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1.
JAMA ; 326(13): 1299-1309, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34609453

RESUMO

Importance: Assessing the scope of acute medication harms to patients should include both therapeutic and nontherapeutic medication use. Objective: To describe the characteristics of emergency department (ED) visits for acute harms from both therapeutic and nontherapeutic medication use in the US. Design, Setting, and Participants: Active, nationally representative, public health surveillance based on patient visits to 60 EDs in the US participating in the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance Project from 2017 through 2019. Exposures: Medications implicated in ED visits, with visits attributed to medication harms (adverse events) based on the clinicians' diagnoses and supporting data documented in the medical record. Main Outcomes and Measures: Nationally weighted estimates of ED visits and subsequent hospitalizations for medication harms. Results: Based on 96 925 cases (mean patient age, 49 years; 55% female), there were an estimated 6.1 (95% CI, 4.8-7.5) ED visits for medication harms per 1000 population annually and 38.6% (95% CI, 35.2%-41.9%) resulted in hospitalization. Population rates of ED visits for medication harms were higher for patients aged 65 years or older than for those younger than 65 years (12.1 vs 5.0 [95% CI, 7.4-16.8 vs 4.1-5.8] per 1000 population). Overall, an estimated 69.1% (95% CI, 63.6%-74.7%) of ED visits for medication harms involved therapeutic medication use, but among patients younger than 45 years, an estimated 52.5% (95% CI, 48.1%-56.8%) of visits for medication harms involved nontherapeutic use. The proportions of ED visits for medication harms involving therapeutic use were lowest for barbiturates (6.3%), benzodiazepines (11.1%), nonopioid analgesics (15.7%), and antihistamines (21.8%). By age group, the most frequent medication types and intents of use associated with ED visits for medication harms were therapeutic use of anticoagulants (4.5 [95% CI, 2.3-6.7] per 1000 population) and diabetes agents (1.8 [95% CI, 1.3-2.3] per 1000 population) for patients aged 65 years and older; therapeutic use of diabetes agents (0.8 [95% CI, 0.5-1.0] per 1000 population) for patients aged 45 to 64 years; nontherapeutic use of benzodiazepines (1.0 [95% CI, 0.7-1.3] per 1000 population) for patients aged 25 to 44 years; and unsupervised medication exposures (2.2 [95% CI, 1.8-2.7] per 1000 population) and therapeutic use of antibiotics (1.4 [95% CI, 1.0-1.8] per 1000 population) for children younger than 5 years. Conclusions and Relevance: According to data from 60 nationally representative US emergency departments, visits attributed to medication harms in 2017-2019 were frequent, with variation in products and intent of use by age.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Serviço Hospitalar de Emergência/estatística & dados numéricos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Doença Aguda , Adolescente , Adulto , Distribuição por Idade , Fatores Etários , Idoso , Analgésicos não Narcóticos/efeitos adversos , Antibacterianos/efeitos adversos , Anticoagulantes/efeitos adversos , Barbitúricos/efeitos adversos , Benzodiazepinas/efeitos adversos , Criança , Pré-Escolar , Intervalos de Confiança , Feminino , Antagonistas dos Receptores Histamínicos/efeitos adversos , Hospitalização/estatística & dados numéricos , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Medicamentos sem Prescrição/efeitos adversos , Vigilância em Saúde Pública , Distribuição por Sexo , Fatores de Tempo , Estados Unidos/epidemiologia , Adulto Jovem
3.
J Med Chem ; 64(15): 11395-11417, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34314189

RESUMO

We report a series of synthetic cationic amphipathic barbiturates inspired by the pharmacophore model of small antimicrobial peptides (AMPs) and the marine antimicrobials eusynstyelamides. These N,N'-dialkylated-5,5-disubstituted barbiturates consist of an achiral barbiturate scaffold with two cationic groups and two lipophilic side chains. Minimum inhibitory concentrations of 2-8 µg/mL were achieved against 30 multi-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including isolates with extended spectrum ß-lactamase-carbapenemase production. The guanidine barbiturate 7e (3,5-di-Br) demonstrated promising in vivo antibiotic efficacy in mice infected with clinical isolates of Escherichia coli and Klebsiella pneumoniae using a neutropenic peritonitis model. Mode of action studies showed a strong membrane disrupting effect and was supported by nuclear magnetic resonance and molecular dynamics simulations. The results express how the pharmacophore model of small AMPs and the structure of the marine eusynstyelamides can be used to design highly potent lead peptidomimetics against multi-resistant bacteria.


