrutinib is indicated in Europe for the treatment of several B-cell malignancies, including chronic lymphocytic leukaemia (CLL). However, despite the high efficacy and favourable toxicity profile of ibrutinib, recent data suggest that it is not always administered optimally in clinical practice, with an increased tendency for dose reduction and a higher frequency of discontinuation. An expert panel of European haematologists was convened to identify practical issues pertinent to physicians involved in the therapeutic management of ibrutinib-treated CLL patients and here we outline the findings. Practical management recommendations are given for treating patients with ibrutinib and clinical considerations for the management of adverse events (AEs) that can be associated with ibrutinib treatment are addressed. This article highlights that patients should be monitored for treatment emergent adverse events, most of which are mild, transient and generally occur early in therapy and that, even with more challenging AEs, patients can often be maintained on therapy with minimal disruption through careful management. The necessity to use the correct ibrutinib dose, along with increased awareness, vigilance, mitigation and management of AEs, are all recommended to maximise outcomes for CLL patients treated with ibrutinib.

Topics: Adenine; Anticoagulants; Antineoplastic Agents; Arthralgia; Atrial Fibrillation; Diabetes Mellitus, Type 1; Diarrhea; Drug Eruptions; Drug Interactions; Exanthema; Fatigue; Hemorrhage; Humans; Hypertension; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Medication Adherence; Myalgia; Piperidines; Platelet Aggregation Inhibitors; Pyrazoles; Pyrimidines; Treatment Outcome

The Bruton tyrosine kinase inhibitor ibrutinib (IB) has attained an important role in the treatment of patients with chronic lymphocytic leukaemia, mantle cell lymphoma, and Waldenström macroglobulinemia, significantly improving clinical outcomes. However, IB therapy has been associated with an increased risk of atrial fibrillation (AF) and bleeding. We report on the expert opinion that a group of Italian haematologists, cardiologists, and pharmacologists jointly released to improve the practical management of patients at risk for AF and bleeding during treatment with IB. A proper pretreatment assessment to identify patients who are at a higher risk, careful choice of concomitant drugs, regular monitoring, and multispecialist approach were characterized as the main principles of clinical management of these patients. For patients developing AF, anticoagulant and antiarrhythmic therapy must be guided by considerations about efficacy, safety, and risk of pharmacokinetic interactions with IB. For patients experiencing bleeding or requiring procedures that increase the risk of bleeding, considerations about platelet turnover, IB-related platelet dysfunctions, and bleeding worsening by concomitant anticoagulants or antiplatelet agents provide clues to manage bleeding. Overall, AF and bleeding are manageable clinical events in patients receiving IB, not requiring drug interruption in most cases. Preexisting AF should not represent an absolute contraindication to IB therapy. For each patient candidate for IB, strategies of risk assessment and mitigation may allow to exploit the life-saving effects of in chronic lymphocytic leukaemia and mantle cell lymphoma.

Topics: Adenine; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Hematologic Neoplasms; Hemorrhage; Humans; Piperidines; Platelet Aggregation Inhibitors; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Risk Factors

B cell signaling agents, including ibrutinib, idelalisib, and the BCL-2 inhibitor venetoclax have become an integral part of therapy for patients with non-Hodgkin's lymphomas. The toxicity profiles of these medications is distinct from chemoimmunotherapy. Here, we will review the mechanism of action of these drugs, their efficacy, and toxicity management.. Ibrutinib use is associated with increased risk of atrial fibrillation and bleeding which can be managed using dose interruptions and modifications. Patients on idelalisib require close clinical and frequent laboratory monitoring, particularly of liver function tests to ensure there are no serious adverse events. Monitoring for infections is important in patients on both idelalisib and ibrutinib. Venetoclax requires close clinical and laboratory monitoring to prevent significant tumor lysis. Targeted B cell receptor therapies each have unique side effect profiles which require careful clinical monitoring. As we continue to use these therapies, optimal management strategies will continue to be elucidated.

Topics: Adenine; Antineoplastic Agents; Atrial Fibrillation; B-Lymphocytes; Bridged Bicyclo Compounds, Heterocyclic; Hemorrhage; Humans; Lymphoma, Non-Hodgkin; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Sulfonamides

Ibrutinib, a novel and potent Bruton tyrosine kinase inhibitor, is an effective and well-tolerated treatment for a variety of B-cell lymphomas. However, its use is associated with an increased incidence of atrial fibrillation (AF), ranging from 4% to 16%. We reviewed the original clinical trials that led to the approval of ibrutinib, as well as several other prospective and retrospective studies, to better appreciate the incidence of ibrutinib-associated AF. Based on 16 studies included in our analysis, the incidence of ibrutinib-associated AF was 5.77 per 100 person-years, which is much higher than rates previously reported with ibrutinib and compared with the general adult population. New onset AF in cancer patients is associated with a significantly higher risk of heart failure and thromboembolism, even after adjusting for known risk factors. In addition, ibrutinib poses unique challenges due to its interactions with many medications that are commonly used to manage AF. Ibrutinib also inhibits platelet activation and decisions regarding anticoagulation have to be carefully weighed against this increased risk of bleeding. Ibrutinib's interaction with calcium channel blockers, digoxin, amiodarone, and direct oral anticoagulants can result in either ibrutinib or other drug-related toxicity and careful selection and dose adjustment may be needed. Ibrutinib-associated AF can be a therapy-limiting side effect and physicians should be familiar with the special management considerations imposed by this agent. We review the potential mechanisms and incidence of ibrutinib-associated AF and propose an algorithm for its management.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Atrial Fibrillation; Female; Humans; Lymphoma, B-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Young Adult

The management of AF represents a major challenge in patients with CLL, especially in elderly patients with multiple comorbidities who are representative of the majority of patients with CLL. This is especially complex in the case of ibrutinib. Many anticoagulants have potential for pharmacological interaction with ibrutinib, and ibrutinib itself has antiplatelet properties. Use of ibrutinib therapy in these patients mandates review and revision of the need for anticoagulation and best anticoagulant to use. Herein, we review the current knowledge of the metabolism of common anticoagulants and how they may interact with ibrutinib.

Topics: Adenine; Anticoagulants; Antineoplastic Agents; Atrial Fibrillation; Disease Management; Drug Interactions; Humans; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Risk Assessment; Stroke

The B-cell receptor (BCR) pathway plays an important role in the survival, proliferation and trafficking of cancer cells in a variety of B-cell malignancies. Recently, a number of agents have been developed to target various components of the BCR pathway. One such target is Bruton's tyrosine kinase (BTK), a Tec family kinase member found near the cell membrane that is involved in upstream BCR signaling. The biological function of BTK in several B-cell lymphoid malignancies has led to the development of the oral BTK inhibitor ibrutinib. In chronic lymphocytic leukemia (CLL), ibrutinib has demonstrated durable clinical responses in relapsed/refractory (R/R) patients, including those with the high-risk del(17p) cytogenetic abnormality. These findings have paved the way for trials evaluating ibrutinib in previously untreated CLL patients, and also in combination with chemoimmunotherapy or other novel agents. Durable clinical responses have also been demonstrated in mantle cell lymphoma (MCL) and Waldenström's macroglobulinemia (WM) patients treated with ibrutinib. Ibrutinib is generally well tolerated, although current follow-up remains short and patients of advanced age are more likely to discontinue treatment for toxicity. Treatment-specific side effects such as bleeding and atrial fibrillation may, at least partly, be related to off-target inhibition of non-BTK kinases. Studies evaluating other potential indications for BTK inhibition are ongoing, including in post-allogeneic hematopoietic stem cell transplant patients for whom ibrutinib may be effective in modulating graft-versus-host disease. Combination trials of ibrutinib with venetoclax, a Bcl-2 inhibitor, are underway and are supported by sound preclinical rationale. Several next-generation BTK inhibitors are under development with the goal of decreasing treatment-related toxicity and resistance.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Atrial Fibrillation; Drug Discovery; Graft vs Host Disease; Hemorrhage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Signal Transduction

Clinical trials raised concern that ibrutinib may increase the risk of atrial fibrillation/flutter (Afib/Aflutter) and major bleeding. However, the association has not been statistically validated, and there is no consensus regarding optimal management of anticoagulation among patients receiving ibrutinib who develop Afib/Aflutter. We performed a systematic review and pooled analysis to precisely assess the risk of Afib/Aflutter and bleeding associated with ibrutinib treatment in patients with hematologic malignancies.. We searched PubMed, EMBASE, Cochrane Database, and meeting abstracts up to May 15, 2016, for randomized controlled trials comparing ibrutinib to chemotherapy, monoclonal antibody, or a combination. Primary outcomes were serious Afib/Aflutter and major bleeding. Secondary outcomes were all-grade Afib/Aflutter and bleeding. We calculated the Mantel-Haenszel risk ratio (RR) and estimated the effect of the treatments using a fixed-effects model.. Ibrutinib treatment was associated with a significantly higher incidence of serious Afib/Aflutter (3.03% vs. 0.80%, RR = 3.80, 95% confidence interval [CI] = 1.56-9.29, P = .003), all-grade Afib/Aflutter (8.18% vs. 0.93%, RR = 8.81, 95% CI = 2.70-28.75, P = .0003), and all-grade bleeding (4.85% vs. 1.55%, RR = 2.93, 95% CI = 1.14-7.52, P = .03) compared to control treatments. The observed between-treatment difference in major bleeding rates was not statistically significant (3.69% vs. 2.13%, RR = 1.72, 95% CI = 0.95-3.11, P = .07). The risk of these adverse events was not different between subgroups on the basis of pathology, treatment setting, dose, and duration of ibrutinib exposure.. The risks of Afib/Aflutter and all-grade bleeding were significantly higher in the ibrutinib group. These results indicate the need for vigilant monitoring while the patient is receiving ibrutinib therapy, and careful assessment of the risks and benefits of anticoagulation is required.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Atrial Fibrillation; Disease Susceptibility; Female; Hemorrhage; Humans; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Risk

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Atrial Fibrillation; Humans; Incidence; Leukemia; Lymphoma; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Inhibitors of the B cell receptor (BCR) represent an attractive therapeutic option for patients with chronic lymphocytic leukemia. Recently approved inhibitors of Bruton's tyrosine kinase (ibrutinib) and phosphatidylinositol 3-kinase (idelalisib), are promising agents because they are generally well tolerated and highly effective. These agents may be particularly important in the treatment of older patients who are less able to tolerate the myelosuppression (and infections) associated with chemoimmunotherapy. As a class of medications, BCR inhibitors have some unique side effects including redistribution lymphocytosis. Ibrutinib has specific toxicities including increased risk for bleeding and atrial fibrillation. Idelalisib also has some unique toxicities consisting of transaminitis, diarrhea and pneumonitis. Ongoing clinical trials are evaluating these agents in combination with antibodies, chemotherapy and other small molecules.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Age Factors; Atrial Fibrillation; Diarrhea; Hemorrhage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Neoplasm Proteins; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Pneumonia; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell

Ibrutinib (Imbruvica™) is an irreversible, potent inhibitor of Bruton's tyrosine kinase (BTK). Over the last few years, ibrutinib has developed from a promising drug candidate to being approved by FDA for the treatment of three B cell malignancies, a truly remarkable feat. Few, if any medicines are monospecific and ibrutinib is no exception; already during ibrutinib's initial characterization, it was found that it could bind also to other kinases. In this review, we discuss the implications of such interactions, which go beyond the selective effect on BTK in B cell malignancies. In certain cases, the outcome of ibrutinib treatment likely results from the combined inhibition of BTK and other kinases, causing additive or synergistic, effects. Conversely, there are also examples when the clinical outcome seems unrelated to inhibition of BTK. Thus, more specifically, adverse effects such as enhanced bleeding or arrhythmias could potentially be explained by different interactions. We also predict that during long-term treatment bone homoeostasis might be affected due to the inhibition of osteoclasts. Moreover, the binding of ibrutinib to molecular targets other than BTK or effects on cells other than B cell-derived malignancies could be beneficial and result in new indications for clinical applications.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Atrial Fibrillation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoproliferative Disorders; Mice; Multiple Myeloma; Osteoclasts; Phosphorylation; Piperidines; Protein Binding; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

This article reviews experimental and clinical studies of a novel antiarrhythmic agent niferidile. Niferidile, a class III antiarrhythmic agent, blocks potassium outward currents, prolongs repolarization and refractory periods predominantly in atria than in ventricles. Intravenous Niferidile was efficient for interruption of AV-nodal and orthodromic re-entrant tachycardias with rates of 75% to 80%. Niferidile had a conversion rate of up to 87.3% in persistent atrial fibrillation and up to 100% in persistent atrial flutter. Proarrhythmic action of niferidil administration manifested as nonsustained torsade de pointes and monomorphic ventricular tachycardia in 1.2 and 3.7% of cases, respectively. Niferidile can be used for pharmacological cardioversion of persistent atrial fibrillation and flutter as an alternative to electrical cardioversion.

Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Dogs; Heart Atria; Humans; Myocytes, Cardiac; Piperidines; Potassium Channel Blockers; Rats; Tachycardia, Supraventricular

Topics: Anti-Obesity Agents; Atrial Fibrillation; Fatty Acids, Nonesterified; Humans; Male; Piperidines; Pyrazoles; Rimonabant

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; 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Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; 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Ibrutinib has superior progression-free survival compared with bendamustine plus rituximab (BR) in older CLL patients, however, differences in treatment duration, six monthly BR cycles versus continuous ibrutinib, complicate adverse event (AE) comparisons. We introduce the AE burden score (AE

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Bendamustine Hydrochloride; Female; Follow-Up Studies; Humans; Hypertension; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Prognosis; Rituximab; Survival Rate

Ibrutinib, an inhibitor of Bruton's tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination.. We conducted an investigator-initiated phase 2 study of combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL. All patients had at least one of the following features: chromosome 17p deletion, mutated. A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated. In this study, combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL. (Funded by AbbVie and others; ClinicalTrials.gov number, NCT02756897.).

