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1.
Chemosphere ; 255: 126871, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32413796

RESUMO

Research efforts into the potential side-effects of pesticides on beneficial organisms have focused on temperate test species and conditions. There is thus a need for studies into the ecotoxicity of a vaster range of pesticides under tropical conditions. The present study therefore aimed to compare the acute and chronic toxicity of the fungicide carbendazim to the earthworm Eisenia fetida under tropical and temperate conditions. To this end, laboratory toxicity tests were conducted with a tropical and European strain of E. fetida, using different artificial (OECD and TAS) and natural (LUFA and TNS) soils, and under different test temperatures (20 °C and 28 °C). In the acute lethality tests with artificial soils, the tropical strain of E. fetida was three to four order of magnitude less sensitive than the European strain, which is ascribed to the higher test temperature and (hence) higher microbial activity/pesticide degradation. The tropical strain was particularly sensitive in the tropical natural soil, which was attributed to the low pH (3.9) of this soil. The chronic toxicity tests overall also showed a lower sensitivity of the tropical strain on reproduction. These findings thus support the use of toxicity data generated under temperate conditions in tropical pesticide effect assessments. However, intensive agricultural practices in the tropics may dictate that exposure levels (and hence potentially also risks) are higher.


Assuntos
Benzimidazóis/toxicidade , Carbamatos/toxicidade , Fungicidas Industriais/toxicidade , Agricultura , Animais , Laboratórios , Oligoquetos/efeitos dos fármacos , Praguicidas/toxicidade , Solo/química , Poluentes do Solo/análise , Poluentes do Solo/toxicidade
2.
Z Gastroenterol ; 58(5): 451-455, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32392606

RESUMO

BACKGROUND: Relapses after therapy with direct-acting antiviral agents (DAA) in chronic hepatitis C virus (HCV) infections are rare due to high efficacy of interferon-free therapy regimens. The presence of resistance-associated substitutions (RAS) in proteins targeted by therapy can lead to lower rates of sustained virological response (SVR) in patients receiving DAA-therapy, and little evidence exists as to how to treat these patients. CASE SUMMARY: We present a case of a multi-drug-resistant HCV-genotype-3a-infection in a 50-year-old female without confirmed cirrhosis but with advanced fibrosis (liver stiffness 11.6 kPa) and low viral load. Resistance testing revealed a Y93H mutation in the NS5A gene. Therapies using sofosbuvir and daclatasvir (1st), sofosbuvir, velpatasvir and ribavirin (2nd), and subsequently with sofosbuvir, velpatasvir, and voxilaprevir (3st) did not achieve SVR. Compliance was good with rapid negativity of HCV RNA at 4 weeks of treatment on all 3 occasions. No virological breakthrough was recorded with all regimens. As a rescue attempt, the patient received 24 weeks of sofosbuvir, glecaprevir/pibrentasvir, and weight-based ribavirin at 1000 mg. With this approach, she achieved SVR but developed hepatocellular carcinoma. CONCLUSION: The combination of sofosbuvir, glecaprevir/pibrentasvir and ribavirin could be a rescue therapy after previous relapses on DAA-therapy, especially in patients with relapse after therapy with sofosbuvir, velpatasvir, and voxilaprevir.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Benzimidazóis/uso terapêutico , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Quinoxalinas/uso terapêutico , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Resultado do Tratamento
4.
Science ; 368(6486)2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32241924

RESUMO

The success of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (PARPi) to treat cancer relates to their ability to trap PARP-1 at the site of a DNA break. Although different forms of PARPi all target the catalytic center of the enzyme, they have variable abilities to trap PARP-1. We found that several structurally distinct PARPi drive PARP-1 allostery to promote release from a DNA break. Other inhibitors drive allostery to retain PARP-1 on a DNA break. Further, we generated a new PARPi compound, converting an allosteric pro-release compound to a pro-retention compound and increasing its ability to kill cancer cells. These developments are pertinent to clinical applications where PARP-1 trapping is either desirable or undesirable.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Quebras de DNA/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Neoplasias/enzimologia , Poli(ADP-Ribose) Polimerase-1/química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Benzimidazóis/química , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Humanos , Isoindóis/química , Isoindóis/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Domínios Proteicos
5.
Plant Dis ; 104(6): 1621-1628, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32320371

