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1.
Pediatr Infect Dis J ; 41(7): 556-562, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35675525

RESUMO

BACKGROUND: Solithromycin is a new macrolide-ketolide antibiotic with potential effectiveness in pediatric community-acquired bacterial pneumonia (CABP). Our objective was to evaluate its safety and effectiveness in children with CABP. METHODS: This phase 2/3, randomized, open-label, active-control, multicenter study randomly assigned solithromycin (capsules, suspension or intravenous) or an appropriate comparator antibiotic in a 3:1 ratio (planned n = 400) to children 2 months to 17 years of age with CABP. Primary safety endpoints included treatment-emergent adverse events (AEs) and AE-related drug discontinuations. Secondary effectiveness endpoints included clinical improvement following treatment without additional antimicrobial therapy. RESULTS: Unrelated to safety, the sponsor stopped the trial prior to completion. Before discontinuation, 97 participants were randomly assigned to solithromycin (n = 73) or comparator (n = 24). There were 24 participants (34%, 95% CI, 23%-47%) with a treatment-emergent AE in the solithromycin group and 7 (29%, 95% CI, 13%-51%) in the comparator group. Infusion site pain and elevated liver enzymes were the most common related AEs with solithromycin. Study drug was discontinued due to AEs in 3 subjects (4.3%) in the solithromycin group and 1 (4.2%) in the comparator group. Forty participants (65%, 95% CI, 51%-76%) in the solithromycin group achieved clinical improvement on the last day of treatment versus 17 (81%, 95% CI, 58%-95%) in the comparator group. The proportion achieving clinical cure was 60% (95% CI, 47%-72%) and 68% (95% CI, 43%-87%) for the solithromycin and comparator groups, respectively. CONCLUSIONS: Intravenous and oral solithromycin were generally well-tolerated and associated with clinical improvement in the majority of participants treated for CABP.


Assuntos
Infecções Comunitárias Adquiridas , Pneumonia Bacteriana , Adolescente , Antibacterianos/efeitos adversos , Criança , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , Humanos , Macrolídeos/efeitos adversos , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/microbiologia , Triazóis
2.
Xenobiotica ; 52(4): 380-388, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35656966

RESUMO

Anastrozole (ANA), is an inhibitor of non-steroidal aromatase, widely employed for the treatment of breast cancer. However, ANA-associated liver injury cases have been documented in the application of the drug.The major purposes of the present study were to identify the structure of reactive metabolites derived from ANA and to study related metabolic pathways of ANA.We found ANA itself is an electrophilic species reactive to GSH. ANA can be metabolised to ANA-N+-glucuronide (1) catalysed by UGT1A4. An ANA GSH conjugate (2) was detected in bile and livers of rats treated with ANA. UGT1A4 participated in the phase II metabolic pathway.This work allowed us to better understand the mechanisms of the hepatotoxicity of ANA and provided new avenue to define the possible role of metabolic activation in hepatotoxicity.


Assuntos
Neoplasias da Mama , Doença Hepática Induzida por Substâncias e Drogas , Anastrozol/uso terapêutico , Animais , Neoplasias da Mama/tratamento farmacológico , Feminino , Ácido Glucurônico/uso terapêutico , Humanos , Nitrilas , Ratos , Triazóis
3.
Gynecol Oncol ; 166(1): 126-137, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35688655

RESUMO

OBJECTIVE: Iron depletion may be a novel therapeutic strategy for cancer. This study aimed to assess the inhibition effects of deferasirox (DFX), an oral iron chelator, on cervical cancer. METHODS: In this study, we performed immunohistochemical analysis, enzyme-linked immunoassay, cell viability and invasive ability assay, cell cycle and apoptosis analysis, protein expression investigation, molecular mechanism investigation, and in vivo murine xenograft model to evaluate the impact of DFX on cervical cancer. RESULTS: The cervical cancer cell lines viability decreased and cell apoptosis was induced after DFX incubation. Additionally, DFX promoted cell cycle arrest by regulating the expression of cell cycle regulators cyclin D1, cyclin E and proliferating cell nuclear antigen (PCNA) in cervical cancer cell lines. DFX also decreased cell invasion by upregulating the expression of NDRG1 and downregulating c-Myc. The activation of Akt and the MEK/ERK signaling pathway was inhibited by DFX. DFX also significantly suppressed xenograft tumor growth, decreased the levels of ferritin in serum and tumor tissue, reduced iron deposits and reactive oxygen species (ROS) levels in xenografts of DFX-treated group compared with the control group, with no serious side effects. CONCLUSION: Present study demonstrated the inhibitory effect of DFX against cervical cancer, and provided a potential therapeutic agent for cervical cancer.