Topics: Adenine; Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Induction Chemotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Count; Male; Middle Aged; Mutation; Neoplasm, Residual; Neutropenia; Piperidines; Pyrazoles; Pyrimidines; Remission Induction; Sulfonamides

Ibrutinib, a first-in-class once-daily oral Bruton tyrosine kinase inhibitor indicated for chronic lymphocytic leukemia (CLL), is continued until progressive disease or unacceptable toxicity. We conducted an integrated safety analysis of single-agent ibrutinib from randomized phase 3 studies PCYC-1112 (RESONATE, n = 195) and PCYC-1115/1116 (RESONATE-2, n = 135), and examined longer-term safety separately in the phase 1b/2 PCYC-1102/1103 study (n = 94, 420 mg/d). In the integrated analysis (ibrutinib treatment up to 43 months), the most common adverse events (AEs) were primarily grade 1/2; diarrhea (n = 173, 52% any-grade; n = 15, 5% grade 3) and fatigue (n = 119, 36% any-grade; n = 10, 3% grade 3). The most common grade 3/4 AEs were neutropenia (n = 60, 18%) and pneumonia (n = 38, 12%). Over time, prevalence of AEs of interest (diarrhea, fatigue, grade ≥3 infection, bleeding, and neutropenia) trended down; prevalence of hypertension increased, but incidence decreased after year 1. AEs led to dose reductions in 42 (13%) patients and permanent discontinuations in 37 (11%); dose modifications due to AEs were most common during year 1 and decreased in frequency thereafter. The most common AEs (preferred term) contributing to discontinuation included pneumonia (n = 4), anemia (n = 3), and atrial fibrillation (n = 3). With long-term follow-up on PCYC-1102/1103 (ibrutinib treatment up to 67 months), grade 3/4 AEs were generally similar to those in the integrated analysis. Overall, AEs were primarily grade 1/2 and manageable during prolonged ibrutinib treatment in patients with CLL. These trials were registered at www.clinicaltrials.gov as #NCT01578707, #NCT01722487, #NCT01724346, #NCT01105247, and #NCT01109069.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Anemia; Atrial Fibrillation; Diarrhea; Drug Tolerance; Fatigue; Female; Follow-Up Studies; Hemorrhage; Humans; Hypertension; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neutropenia; Piperidines; Pneumonia; Prevalence; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Safety

Ibrutinib increases the risk of atrial fibrillation (AF) and is associated with bleeding tendencies. Reported rates of arrhythmia are variable in different studies. The aim of the current analysis was to evaluate the incidence of AF in a single-center cohort of patients.. This analysis was conducted at Hunter New England Local Health District, Australia between April 1, 2015 and June 30, 2017. We included all consecutive patients commenced on ibrutinib for hematological malignancies. Patients with a history of paroxysmal AF were excluded. The primary end point was incidence of AF. Time to diagnosis and management were secondary outcomes of interest.. A total of 24 patients (age 73 ± 9 years, males n = 16 [67%]) were commenced on ibrutinib treatment during the study period with chronic lymphocytic leukemia (n = 21, 88%) as the main indication. During a median follow-up of 12 months, four (17%) patients were diagnosed with AF with increasing age, duration of ibrutinib treatment as associations. The median time to AF diagnosis was 9 (interquartile range [IQR]: 7-18) months. All patients were managed with a rate control strategy with beta blockers as the preferred agents. Three (75%) patients were commenced on anticoagulation for stroke prevention. During a follow-up of 18 (IQR: 17-23) months following AF onset, one patient required hospitalization for AF. There were no bleeding complications reported.. In conclusion, this series noted a higher incidence of AF than previously reported. Oncologists and cardiologists need to be aware of the increased risk of AF in patients receiving ibrutinib.

Topics: Adenine; Aged; Aged, 80 and over; Atrial Fibrillation; Australia; Female; Hematologic Neoplasms; Hospitalization; Humans; Incidence; Male; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Survival Rate

Single-agent ibrutinib has shown substantial activity in patients with relapsed Waldenström's macroglobulinemia, a rare form of B-cell lymphoma. We evaluated the effect of adding ibrutinib to rituximab in patients with this disease, both in those who had not received previous treatment and in those with disease recurrence.. We randomly assigned 150 symptomatic patients to receive ibrutinib plus rituximab or placebo plus rituximab. The primary end point was progression-free survival, as assessed by an independent review committee. Key secondary end points were response rates, sustained hematologic improvement from baseline, and safety. The mutational status of MYD88 and CXCR4 was assessed in bone marrow samples.. At 30 months, the progression-free survival rate was 82% with ibrutinib-rituximab versus 28% with placebo-rituximab (hazard ratio for progression or death, 0.20; P<0.001). The benefit in the ibrutinib-rituximab group over that in the placebo-rituximab group was independent of the MYD88 or CXCR4 genotype. The rate of major response was higher with ibrutinib-rituximab than with placebo-rituximab (72% vs. 32%, P<0.001). More patients had sustained increases in hemoglobin level with ibrutinib-rituximab than with placebo-rituximab (73% vs. 41%, P<0.001). The most common adverse events of any grade with ibrutinib-rituximab included infusion-related reactions, diarrhea, arthralgia, and nausea. Events of grade 3 or higher that occurred more frequently with ibrutinib-rituximab than with placebo-rituximab included atrial fibrillation (12% vs. 1%) and hypertension (13% vs. 4%); those that occurred less frequently included infusion reactions (1% vs. 16%) and any grade of IgM flare (8% vs. 47%). The major hemorrhage rate was the same in the two trial groups (4%).. Among patients with Waldenström's macroglobulinemia, the use of ibrutinib-rituximab resulted in significantly higher rates of progression-free survival than the use of placebo-rituximab, both among those who had received no previous treatment and among those with disease recurrence. Atrial fibrillation and hypertension were more common with ibrutinib-rituximab, whereas infusion reactions and IgM flare were more common with placebo-rituximab. (Funded by Pharmacyclics and Janssen Research and Development; ClinicalTrials.gov number, NCT02165397 .).

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Disease-Free Survival; Female; Hemoglobins; Humans; Immunoglobulin M; Infusions, Intravenous; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Rituximab; Survival Analysis; Waldenstrom Macroglobulinemia

Ibrutinib is approved in the EU, USA, and other countries for patients with mantle cell lymphoma who received one previous therapy. In a previous phase 2 study with single-agent ibrutinib, the proportion of patients who achieved an objective response was 68%; 38 (34%) of 111 patients had transient lymphocytosis. We hypothesised that adding rituximab could target mantle cell lymphoma cells associated with redistribution lymphocytosis, leading to more potent antitumour activity.. Patients with a confirmed mantle cell lymphoma diagnosis (based on CD20-positive and cyclin D1-positive cells in tissue biopsy specimens), no upper limit on the number of previous treatments received, and an Eastern Cooperative Oncology Group performance status score of 2 or less were enrolled in this single-centre, open-label, phase 2 study. Patients received continuous oral ibrutinib (560 mg) daily until progressive disease or unacceptable toxic effects. Rituximab 375 mg/m(2) was given intravenously once per week for 4 weeks during cycle 1, then on day 1 of cycles 3-8, and thereafter once every other cycle up to 2 years. The primary endpoint was the proportion of patients who achieved an objective response in the intention-to-treat population and safety assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT01880567, and is still ongoing, but no longer accruing patients.. Between July 15, 2013, and June 30, 2014, 50 patients were enrolled. Median age was 67 years (range 45-86), and the median number of previous regimens was three (range 1-9). At a median follow-up of 16·5 months (IQR 12·09-19·28), 44 (88%, 95% CI 75·7-95·5) patients achieved an objective response, with 22 (44%, 30·0-58·7) patients achieving a complete response, and 22 (44%, 30·0-58·7) a partial response. The only grade 3 adverse event in >=10% of patients was atrial fibrillation, which was noted in six (12%) patients. Grade 4 diarrhoea and neutropenia occurred in one patient each. Adverse events led to discontinuation of therapy in five (10%) patients (atrial fibrillation in three [6%] patients, liver infection in one [2%], and bleeding in one [2%]). Two patients died while on-study from cardiac arrest and septic shock; the latter was deemed possibly related to treatment.. Ibrutinib combined with rituximab is active and well tolerated in patients with relapsed or refractory mantle cell lymphoma. Our results provide preliminary evidence for the activity of this combination in clinical practice. A phase 3 trial is warranted for more definitive data.. Pharmacyclics LLC, an AbbVie Company.

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Diarrhea; Epistaxis; Female; Follow-Up Studies; Humans; Intention to Treat Analysis; Lymphoma, Mantle-Cell; Male; Middle Aged; Neutropenia; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Retreatment; Rituximab; Treatment Outcome

Most patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma relapse after initial therapy. Bendamustine plus rituximab is often used in the relapsed or refractory setting. We assessed the efficacy and safety of adding ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK), to bendamustine plus rituximab in patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma.. The HELIOS trial was an international, double-blind, placebo-controlled, phase 3 study in adult patients (≥18 years of age) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease (>1·5 cm) by CT scan, and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy-containing regimen, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate bone marrow, liver, and kidney function. Patients with del(17p) were excluded because of known poor response to bendamustine plus rituximab. Patients who had received previous treatment with ibrutinib or other BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or haemopoietic stem-cell transplant were also excluded. Patients were randomly assigned (1:1) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks' duration (bendamustine: 70 mg/m(2) intravenously on days 2-3 in cycle 1, and days 1-2 in cycles 2-6; rituximab: 375 mg/m(2) on day 1 of cycle 1, and 500 mg/m(2) on day 1 of cycles 2-6 for a maximum of six cycles) with either ibrutinib (420 mg daily orally) or placebo until disease progression or unacceptable toxicity. Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy. The primary endpoint was independent review committee (IRC)-assessed progression-free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT01611090.. Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13·7-20·7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13·3 months (11·3-13·9) in the placebo group (hazard ratio [HR] 0·203, 95% CI 0·150-0·276; p<0·0001). IRC-assessed progression-free survival at 18 months was 79% (95% CI 73-83) in the ibrutinib group and 24% (18-31) in the placebo group (HR 0·203, 95% CI 0·150-0·276; p<0·0001). The most frequent all-grade adverse events were neutropenia and nausea. 222 (77%) of 287 patients in the ibrutinib group and 212 (74%) of 287 patients in the placebo group reported grade 3-4 events; the most common grade 3-4 adverse events in both groups were neutropenia (154 [54%] in the ibrutinib group vs 145 [51%] in the placebo group) and thrombocytopenia (43 [15%] in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted.. In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile.. Janssen Research & Development.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Bendamustine Hydrochloride; Disease Progression; Disease-Free Survival; Double-Blind Method; Female; Hemorrhage; Humans; Intention to Treat Analysis; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Nausea; Neutropenia; Piperidines; Pyrazoles; Pyrimidines; Retreatment; Rituximab; Thrombocytopenia

Topics: Adenine; Adult; Aged; Aged, 80 and over; Atrial Fibrillation; Female; Humans; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Risk Factors; Time Factors; Waldenstrom Macroglobulinemia

Electrical cardioversion (EC) is a short but painful procedure to restore sinus rhythm. The aim of this study is to compare the effect of fentanyl, remifentanil and alfentanil in association with propofol and midazolam for elective EC.. Ninety-nine patients older than 18-years, American Society of Anesthesiologists I/II/III grades undergoing elective EC were randomized into 3 groups. All patients received 2 mg midazolam and propofol (0.5 mg/kg). Group A received alfentanil (5 µg/kg i.v. bolus), Group F received fentanyl (0.5 µg/kg i.v. bolus) and Group R received remifentanil (0.25 µg/kg i.v. bolus). Hemodynamics and respiratory variables [Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), SpO2, respiratory rate (RR)], and Modified Aldrete recovery score (MARS) were assessed at six different time points (baseline, right after EC, and 3rd min, 5th min, 10th min, 30th min following EC). Also, induction times (time to reach RSS to 5) and recovery times (time to reach MARS to 8) were recorded. The incidence of respiratory depression, bradycardia, hypotension and adverse effects were also recorded.. Hemodynamic variables were similar in all groups. SpO2 values in Group R were significantly lower at 3rd min (p = 0.005). Induction and recovery times were longest in Group F. There were significant differences at 3rd, 5th and 10th minute MARS values between groups. The incidence of hypotension and bradycardia were similar in all groups (p > 0.05) but respiratory depression was higher in Group R (p = 0.047).. Propofol alfentanil combination has more beneficial advantages in their rapid onset, early recovery time and less respiratory depression than remifentanil and fentanyl.

Topics: Alfentanil; Anesthetics, Intravenous; Atrial Fibrillation; Double-Blind Method; Electric Countershock; Female; Fentanyl; Humans; Male; Midazolam; Middle Aged; Piperidines; Propofol; Prospective Studies; Remifentanil

To evaluate the efficacy and safety of refralon (niferidil), a new class III antiarrhythmic agent whose activity is related to the block of delayed rectifying potassium current and to the prolongation of atrial and ventricular action potential and refractory periods, when it is used as an agent for pharmacological cardioversion for atrial fibrillation (AF) and atrial flutter (AFL).. The efficacy of the drug as 3 intravenous boluses of 10 μg/kg was evaluated in 134 patients (90 men; 57.8 ± 11 years) with a mean AF duration of 3 (1.5; 6) months. Its effect was controlled by 24-hour Holter ECG monitoring. The criterion for its antiarrhythmic effect was 24-hour sinus rhythm (SR) recovery.. Niferidil restored SR in 47.7% of the patients with AF after administration of bolus 1, in 62% after bolus 2, and in 84.6% after bolus 3. SR was restored in all 100% patients with AFL. With the AF duration of less than 3 months, the efficacy of niferidil was 91.8%. There was nonsustained polymorphic ventricular tachycardia (VT) (torsade de pointes) in 1 (0.7%) patient and nonsustained monomorphic VT was stated in 5 (3.7%) patients. CONCLUSION> Pharmacological cardioversion with niferidil for persistent AF and VT may be regarded as a possible alternative to electrical cardioversion.. Цель исследования. Оценка эффективности и безопасности рефралона (ниферидила) - нового антиаритмического препарата III класса, действие которого связано с блокадой калиевых токов задержанного выпрямления, удлинением потенциала действия и рефрактерных периодов в предсердиях и желудочках, при его применении в качестве средства для медикаментозной кардиоверсии при фибрилляции предсердий (ФП) и трепетании предсердий (ТП). Материалы и методы. Эффективность препарата в виде 3 болюсов по 10 мкг/кг внутривенно оценена у 134 больных (57,8±11 лет, 90 мужчин) при средней длительности ФП 3 (1,5; 6) мес. Действие препарата контролировалось при 24-часовом холтеровском мониторировании электрокардиограммы. Критерием антиаритмического эффекта было восстановление синусового ритма (СР) в течение 24 ч. Результаты. Ниферидил восстановил СР у 47,7% больных с ФП после введения 1-го болюса, у 62% - после введения 2-го и у 84,6% - после введения 3-го болюса. СР восстановлен у всех 100% больных с ТП. При длительности ФП менее 3 мес эффективность ниферидила составила 91,8%. Неустойчивая полиморфная желудочковая тахикардия (ЖТ) типа torsades de pointes отмечена в 1 (0,7%) случае. Неустойчивая мономорфная желудочковая тахикардия (ЖТ) констатирована у 5 (3,7%) больных. Заключение. Медикаментозная кардиоверсия персистирующей ФП и ТП с использованием ниферидила может рассматриваться как возможная альтернатива электрической кардиоверсии.

