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1.
Medicina (Kaunas) ; 57(1)2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-33435164

RESUMO

This article aims to critically review the evidence on the available therapeutic strategies for the treatment of hyperuricemia. For this reason, several papers were reviewed. Xanthine oxidase inhibitors are the safest and most effective uric acid lowering drugs for the management of chronic hyperuricemia, while the efficacy of uricosuric agents is strongly modulated by pharmacogenetics. Emergent drugs (lesinurad, peglotidase) were found to be more effective for the acute management of refractory hyperuricemia, but their use is supported by a relatively small number of clinical trials so that further well-designed clinical research is needed to deepen their efficacy and safety profile.


Assuntos
Hiperuricemia/tratamento farmacológico , Uricosúricos/uso terapêutico , Xantina Oxidase/antagonistas & inibidores , Acetamidas/uso terapêutico , Alopurinol/uso terapêutico , Benzobromarona/uso terapêutico , Doença Crônica , Medicina Baseada em Evidências , Febuxostat/uso terapêutico , Supressores da Gota/uso terapêutico , Humanos , Naftalenos/uso terapêutico , Nitrilos/uso terapêutico , Fenilacetatos/uso terapêutico , Polietilenoglicóis/uso terapêutico , Probenecid/uso terapêutico , Propionatos/uso terapêutico , Piridinas/uso terapêutico , Tioglicolatos/uso terapêutico , Triazóis/uso terapêutico , Urato Oxidase/uso terapêutico
2.
Anal Chem ; 93(5): 2767-2775, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33474935

RESUMO

Clinical tissue specimens are often unscreened, and preparation of tissue sections for analysis by mass spectrometry imaging (MSI) can cause aerosolization of particles potentially carrying an infectious load. We here present a decontamination approach based on ultraviolet-C (UV-C) light to inactivate clinically relevant pathogens such as herpesviridae, papovaviridae human immunodeficiency virus, or SARS-CoV-2, which may be present in human tissue samples while preserving the biodistributions of analytes within the tissue. High doses of UV-C required for high-level disinfection were found to cause oxidation and photodegradation of endogenous species. Lower UV-C doses maintaining inactivation of clinically relevant pathogens to a level of increased operator safety were found to be less destructive to the tissue metabolome and xenobiotics. These doses caused less alterations of the tissue metabolome and allowed elucidation of the biodistribution of the endogenous metabolites. Additionally, we were able to determine the spatially integrated abundances of the ATR inhibitor ceralasertib from decontaminated human biopsies using desorption electrospray ionization-MSI (DESI-MSI).


Assuntos
Descontaminação/métodos , Raios Ultravioleta , Animais , Azetidinas/análise , Azetidinas/uso terapêutico , /virologia , Neoplasias de Cabeça e Pescoço/química , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Metaboloma , Naftalenos/análise , Naftalenos/uso terapêutico , Fotólise/efeitos da radiação , Ratos , Ratos Wistar , /efeitos da radiação , Espectrometria de Massas por Ionização por Electrospray/métodos , Terfenadina/química , Inativação de Vírus/efeitos da radiação
3.
J Ethnopharmacol ; 264: 113246, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32781257

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Cyperus rotundus L. (Cyperaceae) is a widespread herbal in China and widely used in Traditional Chinese Medicine for multiple effects such as anti-arthritic, anti-genotoxic, anti-mutagenic, anti-bacterial effects, and analgesic. α-Cyperone is an active compound in Cyperus rotundus and has analgesic effects, but the exact molecular mechanisms require further investigations. MATERIALS AND METHODS: Tumor-derived DNA isolated from Lewis cell lines was transfected into microglia, and analyzed for stimulator of interferon genes (STING) effects. The downstream protein, such as interferon regulatory factor 3 (IRF3) and p65 nuclear factor-κB (NF-κB) were treated with STING siRNA and 5,6-dimethyllxanthenone-4-acetic acid (DMXAA) in microglia. The α-Cyperone effect on microglia was also investigated. RESULTS: Tumor-derived DNA activate microglia by upregulation of STING and downstream proteins. STING siRNA was reduced to its downstream expression and neuroinflammation inhibition was caused by tumor-derived DNA. However, DMXAA reversed the STING siRNA effect and increased neuroinflammation. α-Cyperone takes inhibitory effects on tumor-derived DNA that trigger microglia by STING pathway. CONCLUSIONS: α-Cyperone inhibition by tumor-derived DNA activated microglial to neuroinflammation in STING signaling pathway.


