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1.
BJU Int ; 128(4): 440-450, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33991045

RESUMO

OBJECTIVE: To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. PATIENTS AND METHODS: This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. RESULTS: Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3-34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1-30.2), UTUC (n = 128) 1.14% (95% CI 0.77-1.52), renal cancer (n = 107) 1.05% (95% CI 0.80-1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32-2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03-1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90-4.15; P < 0.001), male sex 1.30 (95% CI 1.14-1.50; P < 0.001), and smoking 2.70 (95% CI 2.30-3.18; P < 0.001). CONCLUSIONS: A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer.


Assuntos
Neoplasias Renais/diagnóstico , Neoplasias Ureterais/diagnóstico , Neoplasias da Bexiga Urinária/diagnóstico , Adulto , Idoso , Feminino , Hematúria/etiologia , Humanos , Neoplasias Renais/complicações , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Encaminhamento e Consulta , Neoplasias Ureterais/complicações , Neoplasias da Bexiga Urinária/complicações
2.
J Pharmacol Exp Ther ; 375(2): 296-307, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32958629

RESUMO

Infarct expansion can occur after myocardial infarction (MI), which leads to adverse left ventricular (LV) remodeling and failure. An imbalance between matrix metalloproteinase (MMP) induction and tissue inhibitors of MMPs (TIMPs) can accelerate this process. Past studies have shown different biologic effects of TIMP-3, which may depend upon specific domains within the TIMP-3 molecule. This study tested the hypothesis that differential effects of direct myocardial injections of either a full-length recombinant TIMP-3 (F-TIMP-3) or a truncated form encompassing the N-terminal region (N-TIMP-3) could be identified post-MI. MI was induced in pigs that were randomized for MI injections (30 mg) and received targeted injections within the MI region of F-TIMP-3 (n = 8), N-TIMP-3 (n = 9), or saline injection (MI-only, n = 11). At 14 days post-MI, LV ejection fraction fell post-MI but remained higher in both TIMP-3 groups. Tumor necrosis factor and interleukin-10 mRNA increased by over 10-fold in the MI-only and N-TIMP-3 groups but were reduced with F-TIMP-3 at this post-MI time point. Direct MI injection of either a full-length or truncated form of TIMP-3 is sufficient to favorably alter the course of post-MI remodeling. The functional and differential relevance of TIMP-3 domains has been established in vivo since the TIMP-3 constructs demonstrated different MMP/cytokine expression profiles. These translational studies identify a unique and more specific therapeutic strategy to alter the course of LV remodeling and dysfunction after MI. SIGNIFICANCE STATEMENT: Using different formulations of tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), when injected into the myocardial infarction (MI) region, slowed the progression of indices of left ventricular (LV) failure, suggesting that the N terminus of TIMP-3 is sufficient to attenuate early adverse functional events post-MI. Injections of full-length recombinant TIMP-3, but not of the N-terminal region of TIMP-3, reduced relative indices of inflammation at the mRNA level, suggesting that the C-terminal region affects other biological pathways. These unique proof-of-concept studies demonstrate the feasibility of using recombinant small molecules to selectively interrupt adverse LV remodeling post-MI.


Assuntos
Infarto do Miocárdio/patologia , Fragmentos de Peptídeos/farmacologia , Inibidor Tecidual de Metaloproteinase-3/química , Remodelação Ventricular/efeitos dos fármacos , Sequência de Aminoácidos , Colágeno/genética , Citocinas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Injeções , Metaloproteinases da Matriz/genética , Fragmentos de Peptídeos/química , Domínios Proteicos , RNA Mensageiro/genética , Inibidor Tecidual de Metaloproteinase-3/genética
3.
World J Urol ; 38(5): 1215-1220, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31456016

RESUMO

INTRODUCTION: Radical cystectomy (RC) is a challenging procedure with significant morbidity, though remains the standard of care treatment for many patients with bladder cancer. There has been debate regarding the utility of universal risk calculators to aid in point-of-care prediction of complications in individual patients preoperatively. We retrospectively evaluated the predictive value of the ACS NSQIP universal surgical risk calculator in our patients who underwent RC. METHODS: A prospective cohort of patients undergoing RC was retrospectively reviewed between October 2014 and August 2017. Only patients who underwent a RC for genitourinary cancer without significant deviation from NSQIP surgery codes 51590, 51595, and 51596 (n = 29) were included. The accuracy of the risk calculator was assessed by ROC AUC and Brier scores for both NSQIP and Clavien-Dindo defined complications. Additionally, each NSQIP risk factor was individually assessed for association with postoperative complications. RESULTS: 223 patients who underwent open or robotic RC (n = 18) were included for analysis. Determined by AUC C-stat and Brier scores, prediction was good for cardiac complications (0.80 and 0.021), fair for pneumonia (0.75 and 0.017), poor for UTI (0.64 and 0.078), 30-day mortality (0.62 and 0.013), any complication (0.60 and 0.19) and serious complication (0.60 and 0.17). There was a significant discordance between the rate of NSQIP predicted vs. Clavien-Dindo observed any and serious complications: 28.8% vs. 67.3%, and 25.3% vs. 11.7%, respectively. CONCLUSION: The NSQIP universal surgical risk calculator did not perform with enough accuracy to consider adoption into clinical practice.