RESUMO

Postbloom fruit drop (PFD) of citrus is caused by the Colletotrichum acutatum and C. gloeosporioides species complexes. The disease is important when frequent rainfall occurs during the flowering period of citrus trees. In Brazil, until 2012, PFD was mainly controlled by preventive applications of the methyl-benzimidazole carbamate (MBC) carbendazim and demethylation-inhibitor (DMI) fungicides such as difenoconazole. Since then, mixtures containing the DMI tebuconazole and the quinone-outside inhibitor (QoI) trifloxystrobin have been commonly used. Fungicides are often applied preventively, sometimes even when conditions are not conducive for PFD development. Excessive fungicide applications may favor the selection of resistant populations of Colletotrichum spp. In this study, we assessed the fungicide sensitivity of C. acutatum isolates collected during the two distinct periods of PFD management in Brazil: before and after the trifloxystrobin and tebuconazole mixture became widely employed. The sensitivity of 254 C. acutatum isolates to carbendazim and difenoconazole and of 164 isolates to tebuconazole and trifloxystrobin was assessed. Mycelial growth inhibition of these isolates was evaluated for all the fungicides using either serial dilution of fungicide rates or the spiral gradient dilution method. In addition, inhibition of conidial germination was also assessed for trifloxystrobin. Analysis of partial ß-tub, cytb, and cyp51b gene sequences did not reveal any mutations related to resistance to MBCs, QoIs, and DMIs, respectively. In mycelial growth assays, mean EC50 values were 0.14, 0.11, and 0.21 µg/ml for difenoconazole, tebuconazole, and trifloxystrobin, respectively. The conidial germination inhibition by trifloxystrobin was similar among the tested isolates, and the mean EC50 value was 0.002 µg/ml. All isolates had similar mean mycelial growth inhibition for carbendazim, regardless of the fungicide concentrations. Therefore, based on similar EC50 values and molecular analyses, no shift in the sensitivity of isolates has been observed to the fungicides commonly used in different citrus-producing areas in Brazil.


Assuntos
Citrus , Colletotrichum , Acetatos , Benzimidazóis , Brasil , Carbamatos , Dioxolanos , Iminas , Doenças das Plantas , Estrobilurinas , Triazóis
6.
Plant Dis ; 104(6): 1647-1653, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32347789

RESUMO

Gray mold caused by Botrytis cinerea is a fungal disease that critically threatens agricultural production, and carbendazim was the first fungicide used to control B. cinerea. However, B. cinerea developed serious resistance to carbendazim, and this fungicide has thus rarely been used in the past decade in China. Due to the extended discontinuation of carbendazim use, the evolution of the resistance of B. cinerea to carbendazim in recent years is unclear, and whether carbendazim can effectively control gray mold is largely unknown. Therefore, this study determined the sensitivity of 407 B. cinerea isolates collected from 2014 to 2018 to carbendazim and the ability of carbendazim to control gray mold in the field. The results showed that the frequency of B. cinerea isolates resistant to carbendazim remained above 95%. Three different mutation types responsible for the resistance of B. cinerea to carbendazim were identified at codon 198 in the ß-tubulin gene sequence: E198V (changed from GAG to GTG), E198A (changed from GAG to GCG), and E198K (changed from GAG to AAG). Over the last 5 years, E198V was the major mutation. However, an analysis of its evolution revealed that the percentage of the E198V mutation declined after 2017 to 56.5% in 2018. In addition, the proportion of isolates with the E198K mutation decreased over time, and no isolates with this mutation were found in either 2017 or 2018. The proportion of the E198A mutation increased over the 5-year test period to reach 43.5% in 2018. Furthermore, three greenhouse experiments demonstrated that carbendazim has lost its ability to control gray mold. We attribute the above findings to our results showing that the carbendazim-resistant isolates had no fitness penalties compared with the carbendazim-sensitive isolates for sporulation and mycelial growth. In particular, the E198A mutant isolates exhibited a strong ability to sporulate, suggesting that the E198A mutation might become dominant in the future. Interestingly, the results showed that carbendazim-sensitive isolates could be easily controlled by four conventional fungicides, namely boscalid, procymidone, iprodione, and pyrimethanil, with mean EC50 values of 0.71 ± 0.2 mg liter-1, 1.33 ± 0.39 mg liter-1, 0.59 ± 0.33 mg liter-1, and 6.02 ± 3.02 mg liter-1, respectively. In conclusion, carbendazim has lost its application value and is ineffective for the control of gray mold.


