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https://www.readbyqxmd.com/read/30517073/an-engineered-lipocalin-that-tightly-complexes-the-plant-poison-colchicine-for-use-as-antidote-as-well-as-bioanalytical-applications
#1
Arne Skerra, Mikhail Barkovskiy, Elena Ilyukhina, Martin Dauner, Andreas Eichinger
Colchicine is a toxic alkaloid prevalent in autumn crocus (Colchicum autumnale) that binds to tubulin and inhibits polymerization of microtubules. Using combinatorial and rational protein design, we have developed an artificial binding protein based on the human lipocalin 2 that binds colchicine with a dissociation constant of 120 pM, i.e. 10 000-fold stronger than tubulin. Crystallographic analysis of the engineered lipocalin, dubbed Colchicalin, revealed major structural changes in the flexible loop region that forms the ligand pocket at one end of the eight-stranded β-barrel, resulting in a lid-like structure over the deeply buried colchicine...
December 1, 2018: Biological Chemistry
https://www.readbyqxmd.com/read/30516974/accelerated-blood-clearance-of-antibodies-by-nanosized-click-antidotes
#2
Weston J Smith, Guankui Wang, Hanmant Gaikwad, Vivian P Vu, Ernest Groman, David W A Bourne, Dmitri Simberg
Long blood half-life is one of the advantages of antibodies over small molecule drugs. At the same time, prolonged half-life is a problem for imaging applications or in the case of antibody-induced toxicities. There is a substantial need for antidotes that can quickly clear antibodies from systemic circulation and peripheral tissues. Engineered nanoparticles exhibit intrinsic affinity for clearance organs (mainly liver and spleen). trans-Cyclooctene (TCO) and methyltetrazine (MTZ) are versatile copper-free click chemistry components that are extensively being used for in vivo bioorthogonal couplings...
December 5, 2018: ACS Nano
https://www.readbyqxmd.com/read/30513883/human-monoclonal-scfvs-that-neutralize-fribrinogenolytic-activity-of-kaouthiagin-a-zinc-metalloproteinase-in-cobra-naja-kaouthia-venom
#3
Jirawat Khanongnoi, Siratcha Phanthong, Onrapak Reamtong, Anchalee Tungtronchitr, Wanpen Chaicumpa, Nitat Sookrung
Snake venom-metalloproteinases (SVMPs) are the primary factors that disturb hemostasis and cause hemorrhage in the venomous snake bitten subjects. Kaouthiagin is a unique SVMP that binds and cleaves von Willebrand factor (vWF) at a specific peptide bond leading to inhibition of platelet aggregation, which enhances the hemorrhage. Kaouthiagin is a low abundant venom component of Thai cobra ( Naja kaouthia ); thus, most horse-derived antivenins used for cobra bite treatment do not contain adequate anti-kaouthiagin...
December 3, 2018: Toxins
https://www.readbyqxmd.com/read/30508850/-bleeding-management-under-direct-oral-anticoagulants-doac
#4
Jürgen Koscielny, Christoph Rosenthal, Christian von Heymann
Despite the widespread use of DOAC and recommendations of regulatory agencies and first consensus meetings on handling of bleeding situation under DOAC uncertainty still exists. In case of mild bleeding, the medical care of these patients and the delay of the next dose is advised. A laboratory analysis is indicated i. e. in case of known higher grade liver and kidney failure. The administration of factor concentrates or antidots is not indicated in this situation. In case of moderate to severe bleeding, the primary focus lies on stabilization of cardiopulmonary and circulatory function and parallel on the treatment depending on the localization of the bleeding source...
December 2018: Deutsche Medizinische Wochenschrift
https://www.readbyqxmd.com/read/30508642/protective-effects-of-alpha-ketoglutarate-against-aluminum-toxicity-in-drosophila-melanogaster
#5
Maria M Bayliak, Maria P Lylyk, Dmytro V Gospodaryov, Volodymyr O Kotsyubynsky, Nataliia V Butenko, Kenneth B Storey, Volodymyr I Lushchak
In recent years, Drosophila melanogaster has emerged as a model for studies on aluminum toxicity. The current study aimed to disclose the mechanisms of aluminum toxicity in D. melanogaster at larval and adult stages and examined the potential protective effects of dietary alpha-ketoglutarate (AKG). Flies were reared on food containing 10 mM AlCl3 , 10 mM AKG or both additives. Rearing on an AlCl3 -containing diet induced behavioral defects, and decreased fecundity and long-term survival of female flies...