Assuntos
Cistectomia/normas , Complicações Pós-Operatórias/epidemiologia , Melhoria de Qualidade , Medição de Risco , Neoplasias da Bexiga Urinária/cirurgia , Idoso , Idoso de 80 Anos ou mais , Cistectomia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco/normas
4.
Am J Physiol Heart Circ Physiol ; 315(4): H814-H825, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29979624

RESUMO

Although improvements in timing and approach for early reperfusion with acute coronary syndromes have occurred, myocardial injury culminating in a myocardial infarction (MI) remains a common event. Although a multifactorial process, an imbalance between the induction of proteolytic pathways, such as matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of metalloproteinase (TIMPs), has been shown to contribute to this process. In the present study, a full-length TIMP-3 recombinant protein (rTIMP-3) was encapsulated in a specifically formulated hyaluronic acid (HA)-based hydrogel that contained MMP-cleavable peptide cross-links, which influenced the rate of rTIMP-3 release from the HA gel. The effects of localized delivery of this MMP-sensitive HA gel (HAMMPS) alone and containing rTIMP-3 (HAMMPS/rTIMP-3) were examined in terms of the natural history of post-MI remodeling. Pigs were randomized to one of the following three different groups: MI and saline injection (MI/saline group, 100-µl injection at nine injection sites, n = 7), MI and HAMMPS injection (MI/HAMMPS group; 100-µl injection at nine injection sites, n = 7), and MI and HAMMPS/rTIMP-3 injection (MI/HAMMPS/rTIMP-3 group; 20-µg/100-µl injection at nine injection sites, n = 7). Left ventricular (LV) echocardiography was serially performed up to 28 days post-MI. LV dilation, as measured by end-diastolic volume, and the degree of MI wall thinning were reduced by ~50% in the HAMMPS/rTIMP-3 group ( P < 0.05). Furthermore, indexes of heart failure progression post-MI, such as LV filling pressures and left atrial size, were also attenuated to the greatest degree in the HAMMPS/rTIMP-3 group. At 28 days post-MI, HAMMPS/rTIMP-3 caused a relative reduction in the transcriptional profile for myofibroblasts as well as profibrotic pathways, which was confirmed by subsequent histochemistry. In conclusion, these findings suggest that localized delivery of a MMP-sensitive biomaterial that releases a recombinant TIMP holds promise as a means to interrupt adverse post-MI remodeling. NEW & NOTEWORTHY The present study targeted a myocardial matrix proteolytic system, matrix metalloproteinases (MMPs), through the use of a recombinant tissue inhibitor of MMPs incorporated into a MMP-sensitive hydrogel, which was regionally injected using a large animal model of myocardial infarction. Left ventricular geometry and function and indexes of myocardial remodeling were improved with this approach and support the advancement of localized therapeutic strategies that specifically target the myocardial matrix.


Assuntos
Fármacos Cardiovasculares/administração & dosagem , Sulfato de Dextrana/química , Portadores de Fármacos , Ventrículos do Coração/efeitos dos fármacos , Ácido Hialurônico/química , Infarto do Miocárdio/tratamento farmacológico , Inibidor Tecidual de Metaloproteinase-3/administração & dosagem , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Fármacos Cardiovasculares/química , Preparações de Ação Retardada , Sulfato de Dextrana/análogos & derivados , Modelos Animais de Doenças , Composição de Medicamentos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Perfilação da Expressão Gênica/métodos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Ácido Hialurônico/análogos & derivados , Hidrogéis , Masculino , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Proteínas Recombinantes/administração & dosagem , Inibidor Tecidual de Metaloproteinase-3/química , Transcrição Gênica/efeitos dos fármacos , Transcriptoma
5.
Curr Opin Urol ; 28(6): 563-569, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30148753

