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1.
J Pharmacol Toxicol Methods ; 128: 107535, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38955285

RESUMEN

Quantification of the unbound portion of platinum (Pt) in human plasma is important for assessing the pharmacokinetics of the chemotherapeutic drug cisplatin. In this study, we sought to compare the recovery of unbound Pt using Nanosep® filters to 1) traditional filters (Centrifree®, Centrisart®, Amicon®) or trichloroacetic acid (TCA) protein precipitation, and 2) unbound, bound, and total Pt concentrations in clinical specimens. For the tested filters, the impact of 1) molecular weight cut-offs, 2) centrifugation force, and 3) total Pt concentration on Pt binding in human plasma was evaluated. Pt was quantified using inductively coupled-plasma mass spectrometry. In human plasma spiked with 0.9 µg/mL Pt, the percent of unbound Pt increased at higher centrifugation speeds. By comparison, the percent of unbound Pt was highest (42.1%) following TCA protein precipitation. When total Pt was ≤0.9 µg/mL, unbound Pt (∼20-30%) was consistent across filters. Conversely, when plasma was spiked with Pt exceeding 0.9 µg/mL, the percent of unbound Pt increased from 36.5 to 48% using ultrafiltration, compared to 63.4% to 79% with TCA precipitation. In patients receiving cisplatin-containing chemotherapy, the fraction of unbound Pt at concentrations exceeding 0.9 µg/mL ranged between 35 and 90%. Moreover, the unbound fraction of Pt in plasma correlated with the concentration of unbound (R2 = 0.738) and total Pt (R2 = 0.335). In summary, this study demonstrates that 1) the percent of unbound Pt is influenced by total and unbound Pt levels in vitro and in clinical specimens, and 2) ultrafiltration with Nanosep® filters is a feasible method for quantifying unbound Pt concentrations in human plasma.


Asunto(s)
Precipitación Química , Cisplatino , Ultrafiltración , Humanos , Ultrafiltración/métodos , Cisplatino/sangre , Cisplatino/farmacocinética , Platino (Metal)/sangre , Platino (Metal)/farmacocinética , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Unión Proteica , Ácido Tricloroacético/sangre
2.
Curr Opin Toxicol ; 312022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-36777447

RESUMEN

The kidneys are responsible for maintaining physiologic homeostasis. The kidneys clear a variety of drugs and other substances through passive (filtration) and active processes that utilize transport proteins. Renal clearance is comprised of the processes of glomerular filtration, tubular secretion, and tubular reabsorption. Endogenous biomarkers, such as creatinine and cystatin C, are routinely used to estimate renal clearance. Understanding the contributing components of renal function and clearance, through the use of biomarkers, is necessary in elucidating the renal pharmacology of drugs and other substances. While exogenous markers of kidney function have been known for decades, several complexities have limited their usage. Several endogenous markers are being evaluated and hold promise to elucidate the individual components of kidney function that represent filtration, secretion, and reabsorption.

3.
Clin Transl Sci ; 14(6): 2267-2277, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34121338

RESUMEN

Low-dose methotrexate (MTX) is a first-line therapy for the treatment of arthritis. However, there is considerable interindividual variability in MTX exposure following standard dosing. Polymorphisms in SLCO1B1 significantly effect MTX clearance, altering therapeutic response. One decreased function variant, rs4149056 (c.521T>C, Val174Ala), slows MTX clearance and in vitro uptake of MTX. This phenotype was recapitulated in a mouse model using a knockout (KO) of the murine orthologue, Slco1b2. Our objective was to investigate the impact of this phenotype on the pharmacokinetics and therapeutic outcomes of low-dose MTX in a murine model of collagen-induced arthritis (CIA). We evaluated response to MTX in mice with CIA using wildtype (WT), heterozygous, and KO Slco1b2 mice on a DBA1/J background. Arthritis was macroscopically evaluated daily to quantify disease progression. Mice received 2 mg/kg or a pharmacogenetically guided MTX dose subcutaneously 3 times a week for 2 weeks. MTX concentrations were collected at the end of the study and exposure (day*µM) was estimated using a two-compartment model. Mice displayed a seven-fold range in MTX exposure and revealed a significant exposure-response relationship (p = 0.0027). KO mice receiving the 2 mg/kg dosing regimen had 2.3-fold greater exposure to MTX (p < 0.0001) and a 66% reduction in overall disease progression (p = 0.011) compared to WT mice. However, exposure and response were equivalent when pharmacogenetically guided dosing was used. These studies demonstrate that an exposure-response relationship exists for MTX and that Slco1b2 genotype affects MTX exposure and therapeutic response. Such evidence supports the use of SLCO1B1-pharmacogenetic dosing of low-dose MTX for patients with arthritis.


