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1.
Management of Hyperkalemia in Heart Failure.
Altay, H, Çavuşoğlu, Y, Çelik, A, Demir, Ş, Kılıçarslan, B, Nalbantgil, S, Temizhan, A, Tokgöz, B, Ural, D, Yeşilbursa, D, et al
Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir. 2021;(Supp1):1-32
Abstract
Hyperkalemia is a common electrolyte abnormality in heart failure (HF) that can cause potentially life-threatening cardiac arrhythmias and sudden cardiac death. HF patients with diabetes, chronic kidney disease and older age are at higher risk of hyperkalemia. Moreover, hyperkalemia is also often associated with the use of renin-angiotensin-aldosterone system inhibitors (RAASi) including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists and sacubitril-valsartan. In clinical practice, the occurrence of hyperkalemia is a major concern among the clinicians and often limits RAASi use and/or lead to dose reduction or discontinuation, thereby reducing their potential benefits for HF. Furthermore, recurrent hyperkalemia is frequent in the long-term and is associated with an increase in hyperkalemia-related hospitalizations. Therefore, management of hyperkalemia has a special importance in HF patients. However, treatment options in chronic management are currently limited. Dietary restriction of potassium is usually ineffective with variable adherence. Sodium polystyrene sulfonate is commonly used, but its effectiveness is uncertain and reported to be associated with intestinal toxicity. New therapeutic options such as potassium binders have been suggested as potentially beneficial agents in the management of hyperkalemia. This document discusses prevalence, predictors and management of hyperkalemia in HF, emphasizing the importance of careful patient selection for medical treatment, uptitration of the doses of RAASi, regular surveillance of potassium and treatment options of hyperkalemia.
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2.
Transition metal chelators, pro-chelators, and ionophores as small molecule cancer chemotherapeutic agents.
Steinbrueck, A, Sedgwick, AC, Brewster, JT, Yan, KC, Shang, Y, Knoll, DM, Vargas-Zúñiga, GI, He, XP, Tian, H, Sessler, JL
Chemical Society reviews. 2020;(12):3726-3747
Abstract
Cancer is among the leading causes of death worldwide. Although a number of new treatment options have been developed in recent years, there remains a need for improved chemotherapies. The primary challenges facing new cancer drugs include: (1) improving patient quality of life, (2) overcoming drug resistance and (3) lowering reoccurrence rates. Major drawbacks of current chemotherapeutics arise from poor selectivity towards cancer cells, dose limiting toxicities, compliance-reducing side effects, and an inability to address resistance mechanisms. Chemotherapeutics that fail to achieve complete eradication of the disease can also lead to relapse and promote treatment resistance. New strategies to overcome these drawbacks include the use of transition metal chelators and ionophores to alter selectively the concentrations of iron, copper, and zinc in cancer cells. A number of metal chelators have successfully demonstrated cytotoxicity and targeted activity against drug-resistant cancer cells; several have proved effective against cancer stem cells, a significant cause of tumour reoccurrence. However, problems with formulation and targeting have been noted. Recent efforts have thus focused on the design of pro-chelators, inactive versions of chelators that are designed to be activated in the tumour. This is an appealing strategy that may potentially increase efficacy towards cancer-resistant malignant cells. This Tutorial Review summarizes recent progress involving transition metal chelators, pro-chelators, and ionophores as potential cancer chemotherapeutics. We will focus on the reported agents that are able to coordinate iron, copper, and zinc.
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3.
Phosphate Binders and Nonphosphate Effects in the Gastrointestinal Tract.
Biruete, A, Hill Gallant, KM, Lindemann, SR, Wiese, GN, Chen, NX, Moe, SM
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2020;(1):4-10
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Abstract
Phosphate binders are commonly prescribed in patients with end-stage kidney disease to prevent and treat hyperphosphatemia. These binders are usually associated with gastrointestinal distress, may bind molecules other than phosphate, and may alter the gut microbiota, altogether having systemic effects unrelated to phosphate control. Sevelamer is the most studied of the available binders for nonphosphate-related effects including binding to bile acids, endotoxins, gut microbiota-derived metabolites, and advanced glycation end products. Other binders (calcium- and noncalcium-based binders) may bind vitamins, such as vitamin K and folic acid. Moreover, the relatively new iron-based phosphate binders may alter the gut microbiota, as some of the iron or organic ligands may be used by the gastrointestinal bacteria. The objective of this narrative review is to provide the current evidence for the nonphosphate effects of phosphate binders on gastrointestinal function, nutrient and molecule binding, and the gut microbiome.
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4.
Corrosive attacks in the UK - Psychosocial perspectives and decontamination strategies.