Topics: Action Potentials; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Echocardiography; Electrocardiography, Ambulatory; Female; Heart; Humans; Male; Middle Aged; Piperidines; Potassium Channels; Treatment Outcome

Anaesthesia is required for catheter ablation of atrial fibrillation (A-fib) to achieve patient comfort and immobilization to avoid map shifts. This study compared the analgesic and sedative efficacies of dexmedetomidine-remifentanil with those of midazolam-remifentanil for catheter ablation of A-fib.. Ninety patients were randomized to receive either intermittent midazolam boluses (1-2 mg) with 3.6-7.2 µg/kg/h of remifentanil (MR group) or dexmedetomidine 0.2-0.7 µg/kg/h after a loading dose of 1 µg/kg with 1.2-2.4 µg/kg/h of remifentanil (DR group). The sedation level assessed by the Ramsay sedation and bispectral index scores, haemodynamic variables, pain score (10-point numerical scale), and satisfaction levels of the patients and cardiologists (5-point numerical scale) were recorded. The Ramsay sedation score was significantly higher, and the bispectral index score was lower in the DR group (P< 0.001) compared with the MR group starting 10 min after drug administration. The incidence of desaturation (SpO2 < 90%) was significantly greater in the MR group compared with the DR group (15 vs. 1, P < 0.001). The pain score was significantly lower (1.72 ± 1.65 vs. 0.95 ± 1.10, P = 0.021), and the satisfaction levels of interventionists were significantly higher (2.50 ± 0.71 vs. 3.00 ± 0.63, P = 0.001) in the DR group compared with the MR group.. The combination of dexmedetomidine and remifentanil provided deeper sedation, less respiratory depression, better analgesia, and higher satisfaction for the interventionist during catheter ablation of A-fib compared with midazolam plus remifentanil, even at a lower dose of remifentanil.

Topics: Adult; Aged; Atrial Fibrillation; Attitude of Health Personnel; Catheter Ablation; Conscious Sedation; Consciousness Monitors; Dexmedetomidine; Drug Administration Schedule; Drug Therapy, Combination; Female; Hemodynamics; Humans; Hypnotics and Sedatives; Intraoperative Neurophysiological Monitoring; Male; Midazolam; Middle Aged; Pain Perception; Pain Threshold; Patient Satisfaction; Piperidines; Prospective Studies; Remifentanil; Republic of Korea; Time Factors; Treatment Outcome

To study the efficacy and safety of the new class III antiarrhythmic agent niferidil for pharmacological cardioversion in patients with persistent atrial fibrillation (AF) and atrial flutter (AFl).. One hundred thirty-four adults (aged 57.8 ± 11 years, 90 males) were included with median AF duration of 3 (1.5-6) months. All patients received a total of 10-30 μg/kg, niferidil, intravenously, in 1-3 (if needed) consecutive boluses at 15-minute intervals. Holter electrocardiogram monitoring was started before infusion and was continued for 24 hours. The criterion for an antiarrhythmic effect was sinus rhythm restoration within 24 hours of the initial bolus. Niferidil converted AF to sinus rhythm in 47.7% of cases after bolus 1, in 62% of cases after bolus 2, and in 84.6% of cases bolus 3. Niferidil induced a 100% recovery rate in patients with AFl and a 91.8% recovery rate in patients with AF of duration from 8 days to 3 months. Nonsustained torsade de pointes occurred in 1 patient (0.7%), and nonsustained monomorphic ventricular tachycardia was observed in 5 patients (3.7%).. The new intravenous class III drug niferidil demonstrated high conversion rates of 84.6% in patients with persistent AF and 100% in patients with persistent AFl. Niferidil may be used as a possible alternative to electrical cardioversion for pharmacological cardioversion of persistent AF/AFl.

Topics: Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Dose-Response Relationship, Drug; Electrocardiography, Ambulatory; Female; Humans; Male; Middle Aged; Piperidines; Treatment Outcome

The objective of this study was to determine the effects of isoproterenol infusion on level of consciousness during ablation using total intravenous anesthesia.. Seven patients undergoing total intravenous anesthesia for atrial fibrillation ablation were monitored for level of consciousness using bispectral EEG levels (BIS). Isoproterenol infusion was performed after the ablation during anesthesia. BIS levels prior to, during, and post-isoproterenol infusion were recorded and correlated to isoproterenol infusion doses. In all patients, BIS levels significantly increased during isoproterenol infusion (median BIS prior to infusion, 46; during infusion, 64 (p < 0.02)). With a subsequent increase in anesthetic medication, BIS levels could again be reduced.. Isoproterenol infusion alters consciousness level during total intravenous anesthesia for atrial fibrillation ablation. BIS monitoring is a novel way to modulate anesthesia during ablation to potentially optimize patient comfort and ablation success.

Topics: Adult; Aged; Anesthetics, Intravenous; Atrial Fibrillation; Catheter Ablation; Consciousness; Electroencephalography; Female; Humans; Infusions, Intravenous; Isoproterenol; Male; Middle Aged; Monitoring, Intraoperative; Piperidines; Remifentanil; Reproducibility of Results; Sensitivity and Specificity; Treatment Outcome

The aim of the study was to evaluate the efficacy and safety of administered intravenously niferidil in doses 10, 20 and 30 mkg per kg in patients with persistent atrial fibrillation (AF) and flutter (AFL) for pharmacological cardioversion. The study included 30 patients (22 male) with persistent AF (n = 28) and AFL (n = 2) without structural heart diseases with median arrhythmia duration 6.1 +/- 4.8 months (2 weeks to 24 months). Niferidil was administered as 3 bolus injections (10 mkg per kg each) performed with the interval of 15 minutes. Antiarrhythmic efficacy of niferidil in dose of 10 mkg per kg was 60%, in dose of 20 mkg per kg it was 70%, and in dose of 30 mkg per kg reached 90% prespectively. The part of the patients, in whom QTc prolongation exceeded potentionally dangerous value of 500 mc, was 22.2% (6 of 27). None of the patients developed proarrhythmic side effect as torsade de pointes.

Topics: Aged; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Depression, Chemical; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Approval; Drug Evaluation, Preclinical; Electrocardiography; Female; Heart Rate; Humans; Injections, Intravenous; Male; Middle Aged; Piperidines; Rabbits; Rats; Time Factors; Torsades de Pointes; Treatment Outcome

Atrial fibrillation and paroxysmal supraventricular tachycardia are common disorders of the heart rhythm for which antiarrhythmic drug therapy is commonly prescribed. The Atrial Fibrillation Investigation with Bidisomide (AFIB) study was a randomized, placebo-controlled clinical trial designed to accomplish three goals in a single protocol: (1) to determine the efficacy of the antiarrhythmic drug bidisomide in the treatment of these two arrhythmias; (2) to establish the appropriate dose range for bidisomide; and (3) to detect an adverse mortality effect of bidisomide if one were present in patients with atrial fibrillation.. In this clinical trial, 1227 patients with atrial fibrillation and 187 with paroxysmal supraventricular tachycardia were randomly assigned to bidisomide (200, 400, or 600 mg BID) or placebo; patient groups with each arrhythmia were analyzed separately. Symptomatic recurrences of atrial fibrillation and paroxysmal supraventricular tachycardia were documented with the use of transtelephonic ECG monitoring. The time to the first symptomatic arrhythmia recurrence was measured in each patient and compared among treatment groups. Among the atrial fibrillation patients, there was no significant difference in the time to first symptomatic recurrence between the placebo group and any of the three bidisomide treatment groups; the hazard ratios (placebo:treatment) were 1.19, 1.03, and 1.14 for bidisomide 200, 400, and 600 mg BID, respectively. Among paroxysmal supraventricular tachycardia patients, there was a similar lack of a significant treatment effect; the hazard ratios were 1.30, 1.93, and 1.59 for bidisomide 200, 400, and 600 mg BID, respectively. In the primary safety analysis of mortality, 3 of 493 patients taking placebo died, compared with 9 of 488 patients taking one of the two higher doses of bidisomide (P>.10).. Bidisomide in the doses tested did not have a clinically important antiarrhythmic effect. The AFIB study provided a novel clinical trial design to test antiarrhythmic drugs for both safety and efficacy.

Topics: Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Double-Blind Method; Electrocardiography; Humans; Middle Aged; Piperidines; Tachycardia, Supraventricular

To establish the clinical efficacy of a single oral dose of pirmenol, we evaluated electrophysiologic and hemodynamic effects simultaneously after drug administration, performing electrophysiologic testing in 20 patients with ECG-documented paroxysmal supraventricular tachycardia (PSVT) before and after a single oral 200-mg dose of pirmenol. Hemodynamic measurements were made with a Swan-Ganz catheter in the first 10 consecutive patients. In a different series of patients, we administered a single 200-mg oral dose of pirmenol to evaluate its acute termination effect in 7 patients with PSVT and 9 with paroxysmal atrial fibrillation. Pirmenol prolonged the refractory period of the retrograde conduction system in patients with or without an accessory pathway, and supraventricular tachycardia was no longer inducible at 60 min in 11 patients [8 of 11 with atrioventricular (AV) reentrant tachycardia and 3 of 5 with AV nodal reentrant tachycardia]. Pirmenol increased the heart rate (p < 0.01) and total systemic resistance (p < 0.05), and reduced the stroke volume index (p < 0.01), all significantly. The plasma concentration of pirmenol at 1 h after administration was 0.75 +/- 0.48 microgram/ml. A single oral dose of pirmenol during tachyarrhythmia successfully restored sinus rhythm in 4 of 7 (57%) patients with PSVT and 4 of 9 (44%) patients with paroxysmal atrial fibrillation. A single oral dose of pirmenol was well tolerated as episodic treatment in patients with supraventricular tachyarrhythmias.

Topics: Administration, Oral; Adult; Anti-Arrhythmia Agents; Atrial Fibrillation; Female; Hemodynamics; Humans; Male; Middle Aged; Piperidines; Tachycardia, Atrioventricular Nodal Reentry; Tachycardia, Supraventricular

The acute effects of pirmenol on atrial fibrillation were investigated in 40 patients with paroxysm of atrial fibrillation. Patients were randomized to receive either pirmenol, 50 or 100 mg intravenously, or placebo. Patients with congestive heart failure or a history of sinus node disorder were excluded. Sinus rhythm was achieved in 12 of 20 patients in 2 to 16 minutes after pirmenol administration and in 3 of 20 patients in the control group within 1 hour. A nodal escape rhythm during sinus slowing was observed in 1 patient. No sinus arrest, atrioventricular conduction disturbance or hypotension appeared. Pirmenol has an antifibrillatory effect on the atria. Sinus rhythm is restored rapidly after intravenous administration. Treatment of atrial fibrillation of recent onset was well tolerated in patients accepted for the study.

Topics: Adrenergic beta-Antagonists; Anti-Arrhythmia Agents; Atrial Fibrillation; Humans; Injections, Intravenous; Piperidines; Placebos; Random Allocation

The efficacy of pirmenol (a class I antiarrhythmic agent) as a converter of paroxysmal atrial fibrillation was investigated. Forty patients without congestive heart failure or a history of sinus node disorder were randomly allocated to receive either intravenous pirmenol (50-100 mg) or placebo in a double blind trial. In 12 of 20 patients sinus rhythm was restored 2-16 minutes after pirmenol, and in 3 of 20 patients in the control group it returned within one hour. A nodal escape rhythm was seen during sinus slowing in one patient, but in other patients there was no sinus arrest, atrioventricular conduction disturbance, or hypotension. The ventricular rate was slightly increased in patients in whom sinus rhythm was not restored by pirmenol. The results indicate that pirmenol has an antifibrillatory effect on the atria. Sinus rhythm was restored rapidly after intravenous administration. It was well tolerated in patients with atrial fibrillation of recent onset.

Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Electrocardiography; Heart Rate; Humans; Middle Aged; Piperidines

The effectiveness and safety of flecainide and quinidine for conversion of atrial fibrillation (AF) to sinus rhythm were compared. Sixty consecutive patients were treated with either flecainide (up to 2 mg/kg intravenously and then orally) or quinidine (up to 1.2 g orally). There was no statistical difference in age, left atrial size, duration of the arrhythmia and underlying cardiac diseases between the 2 groups. The overall conversion rate to sinus rhythm was 63% (38 patients): AF was converted in 18 patients (60%) treated with quinidine and 20 (67%) with flecainide. If AF lasted less than 10 days, the conversion rate was 86% in the flecainide group and 80% in the quinidine group (difference not significant). When AF lasted more than 10 days the rate was 22% in the flecainide group and 40% in the quinidine group. Adverse effects were more frequent in the quinidine group (27%) (gastrointestinal disturbances) than in the flecainide group (7%) (conduction disturbances), but they were less severe in the quinidine group. Thus, flecainide given intravenously appeared to be as effective as quinidine given orally for conversion of AF of recent onset (within 10 days). However, quinidine should probably remain the preferred drug for conversion of AF of long duration (more than 10 days) to sinus rhythm. Adverse effects occurred less often with flecainide therapy, but they were more severe.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Clinical Trials as Topic; Female; Flecainide; Heart; Heart Rate; Humans; Male; Middle Aged; Piperidines; Quinidine; Radiography

Ibrutinib-associated atrial fibrillation (IRAF) emerged among the adverse events of major interests in ibrutinib-treated patients as real-world studies showed a higher incidence compared to clinical trials. We prospectively analyzed predictors of IRAF in 43 single-center consecutive patients affected by chronic lymphocytic leukemia that started therapy with ibrutinib between 2015 and 2017. Key secondary endpoints were to describe the management of IRAF and survival outcomes. During a median follow-up period of 52 months, we registered 45 CV events, with a total of 23 AF events in 13 patients (CI 30.0% (95% CI: 16.5-43.9)). Pre-existent cardiovascular risk factors, in particular hypertension, a previous history of AF and a high Shanafelt risk score emerged as predictors of IRAF. Baseline echocardiographic evaluation of left atrial (LA) dimensions confirmed to predict IRAF occurrence and cut-off values were identified in our cohort: 32 mm for LA diameter and 18 cm

