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1.
A promising outlook for diabetic kidney disease.
Cooper, M, Warren, AM
Nature reviews. Nephrology. 2019;(2):68-70
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2.
Luspatercept for the treatment of anemia in myelodysplastic syndromes and primary myelofibrosis.
Fenaux, P, Kiladjian, JJ, Platzbecker, U
Blood. 2019;(8):790-794
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Abstract
Anemia of lower-risk myelodysplastic syndromes (MDSs) and primary myelofibrosis (PMF) generally becomes resistant to available treatments, leading to red blood cell (RBC) transfusions, iron overload, shortened survival, and poor quality of life. The transforming growth factor-β superfamily, including activins and growth differentiation factors (GDFs), is aberrantly expressed in lower-risk MDSs and PMF. Luspatercept (and sotatercept), ligand traps that particularly inhibit GDF11, lead to RBC transfusion independence in 10% to 50% of lower-risk MDSs resistant to available treatments, and have started to be used in PMF.
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Novel therapies in low- and high-risk myelodysplastic syndrome.
Germing, U, Schroeder, T, Kaivers, J, Kündgen, A, Kobbe, G, Gattermann, N
Expert review of hematology. 2019;(10):893-908
Abstract
Introduction: Myelodysplastic syndromes (MDS) comprise a heterogeneous group of myeloid neoplasms with diverse clinical courses. The revised version of the international prognostic scoring system (IPSS-R) provides risk stratification into 5 different groups. Areas covered: For lower-risk patients, red blood cell transfusions and iron chelation are the backbone of supportive care. In addition, erythropoiesis-stimulating agents (ESA) are used to ameliorate anemia. Lenalidomide is approved for the treatment of lower-risk patients with del(5q) who are transfusion-dependent. Patients with higher-risk disease should be offered allogeneic stem cell transplantation whenever possible. If they are unfit for transplantation or an appropriate donor cannot be found, hypomethylating agents may be used. Expert opinion: New therapeutic options for lower-risk patients include thrombopoietin analogues, the TGF-beta family ligand trapping drug Luspatercept, and the telomerase inhibitor Imetelstat. Combinations of hypomethylating agents (HMA) with other compounds, and inhibitors of bcl2, such as venetoclax are being developed for higher-risk patients. Finally, hypomethylating agents in combination with donor lymphocytes may lead to long-term remission following molecular or hematological relapse after allogeneic SCT.
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Intravitreal Aflibercept in Diabetic Macular Edema: Long-Term Outcomes.
Introini, U, Casalino, G
Developments in ophthalmology. 2017;:71-77
Abstract
For decades, macular laser photocoagulation has been the standard of care in the treatment of diabetic macular edema (DME). With the relatively recent advent of anti-vascular endothelial growth factor (VEGF) agents, DME treatment has entered a new era. VEGF is a well-known pro-angiogenic and pro-permeability factor involved in the pathogenesis of DME. VEGF blockade has proven remarkably effective at reducing DME and improving visual acuity (VA) in eyes with center involved DME causing VA loss in several randomized controlled trials (RCTs). Intravitreal aflibercept, ranibizumab, and bevacizumab (the latter used off-label) are 3 anti-VEGF molecules currently available for DME treatment. Aflibercerpt is a 115-kDA recombinant fusion protein consisting of VEGF binding domains of human VEGF receptors-1 and -2 fused to the Fc domain of human immunoglobulin-G1. The ability to bind placental growth factors 1 and 2 (which is another pro-permeability mediator) and a theoretically long half-life are potential advantages of aflibercept over other anti-VEGF agents. The use of intravitreal aflibercept in DME treatment has been investigated in several RCTs. The aim of this chapter is to briefly report on the current evidence for treating DME with intravitreal aflibercept.
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Aflibercept in the Treatment of Diabetic Macular Edema: A Review and Consensus Paper.
Avitabile, T, Azzolini, C, Bandello, F, Boscia, F, De Falco, S, Fornasari, D, Lanzetta, P, Mastropasqua, L, Midena, E, Ricci, F, et al
European journal of ophthalmology. 2017;(6):627-639
Abstract
PURPOSE To reach a consensus, among experts, on the role of aflibercept in diabetic macular edema (DME) through literature review. METHODS Two round tables, involving 12 Italian experts, were organized: in the first one, 6 pharmacologic and clinical questions were selected and analyzed by a systematic literature review, using a population, intervention, control, and outcomes framework; in the second one, the nominal group technique was used to discuss relevant evidence related to each question. The consensus was assessed using the 5-point Delphi score. RESULTS Agreement on statements was reached on 6/6 questions. The final statements were as follows: 1) High levels of both vascular endothelial growth factor (VEGF) and placental growth factor play an important role in the pathogenesis of DME. 2) The aflibercept pharmacologic profile is notably different from that of other anti-VEGF. 3) Aflibercept significantly improves functional and anatomical outcomes, and rapidly improves best-corrected visual acuity up to its peak; these results remain stable over time. 4) Diabetic macular edema aflibercept treatment requires a 5-monthly injection loading phase. Alternatively, a personalized pro re nata (PRN) regimen based on monthly monitoring and strict retreatment criteria can be used. 5) As an alternative to the bimonthly fixed regimen, in the maintenance phase the treatment schedule may be a PRN regimen with strict retreatment criteria or a treat and extend regimen. 6) No concerns on aflibercept ocular and systemic safety emerged from the literature. CONCLUSIONS Consensus was reached among experts on how to best treat patients with DME with aflibercept.
