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1.
A Scoping Review of Alternative Anticoagulation Strategies for Hemodialysis Patients with a Mechanical Heart Valve.
Thomson, BKA, Pilkey, NG, Monteith, B, Holden, RM
American journal of nephrology. 2021;(10-11):861-870
Abstract
INTRODUCTION Patients with end-stage renal disease (ESRD) have high rates of cardiac valvulopathy but can develop contraindications for vitamin K antagonist (VKA) therapy. We explored the evidence for alternative anticoagulation strategies in patients with ESRD with a contraindication for VKA therapy. METHODS A scoping review was completed, searching MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Conference abstracts from inception to March 30, 2021. The study population was patients with ESRD who were on VKA therapy and developed a contraindication to VKA therapy use. All data regarding studies, patient characteristics, anticoagulation strategy, and clinical outcomes were summarized. RESULTS Twenty-three articles met inclusion criteria. These articles included 57 patients. Contraindications to VKA therapy included calcific uremic arteriolopathy (CUA) (n = 55) and warfarin-induced skin necrosis (n = 2). All studies were either case reports or case series. There were 10 anticoagulation strategies identified. Continuation of VKA therapy was associated with increased death and decreased rates of CUA resolution (80.0% and 10.0%, respectively), compared to apixaban (24.0% and 70.8%), subcutaneous (SC) low-molecular-weight heparin (LMWH) (14.3%, 85.7%), and SC unfractionated heparin (0.0%, 100.0%). While only 5 patient cases were reported with mechanical heart valves, SC LMWH use has been reported in this context with good outcomes. CONCLUSIONS In patients with ESRD who develop a contraindication to VKA therapy, several alternative anticoagulation strategies have been reported with superior outcomes to VKA continuation. While outcomes appear superior to continuation of VKA therapy, more data are required before definitive recommendations can be made for the patient with ESRD and a mechanical heart valve.
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2.
Metal Ion Complexes with Pyrazoles, Aziridines and Diaziridines - Synthesis and Biological Activity.
Malinowska, K, Lorenz, IP, Sadowska, B, Mucha, P
Current medicinal chemistry. 2019;(4):648-663
Abstract
Heterocyclic compounds containing nitrogen ions, like pyrazoles, aziridines, diaziridines and their metal ion complexes with Cu(II), Zn(II) and Ru(III) and others exhibit a wide range of biological activity, including mainly anti-inflammatory, antioxidant, anticancer, and antimicrobial properties. Biological significance of these molecules and thus their potential use in medicine has driven growing interest into their coordination chemistry. A knowledge of the relationship between the structure of chemical compounds and their activity is needed for the synthesis of the preparations possessing the most beneficial features. The choice of interposed substituents may improve biocidal and antitumor action, reduce the toxicity of the initial substance, or even completely eliminate its adverse effects for healthy tissues. The main aim of this review paper is to present the current state of knowledge concerning the synthesis and biological activity of complexes with small heterocyclic ligands containing transition metal ions.
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3.
How we manage Bing-Neel syndrome.
Castillo, JJ, Treon, SP
British journal of haematology. 2019;(3):277-285
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Abstract
Bing-Neel syndrome (BNS) is an uncommon presentation of Waldenström macroglobulinaemia (WM), seen during the course of the disease in about 1% of patients. BNS occurs when WM cells gain access to the central nervous system (CNS) causing neurological deficits. The diagnosis of BNS is suggested by the presence of radiological abnormalities, such as leptomeningeal enhancement on magnetic resonance imaging and confirmed by the presence of clonal lymphoplasmacytic cells and MYD88 L265P in the cerebrospinal fluid. The treatment of BNS requires agents with good penetration into the CNS, such as fludarabine, methotrexate and cytarabine. The novel Bruton Tyrosine Kinase inhibitor ibrutinib has shown CNS-penetrating properties, and recent data suggest a therapeutic role in BNS. In this review, we will discuss the clinical and pathological features, diagnostic criteria, treatment options and outcomes of patients with BNS.
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Etoposide combined with ruxolitinib for refractory hemophagocytic lymphohistiocytosis during pregnancy: a case report and literature review.
Wang, S, Wu, J, Jing, X, Zhang, Y, Tang, H, Wu, J
Hematology (Amsterdam, Netherlands). 2019;(1):751-756
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is an immune-mediated disorder caused by uncontrolled inflammatory responses and the activation of T lymphocytes. This life-threatening disease, characterized by fever, cytopenia and hepatosplenomegaly, is extremely rare during pregnancy with high mortality. Despite the improvement of treatment regimen in recent years, HLH is still a great challenge for clinicians. Here, we described a 26-year-old woman who admitted to our hospital at her first pregnancy with pyrexia. Her condition continued to deteriorate after receiving broad-spectrum antimicrobials, presenting with fever, pancytopenia, hepatosplenomegaly, ferritin ≥ 500 μg/L, hemophagocytosis and low NK-cell activity. HLH was eventually diagnosed by clinical manifestation and laboratory examination results. Then the patient recovered well after treatment with etoposide combined with ruxolitinib therapy and underwent successful induced-labor operation. Additionally, we summarized similar cases from the literature to improve the management of HLH during pregnancy. In conclusion, this study highlights the challenges and difficulties in the diagnosis and management of patients with HLH during pregnancy. Moreover, this is the first case report of etoposide combined with ruxolitinib in the treatment of patients with refractory secondary HLH during pregnancy.
