RESUMO
BACKGROUND: Carbapenem-resistant Enterobacterales species and multidrug-resistant Pseudomonas aeruginosa are global health threats. Cefepime-taniborbactam is an investigational ß-lactam and ß-lactamase inhibitor combination with activity against Enterobacterales species and P. aeruginosa expressing serine and metallo-ß-lactamases. METHODS: In this phase 3, double-blind, randomized trial, we assigned hospitalized adults with complicated urinary tract infection (UTI), including acute pyelonephritis, in a 2:1 ratio to receive intravenous cefepime-taniborbactam (2.5 g) or meropenem (1 g) every 8 hours for 7 days; this duration could be extended up to 14 days in case of bacteremia. The primary outcome was both microbiologic and clinical success (composite success) on trial days 19 to 23 in the microbiologic intention-to-treat (microITT) population (patients who had a qualifying gram-negative pathogen against which both study drugs were active). A prespecified superiority analysis of the primary outcome was performed after confirmation of noninferiority. RESULTS: Of the 661 patients who underwent randomization, 436 (66.0%) were included in the microITT population. The mean age of the patients was 56.2 years, and 38.1% were 65 years of age or older. In the microITT population, 57.8% of the patients had complicated UTI, 42.2% had acute pyelonephritis, and 13.1% had bacteremia. Composite success occurred in 207 of 293 patients (70.6%) in the cefepime-taniborbactam group and in 83 of 143 patients (58.0%) in the meropenem group. Cefepime-taniborbactam was superior to meropenem regarding the primary outcome (treatment difference, 12.6 percentage points; 95% confidence interval, 3.1 to 22.2; P = 0.009). Differences in treatment response were sustained at late follow-up (trial days 28 to 35), when cefepime-taniborbactam had higher composite success and clinical success. Adverse events occurred in 35.5% and 29.0% of patients in the cefepime-taniborbactam group and the meropenem group, respectively, with headache, diarrhea, constipation, hypertension, and nausea the most frequently reported; the frequency of serious adverse events was similar in the two groups. CONCLUSIONS: Cefepime-taniborbactam was superior to meropenem for the treatment of complicated UTI that included acute pyelonephritis, with a safety profile similar to that of meropenem. (Funded by Venatorx Pharmaceuticals and others; CERTAIN-1 ClinicalTrials.gov number, NCT03840148.).
Assuntos
Antibacterianos , Ácidos Borínicos , Ácidos Carboxílicos , Cefepima , Meropeném , Infecções Urinárias , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Administração Intravenosa , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , beta-Lactamases/administração & dosagem , beta-Lactamases/efeitos adversos , beta-Lactamases/uso terapêutico , Ácidos Borínicos/administração & dosagem , Ácidos Borínicos/efeitos adversos , Ácidos Borínicos/uso terapêutico , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/efeitos adversos , Ácidos Carboxílicos/uso terapêutico , Cefepima/administração & dosagem , Cefepima/efeitos adversos , Cefepima/uso terapêutico , Quimioterapia Combinada , Hospitalização , Meropeném/administração & dosagem , Meropeném/efeitos adversos , Meropeném/uso terapêutico , Testes de Sensibilidade Microbiana , Pielonefrite/tratamento farmacológico , Pielonefrite/microbiologia , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Farmacorresistência BacterianaRESUMO
BACKGROUND: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. METHODS: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. CONCLUSIONS: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018).
