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1.
Medicine (Baltimore) ; 100(6): e24630, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33578579

RESUMO

RATIONALE: Mucormycosis is a rare fungal infection that typically occurs in immunosuppressed patients following chemotherapy or hematopoietic stem cell transplantation. PATIENT CONCERNS: An 11-year-old child with newly developed acute lymphoblastic leukemia suffered from the paroxysmal left chest pain, fever, and hemoptysis. DIAGNOSES: We made a histopathologic diagnosis aided by bronchoscopy techniques, which indicated invasive fungal hyphae that are characteristic of mucormycosis. INTERVENTIONS: The patient was treated with oral posaconazole and repeated bronchoscopy interventions for 4 months. OUTCOMES: The patient's clinical signs and symptoms and signs were no longer present. The prior lung lesions were also no longer observable using radiologic methods, and a 3-month follow-up with the patient showed no signs of mucormycosis recurrence. Finally, the patient was cured, when the cancer chemotherapy was stopped. Close follow-up for another 2 years showed no evidence of recurrence. LESSONS: Mucormycosis diagnosis is difficult as clinical and imaging findings vary. This case demonstrates that posaconazole monotherapy combined with bronchoscopy interventions may be a safe and effective treatment option for pediatric pulmonary mucormycosis.


Assuntos
Hospedeiro Imunocomprometido , Pneumopatias Fúngicas/diagnóstico , Mucormicose/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras , Administração Oral , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Criança , Diagnóstico Diferencial , Febre/etiologia , Humanos , Pneumopatias Fúngicas/complicações , Pneumopatias Fúngicas/tratamento farmacológico , Pneumopatias Fúngicas/patologia , Masculino , Mucormicose/complicações , Mucormicose/tratamento farmacológico , Mucormicose/patologia , Triazóis/administração & dosagem , Triazóis/uso terapêutico
2.
BMC Infect Dis ; 21(1): 82, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33461505

RESUMO

BACKGROUND: Keratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole. CASE PRESENTATION: We describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud's dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement. CONCLUSIONS: Molecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.


Assuntos
Úlcera da Córnea/diagnóstico , Infecções Oculares Fúngicas/diagnóstico , Sordariales/isolamento & purificação , Idoso , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Úlcera da Córnea/tratamento farmacológico , Úlcera da Córnea/microbiologia , Diagnóstico Diferencial , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Humanos , Masculino , Nitrilos/administração & dosagem , Nitrilos/uso terapêutico , Soluções Oftálmicas , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Triazóis/administração & dosagem , Triazóis/uso terapêutico
3.
Int J Nanomedicine ; 16: 119-132, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33447031

RESUMO

Purpose: This manuscript aimed at encapsulating an antifungal terconazole (TCZ) into innovative novasomes for improving its penetration into the skin and clinically modulating its therapeutic efficacy. Methods: Novasomes containing free fatty acid (FFA) as a penetration enhancer were formulated using ethanol injection technique based on 24 full factorial design to explore the impact of various formulation variables on novasomes characteristics regarding entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP). The optimum formulation was chosen using Design-Expert® software and utilized for further explorations. Results: The chosen formulation (N15; including 100 mg lipid components and Span 80 to oleic acid in a ratio of 2:1 (w/w)) exhibited an EE% = 99.45 ± 0.78%, PS = 623.00 ± 2.97 nm, PDI = 0.40 ± 0.04, and ZP = -73.85 ± 0.64 mV. N15 showed spherical vesicles with a higher deformability index (DI) (9.62 ± 0.15 g) compared to traditional niosomal formulation (0.92 ± 0.12 g). Further, N15 showed superior inhibition of Candida albicans growth relative to TCZ suspension using XTT (2,3-bis-(2-methyloxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) reduction assay. Moreover, in vivo skin deposition tests revealed a superior TCZ deposition inside the skin from N15 in comparison to traditional niosomal formulation and TCZ suspension. Furthermore, histopathological examination for rats assured the safety of N15 for topical use. A clinical study conducted on infants suffering from napkin candidiasis proved the superiority of N15 to placebo in providing a complete cure of such fungal infections. Conclusion: Concisely, the obtained outcomes confirmed the pronounced efficacy of N15 to successfully treat skin fungal infections.


Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Triazóis/administração & dosagem , Administração Tópica , Animais , Antifúngicos/administração & dosagem , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Análise Fatorial , Humanos , Lactente , Lipossomos , Masculino , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Ratos , Ratos Wistar , Pele/efeitos dos fármacos , Pele/microbiologia , Pele/patologia , Absorção Cutânea/efeitos dos fármacos , Eletricidade Estática , Suspensões , Triazóis/farmacologia , Triazóis/uso terapêutico
4.
J Pharmacol Sci ; 144(4): 229-236, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070842

RESUMO

The kidneys are the major organs for erythropoietin (EPO) production in adults, and thus, kidney damage results in reduced EPO levels and anemia. Inhibitors of Hypoxia-inducible factor-prolyl hydroxylase domain-containing protein (HIF-PHD) are awaited as new therapeutic options for renal anemia. It can be predicted that most patients who receive HIF-PHD inhibitors have renal dysfunction as a cause of anemia. Therefore, in the present study, we investigated the effects of the HIF-PHD inhibitor molidustat on anemia and renal dysfunction when initiated after the onset of renal anemia. Male C57BL/6J mice received adenine orally to induce nephropathy. After the onset of nephropathy, the mice were treated with either vehicle or molidustat. After 4 weeks of administration, vehicle-treated mice displayed significant anemia, and molidustat ameliorated this anemia. Vehicle-treated mice exhibited reduced creatinine clearance and body weight, increased blood urea nitrogen levels, histopathological changes, immune cell infiltration, and dehydration. Molidustat reversed immune cell infiltration, dehydration, and renal fibrosis without improving renal functional parameters. In conclusion, molidustat treatment initiated after the onset of nephropathy and renal anemia reversed anemia in mice. Molidustat improved some parameters of renal abnormality, but it did not restore renal function.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/complicações , Adenina/efeitos adversos , Anemia/tratamento farmacológico , Anemia/etiologia , Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Inibidores de Prolil-Hidrolase , Pirazóis/uso terapêutico , Triazóis/uso terapêutico , Lesão Renal Aguda/metabolismo , Animais , Modelos Animais de Doenças , Eritropoetina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Triazóis/administração & dosagem , Triazóis/farmacologia
5.
PLoS One ; 15(9): e0238723, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32916693

RESUMO

The aim of this study was to examine the risk of falls associated with the use of non-gamma amino butyric acid (GABA) sleep medications, suvorexant and ramelteon. This case-control and case-crossover study was performed at the Kudanzaka Hospital, Chiyoda Ward, Tokyo. A total of 325 patients who had falls and 1295 controls matched by sex and age were included. The inclusion criteria for the case group were hospitalized patients who had their first fall and that for the control were patients who were hospitalized and did not have a fall, between January 2016 and November 2018. The internal sleep medications administered were classified as suvorexant, ramelteon, non-benzodiazepines, benzodiazepines, or kampo. In the case-control study, age, sex, clinical department, the fall down risk score, and hospitalized duration were adjusted in the logistic regression model. In the case-control study, multivariable logistic regression showed that the use of suvorexant (odds ratio [OR]: 2.61, 95% confidence interval [CI]: 1.29-5.28), nonbenzodiazepines (OR: 2.49, 95% CI: 1.73-3.59), and benzodiazepines (OR: 1.65, 95% CI: 1.16-2.34) was significantly associated with an increased OR of falls. However, the use of ramelteon (OR: 1.40, 95% CI: 0.60-3.16) and kampo (OR: 1.55, 95% CI: 0.75-3.19) was not significantly associated with an increased OR of falls. In the case-crossover study, the use of suvorexant (OR: 1.78, 95% CI: 1.05-3.00) and nonbenzodiazepines (OR: 1.63, 95% CI: 1.17-2.27) was significantly associated with an increased OR of falls. Similar patterns were observed in several sensitivity analyses. It was suggested that suvorexant increases the OR of falls. This result is robust in various analyses. This study showed that the risk of falls also exists for non-GABA sleep medication, suvorexant, and thus it is necessary to carefully prescribe hypnotic drugs under appropriate assessment.


