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1.
Molecules ; 26(20)2021 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-34684845

RESUMO

4-Hydroxycoumarin (4HC) has been used as a lead compound for the chemical synthesis of various bioactive substances and drugs. Its prenylated derivatives exhibit potent antibacterial, antitubercular, anticoagulant, and anti-cancer activities. In doing this, E. coli BL21(DE3)pLysS strain was engineered as the in vivo prenylation system to produce the farnesyl derivatives of 4HC by coexpressing the genes encoding Aspergillus terreus aromatic prenyltransferase (AtaPT) and truncated 1-deoxy-D-xylose 5-phosphate synthase of Croton stellatopilosus (CstDXS), where 4HC was the fed precursor. Based on the high-resolution LC-ESI(±)-QTOF-MS/MS with the use of in silico tools (e.g., MetFrag, SIRIUS (version 4.8.2), CSI:FingerID, and CANOPUS), the first major prenylated product (named compound-1) was detected and ultimately elucidated as ferulenol, in which information concerning the correct molecular formula, chemical structure, substructures, and classifications were obtained. The prenylated product (named compound-2) was also detected as the minor product, where this structure proposed to be the isomeric structure of ferulenol formed via the tautomerization. Note that both products were secreted into the culture medium of the recombinant E. coli and could be produced without the external supply of prenyl precursors. The results suggested the potential use of this engineered pathway for synthesizing the farnesylated-4HC derivatives, especially ferulenol.


Assuntos
Cumarínicos/metabolismo , Escherichia coli/metabolismo , 4-Hidroxicumarinas/metabolismo , Aspergillus/metabolismo , Simulação por Computador , Dimetilaliltranstransferase/metabolismo , Cinética , Prenilação/fisiologia
2.
Nutrients ; 13(10)2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34684491

RESUMO

Vitamin K dependent proteins (VKDP), such as hepatic coagulation factors and vascular matrix Gla protein (MGP), play key roles in maintaining physiological functions. Vitamin K deficiency results in inactive VKDP and is strongly linked to vascular calcification (VC), one of the major risk factors for cardiovascular morbidity and mortality. In this study we investigated how two vitamin K surrogate markers, dephosphorylated-undercarboxylated MGP (dp-ucMGP) and protein induced by vitamin K absence II (PIVKA-II), reflect vitamin K status in patients on hemodialysis or with calcific uremic arteriolopathy (CUA) and patients with atrial fibrillation or aortic valve stenosis. Through inter- and intra-cohort comparisons, we assessed the influence of vitamin K antagonist (VKA) use, vitamin K supplementation and disease etiology on vitamin K status, as well as the correlation between both markers. Overall, VKA therapy was associated with 8.5-fold higher PIVKA-II (0.25 to 2.03 AU/mL) and 3-fold higher dp-ucMGP (843 to 2642 pM) levels. In the absence of VKA use, non-renal patients with established VC have dp-ucMGP levels similar to controls (460 vs. 380 pM), while in HD and CUA patients, levels were strongly elevated (977 pM). Vitamin K supplementation significantly reduced dp-ucMGP levels within 12 months (440 to 221 pM). Overall, PIVKA-II and dp-ucMGP showed only weak correlation (r2 ≤ 0.26) and distinct distribution pattern in renal and non-renal patients. In conclusion, VKA use exacerbated vitamin K deficiency across all etiologies, while vitamin K supplementation resulted in a vascular VKDP status better than that of the general population. Weak correlation of vitamin K biomarkers calls for thoughtful selection lead by the research question. Vitamin K status in non-renal deficient patients was not anomalous and may question the role of vitamin K deficiency in the pathogenesis of VC in these patients.


Assuntos
Biomarcadores/sangue , Proteínas de Ligação ao Cálcio/sangue , Proteínas da Matriz Extracelular/sangue , Precursores de Proteínas/sangue , Calcificação Vascular/sangue , Deficiência de Vitamina K/sangue , Vitamina K/sangue , 4-Hidroxicumarinas/uso terapêutico , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/complicações , Fibrilação Atrial/sangue , Fibrilação Atrial/complicações , Doenças Cardiovasculares/etiologia , Estudos de Coortes , Suplementos Nutricionais , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Indenos/uso terapêutico , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Protrombina , Diálise Renal/efeitos adversos , Uremia/sangue , Uremia/complicações , Calcificação Vascular/complicações , Vitamina K/antagonistas & inibidores , Vitamina K/uso terapêutico , Deficiência de Vitamina K/complicações
3.
Transfusion ; 61(10): 3008-3016, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34358342