Assuntos
DNA de Neoplasias/antagonistas & inibidores , DNA de Neoplasias/genética , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Microglia/efeitos dos fármacos , Naftalenos/farmacologia , Animais , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/genética , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Camundongos , Microglia/fisiologia , Naftalenos/uso terapêutico
4.
Zhonghua Nan Ke Xue ; 26(7): 611-615, 2020 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-33377716

RESUMO

Objective: To observe the clinical effect of priligy (dapoxetine hydrochloride) combined with behavioral therapy and psychological counseling in the treatment of primary premature ejaculation (PPE). METHODS: A total of 202 PPE patients diagnosed from 2017 to 2018 were randomized into a control (n = 100) and an experimental group (n = 102), the former treated with oral priligy at 30 mg 1-3 hours before anticipated sexual activity, and the latter by the same medication combined with 30-minute behavioral therapy and psychological counseling once a month for two times. The therapeutic effects were evaluated according to the Premature Ejaculation Profile (PEP) scores of the patients at 1 and 2 months of treatment. RESULTS: After 1 month of treatment, both groups of the patients showed significant improvement, as compared with the baseline, in the PEP scores on personal distress related to ejaculation (P < 0 05), interpersonal difficulty related to ejaculation (P < 0.05) and satisfaction with sexual intercourse (P < 0.05) but not on perceived control over ejaculation (P > 0.05). At 2 months, however, the patients' scores on all the four PEP items were dramatically improved, even more significantly in the experimental than in the control group, as on perceived control over ejaculation (2.73 ± 0.95 vs 2.22 ± 0.68, P < 0.05), personal distress related to ejaculation (2.97 ± 1.07 vs 2.57 ± 0.69, P < 0.05), interpersonal difficulty related to ejaculation (3.19 ± 1.03 vs 2.77 ± 0.69, P < 0 05) and satisfaction with sexual intercourse (2.85 ± 0.99 vs 2.35 ± 0.63, P < 0.05). There was no statistically significant difference in the incidence rate of adverse events between the experimental and control groups (21.6% vs 20.0%, P > 0.05), and all the symptoms were relieved within 24 hours. CONCLUSIONS: Priligy combined with behavioral therapy and psychological counseling is more effective than priligy alone in improving the sexual function of PPE patients, raise their interest in sexual life and increase the intimacy between the partners, and can even achieve clinical cure in some patients.


Assuntos
Benzilaminas/uso terapêutico , Terapia Cognitivo-Comportamental , Naftalenos/uso terapêutico , Ejaculação Precoce , Psicoterapia , Inibidores de Captação de Serotonina/uso terapêutico , Humanos , Masculino , Ejaculação Precoce/terapia , Resultado do Tratamento
5.
Medicine (Baltimore) ; 99(46): e22566, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33181644

RESUMO

BACKGROUND: Secondary hyperparathyroidism (SHPT) have been associated with poor health outcomes in hemodialysis patients. The cinacalcet has popularized in clinic which has efficacy but more adverse events; the novel oral calcimimetic agents evocalcet has appeared in recent years. However, it is currently unknown whether evocalcet produces more beneficial effects and fewer adverse events in patients with SHPT. The aim of this systematic review is to estimate the safety and efficacy of evocacelt. METHODS: Only randomized controlled trials (RCT) will be included in MEDLINE, EMBASE, the Cochrane Register of Controlled Trials, and PUBMED from July 2010 to July 2020. Two reviewers will screen, select studies, extract data, and assess quality independently. The methodological quality including the risk of bias of the included studies will be evaluated using a modified assessment form, which is based on Cochrane assessment tool. Review Manager 5.3 software will be used for heterogeneity assessment, generating funnel-plots, data synthesis, subgroup analysis, and sensitivity analysis. We will use GRADE system to evaluate the quality of our evidence. RESULTS: We will provide some more practical and targeted results investigating the effect and safety of evocalcet for SHPT on hemodialysis in the current meta-analysis. CONCLUSION: The stronger evidence about evocalcet effect and safety will be provided for clinicians and policymakers. ETHICS AND DISSEMINATION: Ethical approval will be unnecessary because the data being included in this systematic review come from published literature and there will be no concerns regarding privacy. Findings of this research will be disseminated in a peer-reviewed journal or conference presentations. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/N59RB.


Assuntos
Hiperparatireoidismo Secundário/tratamento farmacológico , Naftalenos/normas , Pirrolidinas/normas , Diálise Renal/métodos , Calcimiméticos/normas , Calcimiméticos/uso terapêutico , Protocolos Clínicos , Humanos , Metanálise como Assunto , Naftalenos/uso terapêutico , Pirrolidinas/uso terapêutico , Diálise Renal/tendências , Insuficiência Renal Crônica , Revisões Sistemáticas como Assunto
6.
Medicine (Baltimore) ; 99(34): e21866, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846840