Assuntos
Acidentes por Quedas , Azepinas/efeitos adversos , Indenos/efeitos adversos , Medicamentos Indutores do Sono/efeitos adversos , Triazóis/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Azepinas/administração & dosagem , Benzodiazepinas/administração & dosagem , Benzodiazepinas/efeitos adversos , Estudos Cross-Over , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Indenos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sono/efeitos dos fármacos , Sono/fisiologia , Triazóis/administração & dosagem
6.
Ann Hematol ; 99(9): 2193-2195, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32621180
7.
Int J Clin Pharmacol Ther ; 58(6): 293-298, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32301699

RESUMO

OBJECTIVES: We assessed the relative efficacy and safety of once-daily administration of 100 and 200 mg filgotinib (a JAK1-selective inhibitor) in patients with active rheumatoid arthritis (RA). MATERIALS AND METHODS: We conducted a Bayesian network meta-analysis combining the direct and indirect evidence from randomized controlled trials (RCTs) that examined the efficacy and safety of filgotinib in patients with active RA. RESULTS: Five RCTs involving 3,920 patients met the inclusion criteria. There were 15 pairwise comparisons, including 8 direct comparisons and 7 interventions. The ACR20 response rate was significantly higher in the filgotinib 200 mg + methotrexate (MTX) group than in the placebo or placebo + MTX group (odds ratio (OR): 12.39, 95% credible interval (CrI): 3.36 - 45.98.10; OR: 2.68, 95% CrI: 1.80 - 4.39). Compared to the placebo group, the filgotinib 100 mg, adalimumab 40 mg + MTX, filgotinib 200 mg, and placebo + MTX groups showed a significantly higher ACR20 response rate. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated filgotinib 200 mg + MTX was likely to achieve the best ACR20 response rate (SUCRA = 0.902), followed by filgotinib 100 mg + MTX (SUCRA = 0.694), filgotinib 100 mg (SUCRA = 0.675), adalimumab 40 mg + MTX (SUCRA = 0.661), filgotinib 200 mg (SUCRA = 0.305), placebo + MTX (SUCRA = 0.259), and placebo (SUCRA = 0.005). The safety based on the number of serious adverse events (SAEs) did not differ significantly among 6 six interventions. CONCLUSION: Filgotinib 100 and 200 mg administration once daily in combination with MTX was the most efficacious intervention for active RA, with no significant risk of SAEs.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Piridinas/administração & dosagem , Triazóis/administração & dosagem , Antirreumáticos/efeitos adversos , Teorema de Bayes , Quimioterapia Combinada , Humanos , Janus Quinase 1/antagonistas & inibidores , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Metanálise em Rede , Piridinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Triazóis/efeitos adversos
8.
J Med Chem ; 63(8): 3881-3895, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32223194

RESUMO

Exportin-1 (also named as CRM1) plays a prominent role in autoimmune disorders and has emerged as a potential therapeutic target for colitis. Here we report on the rational structure-based discovery of a small-molecule antagonist of exportin-1, LFS-829, with low-range nanomolar activities. The co-crystallographic structure, surface plasmon resonance binding assay, and cell-based phenotypic nuclear export functional assay validated that exportin-1 is a key target of LFS-829. Moreover, we demonstrated that the C528S mutation or the knockdown on exportin-1 can abolish the cellular activities of LFS-829. Strikingly, oral administration of LFS-829 can significantly reverse the pathological features of colitis model mice. We revealed that LFS-829 can attenuate dual NF-κB signaling and the Nrf2 cytoprotection pathway via targeting exportin-1 in colitis mice. Moreover, LFS-829 has a very low risk of cardiotoxicity and acute toxicity. Therefore, LFS-829 holds great promise for the treatment of colitis and may warrant translation for use in clinical trials.


Assuntos
Colite/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Hidrazinas/administração & dosagem , Carioferinas/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/administração & dosagem , Sequência de Aminoácidos , Animais , Colite/metabolismo , Colite/patologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Hidrazinas/química , Carioferinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Citoplasmáticos e Nucleares/metabolismo , Triazóis/química
9.
Artigo em Inglês | MEDLINE | ID: mdl-32222673

RESUMO

2-(2H-Benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV 328) is an ultraviolet light (UV) absorber which prolongs the stability of plastics and other organic compounds towards UV radiation. Therefore, it is frequently used as a preserving additive and may result in an exposure of consumers. Thus, an analytical method using dispersive liquid-liquid microextraction and subsequent gas chromatography tandem mass spectrometry analysis with advanced electron ionization was developed for a human biomonitoring of UV 328 exposure, which enabled the determination of UV 328 and six of its metabolites in human urine. Sample preparation and derivatization were optimized. Baseline separation of the analytes was assured by the application of a suitable temperature program. The validation resulted in limits of detection of 0.1 µg/L for all analytes, variation coefficients from 1 to 12% for precision in series and from 5 to 12% for interday precision. Furthermore, relative recovery rates between 80 and 120% were determined. Moreover, the procedure was successfully applied to urine samples of a volunteer exposed to UV 328. The method showed excellent sensitivity, repeatability and robustness for all parameters and may be applicable for studies to elucidate the metabolism and kinetics of the investigated UV absorber and for monitoring of individuals with specific exposure to UV 328.


