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Use-case scenarios for an anti-Cryptosporidium therapeutic.
Ashigbie, PG, Shepherd, S, Steiner, KL, Amadi, B, Aziz, N, Manjunatha, UH, Spector, JM, Diagana, TT, Kelly, P
PLoS neglected tropical diseases. 2021;(3):e0009057
Abstract
Cryptosporidium is a widely distributed enteric parasite that has an increasingly appreciated pathogenic role, particularly in pediatric diarrhea. While cryptosporidiosis has likely affected humanity for millennia, its recent "emergence" is largely the result of discoveries made through major epidemiologic studies in the past decade. There is no vaccine, and the only approved medicine, nitazoxanide, has been shown to have efficacy limitations in several patient groups known to be at elevated risk of disease. In order to help frontline health workers, policymakers, and other stakeholders translate our current understanding of cryptosporidiosis into actionable guidance to address the disease, we sought to assess salient issues relating to clinical management of cryptosporidiosis drawing from a review of the literature and our own field-based practice. This exercise is meant to help inform health system strategies for improving access to current treatments, to highlight recent achievements and outstanding knowledge and clinical practice gaps, and to help guide research activities for new anti-Cryptosporidium therapies.
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Edoxaban and the Issue of Drug-Drug Interactions: From Pharmacology to Clinical Practice.
Corsini, A, Ferri, N, Proietti, M, Boriani, G
Drugs. 2020;(11):1065-1083
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Abstract
Edoxaban, a direct factor Xa inhibitor, is the latest of the non-vitamin K antagonist oral anticoagulants (NOACs). Despite being marketed later than other NOACs, its use is now spreading in current clinical practice, being indicated for both thromboprophylaxis in patients with non-valvular atrial fibrillation (NVAF) and for the treatment and prevention of venous thromboembolism (VTE). In patients with multiple conditions, the contemporary administration of several drugs can cause relevant drug-drug interactions (DDIs), which can affect drugs' pharmacokinetics and pharmacodynamics. Usually, all the NOACs are considered to have significantly fewer DDIs than vitamin K antagonists; notwithstanding, this is actually not true, all of them are affected by DDIs with drugs that can influence the activity (induction or inhibition) of P-glycoprotein (P-gp) and cytochrome P450 3A4, both responsible for the disposition and metabolism of NOACs to a different extent. In this review/expert opinion, we focused on an extensive report of edoxaban DDIs. All the relevant drugs categories have been examined to report on significant DDIs, discussing the impact on edoxaban pharmacokinetics and pharmacodynamics, and the evidence for dose adjustment. Our analysis found that, despite a restrained number of interactions, some strong inhibitors/inducers of P-gp and drug-metabolising enzymes can affect edoxaban concentration, just as it happens with other NOACs, implying the need for a dose adjustment. However, our analysis of edoxaban DDIs suggests that given the small propensity for interactions of this agent, its use represents an acceptable clinical decision. Still, DDIs can be significant in certain clinical situations and a careful evaluation is always needed when prescribing NOACs.
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Treatment interventions for diarrhoea in HIV-infected and HIV-exposed children: a systematic review.