RESUMO

PURPOSE OF REVIEW: A bladder-preserving approach for high-grade nonmuscle invasive bladder cancer that has invaded the lamina propria (T1HG) may result in increased recurrence, progression, and even death from bladder cancer in some patients. Initial radical cystectomy does have increased cancer-specific survival (CSS), but represents significant overtreatment for many patients. An evidence-based, risk-stratified approach is required to select patients for immediate radical cystectomy in order to improve CSS. RECENT FINDINGS: A restaging transurethral resection aids in optimal staging and treatment of T1HG. Intravesical Bacillus Calmette-Guerin induction followed by 3 years of maintenance is the standard adjuvant management. However, when very high-risk (hydronephrosis, abnormal bimanual examination, variant histology, lymphovascular invasion, or residual disease on re-resection, and Bacillus Calmette-Guerin failure or early recurrence) or multiple high-risk factors (concomitant CIS, size >3 cm, multifocality, unfavorable tumor location, extensive lamina propria invasion, and elderly) are present, the risk of progression often outweighs the risk associated with radical cystectomy. In these cases, an immediate radical cystectomy likely provides an improved opportunity for cure compared to a bladder-preserving strategy. SUMMARY: In order to increase the CSS of patients diagnosed with T1HG bladder cancer, an aggressive approach may benefit those with increased risk of progression.


Assuntos
Medicina Baseada em Evidências/métodos , Recidiva Local de Neoplasia/terapia , Seleção de Pacientes , Neoplasias da Bexiga Urinária/terapia , Administração Intravesical , Vacina BCG/uso terapêutico , Cistectomia/métodos , Progressão da Doença , Humanos , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Tratamentos com Preservação do Órgão/métodos , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Bexiga Urinária/patologia , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia
6.
Am J Physiol Heart Circ Physiol ; 313(4): H690-H699, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28754718

RESUMO

Ischemia-reperfusion (IR) and myocardial infarction (MI) cause adverse left ventricular (LV) remodeling and heart failure and are facilitated by an imbalance in matrix metalloproteinase (MMP) activation and the endogenous tissue inhibitors of metalloproteinase (TIMPs). We have identified that myocardial injections of recombinant TIMP-3 (rTIMP-3; human full length) can interrupt post-MI remodeling. However, whether and to what degree intracoronary delivery of rTIMP-3 post-IR is feasible and effective remained to be established. Pigs (25 kg) underwent coronary catheterization and balloon occlusion of the left anterior descending coronary artery (LAD) for 90 min whereby at the final 4 min, rTIMP-3 (30 mg, n = 9) or saline was infused in the distal LAD. LV echocardiography was performed at 3-28 days post-IR, and LV ejection fraction (EF) and LV end-diastolic volume were measured. LV EF fell and LV end-diastolic volume increased from baseline (pre-IR) values (66 ± 1% and 40 ± 1 ml, respectively, means ± standard deviation) in both groups; however, the extent of LV dilation was reduced in the rTIMP-3 group by 40% at 28 days post-IR (P < 0.05) and the fall in LV EF was attenuated. Despite equivalent plasma troponin levels (14 ± 3 ng/ml), computed MI size at 28 days was reduced by over 45% in the rTIMP-3 group (P < 0.05), indicating that rTIMP-3 treatment abrogated MI expansion post-IR. Plasma NH2-terminal pro-brain natriuretic peptide levels, an index of heart failure progression, were reduced by 25% in the rTIMP-3 group compared with MI saline values (P < 0.05). Although the imbalance between MMPs and TIMPs has been recognized as a contributory factor for post-MI remodeling, therapeutic strategies targeting this imbalance have not been forthcoming. This study is the first to demonstrate that a relevant delivery approach (intracoronary) using rTIMP can alter the course of post-MI remodeling.NEW & NOTEWORTHY Myocardial ischemia and reperfusion injury remain significant causes of morbidity and mortality whereby alterations in the balance between matrix metalloproteinase and tissue inhibitor of metalloproteinase have been identified as contributory biological mechanisms. This novel translational study advances the concept of targeted delivery of recombinant proteins to modify adverse myocardial remodeling in ischemia-reperfusion injury.


Assuntos
Infarto do Miocárdio , Traumatismo por Reperfusão , Inibidor Tecidual de Metaloproteinase-3/farmacologia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Vasos Coronários , Ecocardiografia , Infusões Intra-Arteriais , Peptídeo Natriurético Encefálico/sangue , Peptídeo Natriurético Encefálico/efeitos dos fármacos , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Volume Sistólico/efeitos dos fármacos , Suínos , Troponina/sangue , Troponina/efeitos dos fármacos
7.
J Pharmacol Exp Ther ; 351(1): 190-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25100753