Assuntos
Corantes/análise , Corantes/metabolismo , Triazóis/análise , Triazóis/metabolismo , Corantes/administração & dosagem , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Limite de Detecção , Microextração em Fase Líquida , Metabolômica , Oxirredução , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Temperatura , Triazóis/administração & dosagem , Raios Ultravioleta , Coleta de Urina
10.
Life Sci ; 253: 117539, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32165213

RESUMO

AIMS: Lipopolysaccharide (LPS)-induced intestinal injury is a common clinical feature of sepsis. Aggravated inflammation and higher sensitivity to infection are associated with high-fat diet (HFD) in patients with type 2 diabetes and/or obesity. However, the mechanism by which HFD exacerbates LPS-induced intestinal injury has not been elucidated. This study aims to examine the effects of HFD on intestinal injury induced by LPS and the underlying mechanism. MAIN METHODS: Mice were fed with HFD or regular chow for 12weeks and were then challenged with LPS. Vas2870 was administered to mice that received HFD before the initiation of the diet. The levels of tight junction protein expression, oxidative stress, organ injury, and nicotinamide adenine dinucleotide phosphate (NADPH)-associated proteins were assessed periodically. KEY FINDINGS: LPS treatment resulted in severe intestinal pathological injury and increased oxidative stress, evidenced by significantly increased serum diamine oxidase, reactive oxygen species, malondialdehyde, and intestinal fatty acid binding protein contents. Additionally, a decrease in tight junction protein expression was observed, indicating a loss of tight junction integrity. LPS treatment induced the expression of Nox2 and Nox4. All the effects were more severe in HFD mice. Treatment with vas2870 conferred protection against LPS-induced intestinal injury in HFD-fed mice, partially reduced oxidative stress, and rescued the expression of tight junction proteins. CONCLUSION: HFD aggravated LPS-induced intestine injury through exacerbating intestinal Nox-related oxidative stress, which led to a loss of the integrity of tight junctions and consequently increased intestinal permeability.


Assuntos
Dieta Hiperlipídica , Intestinos/efeitos dos fármacos , Lipopolissacarídeos/metabolismo , NADP/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Adsorção , Animais , Benzoxazóis/administração & dosagem , Benzoxazóis/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidases/metabolismo , Obesidade/metabolismo , Oxirredução , Permeabilidade , Espécies Reativas de Oxigênio/metabolismo , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/metabolismo , Triazóis/administração & dosagem , Triazóis/metabolismo
11.
Clin Podiatr Med Surg ; 37(2): 401-407, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32146992

RESUMO

Onychomycosis is especially common among diabetic patients. The purpose of this study was to investigate the efficacy of 10% efinaconazole solution among diabetic subjects, without restriction by nail plate involvement or glycemic control. Forty subjects were enrolled, with 36 reaching their final 50-week follow-up visit. Mycological cure was attained by 21 subjects (58.33%); 8 subjects (20%) attained either clinical cure (0% clinical involvement) or treatment success (≤10% clinical involvement). Glycemic control did not affect clinical outcome. The medication was well tolerated, with 4 local adverse events and no significant adverse events. The medication may represent a useful option for diabetic patients.


Assuntos
Antifúngicos/administração & dosagem , Complicações do Diabetes/complicações , Dermatoses do Pé/tratamento farmacológico , Onicomicose/tratamento farmacológico , Triazóis/administração & dosagem , Administração Tópica , Adulto , Idoso , Glicemia , Feminino , Dermatoses do Pé/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Onicomicose/etiologia , Resultado do Tratamento
12.
J Pediatr Hematol Oncol ; 42(4): 261-265, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32218096