Assuntos
Antibacterianos/farmacologia , Barbitúricos/farmacologia , Produtos Biológicos/farmacologia , Guanidinas/farmacologia , Indóis/farmacologia , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Tensoativos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Barbitúricos/síntese química , Barbitúricos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Guanidinas/síntese química , Guanidinas/química , Indóis/síntese química , Indóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Proteínas Citotóxicas Formadoras de Poros/síntese química , Proteínas Citotóxicas Formadoras de Poros/química , Relação Estrutura-Atividade , Tensoativos/síntese química , Tensoativos/química
4.
Vet Clin North Am Equine Pract ; 37(2): 515-519, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34243883

RESUMO

Barbiturate overdose as a method of euthanasia is becoming unacceptable. This has made alternative methods of euthanasia very important. Gunshot or captive bolt euthanasia is among methods that are acceptable, but they may not be esthetically acceptable. This has led to the use of other methods of euthanasia. Inducing anesthesia prior to euthanasia offers an easier method of control. Adjunctive techniques using intravenous potassium or magnesium salts administered intravenously and intracardiac administration of potassium chloride or intrathecal lidocaine offer alternatives that work well and are more environmentally safer than barbiturates. Pithing and exsanguination are also environmentally safer but may not be as esthetically acceptable as the other methods.


Assuntos
Barbitúricos/administração & dosagem , Eutanásia Animal/métodos , Doenças dos Cavalos/tratamento farmacológico , Lidocaína/administração & dosagem , Cloreto de Magnésio/administração & dosagem , Cloreto de Potássio/administração & dosagem , Animais , Cavalos
5.
Neurol Med Chir (Tokyo) ; 61(9): 528-535, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34078830

RESUMO

This study aimed to examine the beneficial effects of a novel prophylactic barbiturate therapy, step-down infusion of barbiturates, using thiamylal with normothermia (NOR+sdB), on the poor outcome in the patients with severe traumatic brain injuries (sTBI), in comparison with mild hypothermia (MD-HYPO). From January 2000 to March 2019, 4133 patients with TBI were admitted to our hospital. The inclusion criteria were: a Glasgow coma scale (GCS) score of ≤8 on admission, age between 20 and 80 years, intracranial hematoma requiring surgical evacuation of the hematoma with craniotomy and/or external decompression, and patients who underwent management of body temperature and assessed their outcome at 6-12 months. Finally, 43 patients were included in the MD-HYPO (n = 29) and NOR+sdB (n = 14) groups. sdB was initiated intraoperatively or immediately after the surgical treatment. There were no significant differences in patient characteristics, including age, sex, past medical history, GCS on admission, type of intracranial hematoma, and length of hospitalization between the two groups. Although NOR+sdB could not improve the patient's poor outcome either at discharge from the intensive care unit (ICU) or at 6-12 months after admission, the treatment inhibited composite death at discharge from the ICU. The mean value of the maximum intracranial pressure (ICP) in the NOR+sdB group was <20 mmHg throughout the first 120 h. NOR+sdB prevented composite death in the ICU in patients with sTBI, and we may obtain novel insights into the beneficial role of prophylactic barbiturate therapy from suppression of the elevated ICP during the first 120 h.


Assuntos
Lesões Encefálicas Traumáticas , Lesões Encefálicas , Hipertensão Intracraniana , Barbitúricos/uso terapêutico , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Criança , Pré-Escolar , Escala de Coma de Glasgow , Humanos , Lactente , Hipertensão Intracraniana/tratamento farmacológico , Hipertensão Intracraniana/etiologia , Hipertensão Intracraniana/prevenção & controle , Pressão Intracraniana , Resultado do Tratamento
6.
Leg Med (Tokyo) ; 53: 101928, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34119997

