Anticoagulation Strategies in Patients With Cancer: JACC Review Topic of the Week

Patients with active cancer are at an increased risk of arterial and venous thromboembolism (VTE) and bleeding events. Historically, in patients with cancer, low molecular weight heparins have been preferred for treatment of VTE, whereas warfarin has been the standard anticoagulant for stroke prevention in patients with atrial fibrillation (AF). More recently, direct oral anticoagulants (DOACs) have been demonstrated to reduce the risk of venous and arterial thromboembolism in large randomized clinical trials of patients with VTE and AF, respectively, thus providing an attractive oral dosing option that does not require routine laboratory monitoring. In this review, we summarize available clinical trial data and guideline recommendations, and outline a practical approach to anticoagulation management of VTE and AF in cancer.     

Premature Ticagrelor Discontinuation in Secondary Prevention of Atherosclerotic CVD: JACC Review Topic of the Week

Ticagrelor is a cornerstone of modern antithrombotic therapy alongside aspirin in patients with acute coronary syndrome and after percutaneous coronary intervention. Adverse effects such as bleeding and dyspnea have been associated with premature ticagrelor discontinuation, which may limit any potential advantage of ticagrelor over clopidogrel. The randomized trials of ticagrelor captured adverse events, offering the opportunity to more precisely quantify these effects across studies. Therefore, a meta-analysis of 4 randomized clinical trials of ticagrelor conducted between January 2007 and June 2017 was performed to quantify the incidence and causes of premature ticagrelor discontinuation. Among 66,870 patients followed for a median 18 months, premature ticagrelor discontinuation was seen in 25%; bleeding was the most common cause of discontinuation followed by dyspnea. Versus the comparators, the relative risk of dyspnea-related discontinuation during follow-up was 6.4-fold higher, the relative risk of bleeding was 3.2-fold higher, and the relative risk of discontinuation due to any adverse event was 59% higher for patients receiving ticagrelor. Understanding these potential barriers to adherence to ticagrelor is crucial for informed patient-physician decision making and can inform future efforts to improve ticagrelor adherence. This review discusses the incidence, causes, and biological mechanisms of ticagrelor-related adverse effects and offers strategies to improve adherence to ticagrelor.     

Verapamil intensifies neuromuscular blockade produced by gallamine and pancuronium at the chick neuromuscular junction

Experiments were performed to study the effect of verapamil on neuromuscular transmission and muscle contraction at a chick skeletal muscle-nerve preparation. In addition, the effects and interactions of verapamil with some muscle relaxants were studied in the same preparation. These effects were explored by studying the effects of verapamil on: directly-and indirectly-elicited twitch contractions, and neuromuscular blockade produced by gallamine and pancuronium. The results showed that verapamil (2-200 microM) had a differential effect on the twitch responses; more reductions occurred in the indirectly-elicited twitch tension, whereas the directly-elicited twitch response was reduced only by 20-30% of maximum indirectly-elicited twitch tension. Furthermore, in low concentrations (1-20 microM), verapamil significantly increased the neuromuscular blockade produced by gallamine (28-1280 nM) and pancuronium (18-573 nM). In high concentrations (greater than 200 microM), verapamil completely blocked the indirectly-elicited twitch response and produced a marked contracture in the chick skeletal muscle (1.0 +/- 0.1 g, n = 6). It was concluded that by reducing twitch tension and inhibiting neuromuscular transmission, verapamil increases (intensifies) neuromuscular blockade produced by muscle relaxants, e.g. gallamine and pancuronium.     

Parkinsonism associated with Addison's disease.

We describe a 35-year-old woman who developed parkinsonism in association with Addison's disease. The parkinsonism disappeared following treatment for Addison's disease without the use of antiparkinsonian drugs. This association stands unique although the pathophysiology remains unclear.     

