RESUMO
The prevalence of chronic kidney disease is increasing globally; however, effective therapeutic options are limited. In this study, we aimed to identify urinary miRNAs reflecting the effect of therapeutic intervention in rats with comorbid hypertension and diabetes. Additionally, the potential beneficial effects of anti-platelet sarpogrelate and cilostazol were investigated. Nephropathy progression in streptozotocin (STZ)-treated spontaneously hypertensive rats (SHRs), including albuminuria, collagen deposition, and histopathological changes, was alleviated by sarpogrelate and antihypertensive agent telmisartan. Global analysis of urinary miRNAs identified that miR-199a-3p was commonly reduced by sarpogrelate and telmisartan treatment. In vitro analysis suggested CD151 as a target gene of miR-199a-3p: miR-199a-3p overexpression repressed CD151 levels and miR-199a-3p interacted with the 3'-untranslated region of the CD151 gene. In addition, we demonstrated that the miR-199a-3p/CD151 axis is associated with the transforming growth factor-ß1 (TGF-ß1)-induced fibrogenic pathway. TGF-ß1 treatment led to miR-199a-3p elevation and CD151 suppression, and miR-199a-3p overexpression or CD151-silencing enhanced TGF-ß1-inducible collagen IV and α-smooth muscle actin (α-SMA) levels. In vivo analysis showed that the decrease in CD151 and the increase in collagen IV and α-SMA in the kidney from STZ-treated SHR were restored by sarpogrelate and telmisartan administration. In an additional animal experiment using cilostazol and telmisartan, there was a correlation between urinary miR-199a-3p reduction and the ameliorating effects of cilostazol or combination with telmisartan. Collectively, these results indicate that urinary miR-199a-3p might be utilized as a marker for nephropathy treatment. We also provide evidence of the benefits of antiplatelet sarpogrelate and cilostazol in nephropathy progression.
Assuntos
Cilostazol/farmacologia , Nefropatias Diabéticas/tratamento farmacológico , Hipertensão Renal/tratamento farmacológico , MicroRNAs/urina , Nefrite/tratamento farmacológico , Succinatos/farmacologia , Animais , Biomarcadores Farmacológicos/urina , Nefropatias Diabéticas/genética , Modelos Animais de Doenças , Hipertensão Renal/genética , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Nefrite/genética , Ratos Wistar , Tetraspanina 24/genética , Tetraspanina 24/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Resultado do TratamentoRESUMO
INTRODUCTION: Determination of renal function is particularly important when prescribing antibiotics to elderly patients. This study aims to determine the correlation between estimated creatinine clearance and the estimated glomerular filtration rate, for a hospitalized population of very elderly patients, and to audit antibiotic prescribing errors. MATERIAL AND METHODS: Retrospective cohort study of all patients ≥ 80 years hospitalized with antibiotic. Creatinine clearance was calculated using Cockcroft-Gault equation and estimated glomerular filtration rate by Modification of Diet in Renal Disease Study and Chronic Kidney Disease Epidemiology Collaboration equations. Dosing errors were determined through adjustment of daily define dose to renal function. RESULTS: The study included 589 patients. The correlation of Cockcroft-Gault with Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration was r = 0.98 and 0.96 for the minimum serum creatinine, and 0.97 and 0.93 for the maximum serum creatinine. Based on Cockcroft-Gault, there were errors in the daily defined dose in 45% in the minimum serum creatinine, and 52% in the maximum serum creatinine day. There was a discrepancy in the recording of errors of 14% to 16% when Cockcroft-Gault was compared with Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration. DISCUSSION: There was a good correlation of Cockcroft-Gault with the estimated glomerular filtration rate by Modification of Diet in Renal Disease or Chronic Kidney Disease Epidemiology Collaboration. Regardless of the equation used to estimate renal function there was a high rate of antibiotic dosing errors documented in this population. CONCLUSION: This study supports the maintenance of the Cockcroft-Gault equation for drug dosing in the very elderly population. Further studies are needed to investigate underlying causes of prescribing errors.
Introdução: A determinação da função renal é particularmente importante na prescrição de antibióticos em doentes idosos. O objetivo deste estudo é correlacionar a clearance de creatinina com a taxa de filtração glomerular estimada, numa população hospitalizada de doentes muito idosos, e auditar os erros de prescrição antibiótica. Material e Métodos: Coorte retrospetivo de todos os doentes ≥ 80 anos hospitalizados com antibioterapia prescrita. A clearance de creatinina foi calculada através da equação Cockcroft-Gault, e a filtração glomerular estimada através das equações Modification of Diet in Renal Disease e Chronic Kidney Disease Epidemiology Collaboration. Os erros de prescrição foram determinados pelo ajuste da dose diária definida à função renal. Resultados: Foram incluídos 589 doentes. A correlação da Cockcroft-Gault com Modification of Diet in Renal Disease e Chronic Kidney Disease Epidemiology Collaboration foi r = 0,98 e 0,96 para a creatinina sérica mínima, e 0,97 e 0,93 para a creatinina sérica máxima. Com base na Cockcroft-Gault, a taxa de erro na dose diária definida foi 45% no dia da creatinina sérica mínima e 52% no dia da creatinina sérica máxima. Quando a Cockcroft-Gault foi comparada com a Modification of Diet in Renal Disease e a Chronic Kidney Disease Epidemiology Collaboration houve uma discrepância no registo de erros de 14% a 16%, respetivamente. Discussão: Verificou-se uma boa correlação entre a Cockcroft-Gault e as equações que calculam a filtração glomerular: Modification of Diet in Renal Disease ou Chronic Kidney Disease Epidemiology Collaboration. Independentemente da equação utilizada para estimar a função renal, foi documentada uma taxa elevada de erros na dose de antibióticos prescrita nesta população. Conclusão: Este estudo reforça a manutenção do uso da equação de Cockcroft-Gault para calcular a dose adequada de antibióticos na população muito idosa. Mais estudos são necessários para investigar as causas subjacentes aos erros de prescrição.