RESUMO

A study was undertaken of 51 cases where barbiturates were detected in post-mortem blood samples from 2000 to 2019 at Forensic Science South Australia, Adelaide, Australia. The cause of death was drug toxicity in only 27 (53%) (M:F = 19:8; age range 19-74yrs, mean 46yrs). In 17 cases, barbiturate toxicity was the primary cause of death, 14 due to pentobarbitone and 3 to phenobarbitone. All were suicides. Barbiturates were obtained by online purchase from overseas sources in 9 cases (33%), and through veterinary practice in 2 cases (7%). Drug toxicity deaths where barbiturates were detected rose from 1 in 2000-2004 to 11 in 2015-2019, and those where deaths were primarily due to barbiturate toxicity rose from 1 in 2000-2004 to 9 in 2015-2019. However, the mere detection of barbiturates in post mortem samples did not equate with illicit use, as 23 of the deaths (45%) were due to natural causes in individuals prescribed barbiturates for epilepsy. The usefulness of examining subset populations separate from accrued national data is also demonstrated in the significantly younger age of decedents in South Australia dying from deliberately administered barbiturates (46 yrs) compared to the national average of 57.9 yrs. The reasons for this difference will require further investigation as this may impact upon local suicide prevention strategies.


Assuntos
Suicídio , Adulto , Idoso , Austrália , Barbitúricos , Humanos , Pessoa de Meia-Idade , Pentobarbital , Adulto Jovem
7.
Chemistry ; 27(50): 12877-12883, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34164869

RESUMO

Bulky hydrophobic counterions (weakly coordinating anions) can insulate ionic dyes against aggregation-caused quenching (ACQ) and enable preparation of highly fluorescent dye-loaded nanoparticles (NPs) for bioimaging, biosensing and light harvesting. Here, we introduce a family of hydrophobic anions based on fluorinated C-acyl barbiturates with delocalized negative charge and bulky non-polar groups. Similarly to fluorinated tetraphenylborates, these barbiturates prevent ACQ of cationic dye alkyl rhodamine B inside polymer NPs made of biodegradable poly(lactic-co-glycolic acid) (PLGA). Their efficiency to prevent ACQ increases for analogues with higher acidity and bulkiness. Their structure controls dye-dye communication, yielding bright NPs with on/off switching or stable emission. They enhance dye encapsulation inside NPs, allowing intracellular imaging without dye leakage. Compared to fluorinated tetraphenylborates known as cytotoxic transmembrane ion transporters, the barbiturates display a significantly lower cytotoxicity. These chemically available and versatile barbiturate derivatives are promising counterion scaffolds for preparation of bright non-toxic fluorescent nanomaterials.


Assuntos
Nanopartículas , Barbitúricos , Corantes Fluorescentes , Interações Hidrofóbicas e Hidrofílicas , Nanopartículas/toxicidade , Polímeros/toxicidade
8.
Environ Pollut ; 284: 117452, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34077898

RESUMO

Pharmaceuticals are considered emerging contaminants in terms of impacts on wildlife. One chemical group of concern is euthanasia agents used in veterinary medicine. Here we present data on the occurrence of barbiturate intoxication using samples collected from 2004 to 2020 of suspected wildlife and domestic animal poisoning cases in Spain (n = 3210). Barbiturate intoxication was seen in 3.4% (45/1334) of the total number of confirmed intoxicated animals. Barbiturates were detected in 0.2% (1/448) of baits containing detectable poisons. The most frequently detected barbiturate was pentobarbital (42/45, 93.3%), but we also detected phenobarbital, barbital, and thiopental (2.2% prevalence for each). Avian scavengers were most frequently affected by barbiturate intoxication (n = 36), especially Eurasian griffon vultures (Gyps fulvus) (n = 28). Median pentobarbital concentrations detected in intoxicated griffon vultures was 27.3 mg kg-1 in gastric content and 38.1 mg kg-1 in liver, which highlights the acute effect of the chemical soon after ingestion. At least two large intoxication events affecting griffon vultures were related to the consumption of carcasses from euthanized livestock. We also found phenobarbital in a prepared bait linked to the intoxication of one Eurasian buzzard (Buteo buteo). This study highlights the need for stronger regulation of barbiturates to avoid secondary intoxications due to improper disposal of euthanized livestock.


Assuntos
Falconiformes , Animais , Barbitúricos , Incidência , Mamíferos , Espanha/epidemiologia
9.
J Am Chem Soc ; 143(15): 5845-5854, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33755463

