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The robust meta-analytical-predictive (rMAP) prior is a popular method to robustly leverage external data. However, a mixture coefficient would need to be pre-specified based on the anticipated level of prior-data conflict. This can be very challenging at the study design stage. We propose a novel empirical Bayes robust MAP (EB-rMAP) prior to address this practical need and adaptively leverage external/historical data. Built on Box's prior predictive p-value, the EB-rMAP prior framework balances between model parsimony and flexibility through a tuning parameter. The proposed framework can be applied to binomial, normal, and time-to-event endpoints. Implementation of the EB-rMAP prior is also computationally efficient. Simulation results demonstrate that the EB-rMAP prior is robust in the presence of prior-data conflict while preserving statistical power. The proposed EB-rMAP prior is then applied to a clinical dataset that comprises 10 oncology clinical trials, including the prospective study.
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Modelos Estadísticos , Proyectos de Investigación , Humanos , Teorema de Bayes , Estudios Prospectivos , Simulación por ComputadorRESUMEN
An accurately identified maximum tolerated dose (MTD) serves as the cornerstone of successful subsequent phases in oncology drug development. Bayesian logistic regression model (BLRM) is a popular and versatile model-based dose-finding design. However, BLRM with original overdose control strategy has been reported to be safe but "excessively conservative." In this article, we investigate the reason for conservativeness and point out that a major reason could be the lack of appropriate underdose control. We propose designs that balance overdose and underdose control to improve the performance over the original BLRM. Simulation results reveal that the new designs have better accuracy and treat more patients at MTD.
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Sobredosis de Droga , Neoplasias , Humanos , Modelos Logísticos , Teorema de Bayes , Neoplasias/tratamiento farmacológico , Dosis Máxima Tolerada , Simulación por Computador , Sobredosis de Droga/tratamiento farmacológico , Sobredosis de Droga/prevención & control , Relación Dosis-Respuesta a DrogaRESUMEN
Detection of test article-related effects and the determination of the adversity of those changes are the primary goals of nonclinical safety assessment studies for drugs and chemicals in development. During these studies, variables that are not of primary interest to investigators may change and influence data interpretation. These variables, often referred to as "nuisance factors," may influence other groups of data and result in "block or batch effects" that complicate data interpretation. Definitions of the terms "nuisance factors," "block effects," and "batch effects," as they apply to nonclinical safety assessment studies, are reviewed. Multiple case examples of block and batch effects in safety assessment studies are provided, and the challenges these bring to pathology data interpretation are discussed. Methods to mitigate the occurrence of block and batch effects in safety assessment studies, including statistical blocking and utilization of study designs that minimize potential confounding variables, incorporation of adequate randomization, and use of an appropriate number of animals or repeated measurement of specific parameters for increased precision, are reviewed. [Box: see text].
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Evaluación Preclínica de Medicamentos , Animales , Humanos , Políticas , Proyectos de InvestigaciónRESUMEN
A framework is proposed for making quality predictions in situations for which only systematically inaccurate data are available. The predictions are based on the systematically inaccurate data, complete data from similar situations, and expert knowledge. The proposed predictive model is well suited to functional data and is computationally simple, fast, and stable. We focus primarily on a particular problem presenting itself in the pharmaceutical industry. Predicting both side effect and endpoint dose responses before the initiation of a clinical trial has enormous ethical and financial importance in the pharmaceutical industry. The proposed Bayesian semiparametric predictive model is used to predict unobserved clinical dose-response curves conditional on preclinical data, data from similar compounds, and prior knowledge. The model allows for nonlinear dose-response curves and the incorporation of relevant prior information. Posterior sampling is achieved through a simple and computationally efficient Gibbs sampler. The predictions from the model are drawn from the posterior distribution of the average dose-response curve for the candidate compound, allowing straightforward incorporation into a risk assessment model unlike the deterministic predictions often used currently. The model is used on actual data from the pharmaceutical industry, showing that the model is capable of predicting lack or presence of trend with appropriate uncertainty.