RESUMO

PURPOSE: Primary objective is to evaluate safety of isavuconazonium sulfate (ISA) in pediatrics below 18 years old. Exploratory endpoint includes mortality due to probable and proven invasive fungal infection (IFI) and overall morality in this population. PATIENTS AND METHODS: Retrospective review of patients below 18 years receiving ISA for ≥7 days for possible, probable, or proven IFI or prophylaxis between June 2015 and March 2018. Descriptive analysis performed to calculate median, frequency, and percentages. RESULTS: Safety analysis included 18 patients and a subgroup of 11/18 patients were assessed for efficacy. Median age 12.5 years (4 to 17 y), median weight 50.25 kg (19 to 118 kg), 50% male, 77% acute leukemias, 94% hematopoietic cell transplant recipients, 50% matched unrelated donors and 78% in remission. Elevated alanine aminotransferase 3 times baseline within 30 days of ISA occurred in 22% (4/18). No patients had elevated bilirubin or increase in serum creatinine. All-cause mortality at 90 days was 22% (4/18) and 27% (3/11) in patients with probable or proven IFI. Clinical response rates: 14-day: 45% (5/11) partial, 27% (3/11) stable; 30-day: 45% (5/11) partial, 36% (4/11) stable; 90-day: 54% (6/11) had either partial (n=3) or complete (n=3) response to ISA. CONCLUSIONS: ISA is safe in pediatric patients for the treatment of IFI. Prospective, randomized controlled trials are warranted to determine efficacy and safety of ISA in pediatric patients with hematologic malignancies and hematopoietic cell transplant.


Assuntos
Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Infecções Fúngicas Invasivas , Nitrilos/administração & dosagem , Piridinas/administração & dosagem , Triazóis/administração & dosagem , Adolescente , Criança , Pré-Escolar , Feminino , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/terapia , Humanos , Infecções Fúngicas Invasivas/sangue , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/etiologia , Masculino , Nitrilos/efeitos adversos , Piridinas/efeitos adversos , Estudos Retrospectivos , Triazóis/efeitos adversos
13.
Toxicology ; 433-434: 152394, 2020 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-32027962

RESUMO

Nongenotoxic chemicals can produce liver tumours in rats and mice by a mitogenic mode of action involving activation of the constitutive androstane receptor (CAR). The aim of this study was to evaluate the usefulness of cultured hepatocytes from normal (wild type; WT) and CAR knockout (KO) rats to screen compounds as potential activators of rat CAR and to validate this test system. Cultured hepatocytes from male Sprague-Dawley WT and CAR KO rats were treated with either 100 and 1000 µM sodium phenobarbital (NaPB), 3-100 µM fluquinconazole (FQZ), or 3-300 µM 3-(difluoromethyl)-1-methyl-N-(3´,4´,6-trifluoro[1,1´-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (TI1) for 96 h. Induction of cytochrome P450 (CYP) enzymes was monitored by measurement of 7-pentoxyresorufin O-depentylase (PROD), 7-benzyloxyresorufin O-debenzylase (BROD) and 7-benzyloxyquinoline O-debenzylase (BQ) activities. Hepatocytes undergoing replicative DNA synthesis (RDS) were labelled by adding 10 µM 5-bromo-2´-deoxyuridine to the culture medium for determination of the hepatocyte labelling index. The treatment of WT, but not of CAR KO, rat hepatocytes with NaPB, FQZ and TI1 increased hepatocyte RDS and induced CYP2B-dependent PROD activity. In contrast, all three compounds increased CYP2B/3A-dependent BROD and CYP3A-dependent BQ activities in both WT and CAR KO rat hepatocytes. Hepatocyte RDS was increased in both WT and CAR KO rat hepatocytes by treatment with 25 ng/ml epidermal growth factor as a positive control. Overall, these results demonstrate that the effects of three CAR activators on RDS and CYP2B enzyme induction are abolished in cultured CAR KO rat hepatocytes. As demonstrated by this validation study, the CAR KO hepatocyte model is a useful in vitro mechanistic tool for the rapid screening of chemicals as potential activators of rat CAR.


Assuntos
Hepatócitos/efeitos dos fármacos , Fenobarbital/farmacologia , Quinazolinonas/farmacologia , Receptores Citoplasmáticos e Nucleares/genética , Triazóis/farmacologia , Animais , Indutores das Enzimas do Citocromo P-450/administração & dosagem , Indutores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , DNA/metabolismo , Relação Dose-Resposta a Droga , Técnicas de Inativação de Genes , Masculino , Camundongos Knockout , Fenobarbital/administração & dosagem , Quinazolinonas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Triazóis/administração & dosagem
14.
Rev Soc Bras Med Trop ; 53: e20190477, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049205