Assuntos
Quelantes de Ferro , Neoplasias do Colo do Útero , Animais , Benzoatos/farmacologia , Benzoatos/uso terapêutico , Deferasirox/farmacologia , Feminino , Humanos , Ferro , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Camundongos , Triazóis/farmacologia , Triazóis/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico
4.
Sci Total Environ ; 839: 156246, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35644405

RESUMO

This study aimed to identify and quantify benzotriazoles (BTRs) emissions from road traffic and paved areas in an urban environment. Heterocyclic organic compounds BTRs are an emerging threat, under-recognized and under-analyzed in most environmental and water legislation. They are hazardous, potentially mutagenic, and carcinogenic micropollutants, not susceptible to effective biodegradation, and they move easily through the trophic chain, contaminating the environment and water resources. Traffic activities are a common source of BTR emissions in the urban environment, directly polluting human habitats through the different routes and numerous vehicles circulating in the cities. Using twelve heterogeneous locations scattered over a metropolitan area in Poland as a case study, this research analyzed the presence of BTRs in water samples from runoff produced from rainwater and snowmelt. 1H-BTR, 4Me-BTR, 5Me-BTR and 5Cl-BTR were detected in the tested runoff water. 5Cl-BTR was present in all samples and in the highest concentrations reaching 47,000 ng/L. Risk quotients calculated on the basis of the determined concentrations indicate that the highest environmental risk is associated with the presence of 5Cl-BTR and the sum of 4Me-BTR and 5Me-BTR, and the most sensitive organisms are bacteria and invertebrates. The results indicate that it is possible to associate the occurrence of these contaminants with the type of cover, traffic intensity, and vehicle type.


Assuntos
Triazóis , Água , Monitoramento Ambiental , Humanos , Polônia , Medição de Risco , Triazóis/análise
5.
Molecules ; 27(11)2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35684308

RESUMO

A series of triazole derivatives containing phenylethynyl pyrazole moiety as side chain were designed, synthesized, and most of them exhibited good in vitro antifungal activities. Especially, compounds 5k and 6c showed excellent in vitro activities against C. albicans (MIC = 0.125, 0.0625 µg/mL), C. neoformans (MIC = 0.125, 0.0625 µg/mL), and A. fumigatus (MIC = 8.0, 4.0 µg/mL). Compound 6c also exerted superior activity to compound 5k and fluconazole in inhibiting hyphae growth of C. albicans and inhibiting drug-resistant strains of C. albicans, and it could reduce fungal burdens in mice kidney at a dosage of 1.0 mg/kg. An in vivo efficacy evaluation indicated that 6c could effectively protect mice models from C. albicans infection at doses of 0.5, 1.0, and 2.0 mg/kg. These results suggested that compound 6c deserves further investigation.


Assuntos
Antifúngicos , Cryptococcus neoformans , Animais , Antifúngicos/química , Candida albicans , Fluconazol/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Pirazóis/farmacologia , Relação Estrutura-Atividade , Triazóis/química
6.
Molecules ; 27(11)2022 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-35684347

RESUMO

A modular platform for the synthesis of tunable aza-oxa-based macrocycles was established. Modulations in the backbone and the side-chain functional groups have been rendered to achieve the tunable property. These aza-oxa-based macrocycles can also differ in the number of heteroatoms in the backbone and the ring size of the macrocycles. For the proof of concept, a library of macrocycles was synthesized with various hanging functional groups, different combinations of heteroatoms, and ring sizes in the range of 17-27 atoms and was characterized by NMR and mass spectrometry. In light of the importance of the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and the significance of triazole groups for various applications, we employed the click-reaction-based macrocyclization. The competence of the synthesized macrocycles in various biomedical applications was proven by studying the interactions with the serum albumin proteins; bovine serum albumin and human serum albumin. It was observed that some candidates, based on their hanging functional groups and specific backbone atoms, could interact well with the protein, thus improving the bioactive properties. On the whole, this work is a proof-of-concept to explore the backbone- and side-chain-tunable macrocycle for different properties and applications.