Topics: Atrial Fibrillation; Follow-Up Studies; Humans; Piperidines; Prospective Studies

Data regarding the safety of co-administration of ibrutinib with anticoagulants in real-life settings are scarce. Using a nationwide database, we conducted a nested case-control study in a cohort of new users of ibrutinib to assess the risk of clinically relevant bleeding (CRB) associated with anticoagulation. Cases were patients with a diagnosis of CRB, defined as hospitalization with a diagnosis of bleeding. The date of CRB constituted the index date. Up to four controls were matched on sex, age at index date and duration of follow-up. The risk of CRB associated with anticoagulation in patients receiving ibrutinib was estimated using conditional logistic regression models, providing odds ratios (OR) adjusted for risk factors of bleeding. Among 614 cases and 2407 matched controls, the risk of CRB was significantly higher in patients receiving both ibrutinib and anticoagulants (adjusted OR [aOR] 2.54, confidence interval [CI] 95% [1.94; 3.32]). When considering anticoagulant class, aOR was 1.99 (CI 95% [1.19; 3.33]) for VKA, 2.48 (CI 95% [1.76; 3.47]) for direct oral anticoagulants and 3.40 (CI 95% [2.01; 5.75]) for parenteral anticoagulants. In conclusion, this study found a 2.5-fold increased risk of CRB in patients receiving both ibrutinib and anticoagulants in real-life settings, and similar aOR among oral anticoagulants.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Case-Control Studies; Hemorrhage; Humans; Piperidines

Zanubrutinib is a selective Bruton tyrosine kinase (BTK) inhibitor evaluated in multiple B-cell malignancy studies. We constructed a pooled safety analysis to better understand zanubrutinib-associated treatment-emergent adverse events (TEAEs) and identify treatment-limiting toxicities. Data were pooled from 6 studies (N = 779). Assessments included type, incidence, severity, and outcome of TEAEs. Median age was 65 years; 20% were ≥75 years old. Most patients had Waldenström macroglobulinemia (33%), chronic lymphocytic leukemia/small lymphocytic lymphoma (29%), or mantle-cell lymphoma (19%). Median treatment duration was 26 months (range, 0.1-65); 16% of patients were treated for ≥3 years. Common nonhematologic TEAEs were upper respiratory tract infection (URI, 39%), rash (27%), bruising (25%), musculoskeletal pain (24%), diarrhea (23%), cough (21%), pneumonia (21%), urinary tract infection (UTI), and fatigue (15% each). Most common grade ≥3 TEAEs were pneumonia (11%), hypertension (5%), URI, UTI, sepsis, diarrhea, and musculoskeletal pain (2% each). Atrial fibrillation and major hemorrhage occurred in 3% and 4% of patients, respectively. Atrial fibrillation, hypertension, and diarrhea occurred at lower rates than those reported historically for ibrutinib. Grade ≥3 adverse events included neutropenia (23%), thrombocytopenia (8%), and anemia (8%). Serious TEAEs included pneumonia (11%), sepsis (2%), and pyrexia (2%).Treatment discontinuations and dose reductions for adverse events occurred in 10% and 8% of patients, respectively. Thirty-nine patients (4%) had fatal TEAEs, including pneumonia (n = 9), sepsis (n = 4), unspecified cause (n = 4), and multiple organ dysfunction syndrome (n = 5). This analysis demonstrates that zanubrutinib is generally well tolerated with a safety profile consistent with known BTK inhibitor toxicities; these were manageable and mostly reversible.

Topics: Adult; Aged; Atrial Fibrillation; Diarrhea; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Lymphoma, Follicular; Musculoskeletal Pain; Piperidines; Pneumonia; Pyrazoles; Pyrimidines; Sepsis

Topics: Adenine; Atrial Fibrillation; Case-Control Studies; Heart Failure; Humans; Piperidines; Risk Factors

Background Ibrutinib and acalabrutinib are Bruton tyrosine kinase inhibitors used in the treatment of B-cell lymphoproliferative disorders. Ibrutinib is associated with new-onset atrial fibrillation. Cases of sinus bradycardia and sinus arrest have also been reported following ibrutinib treatment. Conversely, acalabrutinib is less arrhythmogenic. The basis for these different effects is unclear. Methods and Results The effects of ibrutinib and acalabrutinib on atrial electrophysiology were investigated in anesthetized mice using intracardiac electrophysiology, in isolated atrial preparations using high-resolution optical mapping, and in isolated atrial and sinoatrial node (SAN) myocytes using patch-clamping. Acute delivery of acalabrutinib did not affect atrial fibrillation susceptibility or other measures of atrial electrophysiology in mice in vivo. Optical mapping demonstrates that ibrutinib dose-dependently impaired atrial and SAN conduction and slowed beating rate. Acalabrutinib had no effect on atrial and SAN conduction or beating rate. In isolated atrial myocytes, ibrutinib reduced action potential upstroke velocity and Na

Topics: Action Potentials; Adenine; Animals; Arrhythmias, Cardiac; Atrial Fibrillation; Benzamides; Cardiac Electrophysiology; Mice; Myocytes, Cardiac; Piperidines; Pyrazines; Sinoatrial Node

Ibrutinib therapy is associated with an increased risk of atrial fibrillation (AF) in chronic lymphocytic leukemia (CLL). Risk assessment tools and outcomes of AF in these patients are not well described.. We performed a retrospective review of patients with CLL treated with ibrutinib at Mayo Clinic between October 2012 and November 2018.. Two hundred ninety-eight patients were identified with a median time on ibrutinib of 19 months (range 0.23-69.7 months). Fifty-one patients developed treatment-emergent AF; the risk of treatment-emergent AF at 6 months, 1 year, and 2 years was 9%, 12%, and 16%, respectively. The following were associated with an increased risk of treatment-emergent AF on multivariable analyses: past history of AF (hazard ratio [HR] 3.5, p = 0.0072) and heart failure (HR 3.4, p = 0.0028). Most patients are able to continue ibrutinib therapy (dose reduced in 43%). Development of treatment-emergent AF was associated with shorter event-free survival (EFS; HR 2.0, p = 0.02) and shorter overall survival (OS; HR 3.2, p = 0.001), after adjusting for age, prior treatment status, TP53 disruption, heart failure, valvular disease, and past history of AF.. Patient comorbidities, rather than CLL-related factors, predict risk of treatment-emergent AF in patients treated with ibrutinib. Although the vast majority of patients with treatment-emergent AF are able to continue ibrutinib (with dose reduction in 43%), treatment-emergent AF appears to be associated with worse outcomes, independent of other adverse prognostic factors.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Atrial Fibrillation; Disease Management; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Predictive Value of Tests; Progression-Free Survival; Protein Kinase Inhibitors; Retrospective Studies; Risk Factors; Treatment Outcome

Ibrutinib is the first clinically approved inhibitor of Bruton's tyrosine kinase, an essential enzyme for survival and proliferation of B cells by activating the B-cell receptor-signalling pathway. Ibrutinib has been shown to be highly effective in B-cell malignancies and is recommended in current international guidelines as a first-line and/or second-line treatment of chronic lymphocytic leukemia. The drug has a favorable tolerability and safety profile but the occurrence of specific side effects (e.g. atrial fibrillation, bleeding and hypertension). If atrial fibrillation is diagnosed, anticoagulant therapy may be required. Such patients receiving concomitant anticoagulation should be followed closely. DOAC is preferred over a VKA because of the lower risk of major bleeding events and because of the favorable stroke risk--benefit profile. Of all, Dabigatran offers the availability of an antidote and shows reduced potential for CYP3A4 interactions. We report the cases relating to three patients in concomitant therapy with Ibrutinib and Dabigatran.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Antithrombins; Atrial Fibrillation; Dabigatran; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors

Ibrutinib is associated with atrial fibrillation (AF), though echocardiographic predictors of AF have not been studied in this population. We sought to determine whether left atrial (LA) strain on transthoracic echocardiography could identify patients at risk for developing ibrutinib-related atrial fibrillation (IRAF).. We performed a retrospective review of 66 patients who had an echocardiogram prior to ibrutinib treatment. LA strain was measured with TOMTEC Imaging Systems, obtaining peak atrial longitudinal strain (PALS) and peak atrial contraction strain (PACS) on 4-chamber and 2-chamber views. Statistical analysis was performed with chi-square analysis, t test, or binomial regression analysis, with a P-value < .05 considered statistically significant.. Twenty-two patients developed IRAF (33%). Age at initiation of ibrutinib was significantly associated with IRAF (65.1 years vs 74.1 years, P = .002). Mean ibrutinib dose was lower among patients who developed IRAF (388.2 ± 121.7 vs 448.6 ± 88.4, P = .025). E/e' was significantly higher among patients who developed IRAF (11.5 vs 9.3, P = .04). PALS was significantly lower in patients who developed AF (30.3% vs 36.3%, P = .01). On multivariate regression analysis, age, PALS, and PACS were significantly associated with IRAF. On multivariate regression analysis, only PACS remained significantly associated with IRAF while accounting for age.. Age, ibrutinib dose, E/e', and PALS on pre-treatment echocardiogram were significantly associated with development of IRAF. On multivariate regression analyses, age, PALS, and PACS remained significantly associated with IRAF. Impaired LA mechanics add to the assessment of patients at risk for IRAF.

Topics: Adenine; Atrial Fibrillation; Heart Atria; Humans; Piperidines; Retrospective Studies; Risk Assessment

Ibrutinib is a novel drug used in haematological malignancies. Its use is associated with an increased risk of atrial fibrillation (AF), which, in turn, exposes patients to embolic risk, including stroke. Reducing this risk requires anticoagulant therapy which is a matter of concern in the context of the increased bleeding risk of patients with haematological malignancies. In this context the presence of thrombocytopenia related to haematological disorder, ibrutinib-anticoagulants and ibrutinib-platelets interactions contribute to the amplification of the problem. The correct assessment of the thrombosis vs. haemorrhage balance represents a significant challenge for the clinician. In this paper we discuss practical issues related to anticoagulation in patients treated with ibrutinib and incident AF.

Topics: Adenine; Anticoagulants; Antineoplastic Agents; Atrial Fibrillation; Hematologic Neoplasms; Hemorrhage; Humans; Piperidines; Risk Factors; Stroke; Thromboembolism

Late sodium current (late INa) inhibition has been proposed to suppress the incidence of arrhythmias generated by pathological states or induced by drugs. However, the role of late INa in the human heart is still poorly understood. We therefore investigated the role of this conductance in arrhythmias using adult primary cardiomyocytes and tissues from donor hearts. Potentiation of late INa with ATX-II (anemonia sulcata toxin II) and E-4031 (selective blocker of the hERG channel) slowed the kinetics of action potential repolarization, impaired Ca

Topics: Adult; Atrial Fibrillation; Calcium; Cnidarian Venoms; ERG1 Potassium Channel; Heart Atria; Humans; Membrane Potentials; Models, Cardiovascular; Myocytes, Cardiac; Piperidines; Pyridines; Ranolazine; Sodium; Triazoles

Ibrutinib is the first clinically approved inhibitor of Bruton's tyrosine kinase, an enzyme that is essential for survival and proliferation of B‑cells by activating the B‑cell receptor signalling pathway. Ibrutinib has been shown to be highly effective in B‑cell malignancies in clinical trials and is recommended in current international guidelines as a first and/or second line treatment of chronic lymphocytic leukemia. The drug has a favorable tolerability and safety profile but the occurrence of specific side effects (e.g. atrial fibrillation, bleeding and hypertension) may complicate or be of concern for doctors and patients considering the use of this treatment. In many cases, however, it is not necessary to withhold this effective therapy. In contrast, ibrutinib treatment can be initiated or continued, if certain recommendations are followed. The possibilities of prevention, diagnosis and management of specific clinical situations are discussed in detail and recommendations are derived, which should facilitate ibrutinib use.

Topics: Adenine; Atrial Fibrillation; Cardiovascular Diseases; Humans; Piperidines; Pyrazoles; Pyrimidines; Risk Factors

Atrial fibrillation (AF) occurs in up to 11% of cancer patients treated with ibrutinib. The pathophysiology of ibrutinib promoted AF is complicated, as there are multiple interactions involved; the detailed molecular mechanisms underlying this are still unclear. Here, we aimed to determine the electrophysiological and molecular mechanisms of burst-pacing-induced AF in ibrutinib-treated mice. The results indicated differentially expressed proteins in ibrutinib-treated mice, identified through proteomic analysis, were found to play a role in oxidative stress-related pathways. Finally, treatment with an inhibitor of NADPH oxidase (NOX) prevented and reversed AF development in ibrutinib-treated mice. It was showed that the related protein expression of reactive oxygen species (ROS) in the ibrutinib group was significantly increased, including NOX2, NOX4, p22-phox, XO and TGF-β protein expression. It was interesting that ibrutinib group also significantly increased the expression of ox-CaMKII, p-CaMKII (Thr-286) and p-RyR2 (Ser2814), causing enhanced abnormal sarcoplasmic reticulum (SR) Ca

Topics: Acetophenones; Adenine; Animals; Atrial Fibrillation; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Disease Models, Animal; Humans; Male; Mice; Myocytes, Cardiac; Piperidines; Protein Interaction Maps; Proteomics; Reactive Oxygen Species; Sarcoplasmic Reticulum; Signal Transduction

Topics: Adenine; Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; Piperidines; Plasma; Stroke; Treatment Outcome

Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood.. We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF.. We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving CSK (C-terminal Src kinase) as the strongest candidate for ibrutinib-induced AF. Cardiac-specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3-8.7;. These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov; Unique identifier: NCT03530215.