November 30, 2018: Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP
https://www.readbyqxmd.com/read/30505336/-salvia-hispanica-l-chia-seeds-oil-extracts-reduce-lipid-accumulation-and-produce-stress-resistance-in-caenorhabditis-elegans
#6
Cristiane Freitas Rodrigues, Willian Salgueiro, Matheus Bianchini, Juliana Cristina Veit, Robson Luiz Puntel, Tatiana Emanuelli, Cristiane Casagrande Dernadin, Daiana Silva Ávila
Background: Salvia hispanica seeds have been commonly used by people that seek healthy habits through natural foods to reduce cholesterol and triacylglycerides levels, however, the evidences that support this assumption are still scarce in literature. Here, we aimed to evaluate the lipid lowering effects of chia by using Caenorhabditis elegans as animal model, a nematode that has proven its usefulness for lipid metabolism studies. Methods: We prepared hexane (HE) and Bligh-Dyer (BDE) extracts, evaluated and compared their safety, antioxidant potential and their lipid-lowering activity in the worms...
2018: Nutrition & Metabolism
https://www.readbyqxmd.com/read/30505033/improving-access-to-antidotes-and-antivenoms-thailand
#7
Netnapis Suchonwanich, Winai Wananukul
Problem: Historically in Thailand, access to poison antidotes was limited and antivenom stock management was inefficient. Approach: In 2010, the country established a national antidote programme, which created national and subnational antidote stocks, managed their distribution and trained health-care providers on clinical management and antidote use. In 2013, the programme incorporated antivenoms to improve stock management and avoid wastage due to stock expiry...
December 1, 2018: Bulletin of the World Health Organization
https://www.readbyqxmd.com/read/30476716/effect-of-low-and-moderate-dose-feiba-to-reverse-major-bleeding-in-patients-on-direct-oral-anticoagulants
#8
W E Dager, A J Roberts, D K Nishijima
OBJECTIVE: Management of acute, major or life threatening bleeding in the presence of direct acting oral anticoagulants (DOAC) is unclear. In the absence of a specific antidote, or in situations where there is a need for adjunctive therapy, the ideal prothrombin complex concentrate and dose is unclear. The goal of our study was to evaluate the outcomes of our reduced dosing strategy with FEIBA in patients experiencing a DOAC-related bleeding event. DESIGN: Retrospective analysis of patients treated with FEIBA for a DOAC-related bleeding event...
November 16, 2018: Thrombosis Research
https://www.readbyqxmd.com/read/30475921/a-suppressor-of-a-wtf-poison-antidote-meiotic-driver-acts-via-mimicry-of-the-driver-s-antidote
#9
María Angélica Bravo Núñez, Jeffrey J Lange, Zanders E Sarah
Meiotic drivers are selfish alleles that subvert gametogenesis to increase their transmission into progeny. Drivers impose a fitness cost, putting pressure on the genome to evolve suppressors. Here we investigate the wtf gene family from Schizosaccharomyces pombe, previously shown to contain meiotic drivers in wild isolates. We discovered that wtf13 found in lab stocks is a meiotic driver. wtf13 kills spores that do not inherit it by generating both a diffusible poison and a spore-specific antidote. Additionally, we demonstrate that wtf13 is suppressed by another wtf gene, wtf18-2, that arose spontaneously in the lab and makes only an antidote...
November 26, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/30471141/n-acetylcysteine-prevents-glutathione-decrease-and-does-not-interfere-with-paracetamol-antinociceptive-effect-at-therapeutic-dosage-a-randomized-double-blind-controlled-trial-in-healthy-subjects
#10
Gisèle Pickering, Nicolas Macian, Isabelle Papet, Christian Dualé, Catherine Coudert, Bruno Pereira
Paracetamol (APAP) may lead to hepatic changes even at therapeutic dosages. Glutathione (GSH) plays a pivotal role in APAP metabolism as it allows the detoxification of a toxic metabolite. N-Acetylcysteine (NAC) is APAP antidote, is also largely used as a mucoactive drug and is often associated with APAP. This study aims at evaluating if 1- NAC modifies APAP pain efficacy and 2- NAC prevents glutathione depletion with APAP at therapeutic doses. This double-blind randomized controlled study (NCT02206178) was carried out in 24 healthy volunteers...