Assuntos
Química Click , Triazóis , Alcinos/química , Azidas/química , Catálise , Cobre/química , Humanos , Soroalbumina Bovina , Triazóis/química
7.
Molecules ; 27(11)2022 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-35684354

RESUMO

An in situ formation of ionic liquid was used for preconcentration of four triazole fungicides in food samples. The microextraction method was used for the first time in the literature for preconcentration of triazole fungicides. In the developed method, tributylhexadecylphosphonium bromide ([P44412]Br) and potassium hexafluorophosphate (KPF6) were used for the formation of hydrophobic ionic liquid. After centrifugation, the fine microdroplets were produced in one step, providing the extraction step in a quick and environmentally friendly manner. The functional group of the hydrophobic ionic liquid was investigated using FT-IR. Various extraction parameters were studied and optimized. In the extraction method, 0.01 g of [P44412]Br and 0.01 g of KPF6, centrifugation at 4500 rpm for 10 min were used. The optimized technique provided a good linear range (90-1000 µg L-1) and high extraction recovery, with a low limit of detection (30-50 µg L-1). Methods for the proposed in situ formation of ionic liquid were successfully applied to honey, fruit juice, and egg matrices. The recoveries were obtained in a satisfactory range of 62-112%. The results confirmed the suitability of the proposed microextraction method for selective extraction and quantification of triazole fungicides.


Assuntos
Fungicidas Industriais , Líquidos Iônicos , Microextração em Fase Líquida , Cromatografia Líquida de Alta Pressão/métodos , Fungicidas Industriais/análise , Líquidos Iônicos/química , Microextração em Fase Líquida/métodos , Espectroscopia de Infravermelho com Transformada de Fourier , Triazóis/análise
8.
Molecules ; 27(11)2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35684576

RESUMO

New derivatives obtained by the combination of unique 1,2,4,5-tetrazine and 4H-1,2,4-triazole rings have great application potential in many fields. Therefore, two synthetic few-step methodologies, which make use of commercially available 4-cyanobenzoic acid (method A) and ethyl diazoacetate (method B), were applied to produce two groups of the aforementioned heterocyclic conjugates. In both cases, the target compounds were obtained in various combinations, by introducing electron-donating or electron-withdrawing substituents into the terminal rings, together with aromatic or aliphatic substituents on the triazole nitrogen atom. Synthesis of such designed systems made it possible to analyze the influence of individual elements of the structure on the reaction course, as well as the absorption and emission properties. The structure of all products was confirmed by conventional spectroscopic methods, and their luminescent properties were also determined.


Assuntos
Compostos Aza/síntese química , Derivados de Benzeno/síntese química , Luminescência , Triazóis , Compostos Aza/química , Derivados de Benzeno/química , Elétrons , Triazóis/química
9.
Plant Signal Behav ; 17(1): 2084277, 2022 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-35695417

RESUMO

Two key transcription factors (TFs) in brassinosteroid (BR) signaling BRASSINOSTEROID INSENSITIVE 1-EMS-SUPPRESSOR 1 (BES1) and BRASSINAZOLE RESISTANT 1 (BZR1), belong to a small family with four BES1/BZR1 homologs (BEH1-4). To date, in contrast to the wealth of knowledge regarding BES1 and BZR1, little is known about BEH1-4. Here, we show that BEH2 was expressed preferentially in the roots and leaf margins including serrations, which was quite different from another member BEH4, and that BRs downregulated BEH2 through a module containing GSK3-like kinases and BES1/BZR1 TFs, among which BES1, rather than BZR1, contributed to this process. In addition, BEH2 consistently existed in the nucleus, suggesting that its subcellular localization is not under BR-dependent nuclear-cytoplasmic shuttling control. Furthermore, gene ontology analysis on RNA-seq data indicated that BEH2 may be implicated in stress response and photosynthesis. These findings might assist in the future elucidation of the molecular mechanisms underlying BR signaling.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Brassinosteroides , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica de Plantas/genética , Quinase 3 da Glicogênio Sintase/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Triazóis
10.
JCO Precis Oncol ; 6: e2200147, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35704796