Topics: Action Potentials; Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Atrial Fibrillation; Atrial Function, Left; CSK Tyrosine-Protein Kinase; Databases, Genetic; Heart Atria; Heart Rate; Humans; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Piperidines; Protein Kinase Inhibitors; Risk Assessment; Risk Factors

Atrial fibrillation (AF) commonly occurs after surgery and is associated with atrial remodeling. TRPV4 is functionally expressed in the heart, and its activation affects cardiac structure and functions. We hypothesized that TRPV4 blockade alleviates atrial remodeling and reduces AF induction in sterile pericarditis (SP) rats. TRPV4 antagonist GSK2193874 or vehicle was orally administered 1 day before pericardiotomy. AF susceptibility and atrial function were assessed using in vivo electrophysiology, ex vivo optical mapping, patch clamp, and molecular biology on day 3 after surgery. TRPV4 expression increased in the atria of SP rats and patients with AF. GSK2193874 significantly reduced AF vulnerability in vivo and the frequency of atrial ectopy and AF with a reentrant pattern ex vivo. Mechanistically, GSK2193874 reversed the abnormal action potential duration (APD) prolongation in atrial myocytes through the regulation of voltage-gated K+ currents (IK); reduced the activation of atrial fibroblasts by inhibiting P38, AKT, and STAT3 pathways; and alleviated the infiltration of immune cells. Our results reveal that TRPV4 blockade prevented abnormal changes in atrial myocyte electrophysiology and ameliorated atrial fibrosis and inflammation in SP rats; therefore, it might be a promising strategy to treat AF, particularly postoperative AF.

Topics: Action Potentials; Aged; Animals; Atrial Fibrillation; Atrial Remodeling; Female; Fibrosis; Heart Atria; Heart Rate; Humans; Inflammation; Male; Middle Aged; Myocytes, Cardiac; Pericarditis; Piperidines; Quinolines; Rats; Rats, Sprague-Dawley; TRPV Cation Channels

Topics: Adenine; Atrial Fibrillation; Australia; Humans; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Atrial Fibrillation; Humans; Neoplasms; Piperidines; Pyrazoles; Pyrimidines

Ibrutinib is a drug used in several lymphohyperplastic diseases. Its use is associated with an increased risk of atrial fibrillation. New-onset atrial fibrillation in this setting is a true challenge as several antiarrhythmic drugs are not indicated and long-term anticoagulation has several limitations. Herein, we describe our experience in treating a 55-year-old patient receiving ibrutinib who presented with new-onset atrial fibrillation and borderline arterial pressure. Since first-line therapies, electrical cardioversion and ablation, could not be performed, rhythm control with intravenous administration of amiodarone was attempted and led to prompt sinus rhythm restoration. We discuss the therapeutic challenges related to sinus rhythm restoration and anticoagulation in this group of atrial fibrillation patients.

Topics: Adenine; Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Topics: Adenine; Aged; Atrial Fibrillation; Comorbidity; Electrocardiography; Female; Heart Failure; Humans; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Patient Outcome Assessment; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Retrospective Studies; Risk Factors

Ibrutinib is a novel antitumor drug that targets Bruton tyrosine kinase for treatment of chronic lymphocytic leukemia. Atrial fibrillation (AF) occurs in 5%-9% of patients during treatment, but the underlying mechanisms remain unclear.. The purpose of this study was to develop a mouse model of ibrutinib-induced AF and investigate its proarrhythmic mechanisms.. In C57BI/6 mice in the ibrutinib and control groups, ibrutinib (25 mg/kg/d) or vehicle (hydroxypropy1-β-cyclodextrin), respectively, was administered orally for 4 weeks. Transesophageal burst stimulation then was used to induced AF. To evaluate the underlying mechanism of AF, cardiac echocardiography was performed. Ca. Compared with the control group, the ibrutinib group showed (1) a higher incidence and longer duration of AF with transesophageal burst stimulation; (2) increased left atrial mass, as indicated by echocardiography; (3) significant myocardial fibrosis in the left atrium on Masson trichrome staining; (4) Ca. The present study established a mouse model of AF by oral administration of ibrutinib for 4 weeks. The arrhythmogenic mechanisms underlying this model likely are associated with structural remodeling and Ca

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Atrial Fibrillation; Atrial Remodeling; Calcium; Calcium Signaling; Disease Models, Animal; Echocardiography; Heart Atria; Leukemia, Lymphocytic, Chronic, B-Cell; Mice; Myocytes, Cardiac; Piperidines; Pyrazoles; Pyrimidines

Ibrutinib (IB) is an oral Bruton's tyrosine kinase (BTK) inhibitor that has demonstrated benefit in B cell cancers, but is associated with a dramatic increase in atrial fibrillation (AF). We employed cell-specific differentiation protocols and optical mapping to investigate the effects of IB and other tyrosine kinase inhibitors (TKIs) on the voltage and calcium transients of atrial and ventricular human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). IB demonstrated direct cell-specific effects on atrial hPSC-CMs that would be predicted to predispose to AF. Second-generation BTK inhibitors did not have the same effect. Furthermore, IB exposure was associated with differential chamber-specific regulation of a number of regulatory pathways including the receptor tyrosine kinase pathway, which may be implicated in the pathogenesis of AF. Our study is the first to demonstrate cell-type-specific toxicity in hPSC-derived atrial and ventricular cardiomyocytes, which reliably reproduces the clinical cardiotoxicity observed.

Topics: Adenine; Atrial Fibrillation; Cardiotoxicity; Cell Differentiation; Cells, Cultured; Heart; Heart Atria; Heart Ventricles; Humans; Myocardium; Myocytes, Cardiac; Organ Specificity; Piperidines; Pluripotent Stem Cells; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

There is increasing evidence that rates of atrial arrhythmias (AA), specifically atrial fibrillation and flutter are elevated in patients treated with the tyrosine kinase inhibitor, ibrutinib; however, the exact risk of ibrutinib-associated AA is not definitively established. We conducted a retrospective study of 137 patients diagnosed with B-cell malignancies treated with ibrutinib compared with 106 patients treated with chemotherapy for the same cancers in order to quantify the rates and risk of AA in a "real-world" sample of cancer patients. Fisher's exact test was used to evaluate for any statistically significant differences between groups. Logistic regression was used to generate odds ratios, adjusting for potential confounders. Incidence of AA was 14% (n = 17) in ibrutinib-treated patients compared with 3% (n = 3) in patients treated with chemotherapy (p = 0.009). Ibrutinib-treated patients were significantly older (mean age 67 vs 63 years, p = 0.003); however, there were no other significant differences in baseline characteristics. Ibrutinib use, age, hypertension, and previous use of ACE inhibitors, angiotensin receptor blocker use, β blocker use, and aspirin use were independently associated with incident arrhythmias. In multivariable analysis, patients treated with ibrutinib were associated with a 5-fold increased risk of developing AA (odds ratio = 5.18, 95% confidence interval 1.42 to 18.89). In conclusion, the rates and risk of AA are higher in patients treated with ibrutinib compared with chemotherapy, and this study provides strong evidence that ibrutinib itself is an independent risk factor for the development of incident AA.

Topics: Adenine; Age Factors; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antineoplastic Agents; Aspirin; Atrial Fibrillation; Atrial Flutter; Female; Humans; Hypertension; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Male; Middle Aged; Multivariate Analysis; Piperidines; Platelet Aggregation Inhibitors; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Risk Factors; Waldenstrom Macroglobulinemia

Results from several recent studies in chronic lymphocytic leukemia (CLL) have demonstrated an association between ibrutinib exposure and the development of atrial fibrillation, estimated incidence of 11% with long-term follow up. This is a common cause of ibrutinib discontinuation. Risk factors for atrial fibrillation include advanced age, hypertension (HTN), mitral valve disease (MVD), left atrial remodeling, coronary artery disease (CAD) and risk factors for cardiovascular dysfunction We conducted a retrospective case control study using the presence of left atrial abnormality identified on pre-ibrutinib EKGs, defined as either (1) Lead II-bifed p wave, with 40 mcsec between peaks for ≥ 2.5 mm wide ≥ 100 msec in duration, (2) Lead V1-biphasic P wave with terminal portion ≥ 40 msec in duration or terminal portion ≥ 1 mm deep or (3) PR interval ≥ 200 msec (intra-atrial conduction delay) as a predictor for development of atrial fibrillation. 183 consecutively CLL patients treated with ibrutinib were identified. 44 patients met inclusion criteria (20 cases, 24 controls). 20 (11.3%) of patients developed atrial fibrillation. Left atrial enlargement was identified as a significant predictor of development of atrial fibrillation (OR 9.1, 95% CI 2.2-37.3, p=0.02). Age, baseline HTN, CAD, diabetes, age and sex were not significant predictors. Area under the ROC curve for the model was estimated to be 75%. LAA identified by EKG is a moderately specific and sensitive finding that can identify patients at increased risk for this toxicity.

Topics: Adenine; Aged; Antineoplastic Agents; Atrial Fibrillation; Case-Control Studies; Electrocardiography; Follow-Up Studies; Heart Atria; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Retrospective Studies; Risk Factors

Atrial fibrillation is a side effect of ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase used for treatment of B-cell lymphoproliferative disorders. We determined if single (2 or 10 mg/kg), or chronic (14 days) oral ibrutinib followed by 24-hour washout conferred susceptibility to electrically induced arrhythmias in 1-month-old male C57BL/6 mice. A single higher dose of ibrutinib increased arrhythmia inducibility. There was no inducibility difference after chronic dosing with washout. This suggests that high serum drug levels might be responsible for the proarrhythmic effect of ibrutinib and that an altered dosing strategy might mitigate the side effects.

Topics: Adenine; Animals; Atrial Fibrillation; Disease Models, Animal; Disease Susceptibility; Dose-Response Relationship, Drug; Electrocardiography; Male; Mice; Mice, Inbred C57BL; Piperidines; Pulse Therapy, Drug; Pyrazoles; Pyrimidines; Random Allocation; Reference Values; Risk Assessment; Ventricular Fibrillation

Ibrutinib is an oral irreversible inhibitor of Bruton's tyrosine kinase, indicated for the treatment of chronic lymphocytic leukaemia. The drug is generally well tolerated; however, not infrequent side effects are reported, with the major two being bleeding and ibrutinib-related atrial fibrillation. Atrial fibrillation pathogenesis in this setting is not completely clear, and no prospective studies have evaluated the impact of previous cardiologic history and baseline characteristics.. We prospectively performed cardiologic assessment in 43 CLL patients before starting ibrutinib therapy. Cardiologic workup included comorbidity collection and electrocardiographic and echocardiographic baseline evaluation.. After a median observation of 8 months, seven patients developed atrial fibrillation (16.3%). Cases developing atrial fibrillation were all elderly males (p = 0.04), and mostly with a history of previous arterial hypertension (p = 0.009). Atrial fibrillation occurrence also correlated with the presence of one or more pre-existent cardiologic comorbidities (p = 0.03), with a higher atrial fibrillation risk score (calculated with comorbidities and cardiologic risk factor evaluation p < 0.001), and with higher left atrial diameter (p = 0.02) and area (p = 0.03) by echocardiography. The occurrence of atrial fibrillation was managed after an integrated cardio-oncologic evaluation: anticoagulation was started in 4 (57.1%) patients and beta-blockers or amiodarone in 5 (71.4%). One patient underwent electric cardioversion and another patient pacemaker positioning to normalise heart rate in order to continue ibrutinib.. Our data show that echocardiography is a highly informative and reproducible tool that should be included in pre-treatment workup for patients who are candidates for ibrutinib therapy.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Atrial Fibrillation; Echocardiography; Female; Hemorrhage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Prospective Studies; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Reproducibility of Results

Topics: Adenine; Aged; Aged, 80 and over; Atrial Fibrillation; Dabigatran; Female; Humans; Lymphoproliferative Disorders; Piperidines; Pyrazoles; Pyrimidines

There is increasing evidence implicating atrial mitochondrial dysfunction in the pathogenesis of atrial fibrillation. In this study, we explored whether alogliptin, a dipeptidyl peptidase-4 inhibitor, can prevent mitochondrial dysfunction and atrial remodeling in a diabetic rabbit model.. A total of 90 rabbits were randomized into 3 groups as follows: control group (n=30), alloxan-induced diabetes mellitus group (n=30), and alogliptin-treated (12.5 mg/kg per day for 8 weeks) diabetes mellitus group (n=30). Echocardiographic and hemodynamic assessments were performed in vivo. The serum concentrations of glucagon-like peptide-1, insulin, and inflammatory and oxidative stress markers were measured. Electrophysiological properties of Langendorff-perfused rabbit hearts were assessed. Mitochondrial morphology, respiratory function, membrane potential, and reactive oxygen species generation rate were assessed. The protein expression of transforming growth factor β1, nuclear factor κB p65, and mitochondrial biogenesis-related proteins were measured by Western blot analysis. Diabetic rabbits exhibited left ventricular hypertrophy and left atrial dilation without obvious hemodynamic abnormalities, and all of these changes were attenuated by alogliptin. Compared with the control group, higher atrial fibrillation inducibility in the diabetes mellitus group was observed, and markedly reduced by alogliptin. Alogliptin decreased mitochondrial reactive oxygen species production rate, prevented mitochondrial membrane depolarization, and alleviated mitochondrial swelling in diabetic rabbits. It also improved mitochondrial biogenesis by peroxisome proliferator-activated receptor-γ coactivator 1α/nuclear respiratory factor-1/mitochondrial transcription factor A signaling regulated by adiponectin/AMP-activated protein kinase.. Dipeptidyl peptidase-4 inhibitors can prevent atrial fibrillation by reversing electrophysiological abnormalities, improving mitochondrial function, and promoting mitochondrial biogenesis.