Assuntos
Botrytis , Farmacorresistência Fúngica , Benzimidazóis , Carbamatos , China , Doenças das Plantas
7.
Arq Gastroenterol ; 57(1): 39-44, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294734

RESUMO

BACKGROUND: Hepatitis C virus (HCV) infection is the most common hepatotropic viral infection affecting the patients on maintenance hemodialysis. Treatment of chronic HCV infection in stage 4 and 5 CKD includes a combination of elbasvir/grazoprevir and glecaprevir/pibrentasvir, which are not available in many countries. OBJECTIVE: Hence, we have conducted this study to look for the safety and efficacy of sofosbuvir combination therapy in this difficult to treat population. METHODS: We conducted a single-center, prospective, open-label study in which Stage 5 CKD patients on maintenance hemodialysis with HCV infection. Total of 18 patients was included. sofosbuvir with daclatasvir or ledipasvir was used according to genotype for 12 weeks. HCV RNA, genotype, transient elastography (TE) was considered for every patient. HCV RNA was quantified at 4th week, 12th week and 12 weeks post-treatment to look for sustained virologic response (SVR 12). RESULTS: Infection due to genotype 1 was seen in 12 (66.7%) patients followed by genotype 3 in 4 (22.3%) with each patient of genotype 2 and 5. The median value of HCV RNA was 2,35,000 IU/mL. On TE, all had liver stiffness of <9.4 KPa. All patients had HCV RNA of <15 IU/mL at 4th and 12th week of treatment and 12 weeks post-treatment. No significant change in hemoglobin, eGFR and liver stiffness was observed. CONCLUSION: Full dose sofosbuvir i.e. 400 mg, in combination with NS5A inhibitors daclatasvir or ledipasvir is found to be safe and effective in patients with end stage renal disease, who are on maintenance hemodialysis.


Assuntos
Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Fluorenos/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Imidazóis/administração & dosagem , Sofosbuvir/administração & dosagem , Adulto , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Viral , Diálise Renal , Índice de Gravidade de Doença , Resposta Viral Sustentada , Resultado do Tratamento
8.
Cancer Sci ; 111(6): 2132-2145, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32304130

RESUMO

In the cell cycle, the G1 /S transition is controlled by the cyclin-dependent kinase (CDK) 4/6-cyclin D complex. Constitutive activation of CDK4/6 dysregulates G1 /S transition, leading to oncogenic transformation. We found that 3 CDK4/6 inhibitors, abemaciclib, ribociclib, and palbociclib, exerted a cytocidal effect as well as a cytostatic effect at the G1 phase in cancer cell lines, including A549 human non-small cell lung cancer cells. Among these inhibitors, abemaciclib exhibited the most potent cytotoxic effect. The cell-death phenotype induced by abemaciclib, which entailed formation of multiple cytoplasmic vacuoles, was not consistent with apoptosis or necroptosis. Abemaciclib blocked autophagic flux, resulting in accumulation of autophagosomes, however vacuole formation and cell death induced by abemaciclib were independent of autophagy. In addition, methuosis, a cell-death phenotype characterized by vacuole formation induced by excessive macropinocytosis, was excluded because the vacuoles did not incorporate fluorescent dextran. Of note, both formation of vacuoles and induction of cell death in response to abemaciclib were inhibited by vacuolar-type ATPase (V-ATPase) inhibitors such as bafilomycin A1 and concanamycin A. Live-cell imaging revealed that the abemaciclib-induced vacuoles were derived from lysosomes that expanded following acidification. Transmission electron microscopy revealed that these vacuoles contained undigested debris and remnants of organelles. Cycloheximide chase assay revealed that lysosomal turnover was blocked by abemaciclib. Furthermore, mTORC1 inhibition along with partial lysosomal membrane permeabilization occurred after abemaciclib treatment. Together, these results indicate that, in cancer cells, abemaciclib induces a unique form of cell death accompanied by swollen and dysfunctional lysosomes.