Assuntos
Amiloidose , Anticorpos Monoclonais , Ácidos Carboxílicos , Cardiomiopatias , Tomografia por Emissão de Pósitrons , Pirrolidinas , Componente Amiloide P Sérico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Amiloidose/sangue , Amiloidose/diagnóstico por imagem , Amiloidose/tratamento farmacológico , Amiloidose/imunologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Ácidos Carboxílicos/efeitos adversos , Ácidos Carboxílicos/uso terapêutico , Cardiomiopatias/sangue , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/imunologia , Quimioterapia Combinada , Imageamento por Ressonância Magnética , Miocárdio/metabolismo , Miocárdio/patologia , Valor Preditivo dos Testes , Pirrolidinas/efeitos adversos , Pirrolidinas/uso terapêutico , Componente Amiloide P Sérico/antagonistas & inibidores , Componente Amiloide P Sérico/imunologia , Fatores de Tempo , Resultado do Tratamento , Reino Unido , Estados Unidos , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacosRESUMO
RESEARCH QUESTION: Does a once-daily regimen of linzagolix, a new oral gonadotrophin-releasing hormone (GnRH) antagonist, given at a fully suppressive dose (200 mg) for 12 weeks, followed by a partially suppressive dose (100 mg) for a further 12 weeks, reduce adenomyotic uterine size and associated symptoms? DESIGN: Eight women (aged 37-45 years) with adenomyosis confirmed by magnetic resonance imaging (MRI) were enrolled in a single-centre, open-label pilot study. The primary efficacy end-point was the change in uterine volume on MRI at 24 weeks. Secondary efficacy end-points included serum oestradiol, overall pelvic pain, dysmenorrhoea, non-menstrual pelvic pain, dyspareunia, dyschezia and quality of life (QoL). Bone mineral density (BMD) was assessed at baseline and 24 weeks. RESULTS: At baseline, uterine volume (mean ± SD) was 333 ± 250 cm3. After 24 weeks, it was 204 ± 126 cm3, a reduction of 32% from baseline (Pâ¯=â¯0.0057). After 12 weeks, it was 159 ± 95 cm3, a reduction of 55% (Pâ¯<â¯0.0001). Median serum oestradiol was suppressed below 20 pg/ml during the 12 weeks on 200 mg linzagolix, and maintained below 60 pg/ml on 100 mg linzagolix. Improvements in overall pelvic pain, dysmenorrhoea, non-menstrual pelvic pain, dyspareunia, dyschezia and QoL were observed. Mean percentage change in BMD loss at 24 weeks was -2.4%, -1.3% and -4.1% for the spine, femoral neck and total hip, respectively. The most common adverse events were hot flushes. CONCLUSIONS: A once-daily regimen of 200 mg linzagolix for 12 weeks and then 100 mg for another 12 weeks decreased adenomyotic uterine volume and improved associated symptoms.
Assuntos
Adenomiose , Ácidos Carboxílicos , Antagonistas de Hormônios , Pirimidinas , Adenomiose/diagnóstico por imagem , Adenomiose/tratamento farmacológico , Adulto , Ácidos Carboxílicos/efeitos adversos , Constipação Intestinal/epidemiologia , Dismenorreia/epidemiologia , Dispareunia/epidemiologia , Estradiol/sangue , Feminino , Hormônio Liberador de Gonadotropina , Antagonistas de Hormônios/efeitos adversos , Humanos , Pessoa de Meia-Idade , Dor Pélvica/epidemiologia , Projetos Piloto , Pirimidinas/efeitos adversos , Qualidade de VidaRESUMO
Due to its increasing production, durability and multiple applications, plastic is a material we encounter every day. Small plastic particles from the µm to the mm range are classified as microplastics and produced for cosmetic and medical products, but are also a result of natural erosion and decomposition of macroplastics. Although being omnipresent in our environment and already detected in various organisms, less is known about the effects of microplastics on humans in general, or on vascular biology in particular. Here we investigated the effects of carboxylated polystyrene microplastic particles (PS, 1 µm) on murine endothelial and immune cells, which are both crucially involved in vascular inflammation, using in vitro and in vivo approaches. In vitro, PS induced adhesion molecule expression in endothelial cells with subsequent adhesion of leukocytes both under static and flow conditions. In monocytic cells, PS enhanced pro-inflammatory cytokine expression and release. Accordingly, administering mice with PS led to enhanced aortic expression of cytokines and adhesion molecules. Furthermore, we identified neutrophils as the PS-clearing blood leukocyte population. The findings from this study for the first time indicate polystyrene microplastic as a new environmental risk factor for endothelial inflammation.
Assuntos
Células Endoteliais/efeitos dos fármacos , Microplásticos/efeitos adversos , Plásticos/efeitos adversos , Poliestirenos/efeitos adversos , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Ácidos Carboxílicos/efeitos adversos , Linhagem Celular , Citocinas/metabolismo , Células Endoteliais/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismoRESUMO
INTRODUCTION: Uterine myomas and endometriosis are benign hormone-dependent diseases affecting women of reproductive age. Substantial efforts have been made to develop innovative medical options for treating these gynecologic diseases. Elagolix and relugolix have been approved in some countries for treating endometriosis and myomas, respectively; however, linzagolix (OBE 2109, KLH 2109) is a new oral gonadotropin-releasing hormone (GnRH) antagonist in phase II-III trials. Treatment options for women with contraindications for hormonal therapies or who refuse particular options, are the driving force behind the development of new drugs in this area. AREA COVERED: This drug evaluation highlights definitive and preliminary results from previous and ongoing studies of linzagolix for the treatment of endometriosis and myomas. EXPERT OPINION: Linzagolix showed a dose-dependent and rapidly reversible action on the pituitary-gonadal axis. In a recent phase II trial (EDELWEISS), linzagolix significantly reduced pain related to endometriosis and improved quality of life at single daily doses of 75-200 mg. The preliminary results of international, double-blind phase III trials (PRIMROSE 1 and 2) reported its efficacy in treating heavy menstrual bleeding related to myomas with a good safety profile. Further studies will determine the necessity of add-back therapy during long-term use of linzagolix.