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Teorema de Bayes , Técnicas de Apoyo para la Decisión , Relación Dosis-Respuesta a Droga , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Predicción , HumanosRESUMEN
OBJECTIVE: The Direct Assessment of Nonvertebral Fractures in Community Experience (DANCE) study investigated the use of teriparatide in men and women with osteoporosis in the United States (US) and Puerto Rico (PR). In a sub-analysis, we evaluated whether the baseline characteristics of Latinas differed from those of white women in the study population and whether any patient attributes affected physicians' decisions to prescribe teriparatide. METHODS: We assessed 3 patient cohorts treated with teriparatide 20 microg once daily for up to 24 months: 1) PR Latinas, 2) US Latinas, and 3) white women on the US mainland (white women). We analyzed differences related to ethnicity (Latina vs. white) and geography (PR vs. US mainland). RESULTS: Overall, 302 of the 3243 women (9%) enrolled in DANCE were Latina (205 of these 302 Latinas resided in PR). Significant differences were observed in 7 of 11 baseline characteristics. White women had more prior fragility fractures and family history of hip fracture than Latinas, while PR Latinas were generally older than US Latinas and had more comorbid conditions. A similar proportion of subjects in each cohort had received prior osteoporosis therapy. Physicians prescribed teriparatide more often for Latinas based on multiple risk factors for fracture and intolerance to previous osteoporosis therapy and to white women based on inadequate response to previous therapy or new (incident) fractures. Overall, Latinas were less persistent with teriparatide therapy than white women. CONCLUSION: We observed significant differences related to ethnicity and geography in the baseline demographics of Latinas enrolled in the DANCE study, criteria cited by physicians for initiating teriparatide therapy, and treatment persistence.
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Conservadores de la Densidad Ósea/uso terapéutico , Hispánicos o Latinos , Osteoporosis/complicaciones , Osteoporosis/tratamiento farmacológico , Fracturas Osteoporóticas/etiología , Fracturas Osteoporóticas/prevención & control , Teriparatido/uso terapéutico , Anciano , Femenino , Humanos , Puerto Rico , Estados UnidosRESUMEN
Abemaciclib is an orally administered, potent, and selective small molecule inhibitor of cyclin-dependent kinases 4 and 6, approved for advanced or metastatic breast cancer. This study aimed to use an exposure-response approach to investigate the effect of abemaciclib and its active metabolites (M2 and M20) on QTc interval and delay in cardiac repolarization at clinically relevant exposures. This was a single-blind, randomized, and placebo-controlled study of ascending doses of abemaciclib. Thirty-five healthy participants were administered a single dose of 200-600 mg abemaciclib. Twelve-lead electrocardiogram tracings and pharmacokinetic samples were collected serially pre- and post-dose. The primary objective was to study the relationship between abemaciclib and its active metabolites (M2 and M20) and QTc interval following ascending oral doses of abemaciclib. The secondary objective included evaluating the safety and tolerability of single ascending doses of abemaciclib in healthy participants. Exposure-response analysis demonstrated that there was no significant relationship between placebo-corrected change from baseline QTcF (ΔΔQTcF), abemaciclib, and metabolite plasma concentrations. Additionally, the ΔΔQTcF slopes of abemaciclib, its metabolites, and total analyte concentrations were not statistically different from zero. Single doses of abemaciclib, up to 400 mg, were well-tolerated by healthy participants; however, at the 600 mg dose (three times the highest registered dose), the frequency and severity of treatment-related gastrointestinal events (primarily diarrhea, nausea, and vomiting) increased. In conclusion, single doses of abemaciclib, up to 400 mg, had no statistically or clinically relevant effects on QTc, and abemaciclib was well tolerated up to a dose of 400 mg in this study.
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Fluoroquinolonas , Humanos , Moxifloxacino , Voluntarios Sanos , Método Simple Ciego , Método Doble Ciego , Relación Dosis-Respuesta a Droga , Frecuencia CardíacaRESUMEN
INTRODUCTION: Zucker diabetic fatty (ZDF) rats are used widely as an animal model of metabolic syndrome and insulin resistance. Our study focused on the effects of high versus low dietary fat on the development of Type 2 diabetes in obese male ZDF rats (fa/fa), including biomarkers to detect early signs of hypercoagulability and vascular injury in the absence of overt thrombosis. METHODS: In this study, male (5/group) 10-week-old CRL:ZDF370(obese) rats were fed low (LFD, 16.7% fat) or high fat (HFD, 60% fat) diet for 12 or 15 weeks. Cohorts of 5 rats within diet groups were scheduled for sample collection after weeks 12 and 15. RESULTS: HFD-fed ZDF rats had oily coats, lower rates of food consumption, more accelerated weight gain and increased serum cholesterol (+15%) and triglyceride concentrations (+75%) vs. LFD-fed ZDF rats. Urinary ketones were observed only in HFD-fed ZDF rats and greater urine glucose and protein concentrations in HFD-fed ZDF vs. LFD-fed ZDF rats were seen. Hemostasis testing showed ~2-fold greater fibrinogen concentration, increased von Willebrand factor concentration, and high thrombin generation in HFD-fed ZDF vs LFD-fed ZDF rats. Increased mortality in the HFD-fed ZDF rat was attributed to exacerbations of altered carbohydrate metabolism as evidenced by ketonuria and nephropathy leading to renal failure. DISCUSSION: This characterization shows that the ZDF rat at the age, sex and weight used in this study is highly sensitive to dietary fat content that can exacerbate prothrombotic, metabolic and renal disturbances and increase mortality.