RESUMO

INTRODUCTION: Premature ejaculation (PE) affects 8% to 30% of adult men worldwide. Recently, the incidence of PE is on the rise. A series of prior studies suggested that the incidence of PE is related to various biological factors as low testosterone, low serum vitamin D, diabetes, lower urinary tract symptoms, and other psychological factors. At present, the major treatments include selective serotonin reuptake inhibitors antidepressants (dapoxetine, paroxetine), topical anesthetics, phosphodiesterase-5 inhibitor, circumcision, and selective dorsal neurotomy (SDN). The previous study found that SDN is effective for PE. METHODS AND ANALYSIS: The electronic databases of MEDLINE, PubMed, Web of Science, EMBASE, Cochrane Library, Clinicaltrials. org, China National Knowledge Infrastructure Database (CNKI), Wan fang Database, China Biology Medicine Database (CBM), VIP Science Technology Periodical Database, Chinese Clinical Trial Registry will be retrieved. All the randomized controlled trials of selective dorsal penile neurotomy for patients with PE will be included. The outcome includes intravaginal ejaculation latency time and Chinese Index of Sexual Function for Premature Ejaculation-5. We will conduct this study strictly according to the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: The present study is a protocol for systematic review and meta-analysis without results, and data analysis will be carried out after the protocol. We will share our findings on June 30th of 2021. CONCLUSION: SDN can effectively prolong IELT, but its efficacy has not been assessed scientifically and systematically. To address this limitation, this study will inspect the efficacy and safety of the SDN treatment in patients with PE. ETHICS AND DISSEMINATION: Formal ethical approval is not required in this protocol. We will collect and analyze data based on published studies, and since there are no patients involved in this study, individual privacy will not be under concerns. The results of this review will be disseminated to peer-reviewed journals or submit to related conferences. PROTOCOL REGISTRATION NUMBER: INPLASY202070084.


Assuntos
Pênis/inervação , Ejaculação Precoce/terapia , Nervo Pudendo/cirurgia , Adulto , Anestésicos Locais/uso terapêutico , Benzilaminas/uso terapêutico , Circuncisão Masculina/métodos , Ejaculação/fisiologia , Humanos , Incidência , Masculino , Naftalenos/uso terapêutico , Paroxetina/uso terapêutico , Pênis/fisiopatologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Ejaculação Precoce/epidemiologia , Ejaculação Precoce/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores de Captação de Serotonina/uso terapêutico
7.
Am J Kidney Dis ; 76(3): 321-330, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32475604

RESUMO

RATIONALE & OBJECTIVE: Comparative benefits and harms of calcimimetic agents used for the treatment of secondary hyperparathyroidism have not been well characterized. We sought to compare the effectiveness of 3 calcimimetic agents using published data. STUDY DESIGN: Systematic review of randomized controlled trials and network meta-analysis. SETTING & STUDY POPULATION: Adults with chronic kidney disease enrolled in a clinical trial of a calcimetic agent. SEARCH STRATEGY & SOURCES: MEDLINE, EMBASE, CENTRAL (from February 7, 2013, to November 21, 2019), and a published meta-analysis. DATA EXTRACTION: Two reviewers independently extracted the study data, assessed risk of bias, and rated evidence certainty using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. ANALYTICAL APPROACH: Frequentist network meta-analysis was conducted. The primary review outcomes were achievement of a target reduction in serum parathyroid hormone (PTH) levels and hypocalcemia. Additional outcomes were nausea, vomiting, serious adverse events, all-cause mortality, cardiovascular mortality, heart failure, and fracture. RESULTS: 36 trials (11,247 participants) were included. All except 4 trials involved dialysis patients. Median follow-up was 26 weeks (range, 1 week to 21.2 months). Compared with placebo, calcimimetic agents had higher odds of achieving target PTH levels with high or moderate certainty. Etelcalcetide had the highest odds of achieving a PTH target compared with evocalcet (OR, 4.93; 95% CI, 1.33-18.2) and cinacalcet (OR, 2.78; 95% CI, 1.19-6.67). Etelcalcetide appeared to cause more hypocalcemia than cinacalcet and evocalcet. Cinacalcet and to a lesser extent etelcalcetide appeared to cause more nausea than placebo. Differences in risk for mortality, cardiovascular end points, or fractures across calcimimetic agents could not be discerned with sufficient certainty. LIMITATIONS: Lack of longer-term data; heterogeneous end point definitions. CONCLUSIONS: Evidence of the benefits of calcimimetic therapy is limited to short-term assessment of a putative surrogate outcome (serum PTH). Although etelcalcetide was associated with the largest reduction in PTH levels, side-effect profiles differed across the 3 calcimimetic agents, making it not possible to identify 1 preferred agent.


Assuntos
Calcimiméticos/uso terapêutico , Cinacalcete/uso terapêutico , Hiperparatireoidismo Secundário/tratamento farmacológico , Naftalenos/uso terapêutico , Peptídeos/uso terapêutico , Pirrolidinas/uso terapêutico , Adulto , Calcimiméticos/efeitos adversos , Cálcio/sangue , Doenças Cardiovasculares/epidemiologia , Cinacalcete/efeitos adversos , Comorbidade , Feminino , Fraturas Ósseas/epidemiologia , Insuficiência Cardíaca/epidemiologia , Humanos , Hiperparatireoidismo Secundário/sangue , Hiperparatireoidismo Secundário/etiologia , Masculino , Mortalidade , Naftalenos/efeitos adversos , Náusea/induzido quimicamente , Hormônio Paratireóideo/sangue , Peptídeos/efeitos adversos , Pirrolidinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Resultado do Tratamento , Vômito/induzido quimicamente
8.
J Bone Miner Metab ; 38(5): 687-694, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32274572