Assuntos
Envelhecimento/fisiologia , Antibacterianos/efeitos adversos , Creatinina/análise , Creatinina/urina , Taxa de Filtração Glomerular/fisiologia , Erros de Medicação/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Biomarcadores/urina , Biomarcadores Farmacológicos/urina , Estudos de Coortes , Creatinina/sangue , Feminino , Humanos , Testes de Função Renal/métodos , Masculino , Estudos RetrospectivosRESUMO
Aim: Tolvaptan, an oral vasopressin-2 antagonist, sometimes improves hepatic edema including ascites in patients with decompensated cirrhosis. In this study, we examined the effectiveness and survival advantage in patients with the long-term administration of tolvaptan. Methods: A total of 115 patients with refractory ascites who were treated with tolvaptan were retrospectively analyzed based on their clinical records. Patients with a decrease in body weight of ≥1.5 kg from the baseline on day 7 were determined as responders. Re-exacerbation was defined as a return to the baseline BW, dose escalation of conventional diuretics, or abdominal drainage. Results: Of the 115 patients, 84 were included in this analysis. Response to tolvaptan treatment was observed in 55 out of the 84 patients (65.5%), with a mean weight reduction of 2.52 kg. Multivariate analyses demonstrated that body mass index (≥24) and urinary specific gravity (≥1.018) were significant predictors of the response to tolvaptan. However, cumulative re-exacerbation rates in responders at 6 and 12 months were 42.4 and 60.1%, respectively. Child-Pugh (classification C), HCC complication, and serum sodium levels (≥133 mEq/L) were determined as independent prognostic factors impacting overall survival (OS). Although there were no significant differences in OS between tolvaptan responders and non-responders, the responders without re-exacerbation within 3 months showed significantly longer OS than those with re-exacerbation within 3 months. Conclusion: A persistent therapeutic response, but not early response to tolvaptan, was associated with favorable survival of decompensated cirrhotic patients.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/administração & dosagem , Cirrose Hepática/tratamento farmacológico , Tolvaptan/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antagonistas dos Receptores de Hormônios Antidiuréticos/efeitos adversos , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Ascite/tratamento farmacológico , Ascite/etiologia , Ascite/mortalidade , Biomarcadores Farmacológicos/sangue , Biomarcadores Farmacológicos/urina , Índice de Massa Corporal , Feminino , Humanos , Estimativa de Kaplan-Meier , Cirrose Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Sódio/sangue , Tolvaptan/efeitos adversos , Tolvaptan/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Quality control of traditional Chinese medicine (TCM) has always been a hot issue to TCM. However, due to the complexity of TCM ingredients, the current quality standards of TCM have problems that are difficult to guarantee clinical efficacy. American ginseng, the dried roots of Pawajc quinquefolium L. (Araliaceae), is a valuable herbal medicine due to various pharmacological effects and huge health benefit, which are associated with numerous active ingredients such as ginsenosides. Although a large number of studies have investigated the active ingredients of American ginseng, Q-markers reflecting comprehensive review on its efficacies has yet been unrevealed. PURPOSE: The study aims to discover the Q-markers of Panax quinquefolius (American ginseng), provides a powerful method to clarify the significant ingredents of TCM and help further discovering extensive quality evaluation model,contributing to a significant improvement of TCM quality standard. METHODS: Mice general status, biochemical indexes assay, urine metabolic profile, and serum metabolic profile were utilized for model replication and efficacy evaluation. The in vitro and in vivo constituents of American ginseng using ultra-high performance liquid chromatography coupled with mass spectrometry (UPLC-MS) with Serum Pharmacochemistry of TCM were in-depth investigated. Q-markers that were associated with core markers of therapeutic effects were excavated by a plotting of correlation between marker metabolites and serum constituents (PCMS) approach. RESULTS: Correlation analysis of 41 blood and urine labeled metabolites with 14 serum components showed that 24-methyl-7-cholesten-3ß-ol, zizybeoside II, betulin, ginsenoside Rd, cinnamyl alcohol, pseudoginsenoside F11 is highly correlated with the therapeutic effects of Compound Zaofan Pill (CZP), while pseudoginsenoside F11 and ginsenoside Rd are highly correlated with the therapeutic effects of American ginseng. The six absorbed blood compounds can be considered as potential Q-markers for compound, of which two compounds, such as pseudoginsenoside F11 and ginsenoside Rd, can be considered as potential Q-markers for American ginseng. CONCLUSION: The study has demonstrated that the Chinmedomics is an effective, comprehensive and fire-new method for discovering the Q-markers of TCM, and it may be more reasonable choices to establish quality standards of TCM.