RESUMO

BACKGROUND: Antivitamin K agent (AVK) reversal in patients with cirrhosis awaiting liver transplantation (LT) is not defined in guidelines. We investigated the effect of reversion with prothrombin complex concentrate (PCC) on intraoperative transfusion, bleeding, and safety in LT patients on AVK. STUDY DESIGN AND METHODS: In 511 patients undergoing LT, we identified 25 patients treated with AVK (AVK group) and 13 patients with incidental portal vein thrombosis (PVT) without AVK (incidental PVT group). Fifty patients who underwent LT without PVT or AVK matched by age, model for end stage of liver disease (MELD), body mass index (BMI), and cirrhosis etiology were selected as the control group. RESULTS: There were no significant differences between the three groups in intraoperative blood loss, transfusion, and postoperative bleeding. In the AVK group, there were no differences between patients who received PCC and those who did not in intraoperative blood loss, red blood cells, fibrinogen, and platelet transfusion, or postoperative bleeding. PCC use had no effect on RBC transfusion in patients who had international normalized ratio or clotting time above versus below median values of the two parameters at baseline (2.3 and 103 s, respectively). No thrombotic events were detected in patients who received PCC. DISCUSSION: These data suggest that systematic administration of PCC to revert AVK prior to LT should be reconsidered.


Assuntos
4-Hidroxicumarinas/uso terapêutico , Fatores de Coagulação Sanguínea/uso terapêutico , Indenos/uso terapêutico , Cirrose Hepática/terapia , Transplante de Fígado , Vitamina K/antagonistas & inibidores , Transfusão de Sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Vitamina K/uso terapêutico
4.
Ann Rheum Dis ; 80(5): 598-604, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34412027

RESUMO

OBJECTIVES: Vitamin K is hypothesised to play a role in osteoarthritis (OA) pathogenesis through effects on vitamin K-dependent bone and cartilage proteins, and therefore may represent a modifiable risk factor. A genetic variant in a vitamin K-dependent protein that is an essential inhibitor for cartilage calcification, matrix Gla protein (MGP), was associated with an increased risk for OA. Vitamin K antagonist anticoagulants (VKAs), such as warfarin and acenocoumarol, act as anticoagulants through inhibition of vitamin K-dependent blood coagulation proteins. VKAs likely also affect the functioning of other vitamin K-dependent proteins such as MGP. METHODS: We investigated the effect of acenocoumarol usage on progression and incidence of radiographic OA in 3494 participants of the Rotterdam Study cohort. We also examined the effect of MGP and VKORC1 single nucleotide variants on this association. RESULTS: Acenocoumarol usage was associated with an increased risk of OA incidence and progression (OR=2.50, 95% CI=1.94-3.20), both for knee (OR=2.34, 95% CI=1.67-3.22) and hip OA (OR=2.74, 95% CI=1.82-4.11). Among acenocoumarol users, carriers of the high VKORC1(BB) expression haplotype together with the MGP OA risk allele (rs1800801-T) had an increased risk of OA incidence and progression (OR=4.18, 95% CI=2.69-6.50), while this relationship was not present in non-users of that group (OR=1.01, 95% CI=0.78-1.33). CONCLUSIONS: These findings support the importance of vitamin K and vitamin K-dependent proteins, as MGP, in the pathogenesis of OA. Additionally, these results may have direct implications for the clinical prevention of OA, supporting the consideration of direct oral anticoagulants in favour of VKAs.


Assuntos
4-Hidroxicumarinas/efeitos adversos , Acenocumarol/efeitos adversos , Anticoagulantes/efeitos adversos , Indenos/efeitos adversos , Osteoartrite/epidemiologia , Vitamina K/antagonistas & inibidores , Idoso , Alelos , Proteínas de Ligação ao Cálcio/efeitos dos fármacos , Progressão da Doença , Proteínas da Matriz Extracelular/efeitos dos fármacos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Osteoartrite/induzido quimicamente , Osteoartrite/patologia , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Vitamina K/efeitos adversos , Vitamina K Epóxido Redutases/efeitos dos fármacos
5.
J Med Vasc ; 46(4): 175-181, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34238512