RESUMO

The objective of the present studies was to characterize the pharmacologic properties of GSK-961081 [TD-5959; (R)-1-(3-((2-chloro-4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-3-oxopropyl) piperidin-4-yl [1,1'-biphenyl]-2-ylcarbamate], a novel first-in-class inhaled bifunctional compound possessing both muscarinic antagonist (MA) and ß2-adrenoceptor agonist (BA) properties (MABA). In competition radioligand binding studies at human recombinant receptors, GSK-961081 displayed high affinity for hM2 (Ki = 1.4 nM), hM3 muscarinic receptors (Ki = 1.3 nM) and hß2-adrenoceptors (Ki = 3.7 nM). GSK-961081 behaved as a potent hß2-adrenoceptor agonist (EC50 = 0.29 nM for stimulation of cAMP levels) with 440- and 320-fold functional selectivity over hß1- and hß3-adrenoceptors, respectively. In guinea pig isolated tracheal tissues, GSK-961081 produced smooth muscle relaxation through MA (EC50 = 50.2 nM), BA (EC50=24.6 nM), and MABA (EC50 = 11 nM) mechanisms. In the guinea pig bronchoprotection assay, inhaled GSK-961081 produced potent, dose-dependent inhibition of bronchoconstrictor responses via MA (ED50 = 33.9 µg/ml), BA (ED50 = 14.1 µg/ml), and MABA (ED50 = 6.4 µg/ml) mechanisms. Significant bronchoprotective effects of GSK-961081 were evident in guinea pigs via MA, BA, and MABA mechanisms for up to 7 days after dosing. The lung selectivity index of GSK-961081 in guinea pigs was 55- to 110-fold greater than that of tiotropium with respect to systemic antimuscarinic antisialagogue effects and was 10-fold greater than that of salmeterol with respect to systemic ß2-adrenoceptor hypotensive effects. These preclinical findings studies suggest that GSK-961081 has the potential to be a promising next-generation inhaled lung-selective bronchodilator for the treatment of airway diseases, including chronic obstructive pulmonary disease.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 2/farmacologia , Broncodilatadores/farmacologia , Carbamatos/farmacologia , Antagonistas Muscarínicos/farmacologia , Quinolonas/farmacologia , Antagonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Antagonistas de Receptores Adrenérgicos beta 2/farmacocinética , Albuterol/análogos & derivados , Albuterol/farmacocinética , Albuterol/farmacologia , Animais , Broncodilatadores/efeitos adversos , Broncodilatadores/farmacocinética , Células CHO , Carbamatos/efeitos adversos , Carbamatos/farmacocinética , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Avaliação Pré-Clínica de Medicamentos , Cobaias , Células HEK293 , Humanos , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/farmacocinética , Relaxamento Muscular , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Ligação Proteica , Quinolonas/efeitos adversos , Quinolonas/farmacocinética , Receptores Adrenérgicos beta/metabolismo , Receptores Muscarínicos/metabolismo , Xinafoato de Salmeterol , Derivados da Escopolamina/farmacocinética , Derivados da Escopolamina/farmacologia , Brometo de Tiotrópio , Distribuição Tecidual , Traqueia/efeitos dos fármacos , Traqueia/fisiologia
8.
Nature ; 446(7132): 203-7, 2007 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-17322907

RESUMO

Complement-derived anaphylatoxins regulate immune and inflammatory responses through G-protein-coupled receptor (GPCR)-mediated signalling. C5L2 (also known as GPR77) is a relatively new GPCR thought to be a non-signalling receptor binding to C5a, on the basis of sequence information and experimental evidence. Here we show, using gene targeting, that C5L2 is required to facilitate C5a signalling in neutrophils, macrophages and fibroblasts in vitro. Deficiency of C5L2 results in reduced inflammatory cell infiltration, suggesting that C5L2 is critical for optimal C5a-mediated cell infiltration in certain in vivo settings. C5L2 is also involved in optimizing C3a-induced signals. Furthermore, like mice incapable of C3a/complement 3a receptor (C3aR) signalling, C5L2-deficient mice are hypersensitive to lipopolysaccharide (LPS)-induced septic shock, show reduced ovalbumin (OVA)-induced airway hyper-responsiveness and inflammation, and are mildly delayed in haematopoietic cell regeneration after gamma-irradiation. Our data indicate that C5L2 can function as a positive modulator for both C5a- and C3a-anaphylatoxin-induced responses.


Assuntos
Complemento C3a/metabolismo , Complemento C5a/metabolismo , Actinas/química , Actinas/metabolismo , Animais , Bovinos , Células Cultivadas , Ativação do Complemento , Complemento C3a/imunologia , Complemento C5a/imunologia , Fibroblastos , Regulação da Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Humanos , Inflamação , Pulmão/citologia , Neutrófilos/citologia , Neutrófilos/metabolismo , Receptor da Anafilatoxina C5a , Receptores de Quimiocinas/deficiência , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Transdução de Sinais
9.
Top Stroke Rehabil ; 19(6): 479-90, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23192713