RESUMO

PURPOSE: Selinexor is the first selective inhibitor of nuclear export to be approved for the treatment of relapsed or refractory multiple myeloma (MM). Currently, there are no known genomic biomarkers or assays to help select MM patients at higher likelihood of response to selinexor. Here, we aimed to characterize the transcriptomic correlates of response to selinexor-based therapy. METHODS: We performed RNA sequencing on CD138+ cells from the bone marrow of 100 patients with MM who participated in the BOSTON study, followed by differential gene expression and pathway analysis. Using the differentially expressed genes, we used cox proportional hazard models to identify a gene signature predictive of response to selinexor, followed by validation in external cohorts. RESULTS: The three-gene signature predicts response to selinexor-based therapy in patients with MM in the BOSTON cohort. Then, we validated this gene signature in 64 patients from the STORM cohort of triple-class refractory MM and additionally in an external cohort of 35 patients treated in a real-world setting outside of clinical trials. We found that the signature tracks with both depth and duration of response, and it also validates in a different tumor type using a cohort of pretreatment tumors from patients with recurrent glioblastoma. Furthermore, the genes involved in the signature, WNT10A, DUSP1, and ETV7, reveal a potential mechanism through upregulated interferon-mediated apoptotic signaling that may prime tumors to respond to selinexor-based therapy. CONCLUSION: In this study, we present a present a novel, three-gene expression signature that predicts selinexor response in MM. This signature has important clinical relevance as it could identify patients with cancer who are most likely to benefit from treatment with selinexor-based therapy.


Assuntos
Mieloma Múltiplo , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Hidrazinas/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/induzido quimicamente , Triazóis
11.
Chemosphere ; 303(Pt 3): 135282, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35691395

RESUMO

To reduce detrimental effects to the environment, the application of prothioconazole and its metabolites requires comprehensive evaluation, which has been dine for the first time in this study. The behavior of prothioconazole, including degradation and sorption under aerobic and anaerobic conditions, was evaluated in three common soil types and two types of water-sediment systems under different environmental conditions. Individual and joint toxicities of prothioconazole and its metabolites, M01 and M04, on aquatic organisms, including the Gobiocypris rarus, are also investigated in the present study. Under aerobic and anaerobic conditions, the half-life of prothioconazole in the three types of soils ranged from 0.0565 to 2.27 days and 0.138-1.73 days, respectively. Under aerobic conditions, the half-life of prothioconazole in the Hunan paddy area and Beijing Qidu reservoir water-sediment samples were 2.18 and 1.58 days, respectively. In soil and water-sediment samples, prothioconazole degraded to M01 and M04, and the formation rate of M04 was higher than M01 under aerobic condition. M04 and M01 gradually increased to a peak value in soil and water-sediment systems, then decreased over time, while prothioconazole gradually decreased. The half-life of prothioconazole in soils was lower than its metabolites, with the DT50 of metabolites ranging from 16.6 to 99.6 days, 15.8 and 50.7 days for M01 and M04 under aerobic condition, respectively. While the adsorption capacities (Kf values) of M04 and M01 ranged from 2.09 to 88.92 and 8.98 to 243.30 (µg/g)/(mg/L), respectively, in the three soils. Regarding toxicity to aquatic organisms, the metabolites did not show higher toxicity than prothioconazole, except M01 on Gobiocypris rarus. Joint toxicity assays showed that mixtures of prothioconazole with its metabolites exhibited higher toxicity than any compound individually and indicated synergistic interactions could occur at equitoxic ratios and equivalent concentrations. This study provides a comprehensive investigation on the fate and environmental risk posed by prothioconazole.