Assuntos
Aminopiridinas/farmacologia , Benzimidazóis/farmacologia , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Lisossomos/efeitos dos fármacos , Vacúolos/efeitos dos fármacos
9.
F1000Res ; 9: 129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32194944

RESUMO

We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL pro) using the crystal structure of the highly similar (96% identity) ortholog from the SARS-CoV. All residues involved in the catalysis, substrate binding and dimerisation are 100% conserved. Comparison of the polyprotein PP1AB sequences showed 86% identity. The 3C-like cleavage sites on the coronaviral polyproteins are highly conserved. Based on the near-identical substrate specificities and high sequence identities, we are of the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV enzyme can be conferred on its SARS-CoV-2 counterpart.  With the 3CL pro molecular model, we performed virtual screening for purchasable drugs and proposed 16 candidates for consideration. Among these, the antivirals ledipasvir or velpatasvir are particularly attractive as therapeutics to combat the new coronavirus with minimal side effects, commonly fatigue and headache.  The drugs Epclusa (velpatasvir/sofosbuvir) and Harvoni (ledipasvir/sofosbuvir) could be very effective owing to their dual inhibitory actions on two viral enzymes.


Assuntos
Benzimidazóis/farmacologia , Betacoronavirus/efeitos dos fármacos , Carbamatos/farmacologia , Infecções por Coronavirus , Cisteína Endopeptidases/química , Fluorenos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Pandemias , Pneumonia Viral , Proteínas não Estruturais Virais/química , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Humanos , Pneumonia Viral/tratamento farmacológico
10.
Food Chem ; 319: 126539, 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32193060

RESUMO

Two molecularly imprinted microspheres and two fluorescent tracers for benzimidazoles and pyrethroids were synthesized respectively. The two types of microspheres were coated in the wells of conventional microplate simultaneously. Then the sample extracts and the two traces were added for differential competition. The fluorescence intensities at two different emission wavelengths were excited and recorded for quantification of the two classes of drugs respectively. The optimized multiplexed fluorescence method could be used to determine 8 benzimidazoles and 10 pyrethroids in mutton and beef samples simultaneously. The limits of detection of the method for the 18 drugs were in the range of 5.2-17 ng/mL, and the recoveries from the standards fortified blank samples were in the range of 67.7%-109%. From the analysis of 60 real mutton and beef samples, this method could be used for multi-screening the residues of benzimidazoles and pyrethroids in meat samples.


Assuntos
Benzimidazóis/análise , Piretrinas/análise , Carne Vermelha/análise , Animais , Benzimidazóis/química , Fluorescência , Microesferas , Impressão Molecular , Estrutura Molecular , Piretrinas/química
11.
N Engl J Med ; 382(15): 1430-1442, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32187457

RESUMO

BACKGROUND: No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1. METHODS: We conducted an open-label, phase 2 trial of selumetinib to determine the objective response rate among patients with plexiform neurofibromas and to assess clinical benefit. Children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable). RESULTS: A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia. CONCLUSIONS: In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib. (Funded by the Intramural Research Program of the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.).