RESUMO

Helical folding of randomly coiled linear polymers is an essential organization process not only for biological polypeptides but also for synthetic functional polymers. Realization of this dynamic process in supramolecular polymers (SPs) is, however, a formidable challenge because of their inherent lability of main chains upon changing an external environment that can drive the folding process (e.g., solvent, concentration, and temperature). We herein report a photoinduced reversible folding/unfolding of rosette-based SPs driven by photoisomerization of a diarylethene (DAE). Temperature-controlled supramolecular polymerization of a barbiturate-functionalized DAE (open isomer) in nonpolar solvent results in the formation of intrinsically curved, but randomly coiled, SPs due to the presence of defects. Irradiation of the randomly coiled SPs with UV light causes efficient ring-closure reaction of the DAE moieties, which induces helical folding of the randomly coiled structures into helicoidal ones, as evidenced by atomic force microscopy and small-angle X-ray scattering. The helical folding is driven by internal structure ordering of the SP fiber that repairs the defects and interloop interaction occurring only for the resulting helicoidal structure. In contrast, direct supramolecular polymerization of the ring-closed DAE monomers by temperature control affords linearly extended ribbon-like SPs lacking intrinsic curvature that are thermodynamically less stable compared to the helicoidal SPs. The finding represents an important concept applicable to other SP systems; that is, postpolymerization (photo)reaction of preorganized kinetic structures can lead to more thermodynamically stable structures that are inaccessible directly through temperature-controlled protocols.


Assuntos
Etilenos/química , Polímeros/química , Raios Ultravioleta , Barbitúricos/química , Isomerismo , Substâncias Macromoleculares/química , Microscopia de Força Atômica , Polimerização , Temperatura , Termodinâmica
10.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33668791

RESUMO

Interactions between phospholipid membranes and selected drugs affecting the central nervous system (CNS) were investigated. Small, unilamellar liposomes were used as biomimetic cell membrane models. Microelectrophoretic experiments on two-component liposomes were performed using the electrophoretic light scattering technique (ELS). The effect of both positively (perphenazine, PF) and negatively (barbituric acid, BA) charged drugs on zwitterionic L-α-phosphatidylcholine (PC) membranes were analyzed. Experimental membrane surface charge density (δ) data were determined as a function of pH. Quantitative descriptions of the adsorption equilibria formed due to the binding of solution ions to analyzed two-component membranes are presented. Binding constants of the solution ions with perphenazine and barbituric acid-modified membranes were determined. The results of our research show that both charged drugs change surface charge density values of phosphatidylcholine membranes. It can be concluded that perphenazine and barbituric acid are located near the membrane surface, interacting electrostatically with phosphatidylcholine polar heads.


Assuntos
Barbitúricos/farmacologia , Sistema Nervoso Central/fisiologia , Eletricidade , Perfenazina/farmacologia , Fosfatidilcolinas/metabolismo , Animais , Ânions , Cátions , Sistema Nervoso Central/efeitos dos fármacos , Galinhas , Ponto Isoelétrico , Lipossomos , Membranas Artificiais , Modelos Biológicos , Espalhamento de Radiação , Soluções , Eletricidade Estática
11.
Am J Nephrol ; 52(1): 26-35, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33561857

RESUMO

BACKGROUND: Daprodustat is an oral agent that stimulates erythropoiesis by inhibiting the prolyl hydroxylases which mark hypoxia-inducible factor for degradation through hydroxylation. Its safety and efficacy (noninferiority) were assessed in this 52-week, open-label study. METHODS: Japanese patients not on dialysis (ND) (N = 299) with anemia of CKD (stages G3, G4, and G5) with iron parameters of ferritin >100 ng/mL or transferrin saturation >20% at screening were randomized to daprodustat or epoetin beta pegol (continuous erythropoietin receptor activator [CERA], also known as methoxy polyethylene glycol-epoetin beta). After initiation of the study, the daprodustat starting dose for erythropoiesis-stimulating agent (ESA)-naïve participants was revised, and daprodustat was started at 2 or 4 mg once daily depending on baseline hemoglobin. ESA users switched to daprodustat 4 mg once daily. CERA was started at 25 µg every 2 weeks for ESA-naïve patients and 25-250 µg every 4 weeks for ESA users based on previous ESA dose. In both treatment groups, dose was adjusted every 4 weeks based on hemoglobin level and changed according to a prespecified algorithm. The primary endpoint was mean hemoglobin level during weeks 40-52 in the intention-to-treat (ITT) population. ESA-naïve patients who entered before the protocol amendment revising the daprodustat starting dose were excluded from the ITT population. RESULTS: Mean hemoglobin levels during weeks 40-52 were 12.0 g/dL in the daprodustat group (n = 108; 95% confidence interval [CI], 11.8-12.1) and 11.9 g/dL for CERA (n = 109; 95% CI 11.7-12.0); the difference between the groups was 0.1 g/dL (95% CI -0.1 to 0.3 g/dL). The lower limit of the 95% CI of the difference was greater than the prespecified margin of -1.0 g/dL. The mean hemoglobin level was within the target range (11.0-13.0 g/dL) during weeks 40-52 for 92% of participants in both groups. There was no meaningful difference in the frequencies of adverse events. CONCLUSIONS: Oral daprodustat was noninferior to CERA in achieving and maintaining target hemoglobin levels in Japanese ND patients. Daprodustat was well tolerated, with no new safety concerns identified.


