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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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Current and emerging therapeutic options for the management of functional dyspepsia.
Vandenberghe, A, Schol, J, Van den Houte, K, Masuy, I, Carbone, F, Tack, J
Expert opinion on pharmacotherapy. 2020;(3):365-376
Abstract
Introduction: Functional Dyspepsia (FD), defined as chronic symptoms originating from the gastroduodenal region in absence of readily identifiable organic disease, is one of the most common gastrointestinal disorders. FD is divided into two subgroups: Post-Prandial Distress Syndrome (PDS) or meal-related FD, characterized by postprandial fullness and early satiation, and Epigastric Pain Syndrome (EPS) or meal-unrelated FD, characterized by epigastric pain and burning.Areas covered: This review summarizes the existing and off-label therapeutic options for FD.Expert opinion: The identification of mechanisms, the Rome IV classification, the reduction of PDS/EPS overlap and pictograms for symptom identification allow a better diagnosis and a more targeted treatment choice. Acotiamide, a first-in-class prokinetic agent available only in Japan and India, is the only agent of proven efficacy for FD, but clinicians use acid-suppressive therapy, prokinetics, neuromodulators and herbal therapies for treating FD symptoms. New emerging targets are duodenal low-grade inflammation with eosinophils and duodenal or other modified luminal microbiota.
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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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Recent progress on inhibitors of the type II transmembrane serine proteases, hepsin, matriptase and matriptase-2.
Damalanka, VC, Janetka, JW
Future medicinal chemistry. 2019;(7):743-769
Abstract
Members of the type II transmembrane serine proteases (TTSP) family play a vital role in cell growth and development but many are also implicated in disease. Two of the well-studied TTSPs, matriptase and hepsin proteolytically process multiple protein substrates such as the inactive single-chain zymogens pro-HGF and pro-macrophage stimulating protein into the active heterodimeric forms, HGF and macrophage stimulating protein. These two proteases also have many other substrates which are associated with cancer and tumor progression. Another related TTSP, matriptase-2 is expressed in the liver and functions by regulating iron homoeostasis through the cleavage of hemojuvelin and thus is implicated in iron overload diseases. In the present review, we will discuss inhibitor design strategy and Structure activity relationships of TTSP inhibitors, which have been reported in the literature.
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[Edoxaban for stroke prevention in atrial fibrillation and treatment of venous thromboembolism: an expert position paper].
Weiss, TW, Rohla, M, Dieplinger, B, Domanovits, H, Fries, D, Vosko, MR, Gary, T, Ay, C
Wiener medizinische Wochenschrift (1946). 2018;(5-6):133-143
Abstract
Edoxaban is the most recent available representative of the Non-Vitamin K antagonist oral anticoagulants (NOAC). The approval was based on the largest phase III trials of NOACs for stroke prevention in patients with non-valvular atrial fibrillation (AF, ENGAGE-AF), and for the treatment of venous thromboembolism (VTE, HOKUSAI-VTE). In both trials, edoxaban was associated with similar efficacy and a significant reduction in bleeding events with respect to the pre-defined primary safety endpoints, as compared to warfarin.Additionally, the once daily dosing of edoxaban, the clinically investigated strategy for dose-reduction based on clearly defined criteria and the favorable pharmacokinetic profile might further support the clinical applicability of the substance.In the light of recent data, this expert consensus document aims to summarize the latest clinical trial results while providing a concise overview of current guideline recommendations on the management of patients with non-valvular AF and VTE.
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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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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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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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Secondary prevention in non-valvular atrial fibrillation patients: a practical approach with edoxaban.
Masjuan, J, DeFelipe, A
The International journal of neuroscience. 2017;(8):716-725
Abstract
Patients with atrial fibrillation and prior stroke or transient ischemic attack exhibit a very high risk of recurrence. Secondary prevention with oral anticoagulants is mandatory. Overall, clinical guidelines recommend the use of target-specific oral anticoagulants over vitamin K antagonists for secondary prevention of stroke in patients with atrial fibrillation. However, many patients with atrial fibrillation and previous stroke are not receiving the appropriate antithrombotic treatment, perhaps due to the perceived risks of anticoagulation including the risk of hemorrhagic transformation of an ischemic stroke. The ENGAGE AF-TIMI 48 trial showed that although edoxaban 60 mg and warfarin reduced the risk of stroke to a similar extent, edoxaban exhibited a lesser risk of bleeding, particularly intracranial hemorrhage. Importantly, these data were independent of the presence of prior stroke or transient ischemic attack. Therefore, edoxaban can be used in both primary and secondary prevention of stroke in patients with non-valvular atrial fibrillation. The aim of this review was to update the available evidence about edoxaban in the clinical management of secondary prevention in individuals with non-valvular atrial fibrillation.