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Diabetes Mellitus Tipo 2 , Trombofilia , Animales , Grasas de la Dieta/efectos adversos , Masculino , Obesidad/inducido químicamente , Ratas , Ratas Zucker , Trombofilia/inducido químicamenteRESUMEN
INTRODUCTION: JUNIPER compared the efficacy and safety of abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, with erlotinib in patients with non-small cell lung cancer (NSCLC) harboring a Kirsten rat sarcoma (KRAS) mutation. METHODS: JUNIPER was a Phase III, multicenter, randomized, open-label trial of abemaciclib versus erlotinib in patients with stage IV NSCLC and a detectable mutation in codons 12 or 13 of the KRAS oncogene, who progressed after platinum-based chemotherapy and 1 additional therapy (could include immune checkpoint inhibitor therapy). Randomized patients (3:2) received either 200 mg abemaciclib twice daily or 150 mg erlotinib once daily with best supportive care until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS); secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and safety. RESULTS: Between December 2014 and April 2017, 453 patients were randomly assigned to receive abemaciclib (N = 270) or erlotinib (N = 183). Median OS was 7.4 months (95% confidence interval [CI]: 6.5, 8.8) with abemaciclib and 7.8 months (95% CI: 6.4, 9.5) with erlotinib (hazard ratio [HR] = 0.968 [95% CI: 0.768, 1.219]; p = .77). Median PFS was 3.6 months (95% CI: 2.8, 3.8) with abemaciclib and 1.9 months (95% CI: 1.9, 2.0) with erlotinib (HR = 0.583 [95% CI: 0.470, 0.723]; p <.000001). ORR was 8.9% and 2.7% (p = .010), and the disease control rate was 54.4% and 31.7% (p <.001) with abemaciclib and erlotinib, respectively. Safety results reflected the known safety profiles of abemaciclib and erlotinib. CONCLUSIONS: In this study, the primary endpoint of OS was not met; PFS and ORR were improved with manageable toxicity in the abemaciclib arm. The increases in response rates and PFS support further investigation of abemaciclib in other NSCLC subpopulations or in combination with other agents. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier: NCT02152631.
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Mesial temporal lobe epilepsy (MTLE) is a severe neurological condition of unknown pathogenesis for which several animal models have been developed. To obtain a better understanding of the underlying molecular mechanisms and identify potential biomarkers of lesion progression, we used a rat kainic acid (KA) treatment model of MTLE coupled with global gene expression analysis to examine temporal (four hours, days 3, 14, or 28) gene regulation relative to hippocampal histopathological changes. The authors recommend reviewing the companion histopathology paper (Sharma et al. 2008) to get a better understanding of the work presented here. Analysis of filtered gene expression data using Ingenuity Pathways Analysis (Ingenuity Systems, http://www.ingenuity.com) revealed that a number of genes pertaining to neuronal plasticity (RhoA, Rac1, Cdc42, BDNF, and Trk), neurodegeneration (Caspase3, Calpain 1, Bax, a Cytochrome c, and Smac/Diablo), and inflammation/immune-response pathways (TNF-alpha, CCL2, Cox2) were modulated in a temporal fashion after KA treatment. Expression changes for selected genes known to have a role in neuronal plasticity were subsequently validated by quantitative polymerase chain reaction (qPCR). Notably, canonical pathway analysis revealed that a number of genes within the axon guidance signaling canonical pathway were up-regulated from Days 3 to 28, which correlated with aberrant mossy fiber (MF) sprouting observed histologically beginning at Day 6. Importantly, analysis of the gene expression data also identified potential biomarkers for monitoring neurodegeneration (Cox2) and neuronal/synaptic plasticity (Kalrn).