RESUMO

INTRODUCTION: Benznidazole (BZL) and Nifurtimox (NFX) are the pharmacological treatment for acute phase Chagas Disease (CD); however, therapy resistance and residual mortality development remain important unresolved issues. Posaconazole (POS) has shown a trypanocidal effect in vivo and in vitro. Thus, this study aimed at comparing the T. Cruzi parasitic load-reducing effect of the combination of BZL+POS against that of monotherapy with either, during acute phase CD, in an experimental murine model. METHODS: Nineteen Wistar rats were randomly allocated to four groups and inoculated with the trypomastigotes of T. cruzi strain´s JChVcl1. The rats were administered anti-parasites from day 20-29 post-infection. The Pizzi and Brener method was used for parasitemia measurement. Longitudinal data analysis for the continuous outcome of repeated measures was performed using parasitemia as the outcome measured at days 20, 22, 24, 27, and 29 post-infection. RESULTS: All four groups had similar parasitic loads (p=0.143) prior to therapy initiation. Among the three treatment groups, the BZL+POS (n=5) group showed the highest mean parasitic load reduction (p=0.000) compared with the control group. Likewise, the BZL+POS group rats showed an earlier therapeutic effect and were the only ones without parasites in their myocardial samples. CONCLUSIONS: Treatment of acute phase CD with BZL+POS was more efficacious at parasitemia and myocardial injury reduction, compared with monotherapy with either.


Assuntos
Doença de Chagas/tratamento farmacológico , Nitroimidazóis/administração & dosagem , Parasitemia/tratamento farmacológico , Triazóis/administração & dosagem , Tripanossomicidas/administração & dosagem , Doença Aguda , Animais , DNA de Protozoário , Modelos Animais de Doenças , Progressão da Doença , Quimioterapia Combinada , Carga Parasitária , Ratos , Ratos Wistar
15.
Pharmacol Rep ; 72(1): 87-95, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32016835

RESUMO

BACKGROUND: Anticonvulsant and acute toxic effects of 5-[(3-fluorophenyl)ethyl]-4-(n-hexyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPF-34)-a candidate for novel antiepileptic drug-were examined in the maximal electroshock-induced seizure (MES) model and rotarod test in mice. The interaction profile of TPF-34 with four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) was also studied in the mouse MES model. METHODS: Both ED50 and TD50 values for TPF-34 were determined at four treatment times (15, 30, 60 and 120 min after i.p. administration) in the MES model and rotarod test in adult male albino Swiss mice, respectively. The influence of TPF-34 on the protective anticonvulsant action of carbamazepine, phenobarbital, phenytoin and valproate in the mouse MES model was assessed with isobolographic analysis of interaction. Total brain antiepileptic drug concentrations were measured with fluorescence polarization immunoassay. RESULTS: TPF-34, when administered alone at four pretreatment times (15, 30, 60 and 120 min before experiments), possessed a favorable preclinical profile with the protective index (a ratio of TD50 and ED50 values) ranging from 2.89 to 3.53. Moreover, TPF-34, when combined with carbamazepine, phenobarbital, phenytoin and valproate, exerted an additive interaction in the MES model in mice. TPF-34 had no impact on total brain antiepileptic drug concentrations in mice. CONCLUSIONS: A protective index value higher than 3 allows recommending TPF-34 as a promising antiepileptic drug candidate for further preclinical testing using other experimental seizure models. The additive interaction of TPF-34 with carbamazepine, phenobarbital, phenytoin and valproate in the mouse MES model is worthy of recommendation to further clinical studies.


Assuntos
Anticonvulsivantes/administração & dosagem , Convulsões/tratamento farmacológico , Triazóis/administração & dosagem , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/toxicidade , Encéfalo/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Eletrochoque , Masculino , Camundongos , Fatores de Tempo , Distribuição Tecidual , Triazóis/farmacologia , Triazóis/toxicidade
16.
Mycoses ; 63(5): 517-524, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32048351

RESUMO

BACKGROUND: Efinaconazole is non-lacquer-based with a low surface tension that efficiently targets delivery of active ingredient into the nail and nail bed. OBJECTIVES: To develop an optimal, stable formulation of efinaconazole topical solution 10% (ETS10). METHODS: We evaluated the safety and efficacy of ETS10 on 10 Iranian participants in a pilot, single-group and before-after clinical study, for up to 8 weeks in onychomycosis. RESULTS: The study showed reasonable results concerning the short period of treatment. During the period of storage, the formulation showed no variation in colour, odour and pH. The average pH at initial, 1st, 6th and 12th months was 4.65, 4.64, 4.65 and 4.64, respectively. The assay of an active pharmaceutical ingredient in the formulation was desired over the whole period. This indicates that antimicrobial activity has been adequate and efficient. A significant decrease in Investigator Global Assessment (IGA) of the target toenails was also defined as the efficacy endpoint. The median score for IGA at baseline visit was 3 out of 5 which decreased to 2 out of 5 and the decrease was statistically significant. CONCLUSION: The study clarifies the new efficacy of ETS10 in subjects with onychomycosis and passed the safety study successfully. These properties may develop the potentiality of ETS10 as a good treatment option for patients with onychomycosis.