Assuntos
Biomarcadores Farmacológicos/análise , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Panax/química , Animais , Biomarcadores Farmacológicos/sangue , Biomarcadores Farmacológicos/urina , Sangue/efeitos dos fármacos , Sangue/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/análise , Ginsenosídeos/análise , Espectrometria de Massas , Medicina Tradicional Chinesa/normas , Camundongos , Raízes de Plantas/química , Plantas Medicinais/química , Controle de Qualidade , UrináliseRESUMO
Sijunzi decoction (SJZD) is a Chinese classical formula to treat spleen qi deficiency syndrome (SQDS) and has been widely used for thousands of years. However, the quality control (QC) standards of SJZD are insufficient. Chinmedomics has been designed to discover and verify bioactive compounds of a variety of formula rapidly. In this study, we used Chinmedomics to evaluate the SJZD's efficacy against SQDS to discover the potential quality-markers (q-markers) for QC. A total of 56 compounds in SJZD were characterized in vitro, and 23 compounds were discovered in vivo. A total of 58 biomarkers were related to SQDS, and SJZD can adjust a large proportion of marker metabolites to normal level and then regulate the metabolic profile to the health status. A total of 10 constituents were absorbed as effective ingredients that were associated with overall efficacy. We preliminarily determined malonyl-ginsenoside Rb2 and ginsenoside Ro as the q-markers of ginseng; dehydrotumulosic acid and dihydroxy lanostene-triene-21-acid as the q-markers of poria; glycyrrhizic acid, isoglabrolide, and glycyrrhetnic acid as the q-markers of licorice; and 2-atractylenolide as the q-marker of macrocephala. According to the discovery of the SJZD q-markers, we can establish the quality standard that is related to efficacy.
Assuntos
Biomarcadores Farmacológicos/análise , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Baço/efeitos dos fármacos , Baço/fisiopatologia , Animais , Biomarcadores Farmacológicos/sangue , Biomarcadores Farmacológicos/urina , Modelos Animais de Doenças , Ginsenosídeos/análise , Masculino , Medicina Tradicional Chinesa , Qi , Controle de Qualidade , Ratos , Ratos Sprague-DawleyRESUMO
Introduction: Gloriosa superba is a flowering plant that contains colchicine. Deliberate self-poisoning with this plant in Sri Lanka is common and potentially fatal. The objective of this study was to describe the epidemiology, toxicokinetics and selected biomarkers in these patients. Materials and methods: The study consisted of three parts; epidemiologic and outcome data (n = 297), concentrations and toxicokinetics (n = 72), evaluation of urinary and serum biomarkers (n = 45). Plasma colchicine levels were measured by high-performance liquid chromatography (HPLC). We also measured serum biomarkers: creatinine (sCr), cystatin C (sCysC) and creatine kinase (CK), and urinary biomarkers: creatinine, kidney injury molecule-1 (KIM - 1), clusterin, albumin, beta-2-microglobulin (ß2M), cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN) and trefoil factor 3 (TFF3). Results: The case fatality was 10% (29/297), and death was much more common in older patients. Median concentrations of colchicine were higher in those over 65 [median 4.7 ng/mL (IQR: 1.7-6.6) vs. 1.2 (IQR: 0.2-2.7) for those <35]. Admission colchicine concentrations were highly correlated with a fatal outcome [median 7.8 ng/ml (IQR: 5.8-18.7) vs 1.2 (0-2.3) in survivors]. The area under the receiver operating characteristic curve (AUC-ROC) for uncorrected admission colchicine level was highly predictive of a fatal outcome, and this improved even further with two methods we developed to correct for the expected change with time. The best method had an AUC-ROC of 0.98 (95%CI 0.94-1.00) in predicting death, with 100% sensitivity and 96% specificity at the best cut-point. Discussion: Fatal outcomes and high concentrations were both much more common in the elderly following poisoning with Gloriosa superba. Our findings are consistent with kinetic data after medicinal colchicine ingestion. Conclusions: Gloriosa superba self-poisoning causes significant mortality. High concentration of colchicine is highly predictive of a fatal outcome. Ingestion of Gloriosa superba caused only mild acute kidney injury (AKI) and rhabdomyolysis.
Assuntos
Colchicaceae , Colchicina/sangue , Intoxicação por Plantas/epidemiologia , Adolescente , Adulto , Área Sob a Curva , Biomarcadores Farmacológicos/sangue , Biomarcadores Farmacológicos/urina , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/urina , Colchicina/farmacocinética , Colchicina/intoxicação , Creatinina/sangue , Creatinina/urina , Feminino , Receptor Celular 1 do Vírus da Hepatite A/sangue , Humanos , Masculino , Intoxicação por Plantas/mortalidade , Sri Lanka/epidemiologia , Toxicocinética , Adulto JovemRESUMO
BACKGROUND: Prior to clinical trials of new TB drugs or therapeutic vaccines, it is necessary to develop monitoring tools to predict treatment outcomes in TB patients. Urine interferon gamma inducible protein 10 (IP-10) is a potential biomarker of treatment response in chronic hepatitis C virus infection and lung diseases, including tuberculosis. In this study, we assessed IP-10 levels in urine samples from patients with active TB at diagnosis, during treatment, and at completion, and compared these with levels in serum samples collected in parallel from matched patients to determine whether urine IP-10 can be used to monitor treatment response in patients with active TB. METHODS: IP-10 was measured using enzyme-linked immunosorbent assays in urine and serum samples collected concomitantly from 23 patients with active TB and 21 healthy adults (44 total individuals). The Mann-Whitney U test and Wilcoxon matched-pairs signed rank test were used for comparisons among healthy controls and patients at three time points, and LOESS regression was used for longitudinal data. RESULTS: The levels of IP-10 in urine increased significantly after 2 months of treatment (P = 0.0163), but decreased by the completion of treatment (P = 0.0035). Serum IP-10 levels exhibited a similar trend, but did not increase significantly after 2 months of treatment in patients with active TB. CONCLUSIONS: Unstimulated IP-10 in urine can be used as a biomarker to monitor treatment response in patients with active pulmonary TB.