Assuntos
Anemia/tratamento farmacológico , Barbitúricos/uso terapêutico , Eritropoetina/uso terapêutico , Glicina/análogos & derivados , Polietilenoglicóis/uso terapêutico , Adolescente , Adulto , Idoso , Feminino , Glicina/uso terapêutico , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Diálise Renal , Fatores de Tempo , Adulto Jovem
12.
J Antimicrob Chemother ; 76(5): 1221-1228, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33564854

RESUMO

OBJECTIVES: Novel antimicrobials for treatment of gonorrhoea are imperative. The first-in-class spiropyrimidinetrione zoliflodacin is promising and currently in an international Phase 3 randomized controlled clinical trial (RCT) for treatment of uncomplicated gonorrhoea. We evaluated the in vitro activity of and the genetic conservation of the target (GyrB) and other potential zoliflodacin resistance determinants among 1209 consecutive clinical Neisseria gonorrhoeae isolates obtained from 25 EU/European Economic Area (EEA) countries in 2018 and compared the activity of zoliflodacin with that of therapeutic antimicrobials currently used. METHODS: MICs of zoliflodacin, ceftriaxone, cefixime, azithromycin and ciprofloxacin were determined using an agar dilution technique for zoliflodacin or using MIC gradient strip tests or an agar dilution technique for the other antimicrobials. Genome sequences were available for 96.1% of isolates. RESULTS: Zoliflodacin modal MIC, MIC50, MIC90 and MIC range were 0.125, 0.125, 0.125 and ≤0.004-0.5 mg/L, respectively. The resistance was 49.9%, 6.7%, 1.6% and 0.2% to ciprofloxacin, azithromycin, cefixime and ceftriaxone, respectively. Zoliflodacin did not show any cross-resistance to other tested antimicrobials. GyrB was highly conserved and no zoliflodacin gyrB resistance mutations were found. No fluoroquinolone target GyrA or ParC resistance mutations or mutations causing overexpression of the MtrCDE efflux pump substantially affected the MICs of zoliflodacin. CONCLUSIONS: The in vitro susceptibility to zoliflodacin was high and the zoliflodacin target GyrB was conserved among EU/EEA gonococcal isolates in 2018. This study supports further clinical development of zoliflodacin. However, additional zoliflodacin data regarding particularly the treatment of pharyngeal gonorrhoea, pharmacokinetics/pharmacodynamics and resistance selection, including suppression, would be valuable.


Assuntos
Gonorreia , Neisseria gonorrhoeae , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Azitromicina/farmacologia , Barbitúricos , Ceftriaxona/farmacologia , Ciprofloxacina/farmacologia , Farmacorresistência Bacteriana , Europa (Continente) , Gonorreia/tratamento farmacológico , Humanos , Isoxazóis , Testes de Sensibilidade Microbiana , Morfolinas , Neisseria gonorrhoeae/genética , Oxazolidinonas , Compostos de Espiro
13.
Int Urol Nephrol ; 53(2): 283-290, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32770437

RESUMO

PURPOSE: To investigate current treatment practices for anemia in patients with chronic kidney disease (CKD), issues surrounding current treatment practices, and the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) that are currently in clinical trials. Treatment of anemia in patients with CKD has traditionally included iron supplementation and erythropoiesis-stimulating agents (ESAs). However, due to adverse cardiovascular (CV) events and hypo-responsiveness to ESA therapy, new agents are currently in clinical trials to treat anemia in patients with CKD. The HIF-PHIs stimulate erythropoiesis and regulate iron metabolism and are attractive alternatives to iron supplementation and ESAs.