Assuntos
Poluentes do Solo , Solo , Poluentes do Solo/análise , Triazóis/toxicidade , Água
12.
Chemosphere ; 303(Pt 3): 135302, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35697111

RESUMO

Fungicides are a group of chemicals causing pollution of freshwater ecosystems due to their widespread use in agriculture. However, their endocrine disrupting effects are less studied than herbicides and insecticides. The aim of this study was to evaluate the developmental and toxicological effects and recovery patterns of penconazole-based fungicide (PBF) during Xenopus laevis metamorphosis. For this purpose, firstly, the 96 h median lethal (LC50) and effective (EC50) concentrations and minimum concentration to inhibit growth (MCIG) values of PBF were estimated for X. laevis as 4.97, 3.55 and 2.31 mg/L respectively, using Frog Embryo Teratogenesis Assay-Xenopus (FETAX) on Nieuwkoop-Faber (NF) stage 8 embryos. FETAX results showed PBF formulation was slightly teratogenic with a 1.4 teratogenic index; most recorded malformations were gut, abdominal edema, and tail curvature. The Subacute Amphibian Metamorphosis Assay (AMA) was modified based on acute FETAX results, and used to evaluate toxic effects and recovery patterns of relatively low PBF concentrations on metamorphosis using morphological and biochemical markers. NF Stage 51 tadpoles were exposed to two separate groups of each concentration for seven days in the AMA. Secondly, tadpoles of one group of each concentration continued to be exposed to PBF for the next 7 and 14 days while the other group was kept in a pesticide-free environment (depuration/recovery). Various morphological and biochemical markers were measured homogenate samples of tadpoles from exposure and recovery groups. Continuous exposure to relatively low PBF concentrations caused oxidative stress, toxic, and endocrine disrupting effects in the AMA, leading us to conclude that it has negative effects on frog health and development during the recovery period when PBF exposure is terminated. The glutathione S-transferase, glutathione reductase, catalase, carboxylesterase, and acetylcholinesterase activities were higher than the control group transferred to pesticide-free media for 14 days after the 7 days exposure and indicate persistent PBF impact.


Assuntos
Fungicidas Industriais , Teratogênese , Acetilcolinesterase , Animais , Ecossistema , Embrião não Mamífero , Fungicidas Industriais/toxicidade , Larva , Triazóis , Xenopus laevis
13.
Sci Transl Med ; 14(650): eabn8238, 2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35731889

RESUMO

Increased orexin/hypocretin signaling is implicated in opioid withdrawal, sleep disturbances, and drug-seeking behaviors. This study examined whether a dual-orexin receptor antagonist would improve sleep and withdrawal outcomes when compared with placebo during a buprenorphine/naloxone taper. Thirty-eight participants with opioid use disorder were recruited to a clinical research unit and maintained on 8/2 to 16/4 mg of buprenorphine/naloxone treatment for 3 days before being randomized to 20 mg of suvorexant (n = 14), 40 mg of suvorexant (n = 12), or placebo (n = 12); 26 individuals completed the study. After randomization, participants underwent a 4-day buprenorphine/naloxone taper and 4-day post-taper observation period. Total sleep time (TST) was collected nightly with a wireless electroencephalography device and wrist-worn actigraphy; opioid withdrawal symptoms were assessed via the Subjective Opiate Withdrawal Scale (SOWS); and abuse potential was assessed on a 0- to 100-point visual analog scale of "High" every morning. A priori outcomes included two-group (collapsing suvorexant doses versus placebo) and three-group comparisons of area-under-the-curve (AUC) scores for TST, SOWS, and High. In two-group comparisons, participants receiving suvorexant displayed increased TST during the buprenorphine/naloxone taper and decreased SOWS during the post-taper period. In three-group comparisons, participants receiving 20 mg of suvorexant versus placebo displayed increased AUC for TST during the buprenorphine/naloxone taper, but there was no difference in SOWS among groups. There was no evidence of abuse potential in two- or three-group analyses. The results suggest that suvorexant might be a promising treatment for sleep and opioid withdrawal in individuals undergoing a buprenorphine/naloxone taper.