RESUMO

INTRODUCTION: Vitamin K antagonist (VKA) related adverse events are the first cause for iatrogenic events in France, particularly due to the narrow therapeutic margin. The risk of bleeding increases significantly when the INR level is ≥5. The main objective of this study was to assess the prevalence of VKA overdose in a hospital setting (at D2 of hospital entry) and to evaluate physicians' adherence to clinical practice guidelines for the management of VKA overdose according to French National Authority for Health recommendations. METHODS: This single-center retrospective observational study consisted in querying the computerized database of a Parisian hospital on 21275INR determinations (3995 patients, 6813 hospital stays) performed between 2013 and 2018. RESULTS: An INR level ≥5 was noted during 350 (6%) of the hospital stays, in 331 patients (of whom 57% were women). The mean age of the patient population with an INR≥5 was 81.1 years. Infection, heart failure and renal failure were the most frequent acute medical conditions for hospital admission. Twenty-three patients (7%) had a bleeding complication, 11 of which were major bleeding complications. Older age was associated with the severity of bleeding complications. Fifteen in-hospital deaths (4%) were reported, not related to bleeding events. The management of VKA overdose did not comply with the recommendations in 43% of cases, in particular for the highest INRs (50% of noncompliance for an INR>6.4). Non-compliance with recommendations for VKA overdose was related to: the delay until the INR was checked (44% of cases); the indication for prescribing vitamin K (34% of cases); the dose or route of administration of vitamin K therapy (19% of cases); and the interruption or not of VKA therapy (12% of cases). CONCLUSION: The management of VKA overdose in a hospital setting remains non-compliant with the recommendations in almost half of the cases, mainly due to the delayed INR control and inappropriate management of vitamin K therapy. Computerized alert system would be helpful for personalized patient management and improved pharmacovigilance to prevent iatrogenic VKA events.


Assuntos
Hospitais , Vitamina K , 4-Hidroxicumarinas , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Indenos , Coeficiente Internacional Normatizado , Prevalência , Vitamina K/antagonistas & inibidores
6.
J Org Chem ; 86(14): 9658-9669, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34213909

RESUMO

A visible light (white light-emitting diode/direct sunlight)-driven photochemical synthesis of a new series of biologically interesting 3-(alkyl/benzylthio)-4-hydroxy-2H-chromen-2-ones has been achieved through a cross-dehydrogenative C3-H sulfenylation of 4-hydroxycoumarins with thiols at ambient temperature in the presence of rose bengal in acetonitrile under an oxygen atmosphere. The notable features of this newly developed method are mild reaction conditions, energy efficiency, metal-free synthesis, good to excellent yields, use of low-cost materials, and eco-friendliness.


Assuntos
4-Hidroxicumarinas , Rosa Bengala , Luz , Fármacos Fotossensibilizantes , Oxigênio Singlete , Compostos de Sulfidrila
7.
Oxid Med Cell Longev ; 2021: 8849568, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34007407

RESUMO

Two newly synthesized 4-hydroxycoumarin bidentate ligands (L1 and L2) and their palladium(II) complexes (C1 and C2) were screened for their biological activities, in vitro and in vivo. Structures of new compounds were established based on elemental analysis, 1H NMR, 13C NMR, and IR spectroscopic techniques. The obtained compounds were tested for their antioxidative and cytotoxic activities and results pointed to selective antiradical activity of palladium(II) complexes towards •OH and -•OOH radicals and anti-ABTS (2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) cation radical) activity comparable to that of ascorbate. Results indicated the effect of C1 and C2 on the enzymatic activity of the antioxidative defense system. In vitro cytotoxicity assay performed on different carcinoma cell lines (HCT166, A375, and MIA PaCa-2), and one healthy fibroblast cell line (MRC-5) showed a cytotoxic effect of both C1 and C2, expressed as a decrease in carcinoma cells' viability, mostly by induction of apoptosis. In vivo toxicity tests performed on zebrafish embryos indicated different effects of C1 and C2, ranging from adverse developmental effect to no toxicity, depending on tested concentration. According to docking studies, both complexes (C1 and C2) showed better inhibitory activity in comparison to other palladium(II) complexes.