Assuntos
Anemia/tratamento farmacológico , Anemia/etiologia , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Insuficiência Renal Crônica/complicações , Barbitúricos/uso terapêutico , Previsões , Glicina/análogos & derivados , Glicina/uso terapêutico , Humanos , Isoquinolinas/uso terapêutico , Padrões de Prática Médica
14.
Artigo em Inglês | MEDLINE | ID: mdl-33199388

RESUMO

Inactivating tolC in multidrug-resistant Escherichia coli with differing sequence types and quinolone resistance-determining mutations reveals remarkably potentiated activity of the first-in-class topoisomerase inhibitors gepotidacin and zoliflodacin. Differences between both structurally unrelated compounds in comparison to fluoroquinolones regarding the selectivity of E. coli RND (resistance-nodulation-cell division)-type transporters, efflux inhibitors, and AcrB porter domain mutations were demonstrated. The findings should reinforce efforts to develop efflux-bypassing drugs and provide AcrB targets with critical relevance for this purpose.


Assuntos
Proteínas de Escherichia coli , Escherichia coli , Acenaftenos , Antibacterianos/farmacologia , Barbitúricos , Farmacorresistência Bacteriana Múltipla , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Fluoroquinolonas/farmacologia , Compostos Heterocíclicos com 3 Anéis , Isoxazóis , Morfolinas , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Oxazolidinonas , Compostos de Espiro , Inibidores da Topoisomerase
15.
Neuropediatrics ; 52(2): 133-137, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33231274

RESUMO

We describe the efficacy of high-dose barbiturates and early administration of a parenteral ketogenic diet (KD) as initial treatments for acute status epilepticus (SE) in an 8-year-old girl with febrile infection-related epilepsy syndrome (FIRES). The patient was admitted to our hospital with refractory focal SE. Abundant epileptic discharges over the left frontal region were observed on electroencephalogram (EEG). Treatment with continuous infusion of thiamylal for 4 hours, increased incrementally to 40 mg/kg/h, successfully ended the clinical SE, and induced a burst-suppression coma. The infusion rate was then gradually decreased to 4 mg/kg/h over the next 12 hours. Parenteral KD was administered from days 6 to 21 of illness. Continuous infusion of thiamylal was switched to midazolam on day 10 without causing seizures or EEG exacerbations. The patient has remained seizure free in the 15 months since hospital discharge. The effectiveness of KD for the treatment of FIRES has attracted attention amongst clinicians, but KD treatment may need to last for 2 to 4 days before it can stop SE, a time period that could cause irreversible brain damage. Considering the severity of SE in our patient and the dose of barbiturates needed to treat it, we consider this case to have had a good clinical outcome. The results suggest that rapid termination of seizure using high-dose barbiturates in conjunction with early administration of parenteral KD could reduce the development of chronic epilepsy in patients with FIRES.


Assuntos
Barbitúricos/administração & dosagem , Dieta Cetogênica , Síndromes Epilépticas , Estado Epiléptico , Criança , Terapia Combinada , Eletroencefalografia , Síndromes Epilépticas/dietoterapia , Síndromes Epilépticas/tratamento farmacológico , Síndromes Epilépticas/etiologia , Feminino , Febre/complicações , Humanos , Infecções/complicações , Midazolam/administração & dosagem , Nutrição Parenteral , Estado Epiléptico/dietoterapia , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/etiologia , Tiamilal/administração & dosagem
16.
Acta Neurochir (Wien) ; 163(2): 489-498, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33341913

RESUMO

BACKGROUND: The aim was to study the effects of barbiturate coma treatment (BCT) on intracranial pressure (ICP) and intracranial compensatory reserve (RAP index) in children (< 17 years of age) with traumatic brain injury (TBI) and refractory intracranial hypertension (RICH). METHODS: High-resolution monitoring data were used to study the effects of BCT on ICP, mean arterial pressure (MAP), cerebral perfusion pressure (CPP), and RAP index. Four half hour long periods were studied: before bolus injection and at 5, 10, and 24 hours thereafter, respectively, and a fifth tapering period with S-thiopental between < 100 and < 30 µmol/L. S-thiopental concentrations and administered doses were registered. RESULTS: Seventeen children treated with BCT 2007-2017 with high-resolution data were included; median age 15 (range 6-17) and median Glasgow coma score 7 (range 3-8). Median time from trauma to start of BCT was 44.5 h (range 2.5-197.5) and from start to stop 99.0 h (range 21.0-329.0). Median ICP was 22 (IQR 20-25) in the half hour period before onset of BCT and 16 (IQR 11-20) in the half hour period 5 h later (p = 0.011). The corresponding figures for CPP were 65 (IQR 62-71) and 63 (57-71) (p > 0.05). The RAP index was in the half hour period before onset of BCT 0.6 (IQR 0.1-0.7), in the half hour period 5 h later 0.3 (IQR 0.1-0.7) (p = 0.331), and in the whole BCT period 0.3 (IQR 0.2-0.4) (p = 0.004). Eighty-two percent (14/17) had favorable outcome (good recovery = 8 patients and moderate disability = 6 patients). CONCLUSION: BCT significantly reduced ICP and RAP index with preserved CPP. BCT should be considered in case of RICH.