Assuntos
Buprenorfina , Síndrome de Abstinência a Substâncias , Analgésicos Opioides/uso terapêutico , Azepinas , Buprenorfina/uso terapêutico , Fissura , Método Duplo-Cego , Humanos , Naloxona/farmacologia , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/farmacologia , Antagonistas de Entorpecentes/uso terapêutico , Tratamento de Substituição de Opiáceos , Sono , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Resultado do Tratamento , Triazóis
14.
Hematology ; 27(1): 723-732, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35688453

RESUMO

OBJECTIVES: Patients with haematologic malignancies are at high risk of developing invasive fungal infections (IFIs). Current guidelines recommend the use of azoles for IFI prophylaxis; however, in many clinical situations, antifungal prophylaxis is used off-label. We conducted a systematic literature review to provide haematologists with the available evidence on the effectiveness and safety of isavuconazole in IFI prophylaxis in interventional and real-world, observational studies. METHODS: Embase, MEDLINE and Cochrane Library databases, and relevant conference proceedings and clinical trial registries, were searched for studies on the effectiveness and safety of isavuconazole prophylaxis in adults at high risk of IFIs. Studies were assessed for inclusion and risk of bias. RESULTS: Nine studies were eligible for inclusion in the review, eight of which were in haematologic populations (patients undergoing haematopoietic stem cell transplantation or with acute myeloid leukaemia or myelodysplastic syndromes; n = 5) or included haematologic populations (n = 3). Evidence from these studies suggests isavuconazole is effective for IFI prophylaxis in the haematologic setting. However, the studies frequently lacked safety data, most were based on small patient populations from single centres and risk of bias could not be assessed for five studies. DISCUSSION: These findings provide evidence for isavuconazole as an alternative azole for prophylaxis in high-risk populations. Limitations include lack of applicability of risk of bias assessment tools, level of filtering applied in the search strategy and focus on English-language publications. CONCLUSION: Isavuconazole may be an effective azole for IFI prophylaxis in high-risk haematologic populations, although further studies are needed.


Assuntos
Antifúngicos , Infecções Fúngicas Invasivas , Adulto , Antifúngicos/efeitos adversos , Humanos , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/etiologia , Infecções Fúngicas Invasivas/prevenção & controle , Nitrilas/uso terapêutico , Piridinas , Triazóis/efeitos adversos
15.
Mol Autism ; 13(1): 25, 2022 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-35690870

RESUMO

BACKGROUND: Autism spectrum disorder (ASD) is a common and heterogeneous neurodevelopmental condition that is characterized by the core symptoms of social communication difficulties and restricted and repetitive behaviors. At present, there is an unmet medical need for therapies to ameliorate these core symptoms in order to improve quality of life of autistic individuals. However, several challenges are currently faced by the ASD community relating to the development of pharmacotherapies, namely in the conduct of clinical trials. Balovaptan is a V1a receptor antagonist that has been investigated to improve social communication difficulties in individuals with ASD. In this viewpoint, we draw upon our recent first-hand experiences of the balovaptan clinical development program to describe current challenges of ASD trials. DISCUSSION POINTS: The balovaptan trials were conducted in a wide age range of individuals with ASD with the added complexities associated with international trials. When summarizing all three randomized trials of balovaptan, a placebo response was observed across several outcome measures. Placebo response was predicted by greater baseline symptom severity, online recruitment of participants, and less experienced or non-academic trial sites. We also highlight challenges relating to selection of outcome measures in ASD, the impact of baseline characteristics, and the role of expectation bias in influencing trial results. CONCLUSION: Taken together, the balovaptan clinical development program has advanced our understanding of the key challenges facing ASD treatment research. The insights gained can be used to inform and improve the design of future clinical trials with the collective aim of developing efficacious therapies to support individuals with ASD.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno Autístico/complicações , Transtorno Autístico/tratamento farmacológico , Benzodiazepinas , Humanos , Piridinas , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Triazóis
16.
Arerugi ; 71(4): 313-320, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-35691899