Assuntos
Ácidos Carboxílicos/administração & dosagem , Endometriose/tratamento farmacológico , Leiomioma/tratamento farmacológico , Pirimidinas/administração & dosagem , Neoplasias Uterinas/tratamento farmacológico , Ácidos Carboxílicos/efeitos adversos , Ácidos Carboxílicos/farmacologia , Relação Dose-Resposta a Droga , Feminino , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/efeitos adversos , Antagonistas de Hormônios/farmacologia , Humanos , Pirimidinas/efeitos adversos , Pirimidinas/farmacologiaRESUMO
Cardiac safety and plasma concentration-QTc interval analyses were completed using data from 2 phase 1 studies of the selective mouse double minute chromosome 2 antagonist, KRT-232, in patients with solid tumors or multiple myeloma and acute myeloid leukemia (AML) who received KRT-232 doses of 15 to 480 mg once daily (QD; N = 130). A linear mixed-effects model related change from baseline Fridericia-corrected QT interval (ΔQTcF) to KRT-232 plasma concentrations. The final model included parameters for the intercept (with between-subject variability), KRT-232 concentration-ΔQTcF slope, and baseline QTcF effect on the intercept. Diagnostic plots indicated an adequate model fit. Mean (90% confidence interval) predicted ΔQTcF values at the maximum clinical dose (480 mg QD) were 2.04 (0.49-3.60) milliseconds for patients with solid tumors and 4.52 (2.35-6.69) milliseconds for patients with AML. Because the 90% confidence interval upper bound of the mean ΔQTcF was predicted to be below 10 milliseconds at doses up to 480 mg QD in patients with solid tumors, multiple myeloma, or AML, KRT-232 does not result in clinically meaningful QT prolongation at the doses currently under investigation in clinical trials. No significant cardiac safety concerns were identified at these doses.
Assuntos
Ácidos Carboxílicos/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Ácidos Carboxílicos/efeitos adversos , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Eletrocardiografia , Testes de Função Cardíaca/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Mieloma Múltiplo/metabolismoRESUMO
Since heat shock protein (HSP27) is a prognostic marker in cervical cancer, in the present study, the apoptotic mechanism of lambertianic acid (LA) was investigated in human cervical cancers in association with HSP27/STAT3/AKT signaling axis. LA exerted significant cytotoxicity, induced sub-G1 population, and increased the cleavage of Poly (ADP-ribose) polymerase (PARP) and cysteine aspartyl-specific protease 3 (caspase3) in HeLa and Caski cancer cells. Consistently, LA downregulated anti-apopotic genes such as B-cell lymphoma 2 (Bcl-2) and inhibitors of apoptosis proteins (c-IAP) in HeLa and Caski cells. Furthermore, LA-inhibited phosphorylation of HSP27, signal transducer, and activator of transcription 3 (STAT3) and Protein kinase B (AKT) through disturbing the binding of HSP27 with STAT3 or AKT in HeLa cells. Notably, LA upregulated the level of miR216b in HeLa and Caski cells. Consistently, miR216b mimic suppressed phosphorylation of HSP27 and reduced the expression of pro-PARP, while miR216b inhibitor reversed the ability of LA to attenuate phosphorylation of AKT, HSP27, and STAT3 and to reduce the expression of pro-PARP in HeLa cells. Overall, our findings suggest that miRNA216b mediated inhibition of HSP27/STAT3/ AKT signaling axis is critically involved in LA-induced apoptosis in cervical cancers.