Asunto(s)
Antirreumáticos/administración & dosificación , Artritis/tratamiento farmacológico , Transportador 1 de Anión Orgánico Específico del Hígado , Metotrexato/administración & dosificación , Ratones Noqueados , Pruebas de Farmacogenómica , Animales , Antirreumáticos/farmacología , Colágeno/efectos de los fármacos , Colágeno/metabolismo , Genotipo , Humanos , Masculino , Metotrexato/farmacología , Ratones , Farmacogenética
4.
Am J Cardiol ; 125(1): 63-67, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31727262

RESUMEN

The 2018 resistant hypertension scientific statement offers new treatment recommendations. To determine the implications of these changes, we sought to ascertain the prevalence of apparent treatment resistant hypertension (aTRH) and the therapies used to treat it in an US national ambulatory cardiovascular registry before these recent developments. Using the PINNACLE Registry from 2013 to 2014, we identified all patients receiving treatment for hypertension and then determined the proportion with aTRH as those who met the following criteria over ≥2 consecutive visits: (1) 3 blood pressure medication classes including a diuretic and blood pressure >140/90, OR (2) ≥4 blood pressure medications. Among those with aTRH, we examined past use of therapies now recommended in guidelines including: (1) first-line therapy with an angiotensin-converting enzyme inhibitor or angiotensin-II receptor blocker, calcium channel blocker and a thiazide diuretic, (2) use of chlorthalidone, and (3) use of a mineralocorticoid receptor antagonist (MRA) for those requiring a 4th medication. Of 84,624 patients on treatment for hypertension, 11,147 (13.1%) met criteria for prevalent aTRH. Among these patients: (1) Of those on 3 antihypertensive agents (n = 1,255), 315 (25%) were on the first-line regimen now recommended in guidelines, (2) 520 (6.7%) of the 7,930 patients on thiazides were using chlorthalidone, and (3) 3061 (27%) were using a MRA; another 4,523 (40.6%) were eligible for its addition. In conclusion, our findings of low historic use of therapies now recommended in guidelines suggest opportunities to improve care among patients with aTRH.


Asunto(s)
Antihipertensivos/uso terapéutico , Presión Sanguínea/fisiología , Manejo de la Enfermedad , Hipertensión/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Anciano , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Hipertensión/epidemiología , Hipertensión/fisiopatología , Masculino , Prevalencia , Estudios Retrospectivos , Estados Unidos/epidemiología
5.
J Clin Oncol ; 37(23): 2051-2061, 2019 08 10.
Artículo en Inglés | MEDLINE | ID: mdl-31188727

RESUMEN

PURPOSE: Pegaspargase (PEG-ASP) has largely replaced native Escherichia coli asparaginase (L-ASP) in the treatment of acute lymphoblastic leukemia because of its longer half-life and lower immunogenicity. Risk factors for allergic reactions to PEG-ASP remain unclear. Here, we identify risk factors for reactions in a front-line acute lymphoblastic leukemia trial and assess the usefulness of serum antibodies for diagnosing allergy and predicting rechallenge outcome. PATIENTS AND METHODS: PEG-ASP was administered to 598 patients in St Jude's Total XVI study. Results were compared with Total XV study (ClinicalTrials.gov identifiers: NCT00549848 and NCT00137111), which used native L-ASP. Serum samples (n = 5,369) were analyzed for anti-PEG-ASP immunoglobulin G by enzyme-linked immunosorbent assay. Positive samples were tested for anti-polyethylene glycol (PEG) and anti-L-ASP. We analyzed potential risk factors for reactions and associations between antibodies and reactions, rechallenge outcomes, and PEG-ASP pharmacokinetics. RESULTS: Grade 2 to 4 reactions were less common in the Total XVI study with PEG-ASP (81 [13.5%] of 598) than in the Total XV study with L-ASP (169 [41.2%] of 410; P = 1.4 × 10-23). For Total XVI, anti-PEG, not anti-L-ASP, was the predominant component of anti-PEG-ASP antibodies (96%). In a multivariable analysis, more intrathecal therapy (IT) predicted fewer reactions (P = 2.4 × 10-5), which is consistent with an immunosuppressant contribution of IT. Anti-PEG-ASP was associated with accelerated drug clearance (P = 5.0 × 10-6). Failure of rechallenge after initial reactions was associated with anti-PEG-ASP (P = .0078) and was predicted by the occurrence of angioedema with first reaction (P = .01). CONCLUSION: Less IT therapy was the only independent clinical risk factor for reactions to PEG-ASP. PEG, and not L-ASP, is the major antigen that causes allergic reactions. Anti-PEG-ASP has utility in predicting and confirming clinical reactions to PEG-ASP as well as in identifying patients who are most likely to experience failure with rechallenge.