Assuntos
Antituberculosos/uso terapêutico , Biomarcadores Farmacológicos/urina , Quimiocina CXCL10/urina , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , Valor Preditivo dos Testes , Prognóstico , Resultado do Tratamento , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/patologia , Urinálise/métodos , Adulto JovemRESUMO
The Biomarker Qualification Program was established at the Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA) to expedite the integration of promising biomarkers across multiple drug development programs. The first set of biomarkers qualified in 2008 consisted of seven nonclinical safety biomarkers for the detection of acute drug-induced nephrotoxicity in rats, and included urinary kidney injury molecule-1 (KIM-1). This article discusses the use of KIM-1 in drug development and research before and after CDER's qualification of KIM-1. Use was determined by analyzing relevant documents identified by keyword searches using three databases: 1) an FDA internal database, Document Archiving, Reporting, and Regulatory Tracking System (DARRTS); 2) ClinicalTrials.gov; and 3) PubMed. The results indicate increased use of KIM-1 as a biomarker for detection of kidney injury in drug development programs reviewed by CDER, as well as in research following qualification.
Assuntos
Injúria Renal Aguda/urina , Biomarcadores Farmacológicos/urina , Aprovação de Drogas/métodos , Desenvolvimento de Medicamentos/métodos , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , United States Food and Drug Administration , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Animais , Bibliometria , Ensaios Clínicos como Assunto , Bases de Dados Factuais , Humanos , Estudos Observacionais como Assunto , Prognóstico , PubMed , Medição de Risco , Fatores de Tempo , Estados Unidos , UrináliseRESUMO
BACKGROUND: N1-methylnicotinamide (1-NMN) has been proposed as a potential clinical biomarker to assess drug-drug interactions involving organic cation transporters (OCT2) and multidrug and toxin extrusion protein transporters. RESULTS: A hydrophilic interaction liquid chromatography-MS/MS assay, to quantify 1-NMN, in human plasma and urine is reported. MATERIALS & METHODS: A hydrophilic interaction chromatography (HILIC)-tandem mass spectrometry (MS/MS) assay to quantify 1-NMN in human plasma and urine is reported. The basal 1-NMN levels in plasma and urine were 4-120 and 2000-15,000 ng/ml, respectively. CONCLUSION: 1-NMN plasma AUCs increased two- to fourfold versus placebo following the administration of a clinical candidate that in vitro experiments indicated was an OCT2 inhibitor. The described hydrophilic interaction liquid chromatography-MS/MS assay can be used to assess a clinical compound candidate for the inhibition of OCT2 and multidrug and toxin extrusion protein transporter in first-in-human studies.
Assuntos
Biomarcadores Farmacológicos/análise , Rim/metabolismo , Niacinamida/análogos & derivados , Transportador 2 de Cátion Orgânico/metabolismo , Área Sob a Curva , Biomarcadores Farmacológicos/sangue , Biomarcadores Farmacológicos/urina , Cromatografia Líquida/métodos , Confiabilidade dos Dados , Interações Medicamentosas , Humanos , Interações Hidrofóbicas e Hidrofílicas , Niacinamida/análise , Niacinamida/sangue , Niacinamida/urina , Transportador 2 de Cátion Orgânico/antagonistas & inibidores , Placebos , Padrões de Referência , Espectrometria de Massas em Tandem/métodosRESUMO
BACKGROUND: Shengmai San (SMS), a Chinese classic herbal formula, has been widely used for the treatment of Qi-Yin deficiency syndrome in Asia. Modern pharmacological studies have shown that SMS improves the cognitive function. However, the quality markers (Q-markers) for SMS still need further research. PURPOSE: Using chinmedocmics strategy to systematically evaluate the efficacy of SMS in the treatment of APPswe/PS1dE9 (APP/PS1) transgenic model of Alzheimer's disease (AD) and to discover the efficacy-related Q-markers. METHODS: The effect of SMS on APP/PS1 mice was evaluated by behavioral test, immunohistochemistry and urine metabolic profile, and the urine marker metabolites associated with SMS treatment of AD were characterized using metabolomics method. In the premise of efficacy, Serum Pharmacochemistry of Traditional Chinese Medicine was applied to investigate the in vivo constituents of SMS. A correlation analysis between marker metabolites of therapeutic effects and serum constituents was completed by chinmedomics approach. RESULTS: SMS had a therapeutic effect on APP/PS1 mice, and 34 potential urine biomarkers were reversed by SMS treatment. A total of 17 in vivo constituents were detected, including 14 prototype components and 3 metabolites. The correlation analysis showed that eight constituents were extremely correlated with protective effects of SMS in AD, and considered as potential Q-markers of SMS, including schisandrin, isoschisandrin, angeloylgomisin Q, gomisin D, angeloylgomisin H, gomisin M2, ginsenoside F1, 20(R)-ginsenoside Rg3. CONCLUSION: This study has demonstrated that chinmedomics is novel strategy for discovering the potential effective constituents from herbal formula, which are recognized as Q-markers.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Biomarcadores Farmacológicos/análise , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Animais , Biomarcadores Farmacológicos/sangue , Biomarcadores Farmacológicos/urina , Ciclo-Octanos/análise , Dioxóis/análise , Modelos Animais de Doenças , Combinação de Medicamentos , Medicamentos de Ervas Chinesas/análise , Ginsenosídeos/análise , Lignanas/análise , Masculino , Medicina Tradicional Chinesa/métodos , Metabolômica/métodos , Camundongos Transgênicos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Compostos Policíclicos/análiseRESUMO
This study evaluated coproporphyrin I (CPI) as a selective endogenous biomarker of OATP1B-mediated drug-drug interactions (DDIs) relative to clinical probe rosuvastatin using nonlinear mixed-effect modeling. Plasma and urine CPI data in the presence/absence of rifampicin were modeled to describe CPI synthesis, elimination clearances, and obtain rifampicin in vivo OATP Ki. The biomarker showed stable interoccasion baseline concentrations and low interindividual variability (<25%) in subjects with wildtype SLCO1B1. Biliary excretion was the dominant CPI elimination route (maximal >85%). Estimated rifampicin in vivo unbound OATP Ki (0.13 µM) using CPI data was 2-fold lower relative to rosuvastatin. Model-based simulations and power calculations confirmed sensitivity of CPI to identify moderate and weak OATP1B inhibitors in an adequately powered clinical study. Current analysis provides the most detailed evaluation of CPI as an endogenous OATP1B biomarker to support optimal DDI study design; further pharmacogenomic and DDI data with a panel of inhibitors are required.