Assuntos
Antifúngicos/uso terapêutico , Doenças da Unha/tratamento farmacológico , Unhas/microbiologia , Onicomicose/tratamento farmacológico , Triazóis/uso terapêutico , Administração Tópica , Adolescente , Adulto , Idoso , Antifúngicos/administração & dosagem , Feminino , , Humanos , Masculino , Pessoa de Meia-Idade , Doenças da Unha/microbiologia , Onicomicose/microbiologia , Projetos Piloto , Triazóis/administração & dosagem , Adulto Jovem
17.
AAPS PharmSciTech ; 21(3): 91, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32060665

RESUMO

Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus-1 infection, available as a single tablet in combination with other antiretroviral agents or as a fixed-dose regimen with lamivudine and tenofovir disoproxil fumarate (TDF). Alternative formulations of these drugs are being developed for individuals who have difficulty swallowing tablets. Two phase 1 trials were conducted, both in 24 healthy adults, to assess the pharmacokinetics of uncoated and coated oral granule formulations of doravirine, lamivudine, and TDF administered alone and with vanilla pudding or apple sauce. The pharmacokinetics for all uncoated granules, and of coated lamivudine and TDF granules, were similar to those of currently marketed tablets (geometric mean ratios [GMRs] 0.92-1.04). Coated doravirine granules had decreased AUC0-∞ (11%) and Cmax (23%) values versus the tablet. The pharmacokinetics were similar for uncoated and coated doravirine granules administered with or without pudding (GMRs 0.96-1.10); administration with apple sauce increased doravirine AUC0-∞ (26-29%), Cmax (56-59%), and C24 (20-21%) versus administration of granules alone. Lamivudine granules administered with pudding or apple sauce decreased AUC0-∞ and Cmax (14-25%) versus granules alone. Tenofovir AUC0-∞, Cmax, and C24 increased for TDF granules administered with pudding or apple sauce versus alone (11-23%). Pharmacokinetic differences when administering doravirine, lamivudine, or TDF as uncoated or coated granules versus tablets, or when granules were administered with (versus without) pudding or apple sauce, are not considered clinically meaningful, supporting further development of these granule formulations.


Assuntos
Fármacos Anti-HIV/farmacocinética , Antirretrovirais/farmacocinética , Lamivudina/farmacocinética , Piridonas/farmacocinética , Inibidores da Transcriptase Reversa/farmacocinética , Tenofovir/farmacocinética , Triazóis/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Antirretrovirais/administração & dosagem , Disponibilidade Biológica , Estudos Cross-Over , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Humanos , Lamivudina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Piridonas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Comprimidos , Tenofovir/administração & dosagem , Triazóis/administração & dosagem , Adulto Jovem
18.
Nat Biotechnol ; 38(3): 303-308, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31959954

RESUMO

Monitoring drug-target interactions with methods such as the cellular thermal-shift assay (CETSA) is well established for simple cell systems but remains challenging in vivo. Here we introduce tissue thermal proteome profiling (tissue-TPP), which measures binding of small-molecule drugs to proteins in tissue samples from drug-treated animals by detecting changes in protein thermal stability using quantitative mass spectrometry. We report organ-specific, proteome-wide thermal stability maps and derive target profiles of the non-covalent histone deacetylase inhibitor panobinostat in rat liver, lung, kidney and spleen and of the B-Raf inhibitor vemurafenib in mouse testis. In addition, we devised blood-CETSA and blood-TPP and applied it to measure target and off-target engagement of panobinostat and the BET family inhibitor JQ1 directly in whole blood. Blood-TPP analysis of panobinostat confirmed its binding to known targets and also revealed thermal stabilization of the zinc-finger transcription factor ZNF512. These methods will help to elucidate the mechanisms of drug action in vivo.