RESUMO

INTRODUCTION: Primary hyperparathyroidism (PHPT) is caused by parathyroid adenoma, primary parathyroid hyperplasia, or parathyroid carcinoma. For some patients with PHPT controlling serum calcium levels is critical. MATERIALS AND METHODS: We conducted an open-label, single-arm, 52-week, phase III study in Japanese patients with hypercalcemia due to PHPT to demonstrate efficacy and safety of evocalcet, a new calcimimetic. Patients with intractable PHPT (n = 13), postsurgical recurrence (n = 2), and parathyroid carcinoma (n = 3) were enrolled. Evocalcet administration started at a dose of 2 mg once or twice daily and was titrated to achieve the target serum corrected calcium (cCa) concentration (≤ 10.3 mg/dL) for two consecutive weeks (maximal dose 24 mg/day). RESULTS: Fourteen patients achieved the target (77.8%; 95% confidence interval [CI] 52.4-93.6). The lower limit of 95% CI exceeded the predetermined reference limit (11%), and thus, efficacy was confirmed. Of 18 patients, 12 (66.7%; 95% CI 41.0-86.7) showed decreased serum cCa of ≥ 1.0 mg/dL from the baseline for two consecutive weeks during the titration phase. Sixteen patients entered the maintenance phase, and 15 patients completed the study. Treatment-emergent adverse events (TEAEs) were recorded in 18/18 patients (100%) and drug-related TEAEs in 8/18 (44.4%). The most commonly observed drug-related TEAE was nausea (2/18 patients). No unexpected drug-related TEAEs were observed. All drug-related TEAEs were mild in severity. No patient discontinued the study because of drug-related TEAEs. CONCLUSION: Evocalcet demonstrated long-term effectiveness in reducing serum cCa concentrations and safety without any unexpected drug-related TEAEs in PHPT patients.


Assuntos
Hiperparatireoidismo Primário/tratamento farmacológico , Naftalenos/uso terapêutico , Pirrolidinas/uso terapêutico , Cálcio/sangue , Creatinina/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Hiperparatireoidismo Primário/sangue , Masculino , Pessoa de Meia-Idade , Naftalenos/administração & dosagem , Naftalenos/efeitos adversos , Naftalenos/farmacologia , Hormônio Paratireóideo/sangue , Fosfatos/sangue , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacologia
9.
PLoS One ; 15(4): e0232428, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32343734

RESUMO

BACKGROUND: Elevated parathyroid hormone (PTH) levels in secondary hyperparathyroidism (SHPT) lead to vascular calcification, which is associated with cardiovascular events and mortality. Increased PTH production is caused by the excessive proliferation of parathyroid gland cells, which is accelerated by abnormal mineral homeostasis. Evocalcet, an oral calcimimetic agent, inhibits the secretion of PTH from parathyroid gland cells and has been used for the management of SHPT in dialysis patients. We observed the effects of evocalcet on ectopic calcification and parathyroid hyperplasia using chronic kidney disease (CKD) rats with SHPT. METHODS: CKD rats with SHPT induced by adenine received evocalcet orally for 5 weeks. The calcium and inorganic phosphorus content in the aorta, heart and kidney was measured. Ectopic calcified tissues were also assessed histologically. To observe the effects on the proliferation of parathyroid gland cells, parathyroid glands were histologically assessed in CKD rats with SHPT induced by 5/6 nephrectomy (Nx) after receiving evocalcet orally for 4 weeks. RESULTS: Evocalcet prevented the increase in calcium and inorganic phosphorus content in the ectopic tissues and suppressed calcification of the aorta, heart and kidney in CKD rats with SHPT by reducing the serum PTH and calcium levels. Evocalcet suppressed the parathyroid gland cell proliferation and reduced the sizes of parathyroid cells in CKD rats with SHPT. CONCLUSIONS: These findings suggest that evocalcet would prevent ectopic calcification and suppress parathyroid hyperplasia in patients with SHPT.


Assuntos
Hiperparatireoidismo Secundário/complicações , Naftalenos/uso terapêutico , Glândulas Paratireoides/patologia , Pirrolidinas/uso terapêutico , Calcificação Vascular/prevenção & controle , Animais , Calcimiméticos/uso terapêutico , Hiperplasia/etiologia , Hiperplasia/prevenção & controle , Masculino , Ratos , Ratos Sprague-Dawley , Calcificação Vascular/etiologia
10.
Int J Nanomedicine ; 15: 1517-1535, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32189966