Assuntos
4-Hidroxicumarinas/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Paládio/metabolismo , Animais , Humanos , Peixe-Zebra
8.
Sci Total Environ ; 787: 147520, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34000553

RESUMO

Commensal rodent species cause damage to crops and stored products, they transmit pathogens to people, livestock and pets and threaten native flora and fauna. To minimize such adverse effects, commensal rodents are predominantly managed with anticoagulant rodenticides (AR) that can be transferred along the food chain. We tested the effect of the uptake of the AR brodifacoum (BR) by Norway rats (Rattus norvegicus) on spatial behavior because this helps to assess the availability of dead rats and residual BR to predators and scavengers. BR was delivered by oral gavage or free-fed bait presented in bait stations. Rats were radio-collared to monitor spatial behavior. BR residues in rat liver tissue were analyzed using liquid chromatography coupled with tandem mass spectrometry. Norway rats that had consumed BR decreased distances moved and had reduced home range size. Treatment effects on spatial behavior seemed to set in rapidly. However, there was no effect on habitat preference. Ninety-two percent of rats that succumbed to BR died in well-hidden locations, where removal by scavenging birds and large mammalian scavengers is unlikely. Rats that ingested bait from bait stations had 65% higher residue concentrations than rats that died from dosing with two-fold LD50. This suggests an overdosing in rats that are managed with 0.0025% BR. None of the 70 BR-loaded rats was caught/removed by wild predators/scavengers before collection of carcasses within 5-29 h. Therefore, and because almost all dead rats died in well-hidden locations, they do not seem to pose a significant risk of AR exposure to large predators/scavengers at livestock farms. Exposure of large predators may originate from AR-poisoned non-target small mammals. The few rats that died in the open are accessible and should be removed in routine searches during and after the application of AR bait to minimize transfer of AR into the wider environment.


Assuntos
4-Hidroxicumarinas , Rodenticidas , 4-Hidroxicumarinas/toxicidade , Animais , Anticoagulantes/toxicidade , Fazendas , Mamíferos , Ratos , Rodenticidas/toxicidade , Comportamento Espacial
9.
J Mol Biol ; 433(15): 167061, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34023403

RESUMO

Mycobacterium tuberculosis is responsible for more than 1.6 million deaths each year. One potential antibacterial target in M. tuberculosis is filamentous temperature sensitive protein Z (FtsZ), which is the bacterial homologue of mammalian tubulin, a validated cancer target. M. tuberculosis FtsZ function is essential, with its inhibition leading to arrest of cell division, elongation of the bacterial cell and eventual cell death. However, the development of potent inhibitors against FtsZ has been a challenge owing to the lack of structural information. Here we report multiple crystal structures of M. tuberculosis FtsZ in complex with a coumarin analogue. The 4-hydroxycoumarin binds exclusively to two novel cryptic pockets in nucleotide-free FtsZ, but not to the binary FtsZ-GTP or GDP complexes. Our findings provide a detailed understanding of the molecular basis for cryptic pocket formation, controlled by the conformational flexibility of the H7 helix, and thus reveal an important structural and mechanistic rationale for coumarin antibacterial activity.


Assuntos
4-Hidroxicumarinas/farmacologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Proteínas do Citoesqueleto/química , Proteínas do Citoesqueleto/metabolismo , Mycobacterium tuberculosis/metabolismo , 4-Hidroxicumarinas/química , Sítios de Ligação/efeitos dos fármacos , Cristalografia por Raios X , Guanosina Difosfato/metabolismo , Guanosina Trifosfato/metabolismo , Modelos Moleculares , Mycobacterium tuberculosis/química , Ligação Proteica/efeitos dos fármacos , Conformação Proteica em alfa-Hélice
10.
Medicine (Baltimore) ; 100(15): e25546, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33847681