Lewis, CJ, Hodgkinson, EL, Allison, KP
Burns : journal of the International Society for Burn Injuries. 2020;(1):213-218
Abstract
Acid attacks, or vitriolage, are defined as violent assaults involving the deliberate throwing of an acid or similarly corrosive substance with the intention to "maim, disfigure, torture or kill" [1]. The Acid Survivors Trust International suggest a prevalence of 1500 attacks reported worldwide per annum, although this is likely to be an underestimate by 40% [2]. The UK is thought to have one of the highest of rates of recorded corrosive attacks, with an increase from 228 attacks in 2012 to 601 in 2016. Most were reported by the London Metropolitan police force followed by Northumbria, Cambridgeshire, Hertfordshire, Greater Manchester and Humberside [[2]]. The chemical agents involved include acids, alkalis, oxidising and reducing agents, alkylating and chelating agents and solvents. They cause injury by producing a chemical interaction which can lead to extensive tissue destruction and extreme pain. Herein, we present a review on the changing epidemiology of corrosive attacks in the UK and currently employed management strategies.
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Benefits and Detriments of Gadolinium from Medical Advances to Health and Ecological Risks.
Unruh, C, Van Bavel, N, Anikovskiy, M, Prenner, EJ
Molecules (Basel, Switzerland). 2020;(23)
Abstract
Gadolinium (Gd)-containing chelates have been established as diagnostics tools. However, extensive use in magnetic resonance imaging has led to increased Gd levels in industrialized parts of the world, adding to natural occurrence and causing environmental and health concerns. A vast amount of data shows that metal may accumulate in the human body and its deposition has been detected in organs such as brain and liver. Moreover, the disease nephrogenic systemic fibrosis has been linked to increased Gd3+ levels. Investigation of Gd3+ effects at the cellular and molecular levels mostly revolves around calcium-dependent proteins, since Gd3+ competes with calcium due to their similar size; other reports focus on interaction of Gd3+ with nucleic acids and carbohydrates. However, little is known about Gd3+ effects on membranes; yet some results suggest that Gd3+ interacts strongly with biologically-relevant lipids (e.g., brain membrane constituents) and causes serious structural changes including enhanced membrane rigidity and propensity for lipid fusion and aggregation at much lower concentrations than other ions, both toxic and essential. This review surveys the impact of the anthropogenic use of Gd emphasizing health risks and discussing debilitating effects of Gd3+ on cell membrane organization that may lead to deleterious health consequences.
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Management of oxidative stress and other pathologies in Alzheimer's disease.
Simunkova, M, Alwasel, SH, Alhazza, IM, Jomova, K, Kollar, V, Rusko, M, Valko, M
Archives of toxicology. 2019;(9):2491-2513
Abstract
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder, characterized by the formation, aggregation and accumulation of amyloid beta, perturbed metal (copper, iron and zinc) homeostasis, metal-induced oxidative stress, neuroinflammation, aberrant activity of acetylcholinesterase (AChE) and other pathologies. The aim of this review is to discuss the current therapies based on the "combination-drugs-multitargets" strategy to target multiple pathologies to block the progression of pathogenesis of AD. In addition to cholinergic and amyloid targets, a significant effort is focused on targeting the metal-induced oxidative stress component of the disease. The main focus of research is based on modifications of existing drugs with specific biological activity. Tacrine was the first AChE inhibitor to be introduced into clinical practice and has been frequently used for the design of multitarget-directed ligands. A number of hybrid compounds containing tacrine and structural moieties derived from natural sources such as flavonoids [quercetin, rutin, coumarin, gallamine, resveratrol, scutellarin, anisidine, hesperetin, (-)-epicatechin] and other molecules (melatonin, trolox) have also been applied to function as multitarget-directed ligands. Most of these hybrids are potent inhibitors of AChE and butyrylcholinesterase and also of amyloid-beta aggregation. In addition, the antioxidant functionality, represented by coumarins, melatonin and other antioxidant molecules reduces the level of oxidative stress via ROS-scavenging mechanisms, as well as via chelation of redox-active Cu and Fe, thus suppressing the formation of ROS via the Fenton reaction. Various medicinal plants are under investigation for their ability to ameliorate symptoms of AD. The therapeutic potency of huperzine A and B, ginseng, curcumin and other compounds is manifested predominantly by the inhibitory action toward AChE, antioxidant or radical-scavenging and redox metal-chelating activity, inhibition of amyloid-beta aggregation and tau-protein hyperphosphorylation and antiinflammatory activity. Flavonoids not only function as antioxidants and metal-chelating agents, but also interact with protein kinase and lipid kinase signaling pathways, and others involving mitogen-activated protein kinase, NF-kappaB and tyrosine kinase. Among the most promising group of substances with potential activity against AD are the flavonoids, including myricetin, morin, rutin, quercetin, fisetin, kaempferol, apigenin and glycitein, which have been shown, in vitro, to possess antiamyloidogenic and fibril-destabilization activity, as well as being able to act as metal chelators and to suppressing oxidative stress. In terms of the clinical use of multifunctional hybrids, herbal drugs or flavonoids against AD, some remaining challenges are to establish the ideal dose to develop effective formulations to preserve bioavailability and to determine the stage when they should be administered. If the onset of the disease could be delayed by a decade, the number of AD victims would be significantly reduced.