Topics: Animals; Atrial Fibrillation; Atrial Remodeling; Diabetes Mellitus, Experimental; Dipeptidyl-Peptidase IV Inhibitors; Fibrosis; Heart Atria; Heart Rate; Membrane Potential, Mitochondrial; Mitochondria, Heart; NF-E2-Related Factor 1; Organelle Biogenesis; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Piperidines; Rabbits; Time Factors; Transcription Factor RelA; Transforming Growth Factor beta1; Uracil; Ventricular Function

Ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase (BTK), is a novel drug that has shown significant efficacy and survival benefit for treatment of various B-cell malignancies. The primary objective of the present study was to investigate the efficacy of ibrutinib therapy in various B-cell malignancies in the general community. The secondary objectives included studying the adverse effects, ibrutinib-induced peripheral lymphocytosis, and effect on immunoglobulin levels.. The present study was a retrospective observational cohort analysis conducted at Abington Jefferson Health. The clinical response was determined from the hematologist's assessment and evaluated independently using the response criteria for each B-cell malignancy. Adverse effects were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. The Wilcoxon signed-rank test was used to compare immunoglobulin levels before and after ibrutinib. Forty five patients with B-cell malignancies and receiving ibrutinib therapy were eligible.. Ibrutinib is a highly effective and tolerable drug for B-cell malignancies in the general community. In contrast to the previously reported rate of 5% to 7%, we observed a higher rate (11%) of atrial fibrillation, which might have resulted from the smaller sample size in the present study and the multiple comorbidities. Nonetheless, this treatment-limiting side effect requires further elucidation. Paradoxical lymphocytosis at the outset of therapy was a common and benign finding. In conjunction with the reported trials, the IgG levels decreased in the first year of continued therapy. However, the IgA levels did not increase, even after 2 years of therapy.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Atrial Fibrillation; B-Lymphocytes; Disease-Free Survival; Female; Humans; Immunoglobulin G; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Male; Middle Aged; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Retrospective Studies; Treatment Outcome; Waldenstrom Macroglobulinemia

A new class III antiarrhythmic drug niferidil (RG-2) has been introduced as a highly effective therapy for cases of persistent atrial fibrillation, but ionic mechanisms of its action are poorly understood. In the present study, the effects of niferidil on action potential (AP) waveform and potassium currents responsible for AP repolarization were investigated in guinea pig atrial myocardium.. APs were recorded with sharp glass microelectrodes in multicellular atrial preparations. Whole-cell patch-clamp technique was used to measure K. Niferidil prolongs APs in guinea pig atrial myocardium via inhibition of I

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Delayed Rectifier Potassium Channels; Guinea Pigs; Heart Atria; In Vitro Techniques; Male; Microelectrodes; Myocytes, Cardiac; Patch-Clamp Techniques; Piperidines

Although preliminary data suggests that ibrutinib may increase risk of atrial fibrillation (AF), the incidence of AF in a general cohort of chronic lymphocytic leukemia (CLL) patients is unknown. We evaluated the prevalence of AF at CLL diagnosis and incidence of AF during follow-up in 2444 patients with newly diagnosed CLL. A prior history of AF was present at CLL diagnosis in 148 (6.1%). Among the 2292 patients without history of AF, 139 (6.1%) developed incident AF during follow-up (incidence approximately 1%/year). Older age (p < .0001), male sex (p = .01), valvular heart disease (p = .001), and hypertension (p = .04) were associated with risk of incident AF on multivariate analysis. A predictive model for developing incident AF constructed from these factors stratified patients into 4 groups with 10-year rates of incident AF ranging from 4% to 33% (p < .0001). This information provides context for interpreting rates of AF in CLL patients treated with novel therapies.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Atrial Fibrillation; Comorbidity; Female; Humans; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Staging; Piperidines; Prevalence; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Risk Factors; Young Adult

Topics: Adenine; Aged; Amiodarone; Atrial Fibrillation; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Heart Failure; Humans; Male; Piperidines; Pyrazoles; Pyrimidines; Syndrome

Topics: Adenine; Aged; Aged, 80 and over; Atrial Fibrillation; Female; Follow-Up Studies; Humans; Incidence; Lymphoma, Mantle-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Retrospective Studies; Treatment Outcome

Topics: Adenine; Anticoagulants; Atrial Fibrillation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Risk Factors; Stroke; Warfarin

Atrial fibrillation (AF) occurs in 5-9% of patients treated with ibrutinib for chronic lymphocytic leukaemia (CLL); the clinical consequences and optimal management are unclear. We retrospectively studied 56 CLL patients who received ibrutinib and developed AF. Median time to onset was 3·8 months. AF was persistent in 35/56 (62%) cases despite treatment. Clinical consequences included: three episodes of severe cardiac failure (one fatal) and one stroke; eight non-thrombocytopenic patients (14%) experienced severe bleeding adverse events. Altogether, ibrutinib was permanently discontinued in 26/56 cases (46%). Data to guide optimal management are lacking and clinical practice guidelines are urgently needed.

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Agents; Atrial Fibrillation; Disease Management; Female; Hemorrhage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Retrospective Studies

Topics: Adenine; Algorithms; Antineoplastic Agents; Atrial Fibrillation; Humans; Piperidines; Pyrazoles; Pyrimidines

The availability of safe and effective drugs for the management of atrial fibrillation (AF) remains an unmet medical need.. The purpose of this study was to test the hypothesis that the inhibition of the rapidly activating delayed rectifier potassium current (IKr) greatly potentiates the development of atrial-selective sodium channel current (INa) block, leading to more effective suppression of AF.. Electrophysiological and anti-AF effects of highly selective INa and IKr blockers (lidocaine and E-4031) individually and in combination were determined in canine coronary-perfused atrial and ventricular preparations. Acetylcholine (1 µM) was used to induce persistent AF.. Lidocaine (10 µM) caused a relatively small abbreviation of the action potential duration measured at 90% repolarization in both atria and ventricles, but caused atrial-selective prolongation of the effective refractory period owing to the induction of post-repolarization refractoriness. Lidocaine also caused modest atrial-selective depression of other INa-mediated parameters including excitability, maximum rate of rise of the action potential upstroke, and conduction time. E-4031 (1 µM) prolonged the action potential duration measured at 90% repolarization and effective refractory period in an atrial-predominant manner. A combination of lidocaine and E-4031 caused a greater atrial-selective depression of INa-mediated parameters. Persistent acetylcholine-mediated AF developed in 100% of atria under control conditions, in 80% (4 of 5) after pretreatment with lidocaine (10 µM), in 100% (4 of 4) after E-4031 (1 µM), and in only 14% (1 of 7) after the combination of lidocaine and E-4031.. Our results provide a proof of concept that IKr block greatly potentiates the effects of rapidly dissociating INa blockers to depress sodium channel-dependent parameters in the canine atria but not in the ventricles, thus contributing significantly to suppression of AF.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Delayed Rectifier Potassium Channels; Dogs; Electrophysiological Phenomena; Heart Atria; Heart Rate; Heart Ventricles; Lidocaine; Models, Anatomic; Piperidines; Pyridines; Sodium Channel Blockers; Sodium Channels

Topics: Animals; Atrial Fibrillation; Heart Failure; Humans; Male; Oximes; Piperidines

Dipeptidyl peptidase-4 (DPP-4) inhibitors were recently reported to have cardioprotective effects via amelioration of ventricular function. However, the role of DPP-4 inhibition in atrial remodeling, especially of the arrhythmogenic substrate, remains unclear.. We investigated the effects of a DPP-4 inhibitor, alogliptin, on atrial fibrillation (AF) in a rabbit model of heart failure caused by ventricular tachypacing (VTP).. Rabbits subjected to VTP at 380 bpm for 1 or 3 weeks, with or without alogliptin treatment, were assessed using echocardiography, electrophysiology, histology, and immunoblotting and compared with nonpaced animals.. VTP rabbits exhibited increased duration of atrial burst pacing-induced AF, whereas administration of alogliptin shortened this duration by 73%. The extent of atrial fibrosis after VTP was reduced by 39% in the alogliptin-treated group. VTP rabbits treated with alogliptin displayed a 1.6-fold increase in left atrial myocardial capillary density compared with nontreated rabbits. A 2-fold increase in endothelial nitric oxide synthase (eNOS) phosphorylation was observed in the left atrium of alogliptin-treated rabbits compared with nontreated rabbits. Moreover, a nitric oxide synthase inhibitor (N(ω)-nitro-l-arginine methyl ester) blocked the beneficial effects of alogliptin on AF duration, fibrosis, and capillary density.. Alogliptin shortened the duration of AF caused by VTP-induced fibrotic atrial tissue by augmenting atrial angiogenesis and activating eNOS. Our findings suggest that DPP-4 inhibitors may be useful in the prevention of heart failure-induced AF.

Topics: Animals; Atrial Fibrillation; Blotting, Western; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Echocardiography; Electrophysiology; Endothelium; Enzyme-Linked Immunosorbent Assay; Fibrosis; Fluorescent Antibody Technique; Heart Atria; Heart Failure; Male; Neovascularization, Physiologic; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Phosphorylation; Piperidines; Rabbits; Tachycardia, Ventricular; Uracil

Heart failure (HF) and atrial fibrillation (AF) share common risk factors, frequently coexist and are associated with high mortality. Treatment of HF with AF represents a major unmet need. Here we show that a small molecule, BGP-15, improves cardiac function and reduces arrhythmic episodes in two independent mouse models, which progressively develop HF and AF. In these models, BGP-15 treatment is associated with increased phosphorylation of the insulin-like growth factor 1 receptor (IGF1R), which is depressed in atrial tissue samples from patients with AF. Cardiac-specific IGF1R transgenic overexpression in mice with HF and AF recapitulates the protection observed with BGP-15. We further demonstrate that BGP-15 and IGF1R can provide protection independent of phosphoinositide 3-kinase-Akt and heat-shock protein 70; signalling mediators often defective in the aged and diseased heart. As BGP-15 is safe and well tolerated in humans, this study uncovers a potential therapeutic approach for HF and AF.

Topics: Animals; Atrial Fibrillation; Caveolin 1; Caveolin 3; Disease Models, Animal; Electrocardiography; G(M3) Ganglioside; Heart Failure; HSP70 Heat-Shock Proteins; Humans; Male; Mice; Mice, Knockout; Mice, Transgenic; Microarray Analysis; Oximes; Phosphatidylinositol 3-Kinases; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-akt; Receptor, IGF Type 1; Receptors, Somatomedin; Risk Factors; Signal Transduction; Transgenes

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Animals, Newborn; Atrial Fibrillation; Gene Expression Regulation, Enzymologic; Humans; Infant, Newborn; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Myocytes, Cardiac; Phosphatidylinositol 3-Kinases; Piperidines; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyrimidines; Rats; Risk Factors; Signal Transduction

Remifentanil may be beneficial in patients undergoing cardiac surgery, by attenuating the neurohumoral stress response to surgical stimulation and inflammation evoked by cardiopulmonary bypass (CPB).. We retrospectively examined blood glucose monitored every 30 minutes during CPB and insulin dose in patients during CPB under remifentanil anesthesia (remifentanil group) and those under low dose fentanyl anesthesia (fentanyl group) in adult cardiac surgery. Furthermore we also investigated incidence of atrial fibrillation within 72 hours after surgery in both groups.. There were 35 patients in remifentanil group and 22 patients in fentanyl group. Although blood glucose at the beginning and the end of CPB in both groups were not different, remifentanil group showed lower maximum blood glucose (median 172 mg x dl(-1), interquatile range 156-205 mg x dl(-1)) during CPB than in fentanyl group (197 mg x dl(-1), 176-219 mg x dl(-1); P = 0.009). Significantly less insulin was administered during CPB in remifentanil group than in fentanyl group. Incidence of postoperative atrial fibrillation was similar between the groups.. Maximum blood glucose was lower and less insulin was administered during CPB in remifentanil group. These data may suggest that remifentanil reduce stress response to surgical stimulation in cardiac surgery.

Topics: Aged; Anesthetics, Intravenous; Atrial Fibrillation; Blood Glucose; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Female; Fentanyl; Humans; Insulin; Male; Middle Aged; Piperidines; Postoperative Complications; Remifentanil; Retrospective Studies

The most common clinical tachycardia, Atrial Fibrillation (AF), is a progressive disease, caused by cardiomyocyte remodeling, which finally results in contractile dysfunction and AF persistence. Recently, we identified a protective role of heat shock proteins (HSPs), especially the small HSPB1 member, against tachycardia remodeling in experimental AF models. Our understanding of tachycardia remodeling and anti-remodeling drugs is currently hampered by the lack of suitable (genetic) manipulatable in vivo models for rapid screening of key targets in remodeling. We hypothesized that Drosophila melanogaster can be exploited to study tachycardia remodeling and protective effects of HSPs by drug treatments or by utilizing genetically manipulated small HSP-overexpressing strains. Tachypacing of Drosophila pupae resulted in gradual and significant cardiomyocyte remodeling, demonstrated by reduced contraction rate, increase in arrhythmic episodes and reduction in heart wall shortening, compared to normal paced pupae. Heat shock, or pre-treatment with HSP-inducers GGA and BGP-15, resulted in endogenous HSP overexpression and protection against tachycardia remodeling. DmHSP23 overexpressing Drosophilas were protected against tachycardia remodeling, in contrast to overexpression of other small HSPs (DmHSP27, DmHSP67Bc, DmCG4461, DmCG7409, and DmCG14207). (Ultra)structural evaluation of the tachypaced heart wall revealed loss of sarcomeres and mitochondrial damage which were absent in tachypaced DmHSP23 overexpressing Drosophila. In addition, tachypacing induced a significant increase in calpain activity, which was prevented in tachypaced Drosophila overexpressing DmHSP23. Tachypacing of Drosophila resulted in cardiomyocyte remodeling, which was prevented by general HSP-inducing treatments and overexpression of a single small HSP, DmHSP23. Thus, tachypaced D. melanogaster can be used as an in vivo model system for rapid identification of novel targets to combat AF associated cardiomyocyte remodeling.

Topics: Animals; Atrial Fibrillation; Calpain; Disease Models, Animal; Diterpenes; Drosophila melanogaster; Drosophila Proteins; Gene Expression; Gene Expression Regulation; Heart; Heat-Shock Proteins; Heat-Shock Proteins, Small; Myocardial Contraction; Oximes; Piperidines; Tachycardia

Adenosine-induced transient flow arrest has been used to facilitate clip ligation of intracranial aneurysms. However, the starting dose that is most likely to produce an adequate duration of profound hypotension remains unclear. We reviewed our experience to determine the dose-response relationship and apparent perioperative safety profile of adenosine in intracranial aneurysm patients.. This case series describes 24 aneurysm clip ligation procedures performed under an anesthetic consisting of remifentanil, low-dose volatile anesthetic, and propofol in which adenosine was used. The report focuses on the doses administered; duration of systolic blood pressure <60 mm Hg (SBP(<60 mm Hg)); and any cardiovascular, neurologic, or pulmonary complications observed in the perioperative period.. A median dose of 0.34 mg/kg ideal body weight (range: 0.29-0.44 mg/kg) resulted in a SBP(<60 mm Hg) for a median of 57 seconds (range: 26-105 seconds). There was a linear relationship between the log-transformed dose of adenosine and the duration of a SBP(<60 mm Hg) (R(2) = 0.38). Two patients developed transient, hemodynamically stable atrial fibrillation, 2 had postoperative troponin levels >0.03 ng/mL without any evidence of cardiac dysfunction, and 3 had postoperative neurologic changes.. For intracranial aneurysms in which temporary occlusion is impractical or difficult, adenosine is capable of providing brief periods of profound systemic hypotension with low perioperative morbidity. On the basis of these data, a dose of 0.3 to 0.4 mg/kg ideal body weight may be the recommended starting dose to achieve approximately 45 seconds of profound systemic hypotension during a remifentanil/low-dose volatile anesthetic with propofol induced burst suppression.