Assuntos
Barbitúricos/farmacologia , Lesões Encefálicas Traumáticas/terapia , Coma/induzido quimicamente , Convulsoterapia/métodos , Hipertensão Intracraniana/terapia , Pressão Intracraniana/efeitos dos fármacos , Adolescente , Anticonvulsivantes/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Barbitúricos/administração & dosagem , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Circulação Cerebrovascular/efeitos dos fármacos , Criança , Feminino , Humanos , Hipertensão Intracraniana/tratamento farmacológico , Hipertensão Intracraniana/etiologia , Masculino , Estudos Retrospectivos , Tiopental/uso terapêutico
17.
Biophys Chem ; 269: 106522, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33352334

RESUMO

Neurodegenerative disease is caused by the abnormal build-up of proteins in and around cells called amyloid. The amyloid fibril formation and its mechanism have been investigated with various techniques, including dye-binding assay. Thioflavin T (ThT) has been one of the most widely used dyes for quantifying amyloid deposits, but ThT has a weak fluorescence signal especially at low concentration of amyloid fibrils, low lipophilicity and positive charge that makes it unable to cross the blood-brain barrier (BBB) to detect amyloid fibrils in vivo. Hence, there is a strong motivation for designing and developing the new compounds for in vitro amyloid quantification and in vivo amyloid imaging. The need for new probes to detect amyloid fibrils, especially within the cell, is highlighted by the fact that an accurate understanding of the molecular details of amyloid fibril formation is required to design and develop strategies for controlling the amyloid formation, and this needs more reliable probes for amyloid identification. In this work, we synthesized and applied barbituric and thiobarbituric acid-based chromene derivatives, as new fluorescent dyes to quantitatively detect the amyloid fibrils of bovine serum albumin (BSA) and human insulin in comparison with native soluble proteins or amorphous aggregation. Our results showed that among the 14 synthesized compounds, five compounds 4a, 4h, 4j, 4k, and 4l could selectively and specifically bind to amyloid fibrils while other compounds demonstrated a low-affinity binding. Furthermore, according to the cell viability experiment, compounds 4a, 4j and 4l at low concentration of compounds are not toxic, especially compound 4j which could be used as a suitable candidate for in vivo study. Further studies are needed to determine all the properties of compounds, especially in vivo experiments.


Assuntos
Amiloide/química , Barbitúricos/química , Benzopiranos/química , Benzopiranos/farmacologia , Agregados Proteicos/efeitos dos fármacos , Tiobarbitúricos/química , Animais , Benzopiranos/síntese química , Técnicas de Química Sintética
18.
Cancer Lett ; 500: 220-227, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33358698

RESUMO

The ability of chemo-radiation therapy to control locally advanced stage III non-small cell lung cancer (NSCLC) is poor. While addition of consolidation immunotherapy has improved outcomes in subsets of patients there is still an urgent need for new therapeutic targets. Emerging research indicates that nucleophosmin1 (NPM1) is over-expressed in NSCLC, promotes tumor growth and that over-expression correlates with a lower survival probability. NPM1 is critical for APE1 base excision activity and for RAD51-mediated repair of DNA double strand breaks (DSBs). YTR107 is a small molecule radiation sensitizer that has been shown to bind to NPM1, suppressing pentamer formation. Here we show that in irradiated cells YTR107 inhibits SUMOylated NPM1 from associating with RAD51, RAD51 foci formation and repair of DSBs. YTR107 acts synergistically with the PARP1/2 inhibitor ABT 888 to increase replication stress and radiation-induced cell lethality. YTR107 was found to radiosensitize tumor initiating cells. Congruent with this knowledge, adding YTR107 to a fractionated irradiation regimen diminished NSCLC xenograft growth and increased overall survival. These data support the hypothesis that YTR107 represents a therapeutic target for control of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Proteínas Nucleares/genética , Rad51 Recombinase/genética , Barbitúricos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/efeitos da radiação , Humanos , Indóis/farmacologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/genética , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Sumoilação/efeitos dos fármacos , Sumoilação/efeitos da radiação
19.
Artigo em Inglês | MEDLINE | ID: mdl-33318010