Assuntos
Ácidos Carboxílicos/efeitos adversos , Proteínas de Choque Térmico HSP27/genética , Naftalenos/efeitos adversos , Neoplasias do Colo do Útero/fisiopatologia , Apoptose , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Proteínas de Choque Térmico HSP27/metabolismo , Células HeLa , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de SinaisRESUMO
The biological responses of multidimensional carboxylated carbon-based nanomaterials (c-CBNs), including carboxylated graphene, carbon nanotube, and fullerene, on human lung A549 cells were investigated by using metabolomics technology. The structure and components of c-CBNs were characterized, and their biological effects were evaluated through cell apoptosis and viability analysis. Additionally, the metabolomics analysis of the nanomaterial-cell interaction system was performed using the established platform combining liquid chromatography-mass spectrometry (LC-MS) with the bioinformatics system. Results revealed that all tested c-CBNs demonstrated some biological effects in our cell model. However, significant metabolomic alterations induced by c-CBNs were also observed mainly in amino acids, organic acids, glycerophospholipids, and glycerolipids. Further, under the tested concentrations, the multiple dimensions of c-CBNs played a major role in determining the metabolic process in various interaction modes. This study provides an advanced alternative for evaluating metabolic effects of multidimensional nanomaterials through metabolomics technology considering the association between dimension and metabolic characteristics.
Assuntos
Ácidos Carboxílicos , Fulerenos , Grafite , Metaboloma , Nanoestruturas , Células A549 , Apoptose/efeitos dos fármacos , Ácidos Carboxílicos/efeitos adversos , Ácidos Carboxílicos/química , Ácidos Carboxílicos/metabolismo , Fulerenos/efeitos adversos , Fulerenos/química , Fulerenos/metabolismo , Grafite/efeitos adversos , Grafite/química , Grafite/metabolismo , Humanos , Metaboloma/efeitos dos fármacos , Metabolômica , Nanoestruturas/efeitos adversos , Nanoestruturas/química , Nanotubos de Carbono/efeitos adversos , Nanotubos de Carbono/químicaRESUMO
In patients with coronary heart disease undergoing primary prevention, hypertriglyceridemia is a residual risk for cardiovascular events. Omega-3 carboxylic acid (OM3-CA), a mixture of the free fatty acid forms of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may be beneficial in reducing triglyceride levels. As part of the clinical development program of OM3-CA in China, this phase I study evaluated the pharmacokinetics, safety, and tolerability profile of OM3-CA in healthy subjects. The pharmacokinetic results of this study were also compared with those of available data for Western populations. Fourteen healthy Chinese subjects (aged 18-45 years) received once-daily oral OM3-CA 4 g for 14 consecutive days. Pharmacokinetic parameters were assessed from both baseline-uncorrected and baseline-corrected plasma concentrations vs time profile of EPA, DHA, and EPA plus DHA. Following single and multiple oral doses of OM3-CA, the absorption of EPA, DHA, and EPA plus DHA was steady with median tmax occurring at 5.5-6 hours after both single and multiple dosing. Close to steady-state concentrations in plasma were reached after 14 days of continuous once-daily dosing, and accumulation was confirmed for EPA, DHA, and EPA plus DHA. Of the 14 subjects treated with OM3-CA, 6 (42.9%) reported at least 1 adverse event (diarrhea) during the study, which was determined as mild and treatment emergent. No serious adverse events were reported. In summary, the pharmacokinetic profile of oral OM3-CA 4 g after single and multiple dosing in healthy Chinese subjects is consistent with that observed in other ethnic populations.
Assuntos
Ácidos Carboxílicos/farmacocinética , Ácidos Docosa-Hexaenoicos/farmacocinética , Ácido Eicosapentaenoico/farmacocinética , Ácidos Graxos não Esterificados/farmacocinética , Ácidos Graxos Ômega-3/farmacocinética , Voluntários Saudáveis/estatística & dados numéricos , Hipertrigliceridemia/tratamento farmacológico , Administração Oral , Adulto , Área Sob a Curva , Povo Asiático/etnologia , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/efeitos adversos , Ácidos Carboxílicos/sangue , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/sangue , Relação Dose-Resposta a Droga , Esquema de Medicação , Tolerância a Medicamentos , Ácido Eicosapentaenoico/administração & dosagem , Ácido Eicosapentaenoico/sangue , Ácidos Graxos não Esterificados/administração & dosagem , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/efeitos adversos , Ácidos Graxos Ômega-3/sangue , Feminino , Humanos , Hipertrigliceridemia/prevenção & controle , Masculino , Pessoa de Meia-Idade , SegurançaRESUMO