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Rebalancing metal dyshomeostasis for Alzheimer's disease therapy.
Yang, GJ, Liu, H, Ma, DL, Leung, CH
Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry. 2019;(8):1159-1170
Abstract
Alzheimer's disease (AD) is a type of neurodegenerative malady that is associated with the accumulation of amyloid plaques. Metal ions are critical for the development and upkeep of brain activity, but metal dyshomeostasis can contribute to the development of neurodegenerative diseases, including AD. This review highlights the association between metal dyshomeostasis and AD pathology, the feasibility of rebalancing metal homeostasis as a therapeutic strategy for AD, and a survey of current drugs that action via rebalancing metal homeostasis. Finally, we discuss the challenges that should be overcome by researchers in the future to enable the practical use of metal homeostasis rebalancing agents for clinical application.
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8.
Copper Depletion as a Therapeutic Strategy in Cancer.
Lopez, J, Ramchandani, D, Vahdat, L
Metal ions in life sciences. 2019
Abstract
Copper is an essential trace element that plays a critical role in a variety of basic biological functions, and serves as a key component in a number of copper-dependent enzymes that regulate such processes as cell proliferation, angiogenesis, and motility. A growing body of preclinical work has demonstrated that copper is essential to metastatic cancer progression, and may have a role in tumor growth, epithelial-mesenchymal transition, and the formation of the tumor microenvironment and pre-metastatic niche. As a result, copper depletion has emerged as a novel therapeutic strategy in the treatment of metastatic cancer. We present a review of the physiologic role of copper with a discussion of relevant enzymes of the copper proteome in both normal tissue and in cancer. We conducted a comprehensive review of the available preclinical data of several copper chelation agents, including penicillamine, trientine, disulfiram, clioquinol, and tetrathiomolybdate (TM), across a variety of tumor types. We also present the existing early phase clinical trial data for the use of the copper chelator TM in the treatment of breast cancer and other malignancies.
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9.
[Diagnosis and treatment of Wilson disease in Japan].
Shimizu, N
Rinsho shinkeigaku = Clinical neurology. 2019;(9):565-569
Abstract
Wilson disease is an autosomal recessive disorder based on inborn error of copper metabolism. The copper accumulates in the liver, brain, cornea, kidney, and other organs. This disease should be considered any individual with liver abnormality except infant, any patient older than teenage with neurological (especially for extra pyramidal signs) or neuropsychiatric disorder with or without liver disease and sibling of Wilson disease patient. Typically, a combination of low serum ceruloplasmine levels and high levels of urinary copper contents is sufficient to establish a diagnosis. As other diagnostic tests, measurement of hepatic copper content and ATP7B gene analysis are available. The key strategy of treatment is to reduce the amount of copper in the liver and other tissues by administering both copper-chelating agents, such as D-penicillamine or Trientine, and/or zinc acetate. The author recommend zinc acetate monotherapy for mild to moderate hepatic disorder, Trientine mono therapy for mild to moderate neurologic disorder and combination therapy of Trientine and zinc acetate for sever hepatic or neurologic disorder.
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10.
Successful Treatment of Single Infected Calciphylaxis Lesion With Intralesional Injection of Sodium Thiosulfate at High Concentration.
Zuhaili, B, Al-Talib, K
Wounds : a compendium of clinical research and practice. 2019;(8):E54-E57
Abstract
INTRODUCTION Calciphylaxis is a very complicated disease that usually presents in patients with end-stage renal disease (ESRD). Treatment for calciphylaxis is not well standardized and typically involves a multidisciplinary approach. One of the common medications used in calciphylaxis treatment is sodium thiosulfate (STS). However, its intravenous injection is associated with multiple side effects. CASE REPORT The authors present a case report of an intralesional injection of STS followed by a literature review of the common treatment modalities and possible further use of intralesional injections. A 51-year-old man with ESRD on peritoneal dialysis presented with a right calf biopsy-proven calciphylaxis lesion measuring 3.1 cm x 3.9 cm. About the same time, he had Pseudomonas-associated peritoneal catheter peritonitis. The calciphylaxis lesion was treated with bimonthly intralesional injections of STS. The lesion had a complete resolution by week 9. CONCLUSIONS The authors believe a higher local concentration of STS leading to a faster resolution and requiring less frequent injections needs to be further evaluated. Following additional studies, they also propose a greater use of intralesional STS injections in a select set of patients in the future.