Assuntos
Antibióticos Antituberculose/farmacocinética , Biomarcadores Farmacológicos/sangue , Simulação por Computador , Coproporfirinas/sangue , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Modelos Biológicos , Rifampina/farmacocinética , Antibióticos Antituberculose/administração & dosagem , Antibióticos Antituberculose/efeitos adversos , Antibióticos Antituberculose/sangue , Biomarcadores Farmacológicos/urina , Coproporfirinas/urina , Interações Medicamentosas , Genótipo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Masculino , Dinâmica não Linear , Variantes Farmacogenômicos , Rifampina/administração & dosagem , Rifampina/efeitos adversos , Rifampina/sangue , Medição de Risco , Rosuvastatina Cálcica/sangueRESUMO
PURPOSE: Desmopressin is a synthetic V2 specific analogue of antidiuretic hormone (arginine vasopressin) that is widely used as first line treatment for monosymptomatic nocturnal enuresis. However, no biomarkers to predict desmopressin effectiveness have yet been established. Because arginine vasopressin is unstable, we prospectively measured the major urine concentration factor aquaporin 2 and serum copeptin (as a surrogate marker for vasopressin) in patients with monosymptomatic nocturnal enuresis, and evaluated whether they are useful for predicting desmopressin treatment outcome. MATERIALS AND METHODS: The study included 32 children 6 to 11 years old with monosymptomatic nocturnal enuresis and nocturnal polyuria. Exclusion criteria were daytime urinary symptoms and underlying diseases causing nocturnal enuresis. Subjects were treated with 120 µg or 240 µg desmopressin oral disintegrating tablet and were divided into responders (at 120 or 240 µg) and nonresponders (at 240 µg). Day/night ratios of plasma copeptin and urinary aquaporin 2 were measured during desmopressin treatment. RESULTS: There was no significant difference in baseline day/night ratio of urinary aquaporin 2 between desmopressin responders and nonresponders. After 8 weeks of treatment there was a significant correlation between day/night ratio of aquaporin 2 and percentage of wet nights. In responders (but not nonresponders) there was a significant difference in the change in aquaporin 2 day/night ratio from before treatment to complete remission (p = 0.0004). For plasma copeptin the baseline day/night ratio for responders at 120 µg was significantly lower than in the 240 µg nonresponder group (p = 0.02). CONCLUSIONS: Urinary aquaporin 2 appears to be a biomarker of desmopressin treatment effectiveness during therapy, while plasma copeptin levels before treatment are predictive of desmopressin response.
Assuntos
Antidiuréticos/uso terapêutico , Aquaporina 2/urina , Desamino Arginina Vasopressina/uso terapêutico , Glicopeptídeos/sangue , Enurese Noturna/tratamento farmacológico , Biomarcadores Farmacológicos/sangue , Biomarcadores Farmacológicos/urina , Criança , Feminino , Humanos , Masculino , Enurese Noturna/sangue , Enurese Noturna/urina , Valor Preditivo dos Testes , Estudos Prospectivos , Recidiva , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Antileukotriene has been used for alleviating disease severity in children with adenotonsillar hypertrophy (ATH) and mild obstructive sleep apnea (OSA). Previous study showed the relationship between urinary cysteinyl leukotriene E4 (uLTE4) level and therapeutic response to montelukast in asthmatic adults. However, this relationship has never been investigated in pediatric OSA. OBJECTIVES: To determine the relationship between uLTE4 level and therapeutic response to montelukast in children with ATH and mild OSA. METHODS: Children aged 3-15 yrs who had ATH and mild OSA were enrolled. All had quality of life (assessed by Thai version OSA-18 QoL questionnaire) and uLTE4 levels measured prior to start a 6-week course of montelukast treatment. Overnight polysomnography (PSG) and QoL reassessment were performed after completing the treatment. Those who demonstrated a large improvement of mean total QoL score or ≥ 50% decrease of obstructive apnea-hypopnea index (OAHI) after the treatment were defined as responders. RESULTS: Twenty-six children were enrolled (mean age 7.5 ± 2.9 yrs, 38.5% male). After 6-week course of montelukast, nine (34.6%) children showed significant improvement. The mean uLTE4 level from the responders was higher comparing to the non-responders (2,952.56 ± 966.9 vs. 978.6 ± 460.8 pg/mg creatinine; p < 0.001). uLTE4 level of ≥ 1,457 pg/mg creatinine had 100% sensitivity and 88.2% specificity in identifying the responders. CONCLUSIONS: We found the association between ULTE4 and therapeutic response to monteleukast. The uLTE4 level of ≥ 1,457 pg/mg creatinine could predict the therapeutic response to montelukast in children who had ATH and mild OSA.