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The Role of the Pharmacist in Managing Type 2 Diabetes with Glucagon-Like Peptide-1 Receptor Agonists as Add-On Therapy.
Meece, J
Advances in therapy. 2017;(3):638-657
Abstract
UNLABELLED The prevalence and associated clinical burden of type 2 diabetes (T2D) is increasing in the USA and other countries. As a consequence, the role of the pharmacist in managing T2D is expanding, and it is becoming increasingly important for pharmacists to have a complete understanding of the disease course and treatment options. Pharmacists have a key role in the use of injectable therapies, including incretin-based treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs). This article discusses the role of the pharmacist in the management of patients with T2D, particularly with respect to the use of GLP-1RAs to achieve glycemic control. GLP-1RAs are a class of injectable agents used as an adjunct to diet and exercise to improve glycemic control in adults with T2D. GLP-1RAs have been shown to lower glucose levels, slow gastric emptying, enhance satiety, and reduce body weight without increasing the risk of hypoglycemia. GLP-1RAs currently approved in the USA include exenatide twice daily, liraglutide once daily, and albiglutide, dulaglutide, and exenatide once weekly. Pharmacists can work with physicians to help identify patients for whom GLP-1RA therapy is appropriate. In addition, pharmacists can educate patients regarding medication storage, preparation, and injection techniques, glycated hemoglobin (HbA1c) targets, pre- and post-meal blood glucose goals, adverse events and management strategies, and the long-term benefits of reducing HbA1c. As members of the diabetes care team, pharmacists play an important role in improving patient outcomes. FUNDING AstraZeneca.
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Immunomodulation, Acute Renal Failure, and Complications of Basiliximab Use After Liver Transplantation: Analysis of 114 Patients and Literature Review.
de Ataide, EC, Perales, SR, Bortoto, JB, Peres, MAO, Filho, FC, Stucchi, RSB, Udo, E, Boin, IFSF
Transplantation proceedings. 2017;(4):852-857
Abstract
Basiliximab is considered to be effective in preventing cellular rejection (CR) in solid organ transplantation and is commonly used for renal transplants. The aim of this study was describe the population of patients undergoing orthotopic liver transplantation (LT) receiving basiliximab in the period 2012-2016 in the liver transplant service at the State University of Campinas, São Paulo, Brazil. We analyzed 114 patients who underwent LT and received basiliximab; 83 (72.8%) were male and 31 (27.2%) female, with an overall mean age of 54.3 years. Immunosuppression was performed with corticosteroids during anesthetic induction, and postoperatively with tacrolimus in 85.5%, sodium mycophenolate in 81.7%, cyclosporine in 12.7%, and everolimus in 15.5% of patients. CR was observed in 25.43% of patients, confirmed by biopsy in 15 patients: 50% acute CR, 21.42% late acute CR, and 28.57% chronic CR. Thus, the data are consistent with the literature regarding the benefit of using basiliximab as induction therapy while reducing the incidence of CR after LT, but on univariate analysis to evaluate factors associated with the occurrence of CR, the analyzed variables did not present statistical significance. There was acute renal failure (ARF) in 46.84% of patients and hemodialysis was performed in 20% of cases. In a previous series in our service, there was an ARF rate of 50%, so the incidence reduction of ARF after basiliximab use was 3.16%. Moreover, there was 6.95% hepatic artery thrombosis, 2.6% portal vein thrombosis, 2.6% biliary fistulas, 17.4% pneumonia, and 3.4% sepsis, which did not differ from the literature or from our earlier study without the use of basiliximab, suggesting the safety of this medication. In conclusion, in this series, basiliximab influenced the decrease of the CR incidence with no proven benefit on improvement in the ARF.
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The Clinical Effectiveness of Ranibizumab Treat and Extend Regimen in nAMD: Systematic Review and Network Meta-Analysis.