November 24, 2018: Fundamental & Clinical Pharmacology
https://www.readbyqxmd.com/read/30458229/atropine-counteracts-the-depressive-like-behaviour-elicited-by-acute-exposure-to-commercial-chlorpyrifos-in-rats
#11
Alciene Almeida Siqueira, Alexandre Frinhani Cunha, Graziany Leite Moreira Marques, Igor Simões Assunção Felippe, Vitor Sampaio Minassa, Thallis Coelho da Silva Gramelich, Maria Aparecida Cicilini, Tamara Andrea Alarcon, Rita Gomes Wanderley Pires, Karla Nivea Sampaio, Vanessa Beijamini
Acute organophosphate (OP) poisoning induces well-known signs of toxicosis related to acetylcholinesterase (AChE) inhibition. However, the relationship between acute OP poisoning and the onset of psychiatric disorders remains unclear. Thus, we investigated behavioural and biochemical consequences of acute exposure to the OP chlorpyrifos in male rats and also the effectiveness of the antidotes atropine and pralidoxime on reversing these changes. A sub-lethal dose of commercial chlorpyrifos (20 mg/kg, i.p.) elicited signs of acute toxicosis during the first hours after its injection in rats...
November 17, 2018: Neurotoxicology and Teratology
https://www.readbyqxmd.com/read/30458057/reversal-of-tabun-toxicity-enabled-by-a-triazole-annulated-oxime-library-reactivators-of-acetylcholinesterase
#12
Zrinka Kovarik, Jarosław Kalisiak, Nikolina Maček Hrvat, Maja Katalinić, Tamara Zorbaz, Suzana Žunec, Carol Green, Zoran Radić, Valery V Fokin, K Barry Sharpless, Palmer Taylor
Acetylcholinesterase (AChE), an enzyme that degrades the neurotransmitter acetylcholine, when covalently inhibited by organophosphorus compounds (OPs), such as nerve agents and pesticides, can be reactivated by oximes. However, tabun remains among the most dangerous nerve agents due to the low reactivation efficacy of standard pyridinium aldoxime antidotes. Therefore, finding an optimal reactivator for prophylaxis against tabun toxicity and for post-exposure treatment is a continued challenge. In this study, we analyzed the reactivation potency of 111 novel nucleophilic oximes mostly synthesized using the CuAAC triazole ligation between alkyne and azide building blocks...
November 20, 2018: Chemistry: a European Journal
https://www.readbyqxmd.com/read/30456142/a-pilot-study-on-the-management-and-outcomes-of-self-poisoning-in-a-rural-ugandan-emergency-centre
#13
Vinodinee Dissanayake, Erin T Dalka, Cynthia Koh, Mark Bisanzo, Ryan S Brandt, Timothy B Erickson, Stacey Chamberlain
Introduction: The Global Emergency Care Collaborative and Nyakibale Hospital in Rukungiri opened the first functional emergency centre in rural Uganda. We investigated decontamination, management and outcomes of poisoned patients in the emergency centre. Methods: An electronic database started recording charts from 24 March 2012. A search for diagnoses concerning self-poisoning was performed from 24 March 2012 to 30 December 2013 and 192 charts were found and de-identified...
March 2018: African Journal of Emergency Medicine Revue Africaine de la Médecine D'urgence
https://www.readbyqxmd.com/read/30455855/pharmacoinformatic-approach-to-explore-the-antidote-potential-of-phytochemicals-on-bungarotoxin-from-indian-krait-bungarus-caeruleus
#14
Barani Kumar Rajendran, M Xavier Suresh, Shanmuga Priya Bhaskaran, Yarradoddi Harshitha, Uma Gaur, Hang Fai Kwok
Venomous reptiles especially serpents are well known for their adverse effects after accidental conflicts with humans. Upon biting humans these serpents transmit arrays of detrimental toxins with diverse physiological activities that may either lead to minor symptoms such as dermatitis and allergic response or highly severe symptoms such as blood coagulation, disseminated intravascular coagulation, tissue injury, and hemorrhage. Other complications like respiratory arrest and necrosis may also occur. Bungarotoxins are a group of closely related neurotoxic proteins derived from the venom of kraits ( Bungarus caeruleus ) one of the six most poisonous snakes in India whose bite causes respiratory paralysis and mortality without showing any local symptoms...
2018: Computational and Structural Biotechnology Journal
https://www.readbyqxmd.com/read/30455445/thoughts-on-the-limits-of-a-mutual-technique
#15
Jay Frankel
Ferenczi's appreciation of the inherently mutual nature of the analytic encounter led him, and many who followed, to explore the value of mutual openness between patient and analyst. Specifically, Ferenczi saw the analyst's openness as an antidote to his earlier defensive denial of his failings and ambivalence toward the patient, which had undermined his patient's trust. My own view is that, while the analyst's openness with the patient can indeed help reestablish trust and restore a productive analytic process in the short term, it also poses long-term dangers...