RESUMO

BACKGROUND: In this analysis, we aimed to compare the efficacy and safety of dual therapy (DT) with a non-vitamin K oral anticoagulant (NOAC) and an adenosine diphosphate receptor antagonist (P2Y12 inhibitor) vs triple therapy (TT) with aspirin, a P2Y12 inhibitor and a vitamin K antagonist for the treatment of diabetes mellitus (DM) patients with co-existing atrial fibrillation (AF) following percutaneous coronary intervention (PCI). METHODS: Medical Literature Analysis and Retrieval System Online (MEDLINE), http://www.ClinicalTrials.gov, Excerpta Medical data BASE (EMBASE), Web of Science, Cochrane Central and Google Scholar were the searched databases. Studies that were randomized trials or observational studies comparing DT vs TT for the treatment of DM patients with co-existing AF following PCI were included in this analysis. The adverse cardiovascular outcomes and bleeding events were the endpoints. This meta-analysis was carried out by the RevMan version 5.4 software. Risk ratios (RR) with 95% confidence intervals (CI) were used to represent data and interpret the analysis. RESULTS: A total number of 4970 participants were included whereby 2456 participants were assigned to the DT group and 2514 participants were assigned to the TT group. The enrollment period varied from year 2006 to year 2018. Our current results showed that major adverse cardiac events (RR: 1.00, 95% CI: 0.84-1.20; P = .98), mortality (RR: 1.08, 95% CI: 0.78-1.48; P = .66), myocardial infarction (RR: 1.02, 95% CI: 0.74-1.42; P = .90), stroke (RR: 0.94, 95% CI: 0.53-1.67; P = .84) and stent thrombosis (RR: 1.09, 95% CI: 0.56-2.10; P = .80) were similar with DT versus TT in these patients. However, the risks for total major bleeding (RR: 0.66, 95% CI: 0.54-0.82; P = .0001), total minor bleeding (RR: 0.74, 95% CI: 0.64-0.85; P = .0001), Thrombolysis in Myocardial Infarction (TIMI) defined major bleeding (RR: 0.58, 95% CI: 0.35-0.95; P = .03), TIMI defined minor bleeding (RR: 0.62, 95% CI: 0.42-0.92; P = .02), intra-cranial bleeding (RR: 0.34, 95% CI: 0.13-0.95; P = .04) and major bleeding defined by the International Society on Thrombosis and Hemostasis (RR: 0.68, 95% CI: 0.51-0.90; P = .008) were significantly higher with TT. CONCLUSIONS: DT with a NOAC and a P2Y12 inhibitor was associated with significantly less bleeding events without increasing the adverse cardiovascular outcomes when compared to TT with aspirin, a P2Y12 inhibitor and a Vitamin K antagonist for the treatment of DM patients with co-existing AF following PCI. Hence, DT is comparable in efficacy, but safer compared to TT. This interesting hypothesis will have to be confirmed in future studies.


Assuntos
4-Hidroxicumarinas/administração & dosagem , Aspirina/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Cardiomiopatias Diabéticas/tratamento farmacológico , Fármacos Hematológicos/administração & dosagem , Indenos/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Vitamina K/antagonistas & inibidores , Idoso , Fibrilação Atrial/etiologia , Diabetes Mellitus/terapia , Cardiomiopatias Diabéticas/etiologia , Quimioterapia Combinada , Feminino , Humanos , Masculino , Estudos Observacionais como Assunto , Intervenção Coronária Percutânea/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Vitamina K/administração & dosagem
11.
J Org Chem ; 86(9): 6075-6089, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33820419

RESUMO

Herein, we describe a highly effective 1,8-conjugate-addition-mediated formal (3+3)-annulation of (aza)-para-quinone methides in situ generated from propargylic alcohols with 4-hydroxycoumarins and 1,3-dicarbonyl compounds under the catalysis of a Brønsted acid. This methodology affords efficient and practical access to synthetically important and highly functionalized pyranocoumarins and pyrans in excellent yields under mild conditions. Importantly, these products exhibit impressive inhibitory activity toward α-glucosidase.


Assuntos
4-Hidroxicumarinas , Catálise , Indolquinonas , Estrutura Molecular , Estereoisomerismo
12.
PLoS One ; 16(4): e0246134, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33826627

RESUMO

Raptors, including eagles, are geographically widespread and sit atop the food chain, thereby serving an important role in maintaining ecosystem balance. After facing population declines associated with exposure to organochlorine insecticides such as dichlorodiphenyltrichloroethane (DDT), bald eagles (Haliaeetus leucocephalus) have recovered from the brink of extinction. However, both bald and golden eagles (Aquila chrysaetos) are exposed to a variety of other toxic compounds in the environment that could have population impacts. Few studies have focused on anticoagulant rodenticide (AR) exposure in eagles. Therefore, the purpose of this study was to determine the types of ARs that eagles are exposed to in the USA and better define the extent of toxicosis (i.e., fatal illness due to compound exposure). Diagnostic case records from bald and golden eagles submitted to the Southeastern Cooperative Wildlife Disease Study (University of Georgia) 2014 through 2018 were reviewed. Overall, 303 eagles were examined, and the livers from 116 bald eagles and 17 golden eagles were tested for ARs. The percentage of AR exposure (i.e., detectable levels but not associated with mortality) in eagles was high; ARs were detected in 109 (82%) eagles, including 96 (83%) bald eagles and 13 (77%) golden eagles. Anticoagulant rodenticide toxicosis was determined to be the cause of mortality in 12 (4%) of the 303 eagles examined, including 11 bald eagles and 1 golden eagle. Six different AR compounds were detected in these eagles, with brodifacoum and bromadiolone most frequently detected (81% and 25% of eagles tested, respectively). These results suggest that some ARs, most notably brodifacoum, are widespread in the environment and are commonly consumed by eagles. This highlights the need for research to understand the pathways of AR exposure in eagles, which may help inform policy and regulatory actions to mitigate AR exposure risk.