Asunto(s)
Anticuerpos/uso terapéutico , Antineoplásicos/efectos adversos , Asparaginasa/efectos adversos , Hipersensibilidad/etiología , Polietilenglicoles/efectos adversos , Anticuerpos/farmacología , Femenino , Humanos , Hipersensibilidad/patología , Masculino , Factores de Riesgo
6.
Resuscitation ; 123: 58-64, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29102470

RESUMEN

BACKGROUND: Although rates of survival to hospital discharge after in-hospital cardiac arrest (IHCA) have improved over the last decade, it is unknown if these survival gains are sustained after hospital discharge. OBJECTIVE: To examine 1-year survival trends overall and by rhythm after IHCA. METHODS: Using Medicare beneficiaries (age≥65years) with IHCA occurring between 2000 and 2011 at Get With The Guidelines®-Resuscitation Registry participating hospitals we used multivariable regression, to examine temporal trends in risk-adjusted rates of 1-year survival. RESULTS: Among 45,567 patients with IHCA, the unadjusted 1-year survival was 9.4%. Unadjusted 1-year survival was 21.8% among the 9,223 (20.2%) of patients with Ventricular Fibrillation or Pulseless Ventricular Tachycardia (VF/VT) and 6.2% among the 36,344 (79.8%) of patients with Pulseless Electrical Activity or asystole (PEA/asystole). After adjustment for patient and arrest characteristics, 1-year survival increased over time for all IHCA from 8.9% in 2000-2001 to 15.2% in 2011 (adjusted rate ratio [RR] per year, 1.05; 95% CI, 1.03-1.06; P<0.001 for trend). Improvements in 1-year risk adjusted survival were also observed for VF/VT (19.4% in 2000-2001 to 25.6% in 2011 [RR per year, 1.02; 95% CI, 1.01-1.04; P 0.004 for trend]) and PEA/asystole arrests (4.7% in 2000-2001 to 10.2% in 2011 [RR per year, 1.07; 95% CI, 1.05-1.08; P<0.001 for trend]). CONCLUSION: Among Medicare beneficiaries in the GWTG-Resuscitation registry, 1-year survival after IHCA has increased for over the past decade. Temporal improvements in survival were noted for both shockable and non-shockable presenting arrest rhythms.


Asunto(s)
Paro Cardíaco/mortalidad , Anciano , Reanimación Cardiopulmonar/mortalidad , Femenino , Mortalidad Hospitalaria/tendencias , Humanos , Masculino , Medicare , Alta del Paciente/estadística & datos numéricos , Estudios Prospectivos , Sistema de Registros , Ajuste de Riesgo , Análisis de Supervivencia , Factores de Tiempo , Estados Unidos/epidemiología
7.
Clin Cardiol ; 40(12): 1279-1284, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29247532

RESUMEN

BACKGROUND: Anemia at discharge in patients with acute myocardial infarction is associated with poor prognosis; whether this differs in women and men or if there is a threshold value at which these relationships change is unknown. HYPOTHESIS: Women have a lower discharge hemoglobin (Hb) at which outcomes worsen. METHODS: We identified patients with acute myocardial infarction in the TRIUMPH registry between 2005 and 2008. In multivariable models, we evaluated the relationship between discharge Hb and 12-month mortality and tested whether this relationship varied by gender. We assessed whether the relationship with discharge Hb values was nonlinear using a restricted cubic spline term. RESULTS: Of 4243 patients with AMI, 32.9% were female. Mean admission Hb was 12.9 ± 1.9 g/dL in women and 14.5 ± 2.0 g/dL in men, with mean discharge Hb 11.4 ± 1.8 g/dL and 12.9 ± 1.9 g/dL, respectively. Lower discharge Hb was independently associated with increased mortality (P < 0.05). In multivariable models, discharge Hb decline was similarly associated with increased 12-month mortality in women and men (per 1-g/dL decrease Hb; women HR: 1.24, 95% CI: 1.09-1.42, P < 0.01; and men HR: 1.25, 95% CI: 1.13-1.37, P < 0.01; P for gender interaction = 0.99). The relationship between discharge Hb and 12-month mortality was linear (P for nonlinear spline term = 0.12). CONCLUSIONS: Lower discharge Hb levels were similarly associated with increased 12-month mortality in women and men. These relationships are linear without a clear threshold, suggesting any decline in discharge Hb is associated with poor outcomes.