Topics: Adenosine; Adult; Aged; Anesthesia, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Atrial Fibrillation; Cardiovascular Diseases; Cerebrovascular Circulation; Dose-Response Relationship, Drug; Female; Humans; Intracranial Aneurysm; Ligation; Male; Middle Aged; Nervous System Diseases; Neurosurgical Procedures; Piperidines; Postoperative Complications; Propofol; Remifentanil; Vasodilator Agents

A 21-year-old man was scheduled to undergo posterior cruciate ligament reconstruction under arthroscopic control. The patient did not have a previous history of thyroid disease. Low blood cholesterol was revealed in the laboratory data. On arriving at the operating room, he showed sinus tachycardia of 130 beats x min(-1). Anesthesia was induced with remifentanil and propofol intravenously followed by sevoflurane inhalation, and maintained with remifentanil at a rate of 0.3 microg x kg(-1) x min(-1) and 2% sevoflurane. Heart rate was stable around 70-90 beats x min(-1) during the operation. After remifentanil and sevoflurane were discontinued following surgery, his heart rate increased and paroxysmal atrial fibrillation occurred. Although verapamil was administered intravenously, atrial fibrillation and tachycardia persisted. Further investigations revealed an elevated serum free thyroxin level and suppressed thyroid-stimulating hormone (TSH). Serum TSH receptor antibody concentration was elevated. Upon postoperative examination, goiter and the protuberance of the eyes were noticed. We conclude that he was suffering from Basedow disease. Although he had no subjective symptoms in the preoperative period, the possibility of hyperthyroidism should have been predicted from the laboratory data such as hypolipidemia and by conducting a careful medical examination. It seems that remifentanil suppresses sympathetic activity, and is useful for patients with hyperthyroidism.

Topics: Anesthesia Recovery Period; Anesthesia, General; Atrial Fibrillation; Humans; Hyperthyroidism; Male; Piperidines; Plastic Surgery Procedures; Posterior Cruciate Ligament; Postoperative Complications; Remifentanil; Young Adult

Drug discovery efforts have focused recently on atrial-selective targets, including the Kv1.5 channel, which underlies the ultrarapid delayed rectifier current, I(Kur), to develop novel treatments for atrial fibrillation (AF). Two structurally distinct compounds, a triarylethanolamine TAEA and an isoquinolinone 3-[(dimethylamino)-methyl]-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (ISQ-1), blocked I(Kur) in Chinese hamster ovary cells expressing human Kv1.5 with IC(50) values of 238 and 324 nM, respectively. In anesthetized dogs, i.v. infusions of TAEA and ISQ-1 elicited comparable 16% increases in atrial refractory period, with no effect on ventricular refractory period or QTc interval. Plasma concentrations at end infusion for TAEA and ISQ-1 were 58.5 +/- 23.6 and 330.3 +/- 43.5 nM, respectively. The abilities of TAEA and ISQ-1 to terminate AF, with comparison to the rapidly activating component of delayed rectifier potassium current blocker (+)-N-[1'-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro(2H-1-benzopyran-2,4'-piperidin)-6-yl]methanesulfonamide] monohydrochloride (MK-499) and the class IC 1-[2-[2-hydroxy-3-(propylamino)-propoxy]phenyl]-3-phenyl-1-propanone (propafenone), were assessed in conscious dogs with heart failure and inducible AF (entry criterion). All test agents administered in i.v. bolus regimens terminated AF in at least half of animals tested; conversely no agent was universally effective. MK-499, ISQ-1, TAEA, and propafenone terminated AF in five of six, four of seven, four of six, and five of six animals at plasma concentrations of 32.6 +/- 18.7, 817 +/- 274, 714 +/- 622, and 816 +/- 240 nM, respectively. Directed cardiac electrophysiologic studies in anesthetized dogs using i.v. bolus (consistent with AF studies) plus infusion regimens with TAEA and ISQ-1 demonstrated significant increases in atrial refractory period (12-15%), A-H and P-A intervals, but no effects on ventricular refractory period, H-V, and HEG intervals. The demonstration of AF termination with TAEA and ISQ-1 in the dog heart failure model extends the profile of antiarrhythmic efficacy of Kv1.5 blockade.

Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Benzopyrans; Cell Line; Dogs; Female; Heart Atria; Heart Failure; Humans; Isoquinolines; Kv1.5 Potassium Channel; Male; Piperidines; Potassium Channel Blockers; Propafenone; Pyridines; Sodium Channel Blockers

Stimulation of atrial 5-HT4 receptors is associated with arrhythmias. Their blockade prolongs atrial effective refractory period (ERP), following short runs of atrial fibrillation (AF). The role of 5-HT4 receptors during longer periods of AF is unknown. In this study, we investigated the effects of the selective 5-HT4 receptor stimulation and blockade on porcine atria, during 6 h of AF.. Atrial ERP, monophasic action potential (MAP) duration, time to sinus rhythm restoration (TSRR) and ERP/MAP ratio were assessed in 27 pigs, at baseline and every hour, during 6 h of AF, induced by rapid atrial pacing. Ten animals were used as controls, 10 were administered the selective 5-HT4 antagonist SB203186 and seven were administered the selective 5-HT4 agonist RS67333.. During the first few hours of fibrillation, ERP, MAP and TSRR were preserved in SB203186-treated pigs, while they were shortened in controls and RS67333-treated animals. After 6 h of arrhythmia, ERP and MAP were shortened in all three groups, but the decrease was less in SB203186-treated pigs. ERP/MAP ratio increased in controls and RS67333-treated animals, while it remained unchanged in SB203186-treated pigs. Towards the end of the AF period, four of the SB203186-treated pigs developed sustained atrial tachycardia.. Following short periods of AF, 5-HT4 receptors' blockade protects the porcine atria against ERP and MAP shortening, while their stimulation has the opposite result. This beneficial effect, though, is gradually diminished following longer periods of AF and atrial tachycardia may develop.

Topics: Aniline Compounds; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Blood Pressure; Cardiac Pacing, Artificial; Electrocardiography; Electrophysiologic Techniques, Cardiac; Heart Rate; Indoles; Male; Piperidines; Refractory Period, Electrophysiological; Serotonin 5-HT4 Receptor Antagonists; Swine

The case of a 64-year-old man with Wolff-Parkinson-White syndrome and permanent atrial fibrillation (AF) is reported. The patient was admitted due to electrocardiographic feature of AF with rapid conduction over the left-sided accessory pathway. Administration of pirmenol effectively suppressed the ventricular response via an accessory pathway. A transesophageal echocardiography detected an uncertain thrombus in the left atrial appendage. During the 33-month follow-up period, the ventricular response via an accessory pathway was progressively facilitated. Radiofrequency catheter ablation using a transseptal approach was performed during AF, resulting in complete elimination of the antegrade accessory pathway conduction.

Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Bundle of His; Catheter Ablation; Electrocardiography; Follow-Up Studies; Humans; Male; Middle Aged; Piperidines; Wolff-Parkinson-White Syndrome

Although pharmacological agents are frequently used to control ventricular rate or restore sinus rhythm of patients with atrial fibrillation (AF), there are no reports of the relationship between those agents and left atrial appendage (LAA) function. Two cases of a decrease in LAA blood flow velocity caused by negative inotropic agents are presented as an indication that negative inotropic agents are a risk factor for systemic thromboembolism with AF.

Topics: Atenolol; Atrial Fibrillation; Atrial Function, Left; Blood Flow Velocity; Cardiotonic Agents; Echocardiography, Transesophageal; Humans; Male; Middle Aged; Piperidines; Thromboembolism

This study was designed to evaluate the electrophysiologic effects of E4031 (a pure IKr blocker) and azimilide (AZ: a combined Ikr + IKs blocker) at various stages of atrial electrical remodeling. Twelve dogs underwent continuous rapid atrial pacing (400/min) for 14 days. The electrophysiologic study was performed on the day before as well as after 2, 7, and 14 days of rapid atrial pacing both before and after the administration of either E4031 (n = 6) or AZ (n = 6). In response to rapid atrial pacing, the atrial effective refractory period (ERP), conduction velocity, and wavelength decreased significantly at pacing cycle lengths (PCLs) of 200 and 400 ms (P < 0.05). E4031 prolonged ERP in a reverse use-dependent manner throughout the study period. AZ also prolonged ERP during the 14 days of rapid pacing. ERP prolongation at a PCL of 200 ms was significantly greater with AZ than with E4031 (P < 0.05). The effects of blocking IKr by E4031 and IKr + IKs by AZ were well preserved at various stages of atrial electrical remodeling. However, the effect of prolonging ERP at a shorter PCL was more prominent by AZ than by E4031. Thus, IKs blockade may add a favorable anti-fibrillatory effect to IKr blockade even in the remodeled atrium.

Topics: Animals; Atrial Fibrillation; Atrial Function; Cardiac Pacing, Artificial; Dogs; Electric Stimulation; Electrocardiography; Electrodes, Implanted; Female; Hydantoins; Imidazoles; Imidazolidines; Male; Piperazines; Piperidines; Potassium Channel Blockers; Pyridines; Refractory Period, Electrophysiological

Topics: Aged; Aged, 80 and over; Analgesics, Opioid; Atrial Fibrillation; Female; Humans; Intraoperative Complications; Piperidines; Remifentanil

Topics: Animals; Atrial Fibrillation; Heart; Immobilization; Ligands; Male; Myocardial Infarction; Oligopeptides; Piperidines; Pyrrolidines; Rats; Rats, Wistar; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Receptors, sigma; Stress, Physiological

Pirmenol hydrochloride is a new orally effective, long-acting antiarrhythmic agent currently used in patients with supraventricular and ventricular tachyarrhythmias. We report on a 56-year-old female who exhibited drug refractory paroxysmal atrial fibrillation, in which marked prolongation of the QT interval and T wave inversion on electrocardiogram was demonstrated reproducibly shortly after the administration of oral pirmenol therapy. The plasma concentration of pirmenol was at a subtherapeutic level and the lymphocyte stimulation test was positive in this patient. Thus, an immunological mechanism might be involved in the mechanism of pirmenol-induced QT prolongation and T wave inversion on the electrocardiogram.

Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Electrocardiography; Female; Humans; Long QT Syndrome; Middle Aged; Piperidines

We examined the effects of pirmenol and disopyramide on the muscarinic acetylcholine receptor-operated K+ current (I[K.ACh]) in atrial cells and on experimental atrial fibrillation in isolated guinea-pig hearts. In isolated atrial myocytes, both pirmenol and disopyramide concentration-dependently inhibited the I(K.ACh) induced by carbachol or intracellular loading of GTPgammaS. Their inhibitory effects on the carbachol-induced current were more potent than those on GTPgammaS-induced current, suggesting that these drugs inhibit I(K.ACh) mainly by blocking muscarinic receptors. In Langendorff-perfused hearts these drugs reversed the carbachol-induced decreases in effective refractory periods and atrial fibrillation threshold. These drugs may be useful for the prevention of vagally induced atrial fibrillation.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Carbachol; Disopyramide; Electric Stimulation; Guinea Pigs; Heart; Patch-Clamp Techniques; Piperidines; Potassium Channels; Receptors, Muscarinic

It is well known that vagal stimulation increases the vulnerability to atrial fibrillation via muscarinic receptor-mediated shortening of refractory period. Recently it has been reported that some class III antiarrhythmic drugs effectively terminate or prevent atrial flutter and fibrillation by prolonging atrial effective refractory period. However, effects of class III antiarrhythmic drugs on the muscarinic acetylcholine receptor-operated K+ current (IK.ACh), which is important for the repolarization phase of the action potential in atrial cells, have not been thoroughly examined.. Effects of three class III antiarrhythmic drugs, d,l-sotalol, E-4031, and MS-551, on the carbachol (1 mumol/L)-induced action potential shortening and outward K+ current were examined in guinea pig atrial cells by conventional microelectrode and patch clamp techniques. In isolated left atria, d,l-sotalol (100 mumol/L), E-4031 (3 mumol/L), and MS-551 (30 mumol/L) partially reversed the carbachol-induced action potential shortening. In isolated single atrial cells, IK.ACh was activated by extracellular application of carbachol (1 mumol/L) or adenosine (10 mumol/L) or by intracellular loading of GTP gamma S (100 mumol/L). Sotalol (3 to 1000 mumol/L), E-4031 (1 to 100 mumol/L), and MS-551 (1 to 100 mumol/L) inhibited the carbachol-induced IK.ACh in a concentration-dependent manner, and their IC50 (half-maximal inhibition) values were 35.5, 7.8, and 11.4 mumol/L, respectively. However, the GTP gamma S-induced and adenosine-induced IK.ACh were inhibited by high concentrations of E-4031 and MS-551 but not by sotalol.. Sotalol may inhibit IK.ACh by the blockade of the atrial muscarinic receptors, whereas E-4031 and MS-551 may inhibit the current not only by blocking the muscarinic receptors but also by depressing the function of the K+ channel itself and/or G proteins. These drugs may potentially be useful for the prevention and termination of atrial flutter and fibrillation through their inhibitory action on IK.ACh.

Topics: Acetylcholine; Action Potentials; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Atrial Function, Left; Cells, Cultured; Guinea Pigs; Heart Atria; In Vitro Techniques; Myocardial Contraction; Patch-Clamp Techniques; Piperidines; Potassium Channels; Pyridines; Pyrimidinones; Receptors, Muscarinic; Sotalol

R56865 was previously characterized as an inhibitor of Na and Ca overload that has beneficial effects during ischemia and reperfusion. An isolated guinea-pig heart preparation was subjected to 60 minutes of ischemia and 60 minutes of reperfusion. R56865 was given before ischemia and with the onset of reperfusion, applying different dosing schedules, including an initial loading dose. R56865 below 0.1 mumol/l had no cardiodepressant effects in normoxic hearts and at 0.1 mumol/l reduced left ventricular pressure marginally. The onset of ischemic contracture was delayed only at this concentration. R56865 given before ischemia potently inhibits delayed sustained fibrillation occurring during reperfusion in the concentration range between 0.01 mumol/l and 0.1 mumol/l. Analysis of cellular Na+, K+, and Ca2+ concentrations revealed that R56865 substantially improves the ionic homeostasis of myocardial cells. Most importantly, the compound also reduced the incidence of delayed sustained fibrillation when given at the onset of reperfusion. R56865 was most effective when fast equilibration of drug with tissue was achieved by giving an initial loading dose. In particular, the cellular Na+ and Ca2+ contents were improved using this dosing scheme. The results are compatible with the classification of R56865 as an inhibitor of Na+ and Ca2+ overload.

Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Benzothiazoles; Calcium; Calcium Channel Blockers; Extracellular Space; Guinea Pigs; Heart; In Vitro Techniques; Lidocaine; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Piperidines; Potassium; Sodium; Thiazoles; Verapamil

The effects of E-4031, a new class III antiarrhythmic agent, on atrial fibrillation threshold (AFT), atrial effective refractory period (ERP), and interatrial conduction time (ACT) were investigated in Langendorff-perfused guinea pig hearts; the results were then compared with those of the class I agents disopyramide, procainamide, lidocaine, and flecainide. Whole guinea pig hearts were perfused with Tyrode's solution containing acetylcholine (ACh 3 x 10(-7) M). The three indexes were measured before and after administration of the test drugs, using right atrial extrastimulus and 50-Hz continuous stimulation. Disopyramide, procainamide, and flecainide (> or = 10(-6) M) significantly increased AFT. Although E-4031 (> or = 3 x 10(-6) M) also increased AFT, this effect was less potent than that observed with the other drugs. E-4031 (> or = 10(-6) M) significantly prolonged ERP, and this prolongation was less pronounced than that observed with disopyramide but similar to that observed with procainamide or flecainide. E-4031 did not affect ACT, and the greatest prolongation of ACT was observed with flecainide. Lidocaine had no effect on any of the indexes. These findings suggest that in guinea pig hearts E-4031 exerts an antifibrillatory effect by prolonging atrial ERP alone, but this effect is less pronounced than that observed with class I drugs, because AFT measured by 50-Hz continuous stimulation is influenced by both ERP and ACT.

Topics: Acetylcholine; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Function; Disopyramide; Electric Stimulation; Female; Flecainide; Guinea Pigs; Heart Atria; Heart Conduction System; In Vitro Techniques; Lidocaine; Male; Piperidines; Procainamide; Pyridines; Refractory Period, Electrophysiological

Numerous studies have shown that E-4031 generally prolongs the atrial effective refractory period (AERP) without affecting cardiac conduction. The effects of E-4031 on AERP and cardiac conduction at short cycle lengths (CLs) close to the AERP were measured in 12 dogs with sterile pericarditis. Three pairs of electrodes were sutured at three sites in the atria 4 days after the model was created. We measured AERP and maximum conduction delay (MCD) after 8 beats train at CLs of 400, 300, 200 and 150 ms before and during continuous infusion of E-4031 (0.1 microgram/kg/min) that followed an initial dose of 10 micrograms/kg/min/5 min. E-4031 interrupted sustained atrial flutter (AF) (> or = 10 min) in 4 of 5 episodes and atrial fibrillation (> or = 10 min) in 4 of 4. The CL of AF defined as a rapid atrial rhythm (rate > or = 240 beats/min) in five episodes studied in the sterile pericarditis model was significantly (p < 0.005) prolonged from 120 +/- 8 to 160 +/- 17 ms. There were significant (p < 0.005) increases in AERP at each CL, and prolongation of AERP was 39 +/- 18, 31 +/- 14, 23 +/- 14, and 16 +/- 14 ms at CL 400, 300, 200, and 150 ms, respectively. E-4031 produced less prolongation of AERP at short pacing CLs and had no effect on conduction time during atrial rapid pacing at CLs > 150 ms. E-4031 did not prolong MCD at CL 400 ms, but did prolong MCD at CLs of 300, 200, and 150 ms, despite prolongation of AERP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Dogs; Electric Stimulation; Electrophysiology; Heart; Heart Conduction System; Models, Cardiovascular; Pericarditis; Piperidines; Pyridines

The aim was to test the efficacy of a new class III drug, E-4031, on human atrial muscle in vivo.. Electrophysiological measurements were performed in 10 patients, age 54(SD 11) years, before and during the continuous infusion of E-4031 (0.15 microgram.kg-1.min-1) which followed an initial dose of 9 micrograms.kg-1 x 5 min-1. Extrastimuli at 500 ms were delivered from the right atrial appendage, high lateral right atrium, and low lateral right atrium. The effective refractory period, repetitive atrial firing zone, and fragmented atrial activity zone were assessed at three sites in the right atrium. The conduction delay zone from the stimulus artefact to the distal electrode pair at the coronary sinus was also measured.. E-4031 caused a significant increase in overall right atrial effective refractory period from 210(SD 29) to 232(26) ms (p < 0.001, n = 30 sites). There were significant decreases in the incidence of repetitive atrial firing (67% to 37%: p < 0.005), in the repetitive atrial firing zone [23(20) to 11(22) ms: p < 0.01], and in the fragmented atrial activity zone [15(22) to 3(8) ms: p < 0.005], but no significant change in the conduction delay zone. However, E-4031 significantly prolonged the longest coupling interval that elicited conduction delay, from 249(31) ms to 267(28) ms (p < 0.01). E-4031 had no effect on the conduction time except at coupling intervals close to the atrial effective refractory period.. These results suggest that E-4031 has a potential effect in the treatment of human paroxysmal atrial fibrillation.

Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Drug Evaluation; Electrophysiology; Heart; Heart Atria; Humans; Middle Aged; Piperidines; Pyridines

Flecainide acetate (Flecaine) is a new antiarrhythmic which has recently become available; its efficacity in treatment of ventricular rhythm disorders has been amply demonstrated. In this study we have evaluated its efficacity per os in treatment of auricular rhythm disorders refractory to the usual therapies, and its effects on the accessory routes of atrioventricular conduction. The results are very promising and better than those obtained with amiodarone in auricular disorders. They show that flecainide is a drug of importance among therapeutic agents used in treatment of auricular arrhythmia, and its action on Kent's bundle makes it a drug of choice in management of Wolff-Parkinson-White syndrome, especially as it seems equally efficacious in its action on the accessory routes with a short refractory period. Most of our patients did not present organic cardiopathy and the side-effects were generally benign. A non-negligible number of cases of paroxysmal hypertension were noted, in disagreement with literature data, and this point needs to be clarified by further study.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Atrial Flutter; Female; Flecainide; Heart Atria; Humans; Male; Middle Aged; Piperidines; Wolff-Parkinson-White Syndrome

Topics: Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Electrocardiography; Flecainide; Humans; Male; Piperidines

Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Flecainide; Humans; Piperidines

Topics: Adult; Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Female; Flecainide; Heart Rate; Humans; Male; Middle Aged; Piperidines

Flecainide is reported to be effective in patients with paroxysmal tachycardias, but its effect on rapid ventricular response over accessory atrioventricular pathway during atrial fibrillation is not known. The influence of flecainide on various electrophysiological properties of the accessory pathway with special emphasis on ventricular rate during atrial fibrillation was investigated in 9 patients with severe symptomatic Wolff-Parkinson-White syndrome. The shortest ventricular response during atrial fibrillation increased from 218 (190-270) to 320 (240-block) ms. In 4 patients sustained rapid atrial fibrillation converted to sinus rhythm. The rate of circus movement tachycardia decreased from 166/min to 130/min after flecainide, due to a lengthening of retrograde ventriculoatrial conduction time over the accessory pathway. Flecainide caused a significant prolongation of the effective refractory period of the accessory pathway in our subgroup with extremely fast AV conduction during atrial fibrillation and induced a depressant effect on retrograde accessory pathway conduction. This makes the drug very promising for the emergency treatment of dangerous rapid tachyarrhythias complicating this syndrome.

Topics: Adolescent; Adult; Anti-Arrhythmia Agents; Atrial Fibrillation; Cardiac Pacing, Artificial; Electrocardiography; Female; Flecainide; Heart Rate; Humans; Infusions, Parenteral; Male; Middle Aged; Piperidines; Wolff-Parkinson-White Syndrome

Topics: Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Atrioventricular Node; Benzeneacetamides; Encainide; Flecainide; Heart Atria; Humans; Lidocaine; Piperidines; Tachycardia; Tocainide; Wolff-Parkinson-White Syndrome

To determine the effect of flecainide acetate, a Class IC antiarrhythmic drug, The medication was given to 28 patients with ventricular pacing electrodes. Eleven patients with temporary pacing electrodes (Group I) received intravenous flecainide (2 mg/kg over 10 minutes). Ten patients with chronic permanent electrodes (Group II) were given the same dose at the time of elective pulse generator change. Seven, with implanted multiprogrammable pacemakers capable of threshold analysis (Group III), were given intravenous flecainide and 5 of these were then given the drug orally for up to 3 weeks (100 mg/day increasing to 400 mg/day). In Group I the threshold measured at a pulse width of 0.5 ms rose from a control value of 0.66 to 1.44 volts after 10 minutes (p less than 0.01). In Group II the threshold rose from 1.73 to 2.13 volts (p less than 0.01) and 2 patients had total suppression of their ventricular escape rhythm for approximately one hour. In Group III patients, intravenous flecainide resulted in a rise escape rhythm for approximately one hour. In Group III patients, intravenous flecainide resulted in a rise of the pulse width threshold measured at 2.7 volts from 0.14 to 0.22 ms (p less than 0.02) and at 4.9 volts from 0.06 to 0.11 ms (p less than 0.05) after 10 minutes. After 3 weeks of oral therapy the threshold at 2.7 volts had risen to 0.11 ms /ms (p less than 0.05 after 10 minutes. After 3 weeks of oral therapy the threshold at 2.7 volts had risen from 0.09 to 0.28 ms (p less than 0.02) and at 4.9 volts from 0.06 to 0.16 ms (p less than 0.05) Flecainide significantly increased both acute and chronic thresholds and the most marked rise (greater than 200%) occurred during chronic oral therapy. Both intravenous and oral flecainide should be used with care in patients with either temporary or permanent pacing systems.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Dose-Response Relationship, Drug; Electrocardiography; Female; Flecainide; Heart Block; Humans; Male; Middle Aged; Pacemaker, Artificial; Piperidines; Tachycardia

The electrophysiologic effects of lorcainide, a class I antiarrhythmic agent with local anesthetic properties, were studied in 20 patients with the Wolff-Parkinson-White syndrome. After intravenous administration of lorcainide (2 mg/kg), the sinus cycle length decreased in all patients from 705 +/- 117 to 636 +/- 94 ms (p less than 0.001). The atrioventricular conduction time lengthened from 84 +/- 22 to 94 +/- 22 ms (p less than 0.01) and the QRS duration increased from 92 +/- 19 to 120 +/- 29 ms (p less than 0.001). The effective refractory period of the atrium increased from 230 +/- 27 to 243 +/- 35 ms (p less than 0.05), whereas the ventricular refractoriness was unaffected. Retrograde conduction over the accessory pathway was blocked in 5 of 18 patients after lorcainide; in the remaining 13 patients a prolongation from 107 +/- 32 to 162 +/- 57 ms (p less than 0.001) was found. Anterograde conduction over the accessory pathway was blocked in 6 patients, and in all other patients it increased considerably. Circus movement tachycardia could be induced in 14 patients before and in 10 patients after the drug. The shortest R-R interval during tachycardia lengthened from 326 +/- 40 to 364 +/- 67 ms (p less than 0.05). The tachycardia zone was unaffected by lorcainide. In 15 patients atrial fibrillation was induced. After lorcainide anterograde conduction during atrial fibrillation was blocked (n = 5). The shortest R-R interval over the accessory pathway during induced atrial fibrillation increased from 228 +/- 35 to 304 +/- 103 ms (p less than 0.05). Intravenous administration of lorcainide produced a pronounced negative dromotropic effect on the conduction properties of the accessory pathway. Lorcainide appears to be a promising new antiarrhythmic agent in patients with the Wolff-Parkinson-White syndrome.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Benzeneacetamides; Drug Evaluation; Electrocardiography; Female; Heart Conduction System; Humans; Male; Middle Aged; Piperidines; Tachycardia; Wolff-Parkinson-White Syndrome

Sixteen patients were investigated by means of programmed atrial stimulation at two different driving rates: 100 and 120/min. All patients had an increased atrial vulnerability at both driving rates. After intravenous flecainide application (1 mg/kg body weight as a bolus followed by the same amount given by infusion over a period of 20 min) the increased vulnerability was abolished in 11 and 9 patients respectively. In the remaining patients the rate of induced atrial tachyarrhythmia decreased. These findings correlate with a significant prolongation of the effective refractory period of the right atrium and a significant shortening of the relative refractory period of the right atrium. It is concluded that flecainide may be effective in the treatment of atrial arrhythmias in man.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Cardiac Pacing, Artificial; Electrocardiography; Female; Flecainide; Heart Conduction System; Humans; Male; Middle Aged; Piperidines

A novel benzanilide derivative, MJ 9067, has been shown to abolish experimental atrial and ventricular arrhythmiase effectively and promote the return of normal sinus rhythm in a variety of animal models. At intravenous dose levels ranging from 0.5 to 3.2 mg/kg, MJ 9067 successfully converted atrial fibrillation induced by either local application of aconitine or electrical stimulation, and ventricular tachycardia elicited by intravenous injection of ouabain or digoxin. The compound was equally effective in vagotomized or nonvagotomized dogs, and in intact cats and monkeys. The ventricular ectopic rate in conscious dogs 18 to 20 hours after two-stage ligation of a coronary artery was also markedly reduced by the drug at 2 mg/kg i.v. At antiarrhythmic dose levels, there were no undesirable effects noted on peripheral blood pressure, heart rate or the configuration of the electrocardiogram.

Topics: Aconitine; Anilides; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Blood Pressure; Cats; Digoxin; Dogs; Electric Stimulation; Electrocardiography; Female; Haplorhini; Heart Rate; Male; Ouabain; Piperidines; Saimiri; Tachycardia

In a preliminary study which lasted 14 weeks, an anti-anginal preparation, perhexiline maleate (Pexid), was prescribed in a dosage of 200 mg twice a day to 7 patients who were suffering from cardiac arrhythmias associated with ischaemic heart disease. There was a significant reduction in ventricular extrasystoles during the 4th and 8th weeks of the study in 6 of the patients who had multiple ventricular ectopic beats. In 4 of these patients, an effective anti-arrhythmic response was maintained until the end of the study. These findings confirm other studies regarding the efficacy of the preparation in reducing ventricular extrasystoles in patients with cardiac ischaemia.

Topics: Arrhythmias, Cardiac; Atrial Fibrillation; Cardiac Complexes, Premature; Coronary Disease; Female; Heart Ventricles; Humans; Male; Middle Aged; Perhexiline; Piperidines

Topics: Atrial Fibrillation; Humans; Piperidines