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Epilepsia del Lóbulo Temporal/genética , Regulación de la Expresión Génica , Ácido Kaínico , Animales , Conducta Animal/efectos de los fármacos , Análisis por Conglomerados , Modelos Animales de Enfermedad , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/inmunología , Epilepsia del Lóbulo Temporal/metabolismo , Hipocampo/metabolismo , Histocitoquímica , Inflamación/genética , Inflamación/inmunología , Masculino , Degeneración Nerviosa , Plasticidad Neuronal , Ratas , Ratas Endogámicas F344 , Reproducibilidad de los Resultados , Transducción de Señal , Toxicogenética/métodosRESUMEN
Cardiac troponin I is a useful biomarker of myocardial injury, but its use in mice and application to early drug discovery are not well described. The authors investigated the relationship between cTnI concentration in serum and histologic lesions in heart tissue from mice treated with isoproterenol (ISO). Cardiac TnI concentrations in serum increased in a dose-dependant manner and remained increased twenty-four to forty-eight hours after a single administration of isoproterenol. Increased cTnI concentration was of greater magnitude and longer duration than increased fatty acid binding protein 3 concentration, aspartate aminotransferase activity, and creatine kinase activity in serum. Isoproterenol-induced increases in cTnI concentrations were both greater and more sustained in BALB/c than in CD1 mice and correlated with incidence and severity of lesions observed in heart sections from both strains. In drug development studies in BALB/c mice with novel kinase inhibitors, cTnI concentration was a reliable stand-alone biomarker of cardiac injury and was used in combination with measurements of in vivo target inhibition to demonstrate an off-target contribution to cardiotoxicity. Additional attributes, including low cost and rapid turnaround time, made cTnI concentration in serum invaluable for detecting cardiotoxicity, exploring structure-activity relationships, and prioritizing development of compounds with improved safety profiles early in drug discovery.
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Descubrimiento de Drogas/métodos , Cardiopatías/sangre , Cardiopatías/inducido químicamente , Isoproterenol/toxicidad , Inhibidores de Proteínas Quinasas/toxicidad , Troponina I/sangre , Animales , Aspartato Aminotransferasas/sangre , Biomarcadores/sangre , Cardiotónicos/toxicidad , Creatina Quinasa/antagonistas & inhibidores , Creatina Quinasa/sangre , Relación Dosis-Respuesta a Droga , Proteína 3 de Unión a Ácidos Grasos , Proteínas de Unión a Ácidos Grasos/sangre , Femenino , Ventrículos Cardíacos/efectos de los fármacos , Histocitoquímica , Inflamación/metabolismo , Ratones , Ratones Endogámicos BALB C , Miocardio/metabolismo , Miocardio/patología , NecrosisRESUMEN
Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6, is indicated for metastatic breast cancer treatment. Reversible increases in serum creatinine levels of ~15-40% over baseline have been observed following abemaciclib dosing. This study assessed the in vitro and clinical inhibition of renal transporters by abemaciclib and its metabolites using metformin (a clinically relevant transporter substrate), in a clinical study that quantified glomerular filtration and iohexol clearance. In vitro, abemaciclib inhibited metformin uptake by organic cation transporter 2, multidrug and toxin extrusion (MATE)1, and MATE2-K transporters with a half-maximal inhibitory concentration of 0.4-3.8 µM. Clinically, abemaciclib significantly increased metformin exposure but did not significantly affect measured glomerular filtration rate, serum neutrophil gelatinase-associated lipocalin (NGAL), serum cystatin-C, or the urinary markers of kidney tubular injury, NGAL and kidney injury molecule-1.