Asunto(s)
Anemia/sangre , Hemoglobinas/metabolismo , Infarto del Miocardio/mortalidad , Alta del Paciente/estadística & datos numéricos , Medición de Riesgo/métodos , Anemia/epidemiología , Anemia/etiología , Biomarcadores/sangre , Femenino , Estudios de Seguimiento , Mortalidad Hospitalaria/tendencias , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Infarto del Miocardio/sangre , Infarto del Miocardio/complicaciones , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Distribución por Sexo , Factores Sexuales , Factores de Tiempo , Estados Unidos/epidemiología
8.
J Am Heart Assoc ; 6(7)2017 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-28724655

RESUMEN

BACKGROUND: Despite higher thromboembolism risk, women with atrial fibrillation have lower oral anticoagulation (OAC) use compared to men. The influence of the CHA2DS2-VASc score or the introduction of non-vitamin K OACs on this relationship is not known. METHODS AND RESULTS: Using the PINNACLE National Cardiovascular Data Registry from 2008 to 2014, we compared the association of sex with OAC use (warfarin or non-vitamin K OACs) overall and by CHA2DS2-VASc score and examined temporal trends in OAC use by sex. Multivariable regression models assessed the association between sex and OAC use in those with CHA2DS2-VASc scores ≥2. Temporal analyses assessed changes in OAC use by sex over time. Of the 691 906 atrial fibrillation patients, 48.5% were women. Women were significantly less likely than men to use any OAC overall (56.7% versus 61.3%; P<0.001) and at all levels of CHA2DS2-VASc score (adjusted risk ratio 9% to 33% lower, all P<0.001). Compared to other thromboembolic risk factors, female sex was associated with lower use of OAC (risk ratio 0.90, 95%CI 0.90-0.91). Over time, non-vitamin K OAC use increased at a slightly higher rate in women (56.2% increase per year, 95%CI 54.6% to 57.9%) compared to men (53.6% increase per year, 95%CI 52.0% to 55.2%), yet women remained less likely to receive any OAC at all time points (P<0.001). CONCLUSIONS: Among patients with atrial fibrillation, women were significantly less likely to receive OAC at all levels of the CHA2DS2-VASc score. Despite increasing non-vitamin K OAC use, women had persistently lower rates of OAC use compared to men over time.


Asunto(s)
Anticoagulantes/administración & dosificación , Fibrilación Atrial/tratamiento farmacológico , Disparidades en Atención de Salud/tendencias , Pautas de la Práctica en Medicina/tendencias , Accidente Cerebrovascular/prevención & control , Tromboembolia/prevención & control , Warfarina/administración & dosificación , Administración Oral , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/complicaciones , Fibrilación Atrial/diagnóstico , Distribución de Chi-Cuadrado , Técnicas de Apoyo para la Decisión , Factor F , Femenino , Hemorragia/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Sistema de Registros , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/etiología , Tromboembolia/diagnóstico , Tromboembolia/etiología , Estados Unidos
9.
J Womens Health (Larchmt) ; 26(10): 1062-1068, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28498792