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Direct Oral Anticoagulants in End-Stage Renal Disease.
Klil-Drori, AJ, Tagalakis, V
Seminars in thrombosis and hemostasis. 2018;(4):353-363
Abstract
Patients with end-stage renal disease (ESRD) were excluded from pivotal clinical trials with oral anticoagulants. While such patients are at an increased risk of venous and arterial thromboembolism, their risk of bleeding is also elevated. It is thus of little surprise that stroke prevention with vitamin K antagonists (VKAs) in ESRD patients with atrial fibrillation is controversial, with observational evidence ranging from beneficial to harmful. This uncertainty extends to the less studied use of VKAs for venous thromboembolism in ESRD. The direct oral anticoagulants (DOACs) apixaban and rivaroxaban have now permissive labeling in the United States for atrial fibrillation in patients with ESRD; this expanded labeling has not yet occurred either in Europe or for venous thromboembolism. This review summarizes the current evidence for the pharmacology of DOACs in ESRD as well as their utilization and safety in patients with ESRD and atrial fibrillation.
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Minimal residual disease or cure in MPNs? Rationales and perspectives on combination therapy with interferon-alpha2 and ruxolitinib.
Bjørn, ME, Hasselbalch, HC
Expert review of hematology. 2017;(5):393-404
Abstract
The therapeutic landscape of the Philadelphia-negative myeloproliferative neoplasms (MPNs) is markedly changing consequent to the development of JAK-inhibitors and the use of ruxolitinib (RUX) in patients with myelofibrosis (MF) and patients with polycythemia vera (PV) who develop refractoriness or intolerance to hydroxyurea. The use of Interferon-alpha2 (IFN) is rapidly expanding in several countries, based upon favourable safety and efficacy profiles in several single-arm studies during the last 30 years, displaying complete hematological remissions in a large proportion of patients, a reduction in the JAK2V617 F and CALR mutational burden and in a subset of patients with PV with normalisation of the bone marrow after long-term treatment - even being sustained for several years after discontinuation of IFN. To this end the concept of chronic inflammation as the driving force for MPN disease progression is being increasingly recognized. This novel concept has initiated phase II studies in patients with PV and MF of combination therapy with IFN and RUX. Areas covered and Expert commentary: Herein we highlight the background, the rationales and perspectives for this novel combinatorial approach which is foreseen as the most encouraging and promising treatment for patients with MPNs - hopefully with the potential of cure - at least operational cure - in a subset of patients.
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Management of myelofibrosis: JAK inhibition and beyond.
Stahl, M, Zeidan, AM
Expert review of hematology. 2017;(5):459-477
Abstract
Myelofibrosis (MF) is characterized by bone marrow fibrosis with subsequent extramedullary hematopoiesis and abnormal cytokine expression leading to splenomegaly, constitutional symptoms and cytopenias. The discovery of the JAK2 V617F mutation in the majority of MF patients has been followed by significant progress in drug development for MF. Areas covered: In this article, we review advances in the understanding of the underlying disease biology, prognostic assessment and therapeutic modalities for MF. We provide clinical trial evidence behind using the JAK2 inhibitor ruxolitinib, erythropoiesis stimulating agents, androgens, immunomodulatory drugs, interferon, cytoreductive drugs and hypomethylating agents in MF. Finally, we review novel therapeutic options for MF including the new JAK1/2 inhibitors, ruxolitinib based combination approaches as well as novel therapeutic agents. Expert commentary: Despite significant reduction of splenomegaly and improvement of symptom burden and a signal for survival improvement, ruxolitinib does not lead to major reductions in JAK2 V617F allele burden and bone marrow fibrosis. No ruxolitinib-based combination approach has so far demonstrated superiority over ruxolitinib monotherapy. The novel JAK2 inhibitors pacritinib and momelotinib, other JAK inhibitors, telomerase inhibitors, anti-fibrosis agents and hsp90 inhibitors are in different stages of development.
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Modeling covalent-modifier drugs.