Assuntos
Acetatos/uso terapêutico , Antiasmáticos/uso terapêutico , Biomarcadores Farmacológicos/urina , Leucotrieno E4/urina , Quinolinas/uso terapêutico , Apneia Obstrutiva do Sono/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Creatinina/sangue , Ciclopropanos , Progressão da Doença , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Prognóstico , Apneia Obstrutiva do Sono/diagnóstico , SulfetosRESUMO
This study was performed to demonstrate urinary angiotensinogen as a potential prognostic marker of the albuminuria reduction effects of olmesartan in patients with metabolic syndrome. In 24 patients (eight women, 57.88 ± 2.00 years), 5-40 mg/day of olmesartan were given. Urinary concentrations of albumin and angiotensinogen (normalized by urinary concentrations of creatinine) and plasma renin activity were measured before and after the 12- and 24-week marks of olmesartan treatment. Olmesartan treatment increased plasma renin activity and decreased urinary albumin and urinary angiotensinogen significantly (p < 0.05). Based on the % change in urinary albumin, patients were divided into two groups, responders (<-50%) and non-responders (≥-50%), and a logistic analysis of urinary angiotensinogen before treatment showed the area under the curve as 0.694. When the cutoff value of urinary angiotensinogen before the treatment of 13.9 µg/g Cr was used, the maximum Youden index (0.500, specificity: 11/12 = 91.7% and sensitivity: 7/12 = 58.3%) was obtained. When all patients were re-divided into two groups, those with higher values of urinary angiotensinogen before the treatment (Group H, n = 16) and those with lower values, Group H showed significantly decreased urinary albumin (p < 0.05). Therefore, urinary angiotensinogen could be a prognostic marker of the albuminuria reduction effects of olmesartan in patients with metabolic syndrome.
Assuntos
Albuminúria/urina , Angiotensinogênio/urina , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/urina , Adulto , Albuminúria/tratamento farmacológico , Albuminúria/patologia , Biomarcadores Farmacológicos/urina , Creatinina/urina , Feminino , Humanos , Imidazóis/administração & dosagem , Masculino , Síndrome Metabólica/patologia , Pessoa de Meia-Idade , Prognóstico , Tetrazóis/administração & dosagemRESUMO
Response criteria for multiple myeloma are based upon changes in monoclonal protein levels quantified using serum and/or urine protein electrophoresis. The latter lacks sensitivity at low monoclonal protein levels and since 2001, the serum free light chain test has been available and its clinical utility proven, yet guidelines have not recommended it as a replacement for urine assessment. Herein we evaluated responses using serum free light chain measurements and serum and urine electrophoresis after 2 and 4 cycles of therapy and after stem cell transplantation in 25 light chain and 157 intact immunoglobulin myeloma patients enrolled in the IFM 2007-02 MM trial. All 25 light chain patients had measurable disease by serum free light chain and urine methods at presentation. By contrast 98 out of 157 intact immunoglobulin patients had measurable disease by serum free light chain compared to 55 out of 157 by urine electrophoresis. In all patients there was substantial agreement between predicate (serum/urine protein electrophoresis) and test (serum protein electrophoresis and serum free light chain) methods for response assessment (Weighted Kappa=0.83). Urine immunofixation became negative in 47% light chain and 43% intact immunoglobulin patients after 2 cycles of therapy. At this time the serum free light chain ratio normalised in only 11% and 27% patients, respectively. In summary we found good agreement between methods for response assessment, but the serum free light chain test provided greater sensitivity than urine electrophoresis for monitoring. To our knowledge this is the first report comparing both methods for response assignment based on the International Myeloma Working Group guidelines. (Clinical Trials Register.eu identifier: 2007-005204-40).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Cadeias kappa de Imunoglobulina/sangue , Cadeias lambda de Imunoglobulina/sangue , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/terapia , Biomarcadores Farmacológicos/sangue , Biomarcadores Farmacológicos/urina , Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Eletroforese , Humanos , Cadeias kappa de Imunoglobulina/urina , Cadeias lambda de Imunoglobulina/urina , Melfalan/uso terapêutico , Mieloma Múltiplo/sangue , Mieloma Múltiplo/imunologia , Nefelometria e Turbidimetria , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Talidomida/uso terapêutico , Transplante HomólogoRESUMO
INTRODUÇÃO: A leishmaniose visceral (LV) é, principalmente, causada pelo protozoário Leishmania infantum nas Américas, podendo acometer o Homem e animais. Dentre estes, o cão é considerado o principal reservatório doméstico do parasito. O curso da LV canina (LVC) varia entre os animais, podendo alguns se mostrar resistentes à infecção, se mantendo subclínicos, e outros susceptíveis, que irão desenvolver sinais da doença. O estado de resistência ou susceptibilidade à LVC reflete na gravidade da infecção do animal, e não pode ser definido pelo quadro clínico apresentado ou por qualquer parâmetro isolado de resposta imune. OBJETIVO: Avaliar a carga parasitária como biomarcador parasitológico, as proteínas LJM11/LJM17 como biomarcadores de exposição à saliva do vetor, e identificar biomarcadores inflamatórios de gravidade da infecção por L. infantum em cães. Primeiramente, foi realizada a padronização de uma ferramenta diagnóstica de PCR quantitativa (qPCR), utilizando diferentes amostras biológicas (aspirado esplênico, linfonodos, pele, sangue, medula óssea e swab conjuntival) de cães sintomáticos provenientes da área endêmica de Jequié-BA. A avaliação da carga parasitária de L. infantum teve seu desempenho comparado com outras técnicas diagnósticas (cultura de aspirado esplênico, teste rápido e ELISA para LVC) empregando a análise de classe latente (ACL). Para essa análise, foi construída uma variável latente a ser empregada como padrão ouro para avaliação da acurácia desses métodos. Na avaliação inicia dos cães sintomáticos, a qPCR detectou DNA do parasita em 100%...