RESUMO

Purpose: Dapoxetine HCl (DH), a selective serotonin reuptake inhibitor, may be useful for the treatment of rheumatic arthritis (RA). The purpose of this study was to investigate the therapeutic efficacy of transdermal delivery of DH in transethosome nanovesicles (TENVs). This novel delivery of DH may overcome the drawbacks associated with orally administered DH and improve patient compliance. Methods: DH-TENV formulations were prepared using an injection- sonication method and optimized using a 33 Box-Behnken-design with Design Expert® software. The TENV formulations were assessed for entrapment efficiency (EE-%), vesicle size, zeta potential, in vitro DH release, and skin permeation. The tolerability of the optimized DH-TENV gel was investigated using a rat skin irritation test. A pharmacokinetic analysis of the optimized DH-TENV gel was also conducted in rats. Moreover, the anti-RA activity of the optimized DH-TENV gel was assessed based on the RA-specific marker anti-cyclic cirtullinated peptide antibody (anti-CCP), the cartilage destruction marker cartilage oligomeric matrix protein (COMP) and the inflammatory marker interleukin-6 (IL-6). Level of tissue receptor activator of nuclear factor kappa-Β ligand (RANKL) were also assessed. Results: The optimized DH-TENV formulation involved spherical nanovesicles that had an appropriate EE- % and skin permeation characteristic. The DH-TENV gel was well tolerated by rats. The pharmacokinetics analysis showed that the optimized DH-TENV gel boosted the bioavailability of the DH by 2.42- and 4.16-fold compared to the oral DH solution and the control DH gel, respectively. Moreover, it significantly reduced the serum anti-CCP, COMP and IL-6 levels and decreased the RANKL levels. Furthermore, the DH-TENV gel attenuated histopathological changes by almost normalizing the articular surface and synovial fluid. Conclusion: The results indicate that DH-TENVs can improve transdermal delivery of DH and thereby alleviate RA.


Assuntos
Benzilaminas/uso terapêutico , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Naftalenos/uso terapêutico , Febre Reumática/tratamento farmacológico , Administração Cutânea , Animais , Benzilaminas/farmacocinética , Varredura Diferencial de Calorimetria , Feminino , Humanos , Articulações/diagnóstico por imagem , Articulações/patologia , Nanopartículas/ultraestrutura , Naftalenos/farmacocinética , Ligante RANK/metabolismo , Ratos Wistar , Febre Reumática/induzido quimicamente , Febre Reumática/diagnóstico por imagem , Febre Reumática/patologia , Testes de Irritação da Pele
11.
PLoS One ; 15(3): e0230753, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32218595

RESUMO

Rabbits (Oryctolagus cuniculi) are very popular as pets. However, problems of otitits caused by Psoroptes cuniculi are one of the main reasons to visit the veterinarian. Isoxazolines are an alternative treatment to treat this mite, and therefore, an evaluation of the effectiveness of oral afoxalaner with milbemycin oxime in rabbits infected with P. cuniculi was carried out. Nineteen rabbits, of New Zealand breed, with otitis due to an infection with P. cuniculi, were treated, whereas six rabbits were left untreated and formed the control group. The ear canals of each individual were examined, through the collection of otic exudate samples with cotton swabs. These were visualized under the microscope to identify the ectoparasite. Each animal was treated with a single oral dose of 2.50 mg / kg of afoxolaner, and 0.50 mg / kg of milbemycin oxime. Clinical signs and lesions associated with the infection, such as the presence of detritus, cerumen and / or scabs, and erythema, were evaluated. After receiving the treatment, all the lesions were classified as: mild, moderate and intense, with a visual analog scale. A week after providing medication, there was a decrease in the lesions of the group treated with Nexgard Spectra®, without further topical or systemic treatment. The decrease was gradual in the treated group and no recurrence was detected of P. cuniculi infection in both ears. Thus, the administration of a single oral dose of afoxolaner with milbemycin oxime was effective for the treatment of P. cuniculi infection in rabbits.


Assuntos
Isoxazóis/farmacologia , Macrolídeos/farmacologia , Infestações por Ácaros/tratamento farmacológico , Naftalenos/farmacologia , Psoroptidae/fisiologia , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Isoxazóis/uso terapêutico , Macrolídeos/uso terapêutico , Naftalenos/uso terapêutico , Coelhos
12.
Molecules ; 25(4)2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32085460

RESUMO

: Multiple drug resistant fungi pose a serious threat to human health, therefore the development of completely new antimycotics is of paramount importance. The in vitro antifungal activity of the original, 1-amino-5-isocyanonaphthalenes (ICANs) was evaluated against reference strains of clinically important Candida species. Structure-activity studies revealed that the naphthalene core and the isocyano- together with the amino moieties are all necessary to exert antifungal activity. 1,1-N-dimethylamino-5-isocyanonaphthalene (DIMICAN), the most promising candidate, was tested further in vitro against clinical isolates of Candida species, yielding a minimum inhibitory concentration (MIC) of 0.04-1.25 µg/mL. DIMICAN was found to be effective against intrinsically fluconazole resistant Candida krusei isolates, too. In vivo experiments were performed in a severly neutropenic murine model inoculated with a clinical strain of Candida albicans. Daily administration of 5 mg/kg DIMICAN intraperitoneally resulted in 80% survival even at day 13, whereas 100% of the control group died within six days. Based on these results, ICANs may become an effective clinical lead compound family against fungal pathogens.