Assuntos
Benzimidazóis/uso terapêutico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Neurofibroma Plexiforme/tratamento farmacológico , Neurofibromatose 1/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Benzimidazóis/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Náusea/induzido quimicamente , Neurofibroma Plexiforme/complicações , Neurofibroma Plexiforme/patologia , Neurofibromatose 1/complicações , Neurofibromatose 1/patologia , Dor/etiologia , Medidas de Resultados Relatados pelo Paciente , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Carga Tumoral/efeitos dos fármacos
12.
Chemosphere ; 251: 126411, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32169697

RESUMO

To investigate the occurrence and risk of pesticides in the Huangpu River basin, spatial and temporal concentration variations of 29 commonly used pesticides and their risk quotient (RQ) values for three different trophic organisms (fish, daphnia, green algae) from 16 sampling sites were conducted in 2018-2019. These 29 pesticides include 4 carbamates, 2 benzimidazoles, 6 neonicotinoids, 2 organophosphates, 9 triazoles, and 6 others. Of the 29 pesticides analyzed, 18 were present in every sample taken from the Huangpu River. The concentration of target pesticides in water samples ranged from < LOQ (for buprofezin in summer, autumn, and winter) to 607.30 ng L-1 (for carbendazim in spring). From the source (i.e., Taihu Lake) to the estuary of the Huangpu River, with the exception of isocarbophos and isoprothiolane (gradual decrease), the spatial variation of target pesticide concentrations firstly exhibited an increasing trend and then a decreasing trend. Peak spatial variation was seen in metropolitan area, which is closely related to the type of land use and the discharge of tributaries. In addition, the total summed concentration of the 29 pesticides during winter (1037.60 ng L-1) was higher than summer (788.82 ng L-1) in rural and metropolitan areas. For the ecological risk assessments of fish, daphnia, and green algae, the triazoles, carbamates, neonicotinoids were risk-dominant pesticides, respectively. Notably, carbendazim had a 100% detection frequency and the highest concentration of the 29 pesticides analyzed, indicating its high consumption in the Huangpu River basin.


Assuntos
Monitoramento Ambiental , Praguicidas/análise , Poluentes Químicos da Água/análise , Animais , Benzimidazóis , Carbamatos , China , Daphnia , Estuários , Peixes , Lagos , Medição de Risco , Rios/química , Estações do Ano
13.
PLoS One ; 15(3): e0229239, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32155165

RESUMO

BACKGROUND: Directly acting antivirals (DAA) against hepatitis C virus (HCV) infection have facilitated sustained virologic response (SVR) rates >90% in clinical studies. Yet, real life data regarding DAA treatment in people who inject drugs (PWIDs) are scarce. We evaluated the effectiveness of glecaprevir/pibrentasvir (G/P) in difficult-to-treat PWIDs with presumed high risk of non-adherence to DAA therapy using the concept of directly observed therapy involving their opioid substitution therapy (OST) facility. METHODS: N = 145 patients (m/f: 91/54; median age: 41.1 (IQR 19.5) years; HCV-genotype (GT) 1/2/3/4: 82/1/56/5, GT3: 38.6%; cirrhosis: n = 6; 4.1%) treated with G/P were included. PWIDs at high risk for non-adherence to DAA therapy received HCV treatment together with their OST under the supervision of medical staff ("directly observed therapy", DOT). The effectiveness of G/P given as DOT in PWIDs with presumed high risk of non-adherence to DAA therapy was compared to patients with suspected "excellent compliance" in the "standard setting" (SS) of G/P prescription at a tertiary care center and self-managed G/P intake at home. Treatment duration was 8-16 weeks according to the G/P drug label. RESULTS: DOT-patients (n = 74/145; 51.0%) were younger than SS-patients (median 38.7, IQR 12.5 vs. median 50.6, IQR 20.3 years), all had psychiatric co-morbidities and most had a poor socioeconomic status. 50/74 (67.6%) reported ongoing intravenous drug use (IDU). SVR was achieved in n = 70/74 (94.6%) patients with n = 3 being lost to follow-up (FU) and n = 1 showing nonresponse to therapy. SS-patients achieved SVR in 97.2% (69/71) with n = 1 patient being lost to FU and n = 1 patient with GT3 showing HCV relapse. CONCLUSION: G/P given as DOT along with OST in PWIDs with high risk of non-adherence to DAA therapy resulted in similarly high SVR rates (94.6%) as in patients with presumed "excellent compliance" under standard drug intake.