Assuntos
4-Hidroxicumarinas/efeitos adversos , Anticoagulantes/efeitos adversos , Doenças das Aves , Águias/metabolismo , Rodenticidas/efeitos adversos , Animais , Doenças das Aves/induzido quimicamente , Doenças das Aves/metabolismo , Doenças das Aves/patologia , Ecossistema , Fígado/metabolismo , Fígado/patologia , Estados Unidos
13.
Medicine (Baltimore) ; 100(9): e25053, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33655984

RESUMO

RATIONALE: With the easy access, rodenticide poisoning has been a public health problem in many countries. Characteristics of central nervous system (CNS) lesions induced by rodenticides are scarcely reported. PATIENT CONCERNS: We presented a case of a 40-year-old man with seizure and consciousness disorder, coagulation dysfunction, and symmetric lesions in white matter and corpus callosum. DIAGNOSIS: He was diagnosed with rodenticide poisoning due to bromadiolone and fluoroacetamide. INTERVENTIONS: He was treated with vitamin K, hemoperfusion, acetamide, and calcium gluconate. OUTCOMES: His leukoencephalopathy was reversed rapidly with the improvement of clinical symptoms. LESSONS: This report presented the impact of rodenticide poisoning on CNS and the dynamic changes of brain lesions, and highlighted the importance of timely targeted treatments.


Assuntos
4-Hidroxicumarinas/envenenamento , Coagulação Sanguínea/efeitos dos fármacos , Fluoracetatos/envenenamento , Leucoencefalopatias/induzido quimicamente , Adulto , Humanos , Leucoencefalopatias/sangue , Masculino , Rodenticidas/envenenamento
14.
Sci Total Environ ; 779: 146287, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-33752022

RESUMO

The Réunion harrier is an endangered raptor and endemic species to the Réunion Island. Second generation anticoagulant rodenticides (SGARs) are widely used pesticides on the island in order to control rodent populations. The latter are responsible for the transmission of leptospirosis to humans, the damage of sugarcane crops, and the decline of endemic endangered birds. SGARs are very persistent chiral pesticides and consequent secondary exposure or poisoning of the Réunion harrier has been observed (73% of prevalence in a group of 58 harriers). Commercial formulations of SGARs are a mixture of trans- and cis-diastereoisomers. Both diastereoisomers of all SGARs have been shown to inhibit coagulation function with the same potency. On the other hand, they have been shown to have a significant difference in terms of tissue-persistence. This difference has led to residue levels in rats with a significantly lower proportion of one of the isomers compared to the bait composition. In this study, residue levels of the diastereoisomers of all SGARs were evaluated in the livers of 58 harrier carcasses. The respective concentrations and proportions of cis- and trans- diastereoisomers of all SGARs are presented. cis-Brodifacoum and trans-bromadiolone had the highest concentrations (up to 438 and 573 ng/g ww respectively), while trans-brodifacoum was less than 46 ng/g and cis-bromadiolone was barely detected. cis-Difenacoum showed the highest prevalence and the highest concentration was 82 ng/g ww, while trans-difenacoum was never detected. This study demonstrated that only cis-brodifacoum and trans-bromadiolone (and cis-difethialone, but with a low prevalence) had hepatic concentrations above a toxic threshold. The cis- and trans-diastereoisomers of SGARs had differential bioaccumulation in the food chain of the Réunion harrier compared to commercial baits. This suggests that a change of the proportions of SGARs diastereoisomers in baits could reduce the risk of secondary poisoning of predators, but maintain primary toxicity.


Assuntos
4-Hidroxicumarinas , Rodenticidas , 4-Hidroxicumarinas/metabolismo , Animais , Anticoagulantes/metabolismo , Bioacumulação , Cadeia Alimentar , Fígado/química , Ratos , Reunião , Rodenticidas/metabolismo
15.
J Med Chem ; 64(7): 3720-3746, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33769048

RESUMO

Autophagy is the common name for a number of lysosome-based degradation pathways of cytosolic cargos. The key components of autophagy are members of Atg8 family proteins involved in almost all steps of the process, from autophagosome formation to their selective fusion with lysosomes. In this study, we show that the homologous members of the human Atg8 family proteins, LC3A and LC3B, are druggable by a small molecule inhibitor novobiocin. Structure-activity relationship (SAR) studies of the 4-hydroxy coumarin core scaffold were performed, supported by a crystal structure of the LC3A dihydronovobiocin complex. The study reports the first nonpeptide inhibitors for these protein interaction targets and will lay the foundation for the development of more potent chemical probes for the Atg8 protein family which may also find applications for the development of autophagy-mediated degraders (AUTACs).