Assuntos
Antifúngicos/farmacologia , Naftalenos/farmacologia , Animais , Antifúngicos/química , Antifúngicos/uso terapêutico , Candida albicans/efeitos dos fármacos , Candida albicans/isolamento & purificação , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Linhagem Celular , Modelos Animais de Doenças , Feminino , Humanos , Hifas/efeitos dos fármacos , Hifas/crescimento & desenvolvimento , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Naftalenos/química , Naftalenos/uso terapêutico , Relação Estrutura-Atividade
13.
BMC Urol ; 20(1): 11, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32013958

RESUMO

BACKGROUND: The treatment effect of dapoxetine in real-world practice is not well established. This study was to investigate the factors influencing efficacy of dapoxetine for the treatment of Premature ejaculation (PE) in the real-world setting. METHODS: Altogether 154 patients were followed up between Jan 2015 and Dec 2015. The clinical global impression of change (CGIC), premature ejaculation profile (PEP), the estimated intravaginal ejaculation latency time (eIELT) and estimated number of intravaginal thrusts before ejaculation (NITBE) were collected. The clinical characteristics of patients with CGIC = 0 and CGIC≥1 were compared. RESULTS: After 4 weeks treatment, an obvious improvement compared with the baseline was found regarding mean eIELT (2.4 ± 1.6 min vs 1.0 ± 0.7 min, P < 0.001) and mean NITBE (85.9 ± 61.9 times vs 37.4 ± 28.6 times, P < 0.001). The proportion of patients with a self-evaluation of at least "slightly better" and were categorized into "CGIC≥1" group was 70.1%. There were significant differences between patients in the "CGIC = 0" and "CGIC≥1" groups regarding mean NITBE (P = 0.010) and PEDT (P = 0.009) score at baseline. The adverse effects were acceptable. CONCLUSION: Dapoxetine was well-tolerated and improved the sexual satisfaction of patients with PE. The severity of PE based on PEDT and NITBE suggest that there could be an effectiveness change with dapoxetine use in real-world practice.


Assuntos
Benzilaminas/uso terapêutico , Naftalenos/uso terapêutico , Ejaculação Precoce/tratamento farmacológico , Ejaculação Precoce/epidemiologia , Inibidores de Captação de Serotonina/uso terapêutico , Adulto , China/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Ejaculação Precoce/diagnóstico , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
15.
Clin Cancer Res ; 26(2): 354-363, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31619444

RESUMO

PURPOSE: The FGFR1 gene is amplified in 14% of patients with HR + /HER2 - breast cancer. Efficacy and safety of lucitanib, an inhibitor of VEGFR1-3, FGFR1-3, and PDGFRα/ß, were assessed. PATIENTS AND METHODS: Patients with HR + /HER2 - metastatic breast cancer (MBC) received oral lucitanib in three centrally confirmed cohorts: (i) FGFR1 amplified, (ii) FGFR1 nonamplified, 11q13 amplified, and (iii) FGFR1 and 11q13 nonamplified. Key inclusion criteria included Eastern Cooperative Oncology Group Performance Status ≤2, ≥1 line of anticancer therapy, but ≤2 lines of chemotherapy. Primary endpoint was overall response rates (ORR) by RECIST1.1. Simon's two-stage design was used: If ≥2 patients responded among 21 patients, 20 additional patients could be enrolled in each cohort. FGFR1 copy-number variation (CNV) was determined by FISH and droplet digital PCR, whereas FGFR1 expression was determined by IHC. RESULTS: Seventy-six patients (32/18/26 in cohorts 1/2/3) from nine countries were enrolled. The prespecified primary endpoint was met in cohort 1 with ORR of 19% [95% confidence interval (CI), 9%-35%], but not in cohorts 2 and 3 with ORR of 0% (95% CI, 0%-18%) and 15% (95% CI, 6%-34%), respectively. Frequent adverse events included hypertension (87%), hypothyroidism (45%), nausea (33%), and proteinuria (32%). Exploratory biomarker analyses suggested higher ORR in patients with high FGFR1 amplification (≥4 CNV) than those without high amplification (22% vs. 9%). ORR in patients with FGFR1-high tumors (IHC, H-score ≥50) was 25% versus 8% in FGFR1-low cancers. CONCLUSIONS: Lucitanib had modest antitumor activity and significant hypertension-related toxicity in patients with HR + /HER2 - MBC. Although based on small sample sizes, exploratory biomarker analyses suggested that patients with high FGFR1 amplification or expression might derive greater benefit.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/metabolismo , Naftalenos/uso terapêutico , Quinolinas/uso terapêutico , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Amplificação de Genes , Humanos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Metástase Neoplásica , Segurança do Paciente , Inibidores de Proteínas Quinases/uso terapêutico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Resultado do Tratamento
16.
Vet Parasitol Reg Stud Reports ; 18: 100340, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31796179