Motaze, NV, Nwachukwu, C, Humphreys, E
The Pan African medical journal. 2018;:208
Abstract
INTRODUCTION Seventy percent of an estimated 10 million children less than five years of age in developing countries die each year of acute respiratory infections, diarrhoea, measles, malaria, malnutrition or a combination of these conditions. Children living with Human immunodeficiency virus (HIV) are at risk of diarrhoea because of drug interactions with antiretroviral therapy and bottle feeding. This may be aggravated by malnutrition and other infectious diseases which are frequent in children living with HIV. Objective: to evaluate treatment interventions for diarrhoea in HIV infected and exposed children. METHODS A comprehensive search was conducted on 02 June 2016 to identify relevant studies for inclusion. We included randomised controlled trials of HIV infected or exposed children under 15 years of age with diarrhoea. Two authors independently selected studies for inclusion, assessed risk of bias (RoB) and extracted data using a pre-designed data extraction form. RESULTS We included two studies (Amadi 2002 and Mda 2010) that each enrolled 50 participants. The RoB was assessed as low-risk for both included studies. There was no difference in clinical cure and all-cause mortality between nitazoxanide and placebo for cryptosporidial diarrhoea in Amadi 2002. In Mda 2010, there was a reduction in duration of hospitalisation in the micronutrient supplement group (P < 0.005) although there was no difference in all-cause mortality. CONCLUSION There is low certainty evidence on the effectiveness of nitazoxanide for treating cryptosporidial diarrhoea and micronutrient supplementation in children with diarrhoea. Adequately powered trials are needed to assess micronutrients and nitazoxanide, as well as other interventions, for diarrhoea in HIV-infected and-exposed children.
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Nonribosomal peptides for iron acquisition: pyochelin biosynthesis as a case study.
Ronnebaum, TA, Lamb, AL
Current opinion in structural biology. 2018;:1-11
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Abstract
Microbes synthesize small, iron-chelating molecules known as siderophores to acquire iron from the environment. One way siderophores are generated is by nonribosomal peptide synthetases (NRPSs). The bioactive peptides generated by NRPS enzymes have unique chemical features, which are incorporated by accessory and tailoring domains or proteins. The first part of this review summarizes recent progress in NRPS structural biology. The second part uses the biosynthesis of pyochelin, a siderophore from Pseudomonas aeruginosa, as a case study to examine enzymatic methods for generating the observed diversity in NRPS-derived natural products.
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Edoxaban in patients with atrial fibrillation.
Eisen, A, Ruff, CT
Therapeutic advances in cardiovascular disease. 2017;(3):81-90
Abstract
Edoxaban, a direct factor Xa inhibitor, was extensively studied in the prevention and treatment of venous thromboembolism and in patients with nonvalvular atrial fibrillation (AF). The aim of this review is to focus specifically on the efficacy and safety profile of edoxaban in patients with AF from preclinical development through the phase III trial that led to regulatory approval.
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Edoxaban in Atrial Fibrillation and Venous Thromboembolism-Ten Key Questions and Answers: A Practical Guide.
De Caterina, R, Ageno, W, Boriani, G, Colonna, P, Ghirarduzzi, A, Patti, G, Rossini, R, Rubboli, A, Schinco, P, Agnelli, G
Advances in therapy. 2017;(3):620-637
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Abstract
Edoxaban is the fourth non-vitamin K antagonist oral anticoagulant now available for clinical use in the prevention of stroke/systemic embolism in atrial fibrillation (AF) and in the treatment of venous thromboembolism (VTE), after the completion of large-scale randomized comparative clinical trials with the vitamin K antagonist warfarin. Edoxaban has some peculiar pharmacological properties and outcome data. Here a group of experts in AF and VTE answers a set of questions on its practical use, trying to define the profile of patients that would be most appropriate for its use.
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Pharmacokinetics and Pharmacodynamics of Edoxaban, a Non-Vitamin K Antagonist Oral Anticoagulant that Inhibits Clotting Factor Xa.
Parasrampuria, DA, Truitt, KE
Clinical pharmacokinetics. 2016;(6):641-55
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Abstract
Edoxaban, a once daily non-vitamin K antagonist oral anticoagulant, is a direct, selective, reversible inhibitor of factor Xa (FXa). In healthy subjects, single oral doses of edoxaban result in peak plasma concentrations within 1.0-2.0 h of administration, followed by a biphasic decline. Exposure is approximately dose proportional for once daily doses of 15-150 mg. Edoxaban is predominantly absorbed from the upper gastrointestinal tract, and oral bioavailability is approximately 62 %. Food does not affect total exposure to edoxaban. The terminal elimination half-life in healthy subjects ranges from 10 to 14 h, with minimal accumulation upon repeat once daily dosing up to doses of 120 mg. The steady-state volume of distribution is approximately 107 L, and total clearance is approximately 22 L/h; renal clearance accounts for approximately 50 % of total clearance, while metabolism and biliary secretion account for the remaining 50 %. Intrinsic factors, such as age, sex and race, do not affect edoxaban pharmacokinetics after renal function is taken into account. Oral administration of edoxaban results in rapid changes in anticoagulatory biomarkers, with peak effects on anticoagulation markers (such as anti-FXa), the prothrombin time and the activated partial thromboplastin time occurring within 1-2 h of dosing.