RESUMO

Previously, we reported the potent activity of a novel spiropyrimidinetrione, zoliflodacin, against Neisseria gonorrhoeae isolates collected in 2013 from symptomatic men in Nanjing, China. Here, we investigated trends of susceptibilities to zoliflodacin in 986 isolates collected from men between 2014 and 2018. N. gonorrhoeae isolates were tested for susceptibility to zoliflodacin and seven other antibiotics. Mutations in the gyrA, gyrB, parC, parE, and mtrR genes were determined by PCR and sequencing. The MICs of zoliflodacin ranged from ≤0.002 to 0.25 mg/liter; the overall MIC50 and MIC90 were 0.06 mg/liter and 0.125 mg/liter, respectively, in 2018, increasing 2-fold from 2014. However, the percentage of isolates with lower zoliflodacin MICs declined in each year sequentially, while the percentage with higher MICs increased yearly (P ≤ 0.00001). All isolates were susceptible to spectinomycin but resistant to ciprofloxacin (MIC ≥ 1 mg/liter); 21.2% (209/986) were resistant to azithromycin (≥1 mg/liter), 43.4% (428/986) were penicillinase-producing N. gonorrhoeae (PPNG), 26.9% (265/986) were tetracycline-resistant N. gonorrhoeae (TRNG), and 19.4% (191/986) were multidrug-resistant (MDR) isolates. 202 isolates with the lowest (≤0.002 to 0.015 mg/liter) and highest (0.125 to 0.25 mg/liter) zoliflodacin MICs were quinolone resistant with double or triple mutations in gyrA; 193/202 (95.5%) also had mutations in parC There were no D429N/A and/or K450T mutations in GyrB identified in the 143 isolates with higher zoliflodacin MICs; an S467N mutation in GyrB was identified in one isolate. We report that zoliflodacin continues to have excellent in vitro activity against clinical gonococcal isolates, including those with high-level resistance to ciprofloxacin, azithromycin, and extended-spectrum cephalosporins.


Assuntos
Gonorreia , Compostos de Espiro , Antibacterianos/farmacologia , Barbitúricos , China , Ciprofloxacina , Gonorreia/tratamento farmacológico , Humanos , Isoxazóis , Masculino , Testes de Sensibilidade Microbiana , Morfolinas , Neisseria gonorrhoeae/genética , Oxazolidinonas
20.
Clin Toxicol (Phila) ; 59(3): 224-230, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32633579

RESUMO

INTRODUCTION: There have been increasing reports documenting barbiturate-related deaths, despite routine prescribing for only relatively rare indications. The aims of the current study were to examine trends in barbiturate-related deaths in Australia from 2000 to 2019 and determine the case characteristics and circumstances of barbiturate-related deaths. METHODS: All barbiturate-related deaths identified in the Australian National Coronial Information System were examined. Information was collected on cause, manner, demographics, location, psychosocial factors, circumstances of deaths and toxicology. We examined these based on the age categories 18-44 years, 45-64 years and ≥65 years. RESULTS: We identified 511 cases. Mean age was 57.9 years (SD 20.2, range 18-100) and 56% were male. Intentional poisoning was the most common cause of death (87.5%) and was slightly higher in the oldest age group (92.1%) and lowest in the youngest age group (81.1%). Pentobarbitone was the most common barbiturate (75.7%) and pentobarbitone-related deaths increased from 0% in 2000 to 93.6% in 2017. There were notable differences between age categories, with the youngest age group recording more severe psychiatric histories. In contrast, the oldest age group were more likely to have severe physical health problems, such as cancer, chronic non-cancer pain, neurological conditions and significant cardiopulmonary morbidity. Euthanasia resources were commonly documented (33.9%), most frequently in the oldest age group (52.3%). CONCLUSION: Barbiturate-related deaths in Australia are increasing, particularly pentobarbitone-related deaths. Most deaths were intentional and involved adults across the lifespan. Younger people were more likely to have significant mental health problems, whilst the oldest age group were more likely to have severe physical health conditions.


Assuntos
Barbitúricos/toxicidade , Overdose de Drogas/mortalidade , Hipnóticos e Sedativos/toxicidade , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pentobarbital/toxicidade , Psicologia , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
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