INTRODUCTION: In the Americas, visceral leishmaniasis (VL) is caused by the protozoan Leishmania infantum, which can affect humans and animals. Among these, dog is considered the main domestic reservoir of this parasite. Canine VL (CVL) clinical outcome varies among animals, some of which may be resistant to infection remaining subclinical, and others may be susceptible showing signs of the disease. The state of resistance or susceptibility to CVL reflects on the severity of infection in the animal and cannot be defined solely by the clinical condition presented or by any isolated parameter of the immune response. OBJECTIVE: Assess parasite load as parasitological biomarkers, LJM11/LJM17 proteins as sandfly saliva exposure biomarkers, and identify inflammatory biomarkers that indicates L. infantum infection severity in dogs. Firstly, we performed the standardization of a quantitative PCR diagnostic tool (qPCR) using different biological samples (splenic aspirate, lymph nodes, skin, blood, bone marrow and conjunctival swab) of symptomatic dogs from the endemic area of Jequié-BA. The evaluation of the parasitic load of L. infantum had its performance compared to other diagnostic techniques (splenic aspirate culture, rapid test and CVL ELISA) using latent class analysis (LCA). In this analysis, a latent variable was constructed to be used as a gold standard to evaluate the accuracy of these methods. In the initial evaluation of the symptomatic dogs, qPCR detected DNA from the parasite in 100%...
Assuntos
Humanos , Biomarcadores Farmacológicos/análise , Biomarcadores Farmacológicos/sangue , Biomarcadores Farmacológicos/urina , Reação em Cadeia da Polimerase/estatística & dados numéricos , Reação em Cadeia da Polimerase/métodosRESUMO
1. The safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect of LB30870, a new selective thrombin inhibitor, were studied in 16 healthy men. 2. A double-blind, placebo-controlled single ascending dose study was done at oral doses of 5, 15, 30, 60, 120, and 240 mg under fasting conditions. An open, randomized, balanced cross-over food effect study was done at 60 mg dose. Plasma and urinary concentrations were measured up to 48 h post-dose. Coagulation and thrombin activity markers were measured at selected time points. 3. Cmax of LB30870 was at 1.3-3.0 h post-dose with a mean apparent terminal half-life (t1/2) of 2.8-4.1 h. AUC after doses above 15 mg appeared greater than dose-proportional. In fed state, AUC showed 80% reduction relative to fasting condition. 4. At doses 60 and 120 mg, peak activated partial thromboplastin time (aPTT) increased by 1.5- and 2-fold, respectively, from baseline. The aPTT and international normalized ratio (INR) were concentration-dependent, with less within-individual variability than ecarin clotting time (ECT), prothrombin time (PT), or thrombin time (TT). 5. Single oral doses of LB30870 up to 240 mg were well tolerated. The food effect must be overcome if LB30870 is to be used as an oral anti-coagulant.
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Amidinas/administração & dosagem , Amidinas/farmacocinética , Anticoagulantes/farmacocinética , Antitrombinas/farmacocinética , Coagulação Sanguínea/efeitos dos fármacos , Dipeptídeos/administração & dosagem , Dipeptídeos/farmacocinética , Interações Alimento-Droga/fisiologia , Administração Oral , Adulto , Amidinas/sangue , Amidinas/urina , Anticoagulantes/sangue , Anticoagulantes/urina , Antitrombinas/sangue , Antitrombinas/urina , Biomarcadores Farmacológicos/sangue , Biomarcadores Farmacológicos/urina , Estudos Cross-Over , Dipeptídeos/sangue , Dipeptídeos/urina , Relação Dose-Resposta a Droga , Método Duplo-Cego , Fluoracetatos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Ibandronate, a nitrogen-containing bisphosphonate, is a bone resorption inhibitor widely used to prevent and treat osteoporosis. To optimize the design for a long-term clinical study of ibandronate, modeling and simulation (M&S) was performed based on the result of population pharmacodynamic analysis using the data of a short-term clinical study. A population pharmacodynamic model was constructed by the urinary C-terminal telopeptide of type I collagen (uCTx) and the lumbar spine bone mineral density (BMD) data obtained in clinical studies, including a phase II study of Japanese osteoporosis patients treated with ibandronate for 6 months. Changes in BMD over a period of 3 years were simulated from the population pharmacodynamic parameters of the patients in this phase II study. The relationship between uCTx and BMD was well described by this modeling. The functions of disease progression and supplemental treatment were incorporated into the model to simulate a long-term clinical study with high accuracy. A long-term clinical study with a 3-year treatment was conducted after this M&S. The percentage change from baseline in observed BMD values were found to be similar to the prospectively simulated values. This study showed that M&S could be a useful and powerful tool for designing and conducting long-term clinical studies when carried out in the following sequence: (1) conduct a short-term clinical study; (2) perform M&S; and (3) conduct the long-term clinical study. Application of this procedure to various other treatment agents will establish the usefulness of M&S for long-term clinical studies and bring further efficiencies to drug development.