RESUMO

Afoxolaner is a novel insecticidal and acaricidal of the isoxazoline family, which is used in veterinary practice to control infestation of dogs by fleas, ticks, and mites (NexGard, Boehringer Ingelheim). Ivermectin is an avermectin administered at microdoses to prevent infection of dogs with Dirofilaria immitis and is used off-label to control Rhipicephalus sanguineus infestation of dogs in numerous countries, including Thailand. Here we conducted two trials to assess the efficacy of afoxolaner for treating natural R. sanguineus sensu lato (s.l.) infestations of dogs residing in the Chiang Mai area of Thailand. The first trial compared the efficacies of afoxolaner and ivermectin in dogs infested with <500 ticks. A randomized, investigator-blinded, controlled study was conducted of 16 dogs, allocated into the groups as follows: afoxolaner (2.7-6.9 mg/kg, PO, group 1; n = 8), ivermectin (300 µg/kg, SC, group 2; n = 5), untreated (group 3; n = 3). Tick counts and drug administration were performed on days 0, 28, and 56. Mean numbers of ticks on day 0 in groups 1, 2, and 3 were not significantly different (225, 169, and 123, respectively; p = .36). The mean number of ticks (%efficacy to control) in groups 1, 2 and 3 on day 28 were 7 (97.05%), 230 (2.95%), and 237, respectively; on day 56 were 4 (96.11%), 93 (9.71%), and 103, respectively; and on day 84 were 1 (98.65%), 44 (40.54%), and 74, respectively. The efficacy of afoxolaner was >96%, whereas the efficacy of ivermectin was significantly lower compared with that of afoxolaner (p < .05) and never achieved the 90% efficacy threshold claimed by registration agencies. The second trial assessed the efficacy of afoxolaner for treating dogs with heavy tick infestations (>500 ticks/dog), including four dogs from two households. The dogs were treated monthly with Afoxolaner. The mean values of the numbers of ticks on dogs in the 2 households were not significantly different (913 and 800 on day 0, p = .18). The numbers of ticks significantly decreased thereafter, and the efficacy of afoxolaner was >99% on days 28, 56, and 84. Adverse reactions were not observed in either trial. In conclusion, this study confirms the efficacy of afoxolaner against adult R. sanguineus s.l. that naturally infests dogs that inhabit Thailand.


Assuntos
Acaricidas/uso terapêutico , Doenças do Cão/tratamento farmacológico , Isoxazóis/uso terapêutico , Ivermectina/uso terapêutico , Naftalenos/uso terapêutico , Rhipicephalus sanguineus/efeitos dos fármacos , Infestações por Carrapato/veterinária , Animais , Cães , Feminino , Masculino , Tailândia , Infestações por Carrapato/tratamento farmacológico
17.
Eur J Pharmacol ; 865: 172806, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31738934

RESUMO

Δ9-THC suppresses cisplatin-induced vomiting through activation of cannabinoid CB1 receptors. Cisplatin-evoked emesis is predominantly due to release of serotonin and substance P (SP) in the gut and the brainstem which subsequently stimulate their corresponding 5-HT3-and neurokinin NK1-receptors to induce vomiting. Δ9-THC can inhibit vomiting caused either by the serotonin precursor 5-HTP, or the 5-HT3 receptor selective agonist, 2-methyserotonin. In the current study, we explored whether Δ9-THC and related CB1/CB2 receptor agonists (WIN55,212-2 and CP55,940) inhibit vomiting evoked by SP (50 mg/kg, i.p.) or the NK1 receptor selective agonist GR73632 (5 mg/kg, i.p.). Behavioral methods were employed to determine the antiemetic efficacy of cannabinoids in least shrews. Our results showed that administration of varying doses of Δ9-THC (i.p. or s.c.), WIN55,212-2 (i.p.), or CP55,940 (i.p.) caused significant suppression of SP-evoked vomiting in a dose-dependent manner. When tested against GR73632, Δ9-THC also dose-dependently reduced the evoked emesis. The antiemetic effect of Δ9-THC against SP-induced vomiting was prevented by low non-emetic doses of the CB1 receptor inverse-agonist/antagonist SR141716A (<10 mg/kg). We also found that the NK1 receptor antagonist netupitant can significantly suppress vomiting caused by a large emetic dose of SR141716A (20 mg/kg). In sum, Δ9-THC and related cannabinoids suppress vomiting evoked by the nonselective (SP) and selective (GR73632) neurokinin NK1 receptor agonists via stimulation of cannabinoid CB1 receptors.


Assuntos
Benzoxazinas/uso terapêutico , Agonistas de Receptores de Canabinoides/uso terapêutico , Canabinoides/uso terapêutico , Cicloexanóis/uso terapêutico , Dronabinol/uso terapêutico , Morfolinas/uso terapêutico , Naftalenos/uso terapêutico , Receptores da Neurocinina-1/fisiologia , Vômito/tratamento farmacológico , Animais , Feminino , Masculino , Fragmentos de Peptídeos/farmacologia , Musaranhos , Substância P/análogos & derivados , Substância P/farmacologia , Vômito/induzido quimicamente
18.
Parasite ; 26: 63, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31687926