RESUMO

BACKGROUND: Ten percent efinaconazole nail solution (EFCZ solution) is a new topical triazole antifungal drug, and we sometimes encounter patients with allergic contact dermatitis (ACD) caused by EFCZ solution in our outpatient clinic. However, no previous reports have summarized the patch test (PT) results obtained for individual ingredients in several patients with EFCZ solution-induced ACD. OBJECTIVES: This study aimed to 1) confirm the causative agent of EFCZ solution-induced ACD based on PT of individual ingredients and 2) analyze the optimal concentration and vehicle for such PT on the basis of previous studies. PATIENTS AND METHODS: We clinically diagnosed eight patients with EFCZ solution-induced ACD from Sep. 2014 to Aug. 2021, and performed 48-hour closed PT using EFCZ solution and its ingredients. Readings were done on days (D) 2, 3, and 7 according to the International Contact Dermatitis Research Group criteria. RESULTS: Six of the 8 patients underwent PT with EFCZ solution, and all showed + to +++ reactions on D3. The results for the main component, EFCZ, were + to +++ on D3 in all patients. Two patients were patch tested with both 10% EFCZ in ethanol and 10% EFCZ in petrolatum, which produced similar reactions. One patient had an allergic reaction to ethanol. CONCLUSIONS: The causative agent of EFCZ solution-induced ACD was EFCZ in all patients. For PT, we recommend EFCZ solution as is, its 10-fold dilution and 1% and 0.1% EFCZ in petrolatum.


Assuntos
Dermatite Alérgica de Contato , Alérgenos , Dermatite Alérgica de Contato/diagnóstico , Dermatite Alérgica de Contato/etiologia , Etanol , Humanos , Testes do Emplastro/efeitos adversos , Testes do Emplastro/métodos , Vaselina , Triazóis/efeitos adversos
17.
J Food Drug Anal ; 30(1): 128-149, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35647721

RESUMO

Leishmaniasis remains a serious public health problem in many tropical regions of the world. Among neglected tropical diseases, the mortality rate of leishmaniasis is second only to malaria. All currently approved therapeutics have toxic side effects and face rapidly increasing resistance. To identify existing drugs with antileishmanial activity and predict the mechanism of action, we designed a drug-discovery pipeline utilizing both in-silico and in-vitro methods. First, we screened compounds from the Selleckchem Bio-Active Compound Library containing ~1622 FDA-approved drugs and narrowed these down to 96 candidates based on data mining for possible anti-parasitic properties. Next, we completed preliminary in-vitro testing of compounds against Leishmania amastigotes and selected the most promising active compounds, Lansoprazole and Posaconazole. We identified possible Leishmania drug targets of Lansoprazole and Posaconazole using several available servers. Our in-silico screen identified likely Lansoprazole targets as the closely related calcium-transporting ATPases (LdBPK_352080.1, LdBPK_040010.1, and LdBPK_170660.1), and the Posaconazole target as lanosterol 14-alpha-demethylase (LdBPK_111100.1). Further validation showed LdBPK_352080.1 to be the most plausible target based on induced-fit docking followed by long (100ns) MD simulations to confirm the stability of the docked complexes. We present a likely ion channel-based mechanism of action of Lansoprazole against Leishmania calcium-transporting ATPases, which are essential for parasite metabolism and infectivity. The LdBPK_111100.1 interaction with Posaconazole is very similar to the known fungal orthologue. Herein, we present two novel anti-leishmanial agents, Posaconazole and Lansoprazole, already approved by the FDA for different indications and propose plausible mechanisms of action for their antileishmanial activity.


Assuntos
Antiprotozoários , Leishmania , Leishmaniose , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Reposicionamento de Medicamentos , Humanos , Técnicas In Vitro , Lansoprazol/farmacologia , Lansoprazol/uso terapêutico , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologia , Triazóis
18.
BMC Cancer ; 22(1): 627, 2022 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-35672711