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Aminopiridinas/farmacología , Bencimidazoles/farmacología , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Tasa de Filtración Glomerular/efectos de los fármacos , Túbulos Renales , Metformina/farmacología , Antineoplásicos Inmunológicos/farmacología , Transporte Biológico/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Humanos , Hipoglucemiantes/farmacología , Túbulos Renales/efectos de los fármacos , Túbulos Renales/metabolismo , Tasa de Depuración Metabólica/efectos de los fármacos , Proteínas de Transporte de Catión Orgánico/metabolismo , Transportador 2 de Cátion Orgánico/metabolismoRESUMEN
INTRODUCTION: The sensitivity of a given test to detect a treatment-induced effect in a variable of interest is intrinsically related to the variability of that variable observed without treatment and the number of observations made in the study (i.e. number of animals). To evaluate test sensitivity to detect drug-induced changes in myocardial contractility using the variable LVdP/dtmax, a HESI-supported consortium designed and conducted studies in chronically instrumented, conscious dogs using telemetry. This paper evaluated the inherent variability of the primary endpoint, LVdP/dtmax, over time in individual animals as well as the variability between animals for a given laboratory. An approach is described to evaluate test system variability and thereby test sensitivity which may be used to support the selection of the number of animals for a given study, based on the desired test sensitivity. METHODS: A double 4â¯×â¯4 Latin square study design where eight animals each received a vehicle control and three dose levels of a test compound was conducted at six independent laboratories. LVdP/dtmax was assessed via implanted telemetry systems in Beagle dogs (Nâ¯=â¯8) using the same protocol and each of the six laboratories conducted between two and four studies. Vehicle data from each study was used to evaluate the between-animal and within-animal variability in different time averaging windows. Simulations were conducted to evaluate statistical power and type I error for LVdP/dtmax based on the estimated variability and assumed treatment effects in hourly-interval, bi-hourly interval, or drug-specific super interval. RESULTS: We observe that the within-animal variability can be reduced by as much as 30% through the use of a larger time averaging window. Laboratory is a significant source of animal-to-animal variability as between-animal variability is laboratory-dependent and is less impacted by the use of different time averaging windows. The statistical power analysis shows that with Nâ¯=â¯8, the double Latin square design has over 90% power to detect a minimal time profile with a maximum change of up to 15% or approximately 450â¯mmâ¯Hg/s in LVdP/dtmax. With Nâ¯=â¯4, the single Latin square design has over 80% power to detect a minimal time profile with a maximum change of up to 20% or approximately 600â¯mmâ¯Hg/s in LVdP/dtmax. DISCUSSION: We describe a statistical procedure to quantitatively evaluate the acute cardiac effects from studies conducted across six sites and objectively examine the variability and sensitivity that were difficult or impossible to calculate consistently based on previous works. Although this report focuses on the evaluation on LVdP/dtmax, this approach is appropriate for other variables such as heart rate, arterial blood pressure, or variables derived from the ECG.
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Interpretación Estadística de Datos , Contracción Miocárdica/efectos de los fármacos , Telemetría/métodos , Función Ventricular Izquierda/efectos de los fármacos , Animales , Perros , Determinación de Punto Final , Femenino , Masculino , Modelos Animales , Proyectos de Investigación , Tamaño de la Muestra , Sensibilidad y Especificidad , Factores de TiempoRESUMEN
INTRODUCTION: The Health and Environmental Sciences Institute of the International Life Sciences Institute (ILSI/HESI) Cardiovascular Safety Subcommittee outlined a set of in vivo telemetry studies to determine how well this preclinical model identified compounds known to cause torsades de pointes (TdP) and prolong QT interval in humans. In the original analysis of these data, QT, QTcB (Bazett model), QTcF (Fridericia model), and QTcQ (animal-specific model) were evaluated. We further evaluate the statistical properties of these measurements, using a method that can properly account for the sources of variability in the dataset. METHODS: The ILSI/HESI telemetry studies were conducted as a double Latin square design where eight dogs each received a vehicle control and three dose levels of a compound on four separate dosing days. We statistically analyzed the QT/QTc intervals using a repeated measures analysis of covariance and evaluate the powers for QT, QTcF and QTcQ based on simulations. RESULTS: The analyses for QTcF and QTcB intervals show that all six compounds which were known to cause TdP in humans were identified as positive and all six compounds known to be free of TdP events in their clinical use had no statistically significant treatment-related effects, while the analyses for QTcQ identified all positive compounds except pimozide. The power analysis shows that the method can detect a 7% increment of QT, a 5% increment of QTcF, and a 4% increment of QTcQ, with greater than 80% of power when n=8. DISCUSSION: We describe a repeated measures procedure to perform statistical analysis of covariance on Latin square designs and show that it can be used to detect meaningful changes in the analysis of QT/QTc intervals.