RESUMO

BACKGROUND: The long-term management of lower limb spasticity after stroke is an important aspect of an individual's physical recovery and quality of life. OBJECTIVE: To examine the effectiveness of pharmacological interventions in reducing spasticity of the lower limb in chronic stroke survivors. METHODS: PubMed, CINAHL, and EMBASE were searched for studies in which (1) ≥50% of the sample size had sustained a stroke; (2) the research design was a randomized controlled trial (RCT); (3) the mean time since stroke was ≥6 months for both the treatment and control groups, at the time treatment was initiated; (4) the treatment group received a pharmacological intervention aimed at treating lower limb spasticity; and (5) spasticity was assessed pre and post treatment. Methodological quality of each study was assessed using the PEDro tool. RESULTS: Nine RCTs (PEDro scores, 4-9) met inclusion criteria and included a pooled sample size of 605 individuals with a mean age of 54.8 years (range, 14-86). Four RCTs provided evidence that botulinum toxin type A was effective in reducing spasticity compared to persons receiving placebo or a phenol neurolytic. One study provided evidence that both alcohol and phenol neurolytics were effective in reducing spasticity. Finally, 4 studies provided evidence that oral and intrathecal medications were effective in reducing lower limb spasticity compared to placebo. CONCLUSIONS: Pharmacological treatment initiated 6 months post stroke reduced lower limb spasticity. Relevant areas of exploration for future research could include the period of effectiveness, long-term complications, and a cost-benefit analysis of such treatments.


Assuntos
Toxinas Botulínicas Tipo A/uso terapêutico , Fármacos Neuromusculares/uso terapêutico , Paraparesia Espástica/tratamento farmacológico , Paresia/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paraparesia Espástica/etiologia , Paresia/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Adulto Jovem
10.
Eur Urol Focus ; 8(6): 1673-1682, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35760722

RESUMO

BACKGROUND: Patient factors associated with urinary tract cancer can be used to risk stratify patients referred with haematuria, prioritising those with a higher risk of cancer for prompt investigation. OBJECTIVE: To develop a prediction model for urinary tract cancer in patients referred with haematuria. DESIGN, SETTING, AND PARTICIPANTS: A prospective observational study was conducted in 10 282 patients from 110 hospitals across 26 countries, aged ≥16 yr and referred to secondary care with haematuria. Patients with a known or previous urological malignancy were excluded. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcomes were the presence or absence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC], and renal cancer). Mixed-effect multivariable logistic regression was performed with site and country as random effects and clinically important patient-level candidate predictors, chosen a priori, as fixed effects. Predictors were selected primarily using clinical reasoning, in addition to backward stepwise selection. Calibration and discrimination were calculated, and bootstrap validation was performed to calculate optimism. RESULTS AND LIMITATIONS: The unadjusted prevalence was 17.2% (n = 1763) for bladder cancer, 1.20% (n = 123) for UTUC, and 1.00% (n = 103) for renal cancer. The final model included predictors of increased risk (visible haematuria, age, smoking history, male sex, and family history) and reduced risk (previous haematuria investigations, urinary tract infection, dysuria/suprapubic pain, anticoagulation, catheter use, and previous pelvic radiotherapy). The area under the receiver operating characteristic curve of the final model was 0.86 (95% confidence interval 0.85-0.87). The model is limited to patients without previous urological malignancy. CONCLUSIONS: This cancer prediction model is the first to consider established and novel urinary tract cancer diagnostic markers. It can be used in secondary care for risk stratifying patients and aid the clinician's decision-making process in prioritising patients for investigation. PATIENT SUMMARY: We have developed a tool that uses a person's characteristics to determine the risk of cancer if that person develops blood in the urine (haematuria). This can be used to help prioritise patients for further investigation.


Assuntos
Neoplasias Renais , Neoplasias da Bexiga Urinária , Neoplasias Urológicas , Humanos , Masculino , Neoplasias Urológicas/complicações , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/epidemiologia , Neoplasias da Bexiga Urinária/complicações , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/epidemiologia
11.
Bioorg Med Chem Lett ; 21(8): 2472-5, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21398124

RESUMO

A series of benzothiazinone and benzooxazinone derivatives were discovered as SGLT2 inhibitors. The optimization led to the discovery of compounds 31 and 32, which exhibited similar potency and better SGLT1 selectivity compared to dapagliflozin. These compounds may provide novel promising scaffolds, which are different from phlorizin-based SGLT2 inhibitors.


Assuntos
Benzoxazinas/química , Inibidores do Transportador 2 de Sódio-Glicose , Triazóis/química , Animais , Benzoxazinas/síntese química , Benzoxazinas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Ratos , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Tiazinas/síntese química , Tiazinas/química , Tiazinas/farmacologia , Triazóis/síntese química , Triazóis/farmacologia
12.
Bioorg Med Chem Lett ; 21(12): 3774-9, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21565497

RESUMO

Previous efforts have led to the identification of a potent, selective, and nonphlorizin based SGLT2 inhibitor 1. This Letter describes efforts to further optimize the potency, microsomal stability, solubility and pharmacokinetic properties of this series of SGLT2 inhibitors. From these efforts, compounds 28 and 32 have improved solubility and pharmacokinetic properties compared to compound 1.