Assuntos
Sangue/metabolismo , Proteoma/química , Proteoma/metabolismo , Bibliotecas de Moléculas Pequenas/administração & dosagem , Animais , Azepinas/administração & dosagem , Azepinas/farmacologia , Células Hep G2 , Humanos , Rim/química , Rim/metabolismo , Fígado/química , Fígado/metabolismo , Pulmão/química , Pulmão/metabolismo , Masculino , Espectrometria de Massas , Camundongos , Especificidade de Órgãos , Panobinostat/administração & dosagem , Panobinostat/farmacologia , Estabilidade Proteica , Ratos , Bibliotecas de Moléculas Pequenas/farmacologia , Baço/química , Baço/metabolismo , Testículo/química , Testículo/metabolismo , Termodinâmica , Triazóis/administração & dosagem , Triazóis/farmacologia , Vemurafenib/administração & dosagem , Vemurafenib/farmacologia
19.
Ann Neurol ; 87(3): 347-356, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31953863

RESUMO

OBJECTIVE: To evaluate the dose-response relationship of daridorexant, a new dual orexin receptor antagonist, on sleep variables in subjects with insomnia disorder. METHODS: Adults (≤64 years) with insomnia disorder were randomized (1:1:1:1:1:1) to receive daily oral placebo, daridorexant (5, 10, 25, or 50mg), or 10mg zolpidem for 30 days. The primary efficacy outcome was the change in wake time after sleep onset from baseline to days 1 and 2. Secondary outcome measures were change in latency to persistent sleep from baseline to days 1 and 2, change in subjective wake time after sleep onset, and subjective latency to sleep onset from baseline to week 4. Safety was also assessed. RESULTS: Of 1,005 subjects screened, 359 (64% female) were randomized and received ≥1 dose. A significant dose-response relationship (multiple comparison procedure-modeling, 2-sided p < 0.001) was found in the reduction of wake after sleep onset and latency to persistent sleep from baseline to days 1 and 2 with daridorexant. These reductions were sustained through to days 28 and 29 (p = 0.050 and p = 0.042, respectively). Similar dose-dependent relationships were observed for subjective wake after sleep onset and subjective latency to sleep onset. The incidence of treatment-emergent adverse events was 35%, 38%, 38%, and 34% in subjects treated with 5, 10, 25, and 50mg daridorexant, respectively, compared with 30% for placebo, and 40% for 10mg zolpidem. There were no clinically relevant treatment-related serious adverse events. Four subjects withdrew due to adverse events. INTERPRETATION: Daridorexant induced a dose-dependent reduction in wake time after sleep onset in subjects with insomnia disorder (Clinicaltrials.gov NCT02839200). Ann Neurol 2020;87:347-356.


Assuntos
Benzimidazóis/administração & dosagem , Pirrolidinas/administração & dosagem , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/administração & dosagem , Adulto , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Imidazóis , Pessoa de Meia-Idade , Antagonistas dos Receptores de Orexina/efeitos adversos , Antagonistas dos Receptores de Orexina/uso terapêutico , Pirrolidinas/efeitos adversos , Pirrolidinas/uso terapêutico , Resultado do Tratamento , Triazóis/efeitos adversos , Triazóis/uso terapêutico , Zolpidem/uso terapêutico
20.
Expert Opin Pharmacother ; 21(4): 399-408, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31957504

RESUMO

Introduction: Despite unprecedented advances in the treatment of multiple myeloma (MM), almost all patients develop a disease that is resistant to the five most commonly used and active anti-MM agents. The prognosis for this patient population is particularly poor resulting in an unmet need for additional therapeutic options. Exportin-1 (XPO-1) is a major nuclear export protein of macromolecular cargo frequently overexpressed in MM. Selinexor is a first-in-class, oral Selective-Inhibitor-of-Nuclear-Export (SINE) compound that impedes XPO-1. Based on results of the STORM-trial, selinexor in combination with dexamethasone was granted accelerated FDA approval for patients with penta-refractory MM in July 2019.Areas covered: This article summarizes our up-to-date knowledge on the pathophysiologic role of XPO-1 in MM. Furthermore, it reviews the most recent clinical data on selinexor in combination with dexamethasone and other anti-MM agents; and discusses its safety profile, management strategies; and potential future developments.Expert opinion: Selinexor represents a next-generation-novel agent with an innovative mechanism of action that marks a significant advance in the treatment of heavily pretreated MM patients. Ongoing studies investigate its therapeutic potential also in earlier lines of therapy. Additional data is needed to confirm that selinexor and other SINE compounds are a valuable addition to our current therapeutic armamentarium.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hidrazinas/uso terapêutico , Carioferinas/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/uso terapêutico , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Ensaios Clínicos como Assunto , Dexametasona/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Humanos , Hidrazinas/administração & dosagem , Hidrazinas/efeitos adversos , Hidrazinas/farmacocinética , Carioferinas/genética , Mieloma Múltiplo/metabolismo , Prognóstico , Receptores Citoplasmáticos e Nucleares/genética , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Triazóis/farmacocinética
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