Awoonor-Williams, E, Walsh, AG, Rowley, CN
Biochimica et biophysica acta. Proteins and proteomics. 2017;(11 Pt B):1664-1675
Abstract
In this review, we present a summary of how computer modeling has been used in the development of covalent-modifier drugs. Covalent-modifier drugs bind by forming a chemical bond with their target. This covalent binding can improve the selectivity of the drug for a target with complementary reactivity and result in increased binding affinities due to the strength of the covalent bond formed. In some cases, this results in irreversible inhibition of the target, but some targeted covalent inhibitor (TCI) drugs bind covalently but reversibly. Computer modeling is widely used in drug discovery, but different computational methods must be used to model covalent modifiers because of the chemical bonds formed. Structural and bioinformatic analysis has identified sites of modification that could yield selectivity for a chosen target. Docking methods, which are used to rank binding poses of large sets of inhibitors, have been augmented to support the formation of protein-ligand bonds and are now capable of predicting the binding pose of covalent modifiers accurately. The pKa's of amino acids can be calculated in order to assess their reactivity towards electrophiles. QM/MM methods have been used to model the reaction mechanisms of covalent modification. The continued development of these tools will allow computation to aid in the development of new covalent-modifier drugs. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman.
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Meta-analysis of efficacy and safety of apixaban and uninterrupted apixaban therapy compared to vitamin K antagonists in patients undergoing catheter ablation for atrial fibrillation.
Ukaigwe, A, Shrestha, P, Karmacharya, P, Hussain, SK, Samii, S, Gonzalez, MD, Wolbrette, D, Naccarrelli, GV
Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing. 2017;(2):223-233
Abstract
BACKGROUND Apixaban is a Factor Xa inhibitor increasingly being used for stroke prevention in atrial fibrillation (AF). Although several studies have been done, the efficacy and safety of apixaban during the peri-procedural period of AF ablation remains unclear. We sought to systematically review pooled data from these various studies to evaluate thromboembolic and bleeding risks in patients undergoing catheter ablation for AF who are treated with apixaban (interrupted and uninterrupted). METHODS Studies comparing anticoagulation with apixaban or vitamin K antagonists (VKA) in patients undergoing ablation for AF were identified via an electronic search of MEDLINE, EMBASE, clinical trials.gov, and Cochrane Library from inception to January 2016. Study-specific risk ratios were calculated and combined with a fixed-effects model meta-analysis. RESULTS In the analysis of 2100 pooled patients, thromboembolic complications (TE) occurred in 14/778 (1.80 %) patients in the apixaban group (AG) compared to 20/1322 patients in the VKA group (RR 1.03, 95 % CI 0.55-1.90, p = 0.93, I 2 = 0 %). Major bleeding occurred in 9/778 (1.2 %) of the AG compared to 20/1322 (1.51 %) in the VKA group (RR 1.03, 95 % CI 0.55-1.90, p = 0.93, I 2 = 0 %). In uninterrupted apixaban group (uAG), TE occurred in 4/585 (0.68 %) patients in the uAG compared to 6/910 (0.66 %) in VKA group (RR 0.86, 95 % CI 0.25-2.95, p = 0.81, I 2 = 0 %). Major bleeding occurred in 5/585 (0.85 %) in uAG compared to 7/910 (0.77 %) in the VKA group (RR 1.20, 95 % CI 0.37-3.88, p = 0.76, I 2 = 0 %). CONCLUSION Our study demonstrates patients treated with apixaban and VKA during the peri-procedural period for AF ablation have similar rates of TE and bleeding complications. Interrupted and uninterrupted apixaban strategies were associated with similar outcomes.
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Comparative pharmacokinetics of three SGLT-2 inhibitors sergliflozin, remogliflozin and ertugliflozin: an overview.
Dash, RP, Babu, RJ, Srinivas, NR
Xenobiotica; the fate of foreign compounds in biological systems. 2017;(11):1015-1026
Abstract
1. Several sodium-glucose cotransporter-2 (SGLT-2) inhibitors are in clinical use for the management of type 2 diabetes. The objectives of the current review were: (a) to provide a comparative pharmacokinetics including absorption, distribution, metabolism and excretory (ADME) profiles of three SGLT-2 inhibitors namely: sergliflozin, remogliflozin and ertugliflozin; (b) to provide some perspectives on possible developmental issues. 2. Based on the half-life (t1/2) values observed in humans, the rank order of the three SGLT-2 inhibitors was ertugliflozin (16 h) > remogliflozin (2-4 h) > sergliflozin (1-1.5 h). Therefore, while once a day dosing of ertugliflozin is possible, the other two drugs need to be dosed more frequently. Perhaps, the short t1/2 of sergliflozin may have contributed for its discontinuation. 3. Although there was paucity of published data on the metabolism, transporter related and excretory aspects for sergliflozin, the other two drugs provided a differentiating profile. However, the compiled data suggested that there may be a minimal or no risk of pharmacokinetic drug interaction issues associated with any of the reviewed drugs. 4. Because of the crowded development pipeline and approved SGLT-2 inhibitors, the safety and efficacy of sergliflozin, remogliflozin and ertugliflozin appear to be a key from differentiation perspective.