OBJECTIVE: To study the effect of a new investigational oral gonadotropin-releasing hormone antagonist, linzagolix, on endometriosis-associated pain (EAP). DESIGN: A multinational, parallel group, randomized, placebo-controlled, double-blind, dose-ranging trial. SETTING: Clinical centers. PATIENT(S): Women aged 18-45 years with surgically confirmed endometriosis and moderate-to-severe EAP. INTERVENTION(S): The interventions were 50, 75, 100, or 200 mg linzagolix (or matching placebo) administered once daily for 24 weeks. MAIN OUTCOME MEASURE(S): The primary endpoint was the number of responders (≥30% reduction in overall pelvic pain) after 12 weeks. Other endpoints included dysmenorrhea, non-menstrual pelvic pain, serum estradiol, amenorrhea, quality of life (QoL) measures, and bone mineral density (BMD). RESULT(S): Compared with placebo, doses ≥ 75 mg resulted in a significantly greater proportion of responders for overall pelvic pain at 12 weeks (34.5%, 61.5%, 56.4%, and 56.3% for placebo, 75, 100, and 200 mg, respectively). A similar pattern was seen for dysmenorrhea and non-menstrual pelvic pain. The effects were maintained or increased at 24 weeks. Serum estradiol was suppressed, QoL improved, and the rate of amenorrhea increased in a dose-dependent fashion. Mean BMD loss (spine) at 24 weeks was <1% at doses of 50 and 75 mg and increased in a dose-dependent fashion up to 2.6% for 200 mg. BMD of femoral neck and total hip showed a similar pattern. CONCLUSION(S): Linzagolix significantly reduced EAP and improved QoL at doses of 75-200 mg and decreased BMD dose-dependently. CLINICAL TRIAL REGISTRATION NUMBER: NCT02778399.
Assuntos
Ácidos Carboxílicos , Dor Crônica , Endometriose , Antagonistas de Hormônios , Dor Pélvica , Pirimidinas , Doenças Uterinas , Adolescente , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Administração Oral , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/efeitos adversos , Dor Crônica/tratamento farmacológico , Dor Crônica/etiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Endometriose/complicações , Endometriose/tratamento farmacológico , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/efeitos adversos , Compostos Orgânicos , Dor Pélvica/tratamento farmacológico , Dor Pélvica/etiologia , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Resultado do Tratamento , Doenças Uterinas/complicações , Doenças Uterinas/tratamento farmacológicoRESUMO
18F-fluciclovine (18F-FACBC) is a radiotracer already studied for prostate cancer, and its potential role in brain tumors (such as glioma) is not yet well investigated despite promising results. The aim of this review is to evaluate the possible diagnostic role of 18F-FACBC PET/CT or PET/MRI in patients with gliomas and glioblastomas. A comprehensive literature search of the PubMed/MEDLINE, Scopus, Embase, and Cochrane library databases was conducted to find the relevant published articles about the diagnostic performance of FACBC PET/CT or PET/MRI in patients affected by glioma and/or glioblastoma. Seven papers were included in the systematic review. From the analyses of the selected studies, the following main findings were obtained: glioma and glioblastoma are FACBC-avid tumors with a detection rate of about 100%; FACBC PET has high-diagnostic accuracy in defining tumor extent, volumes, and satellite lesions better than MR; compared to methionine, FACBC has similar accuracy but better tumor-to-background contrast; FACBC uptake may help to discriminate between low-grade and high-grade glioma. Radiolabelled fluciclovine (18F-FACBC) imaging seems to be useful in analyzing glioma/glioblastoma. Further studies enrolling a wider population are needed to clarify the real clinical and diagnostic role of 18F-FACBC in this setting and its possible position in the diagnostic flowchart.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Ácidos Carboxílicos/química , Ciclobutanos/química , Glioblastoma/diagnóstico por imagem , Glioma/diagnóstico por imagem , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácidos Carboxílicos/efeitos adversos , Ciclobutanos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Compostos Radiofarmacêuticos/química , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Acne is one of the most common skin problems among human populations. A facial cleanser formulated with alkyl ether carboxylate (AEC) and alkyl carboxylate (AC) can improve acne by cleansing sebum on facial skin but cannot effectively remove keratotic plugs in the skin pores. Recently, we confirmed that Tris (hydroxymethyl) aminomethane and L-arginine (Tris/Arg) is able to reduce sebum levels, disrupt keratotic plugs in vitro and decrease pore size on facial skin. OBJECTIVE: To compare the efficacy of the Tris/Arg-formulated cleanser with the AEC/AC cleanser in Thai subjects with acne. METHODS: We designed a randomized, double-blind, controlled, parallel trial. Thirty-four male Thai subjects with mild to moderate acne were assigned to one of two groups: one group used the Tris/Arg cleanser while the other used the AEC/AC-based cleanser twice a day for 4 weeks. RESULTS: After 4 weeks, significant decreases in noninflammatory acne were observed in both groups, yet significant decreases in inflammatory acne were only observed in the Tris/Arg cleanser group. The sebum level prior to and 30 minutes after facial washing showed no change in either group. The average pore size with keratotic plugs on the cheeks was significantly decreased in the Tris/Arg group. More than half of subjects in both groups observed acne improvement but more subjects in the Tris/Arg group noted pore size improvement. CONCLUSION: The Tris/Arg formulated cleanser has a high efficacy for significantly reducing both noninflammatory and inflammatory acne accompanied by decreases in pore size with keratotic plugs in male Thai subjects.