Assuntos
4-Hidroxicumarinas/farmacologia , Autofagia/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Ligação Proteica/efeitos dos fármacos , Proteína Sequestossoma-1/metabolismo , 4-Hidroxicumarinas/síntese química , 4-Hidroxicumarinas/metabolismo , Células HEK293 , Humanos , Ligantes , Estrutura Molecular , Novobiocina/química , Relação Estrutura-Atividade
16.
Artigo em Inglês | MEDLINE | ID: mdl-33572412

RESUMO

The aim of this study was to analyze the correlation between the participants' self-reported quality of life and their sense of coherence in a sample (n = 85) of patients on treatment with oral antivitamin K anticoagulants. A cross-sectional design was used. The measurement instruments included a questionnaire on sociodemographic variables, the Spanish version of the Abbreviated World Health Organization Quality of Life questionnaire (WHOQOL-BREF), an oral-anticoagulant-treatment-specific quality-of-life questionnaire, and the sense-of-coherence (SOC) scale. We analyzed the correlations between the participants' characteristics and the results from the quality-of-life and SOC scales. Age, level of education, employment status, living arrangement, and treatment length were the determinants of the quality of life in people treated with oral anticoagulants. We found a significant association between the four domains of the WHOQOL-BREF questionnaire and general treatment satisfaction (p < 0.01); no significant correlations were found between the SOC subscales and the oral-anticoagulant-treatment-specific quality of life in our sample. Women had a worse level of self-management than men. Nursing interventions should be tailored to the needs of the populations on treatment with oral anticoagulants in order to facilitate a higher level of self-management.


Assuntos
Qualidade de Vida , Senso de Coerência , 4-Hidroxicumarinas , Anticoagulantes/uso terapêutico , Estudos Transversais , Feminino , Humanos , Indenos , Masculino , Inquéritos e Questionários , Vitamina K/antagonistas & inibidores
17.
Artigo em Inglês | MEDLINE | ID: mdl-33486217

RESUMO

Superwarfarins are second-generation long-acting anticoagulant rodenticides that can cause unintended human and wildlife toxicity due, in part, to their prolonged half-lives. Commercially available superwarfarin rodenticides are synthesized as racemates with two asymmetric carbons, producing four stereoisomers. To support studies of human plasma half-lives of individual superwarfarin stereoisomers, a method was developed based on LC-MS/MS to separate and quantify stereoisomers of the commercially important superwarfarins bromadiolone, difenacoum and brodifacoum. Human plasma samples were prepared using protein precipitation and centrifugation. Chiral-phase HPLC separation was carried out on-line with tandem mass spectrometric quantitative analysis of the eluting stereoisomers using selected-reaction monitoring with positive ion electrospray on a triple quadrupole mass spectrometer. All four stereoisomers of each superwarfarin were resolved within 12.5 min with calibration curves spanning 2-3 orders of magnitude and lower limits of quantitation between 0.87 and 2.55 ng/mL. This method was used to determine the half-lives of superwarfarin stereoisomers in plasma from patients who had inhaled synthetic cannabinoid products contaminated with superwarfarins. These data may be used to guide the development of safer next generation anticoagulant rodenticides stereoisomers.


Assuntos
4-Hidroxicumarinas/sangue , Cromatografia Líquida de Alta Pressão/métodos , Rodenticidas/sangue , Espectrometria de Massas em Tandem/métodos , 4-Hidroxicumarinas/química , Adulto , Feminino , Humanos , Limite de Detecção , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Rodenticidas/química , Estereoisomerismo , Adulto Jovem
18.
BMC Neurol ; 21(1): 8, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33407227