Assuntos
Difosfonatos/administração & dosagem , Osteoporose Pós-Menopausa/tratamento farmacológico , Biomarcadores Farmacológicos/urina , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/administração & dosagem , Ensaios Clínicos como Assunto/métodos , Colágeno Tipo I/metabolismo , Simulação por Computador , Esquema de Medicação , Feminino , Humanos , Ácido Ibandrônico , Modelos Biológicos , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/urina , Peptídeos/metabolismoRESUMO
The predictive value of different urinary and transcriptional biomarkers was evaluated in a proof-of-principle toxicology study in rats using aristolochic acid (AA), a known nephrotoxic agent. Male Wistar rats were orally dosed with 0.1, 1, or 10 mg/kg for 12 days. Urine was collected on days 1, 5, and 12 over 24 hours. Gene expression analysis was also conducted using quantitative real-time polymerase chain reaction and Illumina whole-genome chips. Protein biomarkers (Kim-1, Timp-1, vascular endothelial growth factor, osteopontin, clusterin, cystatin C, calbindin D-28K, ß2-microglobulin, α-glutathione S-transferase, GSTY1b, RPA-1, and neutrophil gelatinase-associated lipocalin) were measured in these urine samples. Treatment with AA resulted in a slight dose- and/or time-dependent increase in urinary ß2-microglobulin, lipocalin 2, and osteopontin before an increase in serum creatinine or serum urea nitrogen was observed. A strong decrease in urinary calbindin D-28K was also detected. The Compugen Ltd. prediction model scored both the 1- and 10-mg/kg AA dose groups as positive for nephrotoxicity despite the absence of renal histopathological changes. In addition, several previously described transcriptional biomarkers were identified as early predictors of renal toxicity as they were detected before morphological alterations had occurred. Altogether, these findings demonstrated the predictive values of renal biomarkers approved by the Food and Drug Administration, European Medicines Agency, and Pharmaceuticals & Medical Devices Agency in AA-induced renal injury in rats and confirmed the utility of renal transcriptional biomarkers for detecting progression of compound-induced renal injury in rats. In addition, several transcriptional biomarkers identified in this exploratory study could present early predictors of renal tubular epithelium injury in rats.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/metabolismo , Ácidos Aristolóquicos/toxicidade , Biomarcadores Farmacológicos/metabolismo , Biomarcadores Farmacológicos/urina , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Relação Dose-Resposta a Droga , Perfilação da Expressão Gênica/veterinária , Lipocalina-2 , Lipocalinas/urina , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/veterinária , Osteopontina/urina , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real/veterinária , Microglobulina beta-2/urinaRESUMO
OBJECTIVES: To evaluate the performance of kidney function estimation equations and to determine the frequency of drug dose discordance in an older population. DESIGN: Cross-sectional analysis of data from community-dwelling volunteers randomly selected from the Baltimore Longitudinal Study of Aging from January 1, 2005, to December 31, 2010. SUBJECTS: A total of 269 men and women with a mean ± SD age of 81 ± 6 years, mean serum creatinine concentration (Scr ) of 1.1 ± 0.4 mg/dl, and mean 24-hour measured creatinine clearance (mClcr ) of 53 ± 13 ml/minute. MEASUREMENTS AND MAIN RESULTS: Kidney function was estimated by using the following equations: Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). The performance of each equation was assessed by measuring bias and precision relative to mClcr . Dose calculation errors (discordance) were determined for 10 drugs requiring renal dosage adjustments to avoid toxicity when compared with the dosages approved by the Food and Drug Administration. The CG equation was the least biased estimate of mClcr . The MDRD and CKD-EPI equations were significantly positively biased compared with CG (mean ± SD 34 ± 20% and 22 ± 15%, respectively, p<0.001) and mClcr (29 ± 47% and 18 ± 40%, respectively, p<0.001). Rounding low Scr values (less than 1.0 mg/dl) up to an arbitrary value of 1.0 mg/dl resulted in CG values (44 ± 10 ml/minute) that were significantly lower than mClcr (56 ± 12 ml/minute, p<0.001) and CG (56 ± 15 ml/minute, p<0.001). The MDRD and CKD-EPI equations had median dose discordance rates of 28.6% and 22.9%, respectively. CONCLUSION: The MDRD and CKD-EPI equations significantly overestimated creatinine clearance (mClcr and CG) in elderly individuals. This leads to dose calculation errors for many drugs, particularly in individuals with severe renal impairment. Thus equations estimating glomerular filtration rate should not be substituted in place of the CG equation in older adults for the purpose of renal dosage adjustments. In addition, the common practice of rounding or replacing low Scr values with an arbitrary value of 1.0 mg/dl for use in the CG equation should be avoided. Additional studies that evaluate alternative eGFR equations in the older populations that incorporate pharmacokinetic and pharmacodynamic outcomes measures are needed.