November 19, 2018: American Journal of Psychoanalysis
https://www.readbyqxmd.com/read/30454770/pharmacological-research-as-a-key-component-in-mitigating-the-opioid-overdose-crisis
#16
Michael H Baumann, Theresa A Kopajtic, Bertha K Madras
The United States is experiencing an epidemic of opioid overdose deaths. Many of the recent fatalities are associated with illicitly manufactured fentanyl, which is being added to heroin and counterfeit pain pills. The crisis is further exacerbated by the emergence of an increasing number of novel synthetic opioids (NSOs), including various fentanyl analogs and non-fentanyl compounds that display potent agonist actions at the μ-opioid receptor. Importantly, most users are unaware of their exposure to fentanyl and NSOs...
December 2018: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/30453607/delayed-ly333013-oral-and-ly315920-intravenous-reverse-severe-neurotoxicity-and-rescue-juvenile-pigs-from-lethal-doses-of-micrurus-fulvius-eastern-coral-snake-venom
#17
Matthew R Lewin, Lyndi L Gilliam, John Gilliam, Stephen P Samuel, Tommaso C Bulfone, Philip E Bickler, José María Gutiérrez
OBJECTIVE: There is a clear, unmet need for effective, lightweight, shelf-stable and economical snakebite envenoming therapies that can be given rapidly after the time of a snake's bite and as adjuncts to antivenom therapies in the hospital setting. The sPLA2 inhibitor, LY315920, and its orally bioavailable prodrug, LY333013, demonstrate surprising efficacy and have the characteristics of an antidote with potential for both field and hospital use. METHODS: The efficacy of the active pharmaceutical ingredient (LY315920) and its prodrug (LY333013) to treat experimental, lethal envenoming by Micrurus fulvius (Eastern coral snake) venom was tested using a porcine model...
November 17, 2018: Toxins
https://www.readbyqxmd.com/read/30447275/neutralizing-properties-of-ly315920-toward-snake-venom-group-i-and-ii-myotoxic-phospholipases-a-2
#18
Wendy Bryan-Quirós, Julián Fernández, José María Gutiérrez, Matthew R Lewin, Bruno Lomonte
A need exists to develop specific and clinically useful inhibitors of toxic enzymes present in snake venoms, responsible for severe tissue damage and life-threatening effects occurring in thousands of people suffering envenomations globally. LY315920 (Varespladib, S-5920, A-001), a low molecular weight drug developed to inhibit several human secreted phospholipases A2 (PLA2 s), was recently shown to also inhibit PLA2 s in whole snake venoms with high potency, yet no studies have examined its direct effect on purified snake venom PLA2 s...
November 14, 2018: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/30430872/intramuscular-cobinamide-versus-saline-for-treatment-of-severe-hydrogen-sulfide-toxicity-in-swine
#19
Patrick C Ng, Tara B Hendry-Hofer, Norma Garrett, Matthew Brenner, Sari B Mahon, Joseph K Maddry, Philippe Haouzi, Gerry R Boss, Thomas F Gibbons, Allyson A Araña, Vikhyat S Bebarta
INTRODUCTION: Hydrogen sulfide (H2 S) is found in petroleum, natural gas, and decaying organic matter. Terrorist groups have attempted to use it in enclosed spaces as a chemical weapon. Mass casualty scenarios have occurred from industrial accidents and release from oil field sites. There is no FDA approved antidote for sulfide poisoning. We have previously reported that intravenous cobinamide is effective for sulfide poisoning. A rapid-acting antidote that is easy to administer intramuscularly (IM) would be ideal for use in a prehospital setting...
November 15, 2018: Clinical Toxicology
https://www.readbyqxmd.com/read/30423822/co-administered-polymeric-nano-antidotes-for-improved-photo-triggered-response-in-glioblastoma
#20
Janel Kydd, Rahul Jadia, Prakash Rai
Polymer-based nanoparticles (NPs) are useful vehicles in treating glioblastoma because of their favorable characteristics such as small size and ability to cross the blood⁻brain barrier, as well as reduced immunogenicity and side effects. The use of a photosensitizer drug such as Verteporfin (BPD), in combination with a pan-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), Cediranib (CED), encapsulated in NPs will provide the medical field with new research on the possible ways to treat glioblastoma...
November 10, 2018: Pharmaceutics
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