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Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Electrocardiografía/estadística & datos numéricos , Síndrome de QT Prolongado/fisiopatología , Preparaciones Farmacéuticas/administración & dosificación , Proyectos de Investigación/normas , Algoritmos , Animales , Cardiología/métodos , Cardiología/organización & administración , Cardiología/estadística & datos numéricos , Bases de Datos Factuales/estadística & datos numéricos , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Electrocardiografía/efectos de los fármacos , Electrocardiografía/métodos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/diagnóstico , Pimozida/farmacología , Propranolol/farmacología , Proyectos de Investigación/estadística & datos numéricos , Telemetría/métodos , Factores de TiempoRESUMEN
INTRODUCTION: The importance of drug-induced effects on the inotropic state of the heart is well known. Unlike hemodynamic and cardiac electrophysiological methods, which have been routinely used in drug safety testing for years, the non-clinical assessment of drug effects on myocardial contractility is used less frequently with no established translation to humans. The goal of these studies was to determine whether assessment of alternate measures of cardiac inotropy could detect drug-induced changes in the contractile state of the heart using drugs known to have clinically relevant positive and negative effects on myocardial contractility. This study also evaluated drug-induced effects on lusitropy (relaxation) parameters of the heart. METHODS: A double 4×4 Latin square study design using Beagle dogs (n=8) was conducted. Drugs were administrated orally. Arterial blood pressure (BP), left ventricular pressure (LVP) and the electrocardiogram (ECG) were assessed across different laboratories using the same protocol. Each of the six laboratories studied at least 2 drugs (one positive inotrope (pimobendan or amrinone) and one negative inotrope (itraconazole or atenolol) at 3 doses selected to match clinical exposure data and a vehicle control). Animals were instrumented with an ITS telemetry system or DSI's D70-PCTP or PhysioTel™ Digital system. The data acquisition and analysis systems used were Ponemah, Notocord or EMKA. RESULTS: The derived inotropic and lusitropic parameters evaluated included peak systolic and end diastolic LVP, LVdP/dtmax, LVdP/dt40, QA interval, LVdP/dtmin and Tau. This study showed that LVdP/dt40 provided essentially identical results to LVdP/dtmax qualifying it as an index to assess drug effects on cardiac contractility. LVdP/dt40 provided an essentially identical assessment to that of LVdP/dtmax. The QA interval did not react sensitively to the drugs tested in this study; however, it did detect large effects and could be useful in early cardiovascular safety studies. The lusitropic parameter, LVdP/dtmin, was modestly decreased, and Tau was increased, by atenolol and itraconazole. At the doses tested, amrinone and pimobendan produced no changes in LVdP/dtmin while Tau was modestly increased. The drugs did not produce effects on BP, HR or the ECG at the doses tested. Blood samples were drawn to confirm drug exposures predicted from independent pharmacokinetic studies. DISCUSSION: These findings indicate that this experimental model can accurately and consistently detect changes in cardiac contractility, across multiple sites and instrumentation systems. While LVdP/dt40 produced responses similar to LVdP/dtmax, the QA interval and lusitropic parameters LVdP/dtmin and Tau were not markedly changed at the dose of drugs tested. Further studies with drugs that affect early diastolic relaxation through calcium handling are needed to better evaluate drug-induced changes on lusitropic properties of the heart.
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Cardiotónicos/farmacología , Frecuencia Cardíaca/fisiología , Contracción Miocárdica/fisiología , Función Ventricular Izquierda/fisiología , Proteínas tau/sangre , Animales , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/fisiología , Itraconazol/farmacología , Masculino , Contracción Miocárdica/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Systemic inflammation co-activates coagulation, which unchecked culminates in a lethal syndrome of multi-organ microvascular thrombosis known as disseminated intravascular coagulation (DIC). We studied an endotoxin-induced inflammatory state in rats to identify biomarkers of hemostatic imbalance favoring hypercoagulability. Intraperitoneal injection of LPS at 15 mg/kg body weight resulted in peripheral leukopenia and widespread neutrophilic sequestration characteristic of an acute systemic inflammatory response. Early indicators of hemostatic pathway activation developed within 4 hours, including increased circulating concentrations of procoagulant extracellular vesicles (EVs), EVs expressing endothelial cell and platelet membrane markers, and high concentration of soluble intercellular adhesion molecule-1 (sICAM-1), plasminogen activator inhibitor-1 (PAI-1), and D-dimers. Inflammation persisted throughout the 48-hour observation period; however, increases were found in a subset of serum microRNA (miRNA) that coincided with gradual resolution of hemostatic protein abnormalities and reduction in EV counts. Dose-adjusted LPS treatment in rats provides a time-course model to develop biomarker profiles reflecting procoagulant imbalance and rebalance under inflammatory conditions.