Danyliv, A, Glanville, J, McCool, R, Ferreira, A, Skelly, A, Jacob, RP
Advances in therapy. 2017;(3):611-619
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Abstract
INTRODUCTION Neovascular age-related macular degeneration (nAMD) is a chronic eye condition that causes severe deterioration of vision and ultimately blindness. Two vascular endothelial growth factor inhibitors are approved for nAMD treatment in Europe: ranibizumab and aflibercept. The European license for ranibizumab was updated with an individualized "treat and extend" (T&E) regimen, which involves more proactive treatment based on changes in best corrected visual acuity (BCVA) and/or anatomical outcomes. The aim of this publication is to compare the efficacy of the ranibizumab T&E regimen with other approved dosing regimens for nAMD on the basis of outcomes identified from a systematic review and subsequent NMA. METHODS Following a systematic search of publications, to identify relevant studies, a repeated-measures network meta-analysis (NMA) was performed to estimate the relative effectiveness of ranibizumab T&E versus approved dosing regimens of ranibizumab and aflibercept. The analysis focused on licensed treatment regimens for nAMD. We examined mean change from baseline in BCVA on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. RESULTS The systematic literature review identified 22,949 records, of which 23 studies were included in the NMA. At 12 months, the ranibizumab T&E dosing regimen vs ranibizumab pro re nata (PRN) was associated with small differences in change in BCVA, between 1.86 letter gain at 12 months and 2.35 letter gain at 24 months. A similar difference was observed in the aflibercept dosing regimen versus ranibizumab T&E ; 1.94 letter gain at 12 months and 3.31 letter gain at 24 months. All doses of ranibizumab and aflibercept showed similar effectiveness, and the differences between treatment options were not significant. CONCLUSION This study used novel repeated-measures NMA to synthesize efficacy results when treatment effects were reported at multiple follow-up times. This repeated-measures NMA suggests that treating patients with the ranibizumab T&E regimen yields similar effectiveness compared to other approved ranibizumab and aflibercept dosing regimens for nAMD treatment. FUNDING Novartis Pharmaceuticals UK Ltd, Surrey, UK.
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Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa.
Kishnani, PS, Rush, ET, Arundel, P, Bishop, N, Dahir, K, Fraser, W, Harmatz, P, Linglart, A, Munns, CF, Nunes, ME, et al
Molecular genetics and metabolism. 2017;(1-2):4-17
Abstract
Hypophosphatasia (HPP) is a rare, inherited, systemic, metabolic disorder caused by autosomal recessive mutations or a single dominant-negative mutation in the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). The disease is associated with a broad range of signs, symptoms, and complications, including impaired skeletal mineralization, altered calcium and phosphate metabolism, recurrent fractures, pain, respiratory problems, impaired growth and mobility, premature tooth loss, developmental delay, and seizures. Asfotase alfa is a human, recombinant enzyme replacement therapy that is approved in many countries for the treatment of patients with HPP. To address the unmet need for guidance in the monitoring of patients receiving asfotase alfa, an international panel of physicians with experience in diagnosing and managing HPP convened in May 2016 to discuss treatment monitoring parameters. The panel discussions focused on recommendations for assessing and monitoring patients after the decision to treat with asfotase alfa had been made and did not include recommendations for whom to treat. Based on the consensus of panel members, this review provides guidance on the monitoring of patients with HPP during treatment with asfotase alfa, including recommendations for laboratory, efficacy, and safety assessments and the frequency with which these should be performed during the course of treatment. Recommended assessments are based on patient age and include regular monitoring of biochemistry, skeletal radiographs, respiratory function, growth, pain, mobility and motor function, and quality of life. Because of the systemic presentation of HPP, a coordinated, multidisciplinary, team-based, patient-focused approach is recommended in the management of patients receiving asfotase alfa. Monitoring of efficacy and safety outcomes must be tailored to the individual patient, depending on medical history, clinical manifestations, availability of resources in the clinical setting, and the clinician's professional judgment.
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The Efficacy and Safety of Current Treatments in Diabetic Macular Edema: A Systematic Review and Network Meta-Analysis.
Zhang, L, Wang, W, Gao, Y, Lan, J, Xie, L
PloS one. 2016;(7):e0159553
Abstract
PURPOSE To compare the efficacy and safety of current treatments in diabetic macular edema (DME). METHODS PubMed, Embase and CENTRAL were systematically reviewed for randomized controlled trials of current treatments in DME through August 2015. Data on the mean change of best-corrected visual acuity (BCVA) and central macular thickness (CMT) were extracted, and adverse events (AEs) were collected. RESULTS A total of 21 trials were included in our network meta-analysis. Intravitreal ranibizumab improved BCVA most significantly (OR: +7.01 95%CI (2.56 to 11.39)) in 6 months and intravitreal aflibercept (+8.19 (5.07 to 11.96)) in 12 months. Intravitreal triamcinolone combined with LASER decreased CMT most significantly (-111.34 (-254.61 to 37.93)) in 6 months and intravitreal aflibercept (-110.83 (-190.25 to -35.27)) in 12 months. Compared with the relatively high rate of ocular AEs in the groups with administration of steroids, systematic AEs occurred more frequently in the groups with vascular endothelial growth factor inhibitors involved. CONCLUSIONS Our analysis confirms that intravitreal aflibercept is most favorable with both BCVA improvement and CMT decrease than other current therapies in the management of DME within 12 months. Vascular endothelial growth factor inhibitors for DME should be used with caution due to systematic AEs. Combined intravitreal triamcinolone with LASER has a stronger efficacy in decreasing CMT than the other interventions in the early stage after injection. More high-quality randomized controlled trials will be necessary.