Assuntos
Acne Vulgar/tratamento farmacológico , Arginina/administração & dosagem , Cosmecêuticos/administração & dosagem , Higiene da Pele/métodos , Trometamina/administração & dosagem , Acne Vulgar/diagnóstico , Adulto , Arginina/efeitos adversos , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/efeitos adversos , Cosmecêuticos/efeitos adversos , Cosmecêuticos/química , Método Duplo-Cego , Humanos , Masculino , Sebo/efeitos dos fármacos , Índice de Gravidade de Doença , Pele/efeitos dos fármacos , Higiene da Pele/efeitos adversos , Tailândia , Resultado do Tratamento , Trometamina/efeitos adversos , Adulto JovemRESUMO
Perfluoroalkyl acids (PFAAs) are ubiquitous environmental contaminants and eggs and nestlings of raptors and fish-eating birds often contain high levels of PFAAs. We studied developmental effects of a mixture of ten PFAAs by exposing chicken embryos to 0.5 or 3 µg/g egg of each compound in the mixture. Histological changes of the thyroid gland were noted at both doses and increased expression of mRNA coding for type III deiodinase was found at 0.5 µg/g egg. Serum concentrations of the free fraction of thyroid hormones (T3 and T4) were reduced by the PFAA mixture at 3 µg/g egg, which is in line with a decreased synthesis and increased turnover of thyroid hormones as indicated by our histological findings and the decreased mRNA expression of type III deiodinase. The relative weight of the bursa of Fabricius increased at a dose of 3 µg/g egg in females. The bursa is the site of B-cell development in birds and is crucial for the avian adaptive immune system. Analysis of plasma and liver concentrations of the mixture components showed differences depending on chain length and functional group. Our results highlight the vulnerability of the thyroid hormone and immune systems to PFAAs.
Assuntos
Bolsa de Fabricius/efeitos dos fármacos , Bolsa de Fabricius/metabolismo , Embrião de Galinha/efeitos dos fármacos , Fluorocarbonos/efeitos adversos , Glândula Tireoide/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Animais , Peso Corporal , Ácidos Carboxílicos/efeitos adversos , Galinhas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Fígado/efeitos dos fármacos , Fígado/metabolismo , RNA Mensageiro/metabolismo , Ácidos Sulfônicos/efeitos adversos , Glândula Tireoide/metabolismoRESUMO
Several retinoid X receptor (RXR) ligands (rexinoids), such as bexarotene (1), exhibit teratogenicity, which is a serious impediment to their clinical application. We considered that rexinoids with a lower level of maximal RXR transcription activation (i.e., partial agonists) and lower lipid solubility might show weaker adverse side effects. Based on this idea, we modified our previously reported pentamethyltetralin-type RXR partial agonists 5 and 6 to reduce their lipophilicity. Here, we report a new RXR partial agonist, 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (8, CATF-PMN), which showed greatly reduced teratogenicity in zebrafish embryos.
Assuntos
Ácidos Carboxílicos/efeitos adversos , Receptores X de Retinoides/efeitos adversos , Teratogênese/efeitos dos fármacos , Animais , Humanos , Peixe-ZebraRESUMO
The aim of this study was to investigate the effect of 3-chloro-5-trifluoromethylpyridine-2-carboxylic acid (PCA), a metabolite of the fungicide fluopyram, on grapevine. During spring and summer 2015, grapevine growth disorders were observed in several countries in Europe. An unprecedented herbicide-like damage was diagnosed on leaves and flowers, causing significant loss of harvest. This study proposes PCA as the causing agent of the observed growth disorders. PCA was shown to cause leaf epinasty, impaired berry development that leads to crop loss, and root growth anomalies in Vitis vinifera similar to auxin herbicides in a dose-dependent manner. Using both field trials and greenhouse experiments, the present study provides first evidence for a link between the application of fluopyram in vineyards 2014, the formation of PCA, and the emergence of growth anomalies in 2015. Our data could be useful to optimize dosage, application time point, and other conditions for an application of fluopyram without phytotoxic effects.