Assuntos
Triazóis/síntese química , Estabilidade de Medicamentos , Estrutura Molecular , Florizina/química , Solubilidade , Relação Estrutura-Atividade , Triazóis/química
13.
Physiol Rep ; 9(21): e15081, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34755490

RESUMO

Influenza remains a major cause of death and disability with limited treatment options. Studies of acute lung injury have identified angiopoietin-2 (Ang-2) as a key prognostic marker and a potential mediator of Acute respiratory distress syndrome. However, the role of Ang-2 in viral pneumonia remains poorly defined. This study characterized the time course of lung Ang-2 expression in severe influenza pneumonia and tested the therapeutic potential of Ang-2 inhibition. We inoculated adult mice with influenza A (PR8 strain) and measured angiopoietin-1 (Ang-1), Ang-2, and Tie2 expressions during the evolution of inflammatory lung injury over the first 7 days post-infection (dpi). We tested a peptide-antibody inhibitor of Ang-2, L1-7, administered at 2, 4, and 6 dpi and measured arterial oxygen saturation, survival, pulmonary edema, inflammatory cytokines, and viral load. Finally, we infected primary human alveolar type II epithelial (AT2) cells grown in air-liquid interface culture with influenza and measured Ang-2 RNA expression. Influenza caused severe lung injury between 5 and 7 dpi in association with increased Ang-2 lung RNA and a dramatic increase in Ang-2 protein in bronchoalveolar lavage. Inhibition of Ang-2 improved oxygenation and survival and reduced pulmonary edema and alveolar-capillary barrier permeability to protein without major effects on inflammation or viral load. Finally, influenza increased the expression of Ang-2 RNA in human AT2 cells. The increased Ang-2 levels in the airspaces during severe influenza pneumonia and the improvement in clinically relevant outcomes after Ang-2 antagonism suggest that the Ang-1/Ang-2 Tie-2 signaling axis is a promising therapeutic target in influenza and potentially other causes of viral pneumonia.


Assuntos
Angiopoietina-2/antagonistas & inibidores , Orthomyxoviridae/patogenicidade , Pneumonia Viral/tratamento farmacológico , Angiopoietina-2/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Anticorpos Neutralizantes/uso terapêutico , Células Cultivadas , Citocinas/metabolismo , Humanos , Pulmão/metabolismo , Pulmão/virologia , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Receptor TIE-2/metabolismo , Carga Viral
14.
Bioorg Med Chem Lett ; 20(2): 493-8, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-20005104

RESUMO

Free fatty acid receptor 2 (FFA2) is a G-protein coupled receptor for which only short-chain fatty acids (SCFAs) have been reported as endogenous ligands. We describe the discovery and optimization of phenylacetamides as allosteric agonists of FFA2. These novel ligands can suppress adipocyte lipolysis in vitro and reduce plasma FFA levels in vivo, suggesting that these allosteric modulators can serve as pharmacological tools for exploring the potential function of FFA2 in various disease conditions.


Assuntos
Acetamidas/síntese química , Receptores de Superfície Celular/agonistas , Receptores Acoplados a Proteínas G/agonistas , Acetamidas/química , Acetamidas/farmacocinética , Regulação Alostérica , Animais , AMP Cíclico/metabolismo , Descoberta de Drogas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ratos , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-Atividade
15.
Can Urol Assoc J ; 14(5): E180-E184, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31793859

RESUMO

INTRODUCTION: Prostate incidentalomas are prostatic lesions suspicious for cancer discovered by imaging patients without a known history of prostatic cancer (PCa) for other reasons. 18-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG PET) is used to diagnose, stage, and assess response to treatment for numerous cancers, but it is not routinely used for PCa. We aimed to determine the rate of detection of prostate incidentalomas in patients undergoing FDG PET and to evaluate the natural history of these lesions. METHODS: A retrospective review was conducted of all FDG PET scans performed between 2005 and 2017 at a single institution. Patients were selected who had prostatic uptake without a history of PCa. Clinical data were collected from electronic medical records to determine how the prostate incidentalomas were further evaluated and to define the rate of malignancy. RESULTS: A prostate incidentaloma was identified in 309 (1.0%) of 31 019 FDG PET scans performed on men. A prostate-specific antigen (PSA) test was obtained in 40.1% of patients within six months of prostate incidentaloma detection. Six patients underwent a multiparametric magnetic resonance imaging (mpMRI) of the prostate, which identified PCa in one case. Overall, PCa was diagnosed in 33 cases, representing 10.7% of the prostate incidentalomas and 0.1% of the scanned patients. PCa was intermediate- or high-risk in 27 (8.7%) of the prostate incidentalomas. CONCLUSIONS: Incidental lesions detected in the prostate by FDG PET may represent clinically significant PCa. Referral to a urologist for further evaluation should be considered if the patient is otherwise in reasonable health.