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Lipopolisacáridos , Trombofilia/inducido químicamente , Trombofilia/fisiopatología , Enfermedad Aguda , Animales , Biomarcadores/sangre , Coagulación Sanguínea/efectos de los fármacos , Plaquetas/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Vesículas Extracelulares/metabolismo , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Leucopenia/inducido químicamente , Masculino , MicroARNs/sangre , Neutrófilos/metabolismo , Neutrófilos/patología , Inhibidor 1 de Activador Plasminogénico/metabolismo , Ratas , Ratas Wistar , Trombofilia/inmunología , Factores de TiempoRESUMEN
INTRODUCTION: To account for heart rate-induced changes in the QT interval, correction formulas are generally applied to normalize the QT interval for heart rate. None of these formulas is entirely accurate because correction or normalization of any parameter in biology may introduce an additional source of variation in estimating the parameter. In this article, a one-step approach for the statistical analysis of the QT interval was proposed based on modeling the functional relationship between the QT interval and heart rate. METHODS: The QT-HR relationship was incorporated into the statistical analysis to provide a model-based correction. This was accomplished by including HR as a covariate in the QT interval analysis. The approach was demonstrated using data generated from Lilly Research Laboratories. We compared the false positive rate and statistical power of QT, QTcF, and the proposed one-step method. RESULTS: We found the one-step method demonstrated the greatest sensitivity in detecting a QT interval change without an increase in the false positive rate. It was shown that the one-step QT analysis could detect a 5%-6% increment of the QT interval. This is approximately equivalent to an increase of 11-13 ms in QT interval in beagle dogs. DISCUSSION: Several advantages and unique features of the one-step method are discussed. These include evaluating treatment effect on QT without applying a heart rate correction formula and estimating QT difference flexibly at any selected heart rate. In addition to the linear QT-HR relationship, other functional relationships can be easily implemented to this approach.
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Síndrome de QT Prolongado/fisiopatología , Telemetría , Algoritmos , Animales , Perros , Relación Dosis-Respuesta a Droga , Electrocardiografía/efectos de los fármacos , Reacciones Falso Positivas , Frecuencia Cardíaca/efectos de los fármacos , Síndrome de QT Prolongado/inducido químicamenteRESUMEN
OBJECTIVE: Vertebral fracture is the most common osteoporotic fracture, affecting quality of life and increasing mortality. Epidemiological data on incidence of vertebral fracture are scarce in Brazil and throughout Latin America. Our aim was to determine vertebral fracture incidence and risk factors in a female Brazilian population. SUBJECTS AND METHODS: Postmenopausal women with low bone mass were studied from the Brazilian placebo group of Arzoxifene Generations Trial (n = 974), followed for up to 5 years. The primary endpoint was new vertebral fractures, detected by X-Ray. Experimental design defined two strata: A. Osteoporosis or previous vertebral fracture with osteopenia; B. Osteopenia without previous fracture. Previous fracture, T-score, ionized calcium, alkaline phosphatase, creatinine and glucose were analyzed at baseline. Crude and adjusted incidence rates of vertebral fractures were estimated and Poisson regression model was used. RESULTS: Incidence rate was 7.7 (95% CI of 5.4 to 10.9) per 1,000 person-years (PY), increasing as a function of age. Women with new vertebral fractures had higher prevalence of previous nonvertebral fracture after menopause, were older and had lower lumbar spine (LS) T-score. Fracture risk increased by 46% for each unit reduction in LS T-score. Variables correlated with new vertebral fracture were age (p = 0.034), LS T-score, stratum A (p = 0.001 for both) and previous nonvertebral fracture after menopause (p = 0.019). In the final model, LS T-score was the strongest predictor. CONCLUSIONS: Incidence rate of vertebral fracture of 7.7 per 1,000 PY. Age and previous fractures were associated with new vertebral fracture, but LS T-score was the most important predictor.