RESUMO

Twelve healthy dogs were included in this laboratory efficacy study. Six dogs were randomly allocated based on body weight to an untreated control group and six to an afoxolaner (NexGard®) treated group. In the treatment group, afoxolaner was administered orally on Day 0 in accordance with label instructions. On Days 1, 14 and 28, each dog was exposed to 60 unfed female and 10 male Phlebotomus perniciosus sandflies for 1 h. At the end of each exposure period, sandflies were counted and assessed for viability and feeding status. There was no statistical difference in mortality (0.0-5.4%), nor in feeding proportion (61.6-78%) between the control and the treated groups at all 1-h post-exposure assessments. After collection, live fed and unfed sandflies were kept for viability assessments at 48 and 72 h post-exposure. In the untreated control group, the average percentages of live, fed, female sandflies after exposure, on Days 1, 14 and 28, ranged from 51% to 74% at 48 h and from 46% to 57% at 72 h, demonstrating model robustness over the 28 days of the study. Significantly fewer live fed sandflies were recorded for the afoxolaner treated group (p < 0.01). The insecticidal efficacy was 100%, 95.9% and 75.2% at 48 h post Days 1, 14 and 28 exposures, respectively, and 100%, 100% and 86.3% at 72 h post Days 1, 14, and 28 exposures, respectively. A single administration of oral afoxolaner (NexGard®) to dogs significantly killed P. perniciosus sandflies 48 and 72 h after blood feeding for 1 month.


Assuntos
Doenças do Cão/tratamento farmacológico , Inseticidas/uso terapêutico , Isoxazóis/uso terapêutico , Naftalenos/uso terapêutico , Phlebotomus/efeitos dos fármacos , Infestações por Carrapato/veterinária , Administração Oral , Animais , Cães , Esquema de Medicação , Feminino , Masculino , Infestações por Carrapato/tratamento farmacológico
19.
Cells ; 8(10)2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31635389

RESUMO

Melanoma is the most aggressive and deadly type of skin cancer. Despite the advent of targeted therapies directed against specific oncogene mutations, melanoma remains a tumor that is very difficult to treat, and ultimately remains incurable. In the past two decades, stabilization of the non-canonical nucleic acid G-quadruplex structures within oncogene promoters has stood out as a promising approach to interfere with oncogenic signaling pathways in cancer cells, paving the way toward the development of G-quadruplex ligands as antitumor drugs. Here, we present the synthesis and screening of a library of differently functionalized core-extended naphthalene diimides for their activity against the BRAFV600E-mutant melanoma cell line. The most promising compound was able to stabilize G-quadruplexes that formed in the promoter regions of two target genes relevant to melanoma, KIT and BCL-2. This activity led to the suppression of protein expression and thus to interference with oncogenic signaling pathways involved in BRAF-mutant melanoma cell survival, apoptosis, and resistance to drugs. This G-quadruplex ligand thus represents a suitable candidate for the development of melanoma treatment options based on a new mechanism of action and could reveal particular significance in the context of resistance to targeted therapies of BRAF-mutant melanoma cells.


Assuntos
Imidas/uso terapêutico , Melanoma/metabolismo , Naftalenos/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Transdução de Sinais/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Dicroísmo Circular , Quadruplex G/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Melanoma/genética , Proteínas Proto-Oncogênicas c-bcl-2 , Proteínas Proto-Oncogênicas c-kit/genética , Transdução de Sinais/genética
20.
Urol Int ; 103(4): 439-443, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31554005

RESUMO

INTRODUCTION: To determine the pre-treatment factors related to the improvement of overactive bladder (OAB) symptom after alpha-1 blocker monotherapy in patients with benign prostatic hyperplasia complicated by OAB (BPH/OAB). METHODS: Post-hoc analysis of a prospective study in patients with BPH/OAB, randomized to receive silodosin 8 mg (n = 157) or naftopidil 75 mg (n = 157) treatment for 12 weeks, was performed. At 12 weeks post-administration, patients were divided into 2 groups (good responder [GR] group and poor responder [PR] group), according to the improvement in the OAB symptom score (OABSS). We compared the pre-administration parameters between both groups and evaluated the factors related to OAB improvement. RESULTS: Of 314 patients, 159 patients (50.6%) were classified into the GR and 155 (49.4%) into the PR. International Prostate Symptom score, total OABSS, OABSS urgency-score, OABSS urgency urinary incontinence (UUI)-score, post-void residual urine volume (PVR), and selection rate of naftopidil were significantly higher in the PR than in the GR. On multivariate logistic regression analysis, larger PVR, higher OABSS-UUI-score, and the choice of naftopidil were significant risk factors for insufficient improvement of OAB symptoms. CONCLUSIONS: Pre-treatment PVR, UUI severity, and the choice of treatment agent are predicting factors related to OAB improvement after alpha-1 blocker monotherapy in patients with BPH/OAB.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Indóis/uso terapêutico , Naftalenos/uso terapêutico , Piperazinas/uso terapêutico , Hiperplasia Prostática/complicações , Bexiga Urinária Hiperativa/complicações , Bexiga Urinária Hiperativa/tratamento farmacológico , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento
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