16.
Circ Cardiovasc Imaging ; 12(11): e009055, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31707811

RESUMO

BACKGROUND: The induction of matrix metalloproteinases (MMPs) and reduction in tissue inhibitors of MMPs (TIMPs) plays a role in ischemia/reperfusion (I/R) injury post-myocardial infarction (MI) and subsequent left ventricular remodeling. We developed a hybrid dual isotope single-photon emission computed tomography/computed tomography approach for noninvasive evaluation of regional myocardial MMP activation with 99mTc-RP805 and dynamic 201Tl for determination of myocardial blood flow, to quantify the effects of intracoronary delivery of recombinant TIMP-3 (rTIMP-3) on I/R injury. METHODS: Studies were performed in control pigs (n=5) and pigs following 90-minute balloon occlusion-induced ischemia/reperfusion (I/R) of left anterior descending artery (n=9). Before reperfusion, pigs with I/R were randomly assigned to intracoronary infusion of rTIMP-3 (1.0 mg/kg; n=5) or saline (n=4). Three days post-I/R, dual isotope imaging was performed with 99mTc-RP805 and 201Tl along with contrast cineCT to assess left ventricular function. RESULTS: The ischemic to nonischemic ratio of 99mTc-RP805 was significantly increased following I/R in saline group (4.03±1.40), and this ratio was significantly reduced with rTIMP-3 treatment (2.22±0.57; P=0.03). This reduction in MMP activity in the MI-rTIMP-3 treatment group was associated with an improvement in relative MI region myocardial blood flow compared with the MI-saline group and improved myocardial strain in the MI region. CONCLUSIONS: We have established a novel hybrid single-photon emission computed tomography/computed tomography imaging approach for the quantitative assessment of regional MMP activation, myocardial blood flow, and cardiac function post-I/R that can be used to evaluate therapeutic interventions such as intracoronary delivery of rTIMP-3 for reduction of I/R injury in the early phases of post-MI remodeling.


Assuntos
Ventrículos do Coração , Metaloproteinases da Matriz , Infarto do Miocárdio , Miocárdio , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Masculino , Circulação Coronária/fisiologia , Modelos Animais de Doenças , Ventrículos do Coração/crescimento & desenvolvimento , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Metaloproteinases da Matriz/metabolismo , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único/métodos , Suínos , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular/fisiologia
17.
Mol Pharmacol ; 74(6): 1599-609, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18818303

RESUMO

FFA2 (GPR43) has been identified as a receptor for short-chain fatty acids (SCFAs) that include acetate and propionate. FFA2 is highly expressed in islets, a subset of immune cells, and adipocytes. Although the potential roles of FFA2 activation in these tissues have previously been described, the physiological functions are still unclear. The potency for SCFAs on FFA2 is low, in the high micromolar to millimolar concentrations. To identify better pharmacological tools to study receptor function, we used high-throughput screening (HTS) to discover a series of small molecule phenylacetamides as novel and more potent FFA2 agonists. This series is specific for FFA2 over FFA1 (GPR40) and FFA3 (GPR41), and it is able to activate both the Galpha(q) and Galpha(i) pathways in vitro on Chinese hamster ovary cells stably expressing FFA2. Treatment of adipocytes with these compounds also resulted in Galpha(i)-dependent inhibition of lipolysis similar to that of endogenous ligands (SCFAs). It is noteworthy that these compounds not only acted as FFA2 agonists but also exhibited positive cooperativity with acetate or propionate. The observed allosteric modulation was consistent in all the functional assays that we have explored, including cAMP, calcium mobilization, guanosine 5'-[gamma-thio]triphosphate binding, and lipolysis. Molecular modeling analysis of FFA2 based on human beta(2)-adrenergic receptor structure revealed potential nonoverlapping binding sites for the endogenous and synthetic ligands, further providing insight into the binding pocket for the allosteric interactions. This is the first report describing the identification of novel allosteric modulators with agonist activity for FFA2, and these compounds may serve as tools for further unraveling the physiological functions of the receptor and its involvement in various diseases.