Assuntos
Benzimidazóis/administração & dosagem , Terapia Diretamente Observada/métodos , Hepatite C Crônica/tratamento farmacológico , Tratamento de Substituição de Opiáceos/métodos , Pirrolidinas/administração & dosagem , Quinoxalinas/administração & dosagem , Abuso de Substâncias por Via Intravenosa/tratamento farmacológico , Sulfonamidas/administração & dosagem , Adulto , Idoso , Áustria , Benzimidazóis/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Cooperação do Paciente , Pirrolidinas/uso terapêutico , Quinoxalinas/uso terapêutico , Classe Social , Sulfonamidas/uso terapêutico , Resposta Viral Sustentada , Resultado do Tratamento , Adulto Jovem
16.
Medicine (Baltimore) ; 99(11): e19140, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176039

RESUMO

Treatment of hepatitis C virus (HCV) infection for patients with human immunodeficiency virus (HIV) has improved with direct acting antivirals. However, outcomes among Black persons treated with ledipasvir/sofosbuvir (LDV/SOF) may be inferior to non-Blacks. We assessed responses to LDV/SOF in a cohort of Black HIV/HCV coinfected persons.Retrospective chart reviews were conducted for Black, genotype 1 (GT1), HIV/HCV coinfected patients treated with LDV/SOF at 3 hospitals in Newark, NJ between January 2014 and July 2016. Data collected included demographics, HCV treatment history, treatment duration, and response.One hundred seventeen HIV/HCV coinfected Black patients started treatment with LDV/SOF but 5 had no follow-up data and 5 prematurely discontinued treatment (1 due to side effects). We included 107 HIV/HCV coinfected patients who completed LDV/SOF at all 3 sites. The study population was 65% male, median age 58 years, 26% had cirrhosis, and 78% had GT1a. Thirty-one percent were treatment experienced but none with prior NS5a treatment. At baseline, median CD4 count was 680 cells/mm, HIV viral load (VL) was <40 copies/mL in 94% and median HCV VL was 2,257,403 IU/mL. Twenty-nine percent of patients changed antiretroviral treatment before LDV/SOF treatment due to drug interactions. Six, 89, and 12 patients completed 8, 12, and 24 weeks of LDV/SOF, respectively. Overall sustained virologic response rate was 93% with 7 relapses.In this real-world cohort of Black, GT1, HIV/HCV coinfected patients, LDV/SOF had high sustained virologic response 12 weeks post completion of treatment rate of 93%. This data supports the overall high efficacy of LDV/SOF in a historically difficult-to-treat patient population.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Coinfecção/tratamento farmacológico , Fluorenos/uso terapêutico , Infecções por HIV/complicações , Hepacivirus/efeitos dos fármacos , Hepatite C/complicações , Uridina Monofosfato/análogos & derivados , Afro-Americanos/estatística & dados numéricos , Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Coinfecção/virologia , Feminino , Fluorenos/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , New Jersey , Estudos Retrospectivos , Resultado do Tratamento , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/uso terapêutico
17.
Rev Soc Bras Med Trop ; 53: e20190155, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32187331

RESUMO

INTRODUCTION: Benzimidazoles are commonly used for the control of veterinary nematodes. Resistance to benzimidazoles has been associated with three single nucleotide polymorphisms in the ß-tubulin gene of common nematodes. However, these mutations are infrequent in the genus Ascaris spp. METHODS: In order to determine mutations associated with benzimidazole resistance in Ascaris suum, worms were collected from slaughtered pigs and a partial region of the ß-tubulin gene was sequenced. RESULTS: All parasites showed the wildtype genotype for codons 167, 198, and 200 of the ß-tubulin gene. CONCLUSIONS: This is the first report of genetic sequences associated with benzimidazole resistance in A. suum.