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) constitutes 10-20% of breast cancers and is challenging to treat due to a lack of effective targeted therapies. Previous studies in TNBC cell lines showed in vitro growth inhibition when JQ1 or GSK2801 were administered alone, and enhanced activity when co-administered. Given their respective mechanisms of actions, we hypothesized the combinatorial effect could be due to the target genes affected. Hence the target genes were characterized for their expression in the TNBC cell lines to prove the combinatorial effect of JQ1 and GSK2801. METHODS: RNASeq data sets of TNBC cell lines (MDA-MB-231, HCC-1806 and SUM-159) were analyzed to identify the differentially expressed genes in single and combined treatments. The topmost downregulated genes were characterized for their downregulated expression in the TNBC cell lines treated with JQ1 and GSK2801 under different dose concentrations and combinations. The optimal lethal doses were determined by cytotoxicity assays. The inhibitory activity of the drugs was further characterized by molecular modelling studies. RESULTS: Global expression profiling of TNBC cell lines using RNASeq revealed different expression patterns when JQ1 and GSK2801 were co-administered. Functional enrichment analyses identified several metabolic pathways (i.e., systemic lupus erythematosus, PI3K-Akt, TNF, JAK-STAT, IL-17, MAPK, Rap1 and signaling pathways) enriched with upregulated and downregulated genes when combined JQ1 and GSK2801 treatment was administered. RNASeq identified downregulation of PTPRC, MUC19, RNA5-8S5, KCNB1, RMRP, KISS1 and TAGLN (validated by RT-qPCR) and upregulation of GPR146, SCARA5, HIST2H4A, CDRT4, AQP3, MSH5-SAPCD1, SENP3-EIF4A1, CTAGE4 and RNASEK-C17orf49 when cells received both drugs. In addition to differential gene regulation, molecular modelling predicted binding of JQ1 and GSK2801 with PTPRC, MUC19, KCNB1, TAGLN and KISS1 proteins, adding another mechanism by which JQ1 and GSK2801 could elicit changes in metabolism and proliferation. CONCLUSION: JQ1-GSK2801 synergistically inhibits proliferation and results in selective gene regulation. Besides suggesting that combinatorial use could be useful therapeutics for the treatment of TNBC, the findings provide a glimpse into potential mechanisms of action for this combination therapy approach.


Assuntos
Azepinas/farmacologia , Carcinoma Hepatocelular , Neoplasias Hepáticas , Triazóis/farmacologia , Neoplasias de Mama Triplo Negativas , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Cisteína Endopeptidases/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Indolizinas , Kisspeptinas/genética , Neoplasias Hepáticas/genética , Fosfatidilinositol 3-Quinases/metabolismo , Receptores Depuradores Classe A/genética , Sulfonas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
19.
Future Med Chem ; 14(12): 867-880, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35642458

RESUMO

Aim: To synthesize and screen phenanthridine and 1,2,3-triazole derivatives for antileishmanial activity. Methodology: Synthesized analogs were tested for antileishmanial activity against transgenic strain of Leishmania infantum promastigotes and ex vivo infections. Results: Compounds T01, T08 and T11 revealed significant activity with EC50 <30 µm and lacked toxicity in mouse spleen and HepG2 cells. T01 with EC50 3.07 µm is fourfold more potent than the drug miltefosine (EC50 12.6 µM) against L. infantum promastigotes. In silico studies indicate that the analogs are nontoxic. A molecular docking analysis was also carried out on the T01 and T08 to investigate the binding pattern at the active site of the chosen target trypanothione reductase. Conclusion: The results of this study reveal that phenanthridine triazoles exhibit antileishmanial activity.


Assuntos
Antiprotozoários , Leishmania infantum , Animais , Antiprotozoários/química , Camundongos , Simulação de Acoplamento Molecular , Fenantridinas/farmacologia , Triazóis/farmacologia
20.
J Org Chem ; 87(12): 7818-7825, 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35671353

RESUMO

In this study, the diverse derivatives of dipyrrolyldiketone boron complexes as anion-responsive π-electronic systems were synthesized via the Huisgen cycloaddition of an ethynyl-substituted anion receptor and azide derivatives. The obtained triazole-substituted anion receptors showed effective anion-binding behaviors and ion-pairing assemblies comprising receptor-anion complexes and countercations. Solid-state ion-pairing structures were modulated according to the introduced azide moieties along with coexisting bulky and π-electronic cations.


Assuntos
Química Click , Triazóis , Ânions/química , Azidas , Cristalografia por Raios X , Eletrônica , Pirróis/química
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