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Enfermedades Óseas Metabólicas/complicaciones , Posmenopausia , Fracturas de la Columna Vertebral/epidemiología , Distribución por Edad , Anciano , Anciano de 80 o más Años , Enfermedades Óseas Metabólicas/tratamiento farmacológico , Brasil/epidemiología , Calcio/uso terapéutico , Suplementos Dietéticos/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Persona de Mediana Edad , Osteoporosis Posmenopáusica/tratamiento farmacológico , Piperidinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Tiofenos/uso terapéutico , Vitamina D/uso terapéuticoRESUMEN
Sclerostin, a SOST protein secreted by osteocytes, negatively regulates formation of mineralized bone matrix and bone mass. We report the results of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin, in postmenopausal women with low bone mineral density (BMD). Postmenopausal women with a lumbar spine T-score -2.0 to -3.5, inclusive, were randomized to subcutaneous blosozumab 180 mg every 4 weeks (Q4W), 180 mg every 2 weeks (Q2W), 270 mg Q2W, or matching placebo for 1 year, with calcium and vitamin D. Serial measurements of spine and hip BMD and biochemical markers of bone turnover were performed. Overall, 120 women were enrolled in the study (mean age 65.8 years, mean lumbar spine T-score -2.8). Blosozumab treatment resulted in statistically significant dose-related increases in spine, femoral neck, and total hip BMD as compared with placebo. In the highest dose group, BMD increases from baseline reached 17.7% at the spine, and 6.2% at the total hip. Biochemical markers of bone formation increased rapidly during blosozumab treatment, and trended toward pretreatment levels by study end. However, bone specific alkaline phosphatase remained higher than placebo at study end in the highest-dose group. CTx, a biochemical marker of bone resorption, decreased early in blosozumab treatment to a concentration less than that of the placebo group by 2 weeks, and remained reduced throughout blosozumab treatment. Mild injection site reactions were reported more frequently with blosozumab than placebo. In conclusion, treatment of postmenopausal women with an antibody targeted against sclerostin resulted in substantial increases in spine and hip BMD. These results support further study of blosozumab as a potential anabolic therapy for osteoporosis.
Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Densidad Ósea/efectos de los fármacos , Proteínas Morfogenéticas Óseas/inmunología , Marcadores Genéticos/inmunología , Posmenopausia , Proteínas Adaptadoras Transductoras de Señales , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores/metabolismo , Remodelación Ósea/efectos de los fármacos , Método Doble Ciego , Femenino , Humanos , Osteoporosis Posmenopáusica/tratamiento farmacológico , Placebos , Posmenopausia/efectos de los fármacos , Resultado del TratamientoRESUMEN
Administration of blosozumab, a humanized monoclonal antibody that binds sclerostin, increases bone formation and bone mineral density (BMD) in postmenopausal women with low BMD. To evaluate the effect of discontinuing blosozumab, we studied women enrolled in a 1-year randomized, placebo-controlled phase 2 trial for an additional year after they completed treatment. Of the 120 women initially enrolled in the study, 106 women completed treatment and continued into follow-up; 88 women completed 1 year of follow-up. At the beginning of follow-up, groups remained balanced for age, race, and body mass index, but lumbar spine and total hip BMD were increased in prior blosozumab groups, reflecting an anabolic treatment effect. At the end of follow-up, 1 year after discontinuing treatment, lumbar spine BMD remained significantly greater than placebo in women initially treated with blosozumab 270 mg every 2 weeks (Q2W) and blosozumab 180 mg Q2W (6.9% and 3.6% above baseline, respectively). Total hip BMD also declined after discontinuation of treatment but at 1 year after treatment remained significantly greater than placebo in women initially treated with blosozumab 270 mg Q2W and blosozumab 180 mg Q2W (3.9% and 2.6% above baseline, respectively). During follow-up, median serum P1NP was not consistently different between the prior blosozumab groups and placebo. A similar pattern was apparent for median serum C-terminal telopeptide of type 1 collagen (CTx) levels, with more variability. Mean serum total sclerostin concentration increased with blosozumab, indicating target engagement, and declined to baseline after discontinuation. There were no adverse events considered related to prior treatment with blosozumab. Anti-drug antibodies generally declined in patients who had detectable levels during prior treatment. These findings support the continued study of blosozumab as an anabolic therapy for treatment of osteoporosis.