Assuntos
Benzenoacetamidas/farmacologia , Receptores de Superfície Celular/agonistas , Tiazóis/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Regulação Alostérica , Sequência de Aminoácidos , Animais , Benzenoacetamidas/química , Células CHO , Cricetinae , Cricetulus , Humanos , Ligantes , Lipólise/efeitos dos fármacos , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Ensaio Radioligante , Relação Estrutura-Atividade , Tiazóis/química
18.
Pharmacol Res Perspect ; 6(3): e00400, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29736245

RESUMO

Revefenacin (TD-4208) is a novel, long-acting, and lung-selective muscarinic cholinergic receptor (mAChR) antagonist in development as a nebulized inhalation solution for the treatment of chronic obstructive pulmonary disease (COPD) patients. This study evaluated the pharmacology of revefenacin at human recombinant mAChRs and in airway tissues from rats, guinea pigs, and humans. At human recombinant mAChRs, revefenacin displayed high affinity (pKI = 8.2-9.8) and behaved as a competitive antagonist (pKI, apparent = 9.4-10.9) at the five human recombinant mAChRs. Kinetic studies demonstrated that revefenacin dissociated significantly slower from the hM3 (t1/2 = 82 minutes) compared to the hM 2 (t1/2 = 6.9 minutes) mAChR at 37°C, thereby making it kinetically selective for the former subtype. Similarly, in functional studies, revefenacin-mediated antagonism of acetylcholine (ACh)-evoked calcium mobilization responses were reversed less rapidly at hM3 compared to the hM2 mAChR. In isolated tracheal tissues from rat and guinea pig and isolated bronchial tissues from humans, revefenacin potently antagonized mAChR-mediated contractile responses. Furthermore, the antagonistic effects of revefenacin in rat, guinea pig, and human airway tissues were slowly reversible (t1/2 of 13.3, >16, and >10 hours, respectively). These data demonstrate that revefenacin is a potent, high affinity, and selective functional mAChR antagonist with kinetic selectivity for the hM3 receptor and produces potent and long-lasting antagonism of mAChR-mediated contractile responses in rat, guinea pig, and human airway tissue. These data suggest that revefenacin has the potential to be a potent once-daily dosed inhaled bronchodilator in COPD patients.


Assuntos
Benzamidas/farmacologia , Brônquios/fisiologia , Carbamatos/farmacologia , Antagonistas Muscarínicos/farmacologia , Proteínas Recombinantes/metabolismo , Traqueia/fisiologia , Administração por Inalação , Animais , Brônquios/efeitos dos fármacos , Cobaias , Humanos , Nebulizadores e Vaporizadores , Ratos , Traqueia/efeitos dos fármacos
19.
Pharmacol Res Perspect ; 6(6): e00442, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30459952

RESUMO

Tissue Inhibitor of Metalloproteinase 3 (TIMP3) is a secreted protein that has a great utility to inhibit elevated metalloproteinase (MMP) activity in injured tissues including infarcted cardiac tissue, inflamed vessels, and joint cartilages. An imbalance between TIMP3 and active MMP levels in the local tissue area may cause worsening of disease progression. To counter balance elevated MMP levels, exogenous administration of TIMP3 appeared to be beneficial in preclinical studies. However, the current form of WT-TIMP3 molecule has a limitation to be a therapeutic candidate due to low production yield, short plasma half-life, injection site retention, and difficulty in delivery, etc. We have engineered TIMP3 molecules by adding extra glycosylation sites or fusing with albumin, Fc, and antibody to improve pharmacokinetic properties. In general, the C-terminal fusion of TIMP3 improved expression and production in mammalian cells and extended half-lives dramatically 5-20 folds. Of note, a site-specific glycosylation at K22S/F34N resulted in a higher level of expression and better cardiac function compared to other fusion proteins in the context of left ventricle ejection fraction (LVEF) changes in a rat myocardial infarction model. It appeared that cardiac efficacy depends on a high ECM binding affinity, in which K22S/F34N and N-TIMP3 showed a higher binding to the ECM compared to other engineered molecules. In conclusion, we found that the ECM binding and sustained residence of injected TIMP3 molecules are important for cardiac tissue localization and inhibition of adverse remodeling activity.


Assuntos
Proteína ADAM17/antagonistas & inibidores , Metaloproteinases da Matriz/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Proteínas Recombinantes de Fusão/farmacologia , Inibidor Tecidual de Metaloproteinase-3/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Proteína ADAM17/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Progressão da Doença , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fibroblastos , Glicosilação , Humanos , Infusões Intravenosas , Injeções Intralesionais , Masculino , Mutação , Infarto do Miocárdio/etiologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/uso terapêutico , Inibidor Tecidual de Metaloproteinase-3/química , Inibidor Tecidual de Metaloproteinase-3/genética , Inibidor Tecidual de Metaloproteinase-3/uso terapêutico , Resultado do Tratamento
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