Assuntos
Ascaris suum/efeitos dos fármacos , Ascaris suum/genética , Benzimidazóis/farmacologia , Resistência a Medicamentos/genética , Mutação , Tubulina (Proteína)/farmacologia , Animais , Genótipo , Polimorfismo de Nucleotídeo Único , Suínos
18.
Artigo em Inglês | MEDLINE | ID: mdl-32004940

RESUMO

Flibanserin (FLB) is the first FDA approved drug showed to have significant activity against sexual desire disorder of premenopausal and postmenopausal women. Unfortunately, FLB is used as an adulterant in dietary supplement products as a performance enhancer in sports. Identification of FLB and its metabolites in the biological samples requires an authenticated analytical technique. The aim of this study was to identify N-oxide metabolite of FLB in microsomal and S9 human liver enzyme fractions, rat urine and feces. There are several N-oxide reported as genotoxic impurity or reactive metabolites based on position of N-oxide in piperazine ring. This study also describes the strategy to utilize degradation chemistry for isolation of N-oxide and its step-wise characterization. An LC-MS method has been developed and employed for identifying the N-oxide metabolite of FLB. The targeted N-oxide metabolite in the extracted ion chromatogram of the in vitro and in vivo samples has been confirmed by analyzing the changes in observed mass at m/z 407.1693. Major distinguished abundant ions at m/z 243.1104, 190.0974, 161.0705, 119.0601 confirmed the structure of the metabolite. This study will help to understand the oxidative potential of FLB in toxicokinetic study. The developed method can be useful to identify FLB or its N-oxide metabolite in dope testing in future. This is the first time to report a strategy to utilize degradation chemistry for N-oxide metabolite characterization. In this study, isolated N-oxidative degradation product was used to confirm N-oxide metabolite which was characterized by LC-MS through H/D exchange and structure was ensured by NMR spectroscopy (1H, COSY).


Assuntos
Benzimidazóis , Medição da Troca de Deutério/métodos , Fezes/química , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Benzimidazóis/administração & dosagem , Benzimidazóis/análise , Benzimidazóis/química , Benzimidazóis/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Espectroscopia de Ressonância Magnética , Masculino , Oxirredução , Ratos , Ratos Sprague-Dawley
19.
Expert Opin Pharmacother ; 21(7): 747-754, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32100585

RESUMO

INTRODUCTION: Approximately 50% of patients with metastatic melanoma have mutations in BRAF. Based on the results of prior phase III trials, the combination of a BRAF inhibitor (BRAFi) and a MEK inhibitor (MEKi) is the standard of care in patients with BRAF-mutant metastatic melanoma. AREAS COVERED: The author summarizes the available data on binimetinib, a reversible inhibitor of the kinase activity of MEK1 and MEK2, in BRAF- and NRAS-mutated melanoma. EXPERT OPINION: With the advent of binimetinib and encorafenib, clinicians can choose between three BRAFi/MEKi combinations. Indirect comparison and a network meta-analysis suggest that binimetinib plus encorafenib is at least as active as the other two BRAFi/MEKi combinations and that safety is similar. The choice should be guided by the slightly different toxicity profile, local availability, and product experience. The optimal sequence of immunotherapy and BRAFi/MEKi in patients with BRAF-mutated tumors is unclear. As the response to BRAF/MEK inhibition is usually prompt and response to immunotherapy can be delayed, clinicians often choose a BRAFi/MEKi combination as first-line therapy in patients with rapidly evolving and threatening disease. Single-agent binimetinib almost doubled median progression-free survival when compared to dacarbazine in patients with NRAS-mutated melanoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/uso terapêutico , Carbamatos/uso terapêutico , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Sulfonamidas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Ensaios Clínicos como Assunto , GTP Fosfo-Hidrolases/genética , Humanos , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/metabolismo , Melanoma/enzimologia , Melanoma/genética , Proteínas de Membrana/genética , Terapia de Alvo Molecular , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos
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