Assuntos
Benzamidas/metabolismo , Ácidos Carboxílicos/efeitos adversos , Fungicidas Industriais/efeitos adversos , Piridinas/efeitos adversos , Piridinas/metabolismo , Vitis/efeitos dos fármacos , Vitis/crescimento & desenvolvimento , Benzamidas/efeitos adversos , Ácidos Carboxílicos/metabolismo , Flores/efeitos dos fármacos , Flores/crescimento & desenvolvimento , Flores/metabolismo , Frutas/efeitos dos fármacos , Frutas/crescimento & desenvolvimento , Frutas/metabolismo , Fungicidas Industriais/metabolismo , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/metabolismo , Vitis/metabolismoRESUMO
This phase 1 study characterized the safety, tolerability, pharmacokinetics, and pharmacodynamics of miridesap (GSK2315698) following an intravenous (IV) infusion in healthy Japanese men. Subjects in Cohort 1 received 1-hour IV infusions of 10, 20, and 40 mg of miridesap or placebo, and subjects in Cohort 2 received a 15-hour IV infusion of 20 mg/h of miridesap or placebo. No treatment-related adverse events were reported. No new safety signals were identified for either vital signs or clinical laboratory parameters. A dose-dependent increase was observed in miridesap exposure (area under the concentration-time curve and maximum observed drug concentration) in the 10 to 40 mg/h dose range after a 1-hour IV infusion of miridesap. Rapid depletion of circulating serum amyloid P component was observed after the initiation of miridesap infusion. Serum amyloid P component concentrations fell in a dose-dependent manner following administration of miridesap.
Assuntos
Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacocinética , Componente Amiloide P Sérico/análise , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/farmacocinética , Adulto , Área Sob a Curva , Ácidos Carboxílicos/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Japão , Ligantes , Masculino , Pessoa de Meia-Idade , Pirrolidinas/efeitos adversos , Componente Amiloide P Sérico/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/efeitos adversos , Fatores de Tempo , Adulto JovemRESUMO
The orally available chymase inhibitor BAY 1142524 is currently being developed as a first-in-class treatment for left-ventricular dysfunction after myocardial infarction. Results from 3 randomized, single-center, phase 1 studies in healthy male volunteers examining the safety, tolerability, and pharmacokinetics of BAY 1142524 are summarized. In this first-in-human study, single oral doses of 1-200 mg were administered in fasted state as liquid service formulation or immediate release (IR) tablets. The relative bioavailability and the effect of a high-fat/high-calorie meal were investigated at the 5-mg dose. In a multiple-dose escalation study, doses of 5-50 mg twice daily and 100 mg once daily were given for 5 consecutive days. BAY 1142524 was safe and well tolerated and had no effects on heart rate or blood pressure compared with placebo. BAY 1142524 was absorbed with peak concentration 1-3 hours after administration for IR tablets; it was eliminated from plasma with a terminal half-life of 6.84-12.0 hours after administration of liquid service formulation or IR tablets. Plasma exposures appeared to be dose-linear, with a negligible food effect. There was only low accumulation of BAY 1142524 after multiple dosing. BAY 1142524 exhibited a pharmacokinetic profile allowing for once-daily dosing. The absence of blood pressure effects after administration of BAY 1142524 supports the combination of this novel anti-remodeling drug with existing standard of care in patients with left-ventricular dysfunction after acute myocardial infarction.