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Apixaban versus edoxaban for stroke prevention in nonvalvular atrial fibrillation.
Xiong, Q, Lau, YC, Lip, GY
Journal of comparative effectiveness research. 2015;(4):367-76
Abstract
Oral anticoagulation therapy is the mainstay of stroke prevention in nonvalvular atrial fibrillation patients. Vitamin K antagonists (such as warfarin) have been effective conventional oral anticoagulants for several decades. However, due to their limitations in clinical use, several nonvitamin K antagonist oral anticoagulants (NOACs, including dabigatran, rivaroxaban, apixaban and edoxaban) have been developed. Nonetheless, no head to head trials have been performed to directly compare these NOACs in patient cohorts. In this review article, two direct factor Xa inhibitors, apixaban and edoxaban, are briefly described with focus on their pharmacokinetic and pharmacodynamic profiles, plus drug interactions. Moreover, both efficacy and safety will be discussed based on the available data from the large Phase III clinical trials and indirect comparison studies.
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Advantages and limitations of the new anticoagulants.
Schulman, S
Journal of internal medicine. 2014;(1):1-11
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During recent years, three new anticoagulants (dabigatran, rivaroxaban and apixaban) have been introduced to the market, probably with one more anticoagulant (edoxaban) in the next 2 years. This review is not intended to compare the efficacy and risks of these new agents, but rather to detail the advantages and limitations. The pharmacokinetic characteristics of these drugs have few drug and food interactions, predictable dose responses, and rapid onset and offset, thus resulting in simplified management of the patient requiring anticoagulant therapy. No routine laboratory monitoring is required. A somewhat unexpected, but exciting observation involving the new anticoagulants, is the uniform reduction in intracranial bleeding by one-half compared with warfarin. The potential limitations of the new anticoagulants include uncertainty regarding assessment of drug levels, safe drug levels for major surgery, management of major bleeding, renal dependence, multiple dose regimens, adherence in the absence of frequent monitoring and unknown, rare side effects that were not captured in the trials. This review should clarify some of these concerns.
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Insights from the sea: structural biology of marine polyketide synthases.
Akey, DL, Gehret, JJ, Khare, D, Smith, JL
Natural product reports. 2012;(10):1038-49
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Abstract
The world's oceans are a rich source of natural products with extremely interesting chemistry. Biosynthetic pathways have been worked out for a few, and the story is being enriched with crystal structures of interesting pathway enzymes. By far, the greatest number of structural insights from marine biosynthetic pathways has originated with studies of curacin A, a poster child for interesting marine chemistry with its cyclopropane and thiazoline rings, internal cis double bond, and terminal alkene. Using the curacin A pathway as a model, structural details are now available for a novel loading enzyme with remarkable dual decarboxylase and acetyltransferase activities, an Fe(2+)/α-ketoglutarate-dependent halogenase that dictates substrate binding order through conformational changes, a decarboxylase that establishes regiochemistry for cyclopropane formation, and a thioesterase with specificity for β-sulfated substrates that lead to terminal alkene offloading. The four curacin A pathway dehydratases reveal an intrinsic flexibility that may accommodate bulky or stiff polyketide intermediates. In the salinosporamide A pathway, active site volume determines the halide specificity of a halogenase that catalyzes for the synthesis of a halogenated building block. Structures of a number of putative polyketide cyclases may help in understanding reaction mechanisms and substrate specificities although their substrates are presently unknown.