RESUMO

BACKGROUND: Clinically, bromadiolone poisoning is characterized by severe bleeding complications in various organs and tissues. Bromadiolone-induced toxic encephalopathy is extremely rare. Here, we report a special case of bromadiolone-induced reversible toxic encephalopathy in a patient who had symmetrical lesions in the deep white matter. CASE PRESENTATION: A 23-year-old woman mainly presented with dizziness, fatigue, alalia and unsteady gait after the ingestion of bromadiolone. The laboratory examinations showed normal coagulation levels. Brain magnetic resonance imaging (MRI) showed apparent diffusion restriction in the bilateral deep white matter. The clinical manifestations and MRI alterations were reversible within one month of treatment with vitamin K. The neuropsychological assessment showed no neurodegenerative changes at the 2-year follow-up. CONCLUSION: With the increased use of bromadiolone as a rodenticide, more cases of ingestion have been reported annually over the past several years. Bromadiolone-induced toxic encephalopathy has no special clinical manifestations and is potentially reversible with timely treatment. Because of the reversible restricted diffusion on diffusion-weighted images (DWI) and low apparent diffusion coefficient (ADC) values, transient intramyelinic cytotoxic oedema is thought to be the cause rather than persistent ischaemia. The underlying pathophysiological mechanism is still unknown and may be coagulant-independent. This clinical case extends the current knowledge about neurotoxicity in cases of bromadiolone poisoning and indicates that MRI is useful for the early detection of bromadiolone-induced toxic encephalopathy.


Assuntos
4-Hidroxicumarinas/envenenamento , Encéfalo/patologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia , Rodenticidas/envenenamento , Antifibrinolíticos/uso terapêutico , Encéfalo/efeitos dos fármacos , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Humanos , Síndromes Neurotóxicas/tratamento farmacológico , Tentativa de Suicídio , Vitamina K 1/uso terapêutico , Adulto Jovem
19.
Methods Mol Biol ; 2174: 31-43, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32813243

RESUMO

Molecular docking is a useful and powerful computational method for the identification of potential interactions between small molecules and pharmacological targets. In reverse docking, the ability of one or a few compounds to bind a large dataset of proteins is evaluated in silico. This strategy is useful for identifying molecular targets of orphan bioactive compounds, proposing new molecular mechanisms, finding alternative indications of drugs, or predicting drug toxicity. Herein, we describe a detailed reverse docking protocol for the identification of potential targets for 4-hydroxycoumarin (4-HC). Our results showed that RAC1 is a target of 4-HC, which partially explains the biological activities of 4-HC on cancer cells. The strategy reported here can be easily applied to other compounds and protein datasets.


Assuntos
4-Hidroxicumarinas/farmacologia , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Simulação de Acoplamento Molecular/métodos , 4-Hidroxicumarinas/química , Antineoplásicos/química , Antineoplásicos/metabolismo , Sítios de Ligação , Simulação por Computador , Bases de Dados de Proteínas , Humanos , Ligantes , Terapia de Alvo Molecular , Conformação Proteica , Software , Proteínas rac1 de Ligação ao GTP/química , Proteínas rac1 de Ligação ao GTP/metabolismo
20.
Ann Palliat Med ; 10(6): 7008-7012, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33183018

RESUMO

Bromadiolone, a widely-used rodent control drug, could act as a long-acting anticoagulant. Patients of bromadiolone poisoning often present with multiorgan hemorrhage. However, neurological symptoms of bromadiolone poisoning are seldom reported. We report a rare case with convulsive status epilepticus as the initial presentation of bromadiolone poisoning. A previously healthy 18-year-old man presented with persistent unconsciousness and repeated convulsive seizures. Magnetic resonance imaging revealed lesions in the corpus callosum. Laboratory test revealed the microscopic hematuria, prolonged prothrombin time, prolonged activated partial thromboplastin time and the presence of bromadiolone. The patient was diagnosed as the bromadiolone poisoning and treated with hemofiltration, vitamin K and prothrombin complex. Consciousness of the patient was regained and all neurological symptoms diminished after 7 days. Coagulopathy was totally corrected after 3 weeks, and a 2-month regimen of vitamin K supplementation was prescribed after discharge. Our case suggests that bromadiolone poisoning may involve the central nervous system. The atypical and initial symptoms of neurological disorders might lead to misdiagnosis of bromadiolone poisoning. Poisoning should be considered when acute neurological symptoms are combined with bleeding tendency. The vitamin K treatment is effective for both coagulopathy and central nervous system disorders in bromadiolone poisoning.


Assuntos
Rodenticidas , Estado Epiléptico , 4-Hidroxicumarinas , Anticoagulantes , Hemorragia , Humanos , Estado Epiléptico/induzido quimicamente
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