Diminution in Kerosene-Mediated Induction of Drug Metabolizing Enzymes by Asbestos in Rat Lungs

Abstract: In order to determine the pulmonary toxicity of kerosene and its ignition product (soot) in asbestos exposed subjects, the activities of phase I and phase II drug metabolizing enzymes in rat lungs after single intratracheal coexposure to Indian chrysotile asbestos and kerosene or its soot and Indian chrysotile were assayed. Exposure to kerosene or its soot resulted in a significant increase in the level of microsomal cytochrome P-450 and the activity of P-450 dependent monooxygenase, benzo(a)pyrene hydroxylase, as well as in the activities of microsomal epoxide hydrase and cytosolic glutathione-S-transferase (GST). However, in chrysotile exposed animals a reverse pattern in these parameters was recorded. The co-exposure to chrysotile and kerosene or chrysotile and soot led to a significant depletion in cytochrome P-450 level and a decrease in the activities of benzo(a)pyrene hydroxylase, epoxide hydrase and GST when compared to kerosene and soot controls, respectively. These results suggest that asbestos by altering the pulmonary drug metabolizing enzyme system may increase the toxic potential of kerosene and its ignition product in the respiratory system.     

The physiological regulation of toll-like receptor expression and function in humans

Eleven mammalian toll-like receptors (TLRs 1–11) have been identified to date and are known to play a crucial role in the regulation of immune responses; however, the factors that regulate TLR expression and function in vivo are poorly understood. Therefore, in the present study, we investigated the physiological regulation of TLR expression and function in humans. To examine the influence of diurnal rhythmicity on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers ( n = 8) at time points coinciding with the peak and nadir in the endogenous circulating cortisol concentration. While no diurnal rhythmicity in the expression of TLRs 1, 2, 4 or 9 was observed, the upregulation of costimulatory (CD80 and CD86) and antigen-presenting (MHC class II) molecules on CD14⁺ monocytes following activation with specific TLR ligands was greater ( P < 0.05) in samples obtained in the evening compared with the morning. To examine the influence of physical stress on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers ( n = 11) at rest and following 1.5 h of strenuous exercise in the heat (34°C). Strenuous exercise resulted in a decrease ( P < 0.005) in the expression of TLRs 1, 2 and 4 on CD14⁺ monocytes. Furthermore, the upregulation of CD80, CD86, MHC class II and interleukin-6 by CD14⁺ monocytes following activation with specific TLR ligands was decreased ( P < 0.05) in samples obtained following exercise compared with at rest. These results demonstrate that TLR function is subject to modulation under physiological conditions in vivo and provide evidence for the role of immunomodulatory hormones in the regulation of TLR function.     

An antibody with specificity for surfactant protein C precursors: identification of pro-SP-C in rat lung.

Surfactant protein C (SP-C) is a lung-specific, hydrophobic peptide found in organic extracts of pulmonary surfactant. Alveolar SP-C (3.5 kD) is produced from proteolytic cleavage of a larger precursor molecule (pro-SP-C; 21 kD). While SP-C is synthesized by type II cells, the pathways for processing and secretion have remained elusive due, in part, to the lack of monospecific antibodies against SP-C or its precursors. This report describes production and characterization of a new antibody directed against pro-SP-C epitopes. Polyclonal antisera (anti-CPRO-SP-C) was prepared using a synthetic peptide corresponding to a portion of rat SP-C cDNA sequence (Ile26-Ser72). This contained amino acids 3-35 of mature SP-C plus additional C-terminal residues (His59-Ser72). On Western blots, anti-CPRO-SP-C competitively reacted to CPRO-SP-C but not to mature SP-C. Immunoblots of in vitro synthesized pro-SP-C confirmed that the antisera also recognized native protein. Immunocytochemistry with anti-CPRO-SP-C demonstrated staining for pro-SP-C peptides in isolated type II cells as well as in alveolar epithelial cells of rat lung sections. Pro-SP-C preferentially co-localized to cells that stained positive for Maclura pomifera antigen. Anti-CPRO-SP-C staining was not observed in lung interstitium, pulmonary vasculature, or several control tissues (brain, heart, and liver were negative). Western blotting of subcellular fractions demonstrated pro-SP-C peptides in plasma membrane (20 kD) and microsomal (20 and 21 kD) fractions with a 16 kD peptide present in lamellar bodies. No pro-SP-C peptides were detected in purified surfactant. These results demonstrate the use of a synthetic peptide to generate specific antiserum against more hydrophilic domains of pro-SP-C sequences and confirm that SP-C propeptides are unique to the lung.