Assuntos
Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/farmacocinética , Quimases/antagonistas & inibidores , Jejum/sangue , Indenos/administração & dosagem , Indenos/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Disponibilidade Biológica , Ácidos Carboxílicos/efeitos adversos , Preparações de Ação Retardada , Esquema de Medicação , Meia-Vida , Voluntários Saudáveis , Humanos , Indenos/efeitos adversos , Masculino , Pirimidinas/efeitos adversos , Soluções , Comprimidos , Adulto JovemRESUMO
The chymase inhibitor fulacimstat is developed as a first-in-class treatment option for the inhibition of adverse cardiac remodeling in patients with left ventricular dysfunction (LVD) after acute myocardial infarction (MI). The aim of the study was to examine the safety and tolerability of fulacimstat in patients with LVD after remote MI. A multicenter, multinational randomized, placebo-controlled study was performed in clinically stable patients (40-79 years of age, left ventricular ejection fraction ≤ 45% because of MI in medical history) who were on stable evidence-based standard-of-care therapies for LVD post-MI including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker at doses of at least half the recommended target dose. Patients were treated for 2 weeks with either placebo (n = 12) or 4 different doses of fulacimstat (5 mg twice daily, n = 9; 10 mg twice daily, n = 9; 25 mg twice daily, n = 10; 50 mg once daily, n = 9). Fulacimstat was safe and well tolerated at all examined doses. There were no clinically relevant effects on vital signs or potassium levels compared with placebo treatment. Mean plasma concentrations of fulacimstat increased with the administered dose and reached exposures predicted to be therapeutically active. The safety profile and the absence of effects on blood pressure or heart rate in a chronic patient population having similar comorbidities and receiving similar comedication as patients after acute MI support future clinical trials with fulacimstat in patients after acute MI.
Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Ácidos Carboxílicos/administração & dosagem , Insuficiência Cardíaca/prevenção & controle , Indenos/administração & dosagem , Infarto do Miocárdio/complicações , Pirimidinas/administração & dosagem , Disfunção Ventricular Esquerda/tratamento farmacológico , Adulto , Idoso , Ácidos Carboxílicos/efeitos adversos , Ácidos Carboxílicos/farmacocinética , Quimases/antagonistas & inibidores , Esquema de Medicação , Feminino , Insuficiência Cardíaca/etiologia , Humanos , Indenos/efeitos adversos , Indenos/farmacocinética , Masculino , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Resultado do Tratamento , Disfunção Ventricular Esquerda/etiologiaRESUMO
OM3-CA (omega-3-carboxylic acids) is a complex mixture of omega-3 carboxylic acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which is approved in the United States for the treatment of hypertriglyceridemia. As part of its clinical development in Japan, we performed a phase 1 study to investigate the safety, tolerability, and pharmacokinetics after single and multiple doses of OM3-CA in healthy male Japanese subjects. Eighteen Japanese subjects were allocated to receive 2 or 4 g/day OM3-CA, or placebo (n = 6 per group). In addition, 6 white subjects received 4 g/day OM3-CA. The primary objective was to determine the safety and tolerability of OM3-CA. Plasma concentrations of EPA and DHA were adjusted for baseline values for pharmacokinetic analysis. Overall, OM3-CA was well tolerated in healthy Japanese subjects. Two Japanese subjects in each group and 5 white subjects experienced adverse events (AEs). Alanine aminotransferase increase was the most common AE in Japanese subjects, also seen with placebo, and diarrhea was the most common AE in white subjects. The maximum plasma concentrations of EPA and DHA were observed 5-6 hours postdose. The pharmacokinetic profiles of EPA and DHA after administration of OM3-CA were comparable between Japanese and white subjects.
Assuntos
Ácidos Carboxílicos/farmacocinética , Adulto , Povo Asiático , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/efeitos adversos , Voluntários Saudáveis , Humanos , Lipídeos/sangue , Masculino , Método Simples-Cego , População Branca , Adulto JovemRESUMO
Consumption of ponderosa pine needles, as well as needles and bark from a number of other trees, can cause abortions in cattle. The abortifacient compounds in these trees are labdane resin acids, including isocupressic acid and agathic acid. Previous research has demonstrated that cattle conditioned to pine needles metabolize the labdane resin acids more quickly than naïve cattle. The results from that study indicated that changes had occurred in the rumen of conditioned cattle. Therefore, in this study, the changes that occurred in the rumen bacterial microflora of cattle during exposure to ponderosa pine needles were evaluated. Cattle were dosed with ground pine needles twice daily for 7 d. Rumen samples were collected on d 0, 3, 7, and 14 (7 d after treatment stopped) and ruminal bacterial microbiome analyses were performed. There were 372 different genera of bacteria identified in the rumen samples. Principal coordinate analysis indicated that there was a significant difference in the rumen bacterial composition between the time points. There were 18 genera that increased in abundance from d 0 to d 7. Twenty three genera decreased in abundance from d 0 to d 7. The results from this study demonstrated that exposure of cattle to pine needles caused a clear shift in the rumen microbiome composition. In general, this shift lasted less than 1 wk post exposure, which indicates that any prophylactic treatment to manipulate the ruminal metabolism of the abortifacient compounds in pine needles would need to be continuously administered to maintain the necessary microbial composition in the rumen.