RESUMEN

BACKGROUND: Advancements in percutaneous coronary intervention (PCI) for treating obstructive coronary artery disease have reduced major adverse events, including mortality. Yet, evidence as to whether women and men experience similar outcomes is mixed. The objective was to examine sex differences in 1-year major adverse cardiac outcomes for the national population of patients undergoing PCI at Veterans Health Administration (VA) cardiac catheterization laboratories. METHODS: All Veterans undergoing PCI at VA hospitals between October 1, 2007 and September 30, 2013 (N = 64,757; Women = 1,040) were included. Cox proportional hazards models compared 1-year postprocedural outcomes [rehospitalization for myocardial infarction (MI), all-cause mortality, and major adverse cardiovascular events (MACE)] by sex. RESULTS: Women Veterans undergoing PCI were more likely to be younger, black, obese, and have chronic depression and less likely to have common cardiovascular risk factors and to have had prior cardiac events than Veteran men. One-year rates for women versus men were 2.1% and 2.5% for rehospitalization (p-value = 0.57); 3.5% and 4.9% for mortality (p-value = 0.14), and 5.4% and 6.9% for MACE (p-value = 0.18). There were no significant sex differences in any of the outcomes in Cox proportional hazards models. CONCLUSIONS: Despite differences in clinical risk factors at the time of PCI, women and men Veterans treated at VA cardiac catheterization laboratories experienced comparable 1-year rehospitalization for MI, mortality, and MACE post-PCI. These results demonstrated similar 1-year post-PCI outcomes for men and women in a national population of patients who have more comorbidities and mental health issues than the general population.


Asunto(s)
Enfermedad de la Arteria Coronaria/cirugía , Intervención Coronaria Percutánea/efectos adversos , Factores Sexuales , Veteranos/estadística & datos numéricos , Comorbilidad , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/epidemiología , Femenino , Humanos , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/mortalidad , Obesidad/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Caracteres Sexuales , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos/epidemiología , United States Department of Veterans Affairs , Salud de los Veteranos
11.
Curr Heart Fail Rep ; 12(3): 236-46, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25703897

RESUMEN

Patient-reported outcomes (PROs) are any report obtained directly from a patient about how they feel or function in relation to their health condition and its therapies. Strong support for PROs exists at multiple levels of the health-care community from regulatory boards to clinical researchers. PROs are particularly important in heart failure because it is a common chronic illness marked with acute exacerbations, often requiring hospitalization, and significant symptom burden. Use of PROs to understand patient perspectives will help providers deliver more patient-centered care, and thus improve the quality of care. This review provides a contemporary overview of the current state of PROs in heart failure and suggests future directions and opportunities to advance PRO use to provide more comprehensive care. Advancing PRO measurement along with incorporating longitudinal measures in national databases and local electronic health records will serve to improve patient-centered care for patients with heart failure.


Asunto(s)
Insuficiencia Cardíaca/terapia , Evaluación del Resultado de la Atención al Paciente , Ensayos Clínicos como Asunto/métodos , Indicadores de Salud , Insuficiencia Cardíaca/psicología , Humanos , Evaluación de Resultado en la Atención de Salud/tendencias , Atención Dirigida al Paciente/métodos , Calidad de Vida
12.
J Am Coll Cardiol ; 61(20): 2070-8, 2013 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-23524046

RESUMEN

OBJECTIVES: This study sought to compared the use and effectiveness of bleeding avoidance strategies (BAS) by sex. BACKGROUND: Women have higher rates of bleeding following percutaneous coronary intervention (PCI). METHODS: Among 570,777 men (67.5%) and women (32.5%) who underwent PCI in the National Cardiovascular Data Registry's CathPCI Registry between July 1, 2009 and March 31, 2011, in-hospital bleeding rates and the use of BAS (vascular closure devices, bivalirudin, radial approach, and their combinations) were assessed. The relative risk of bleeding for each BAS compared with no BAS was determined in women and men using multivariable logistic regressions adjusted for clinical characteristics and the propensity for receiving BAS. Finally, the absolute risk differences in bleeding associated with BAS were compared. RESULTS: Overall, the use of any BAS differed slightly between women and men (75.4% vs. 75.7%, p = 0.01). When BAS was not used, women had significantly higher rates of bleeding than men (12.5% vs. 6.2%, p < 0.01). Both sexes had similar adjusted risk reductions of bleeding when any BAS was used (women, odds ratio: 0.60, 95% confidence interval [CI]: 0.57 to 0.63; men, odds ratio: 0.62, 95% CI: 0.59 to 0.65). Women and men had lower absolute bleeding risks with BAS; however, these absolute risk differences were greater in women (6.3% vs. 3.2%, p < 0.01). CONCLUSIONS: Women continue to have almost twice the rate of bleeding following PCI. The use of any BAS was associated with a similarly lower risk of bleeding for men and women; however, the absolute risk differences were substantially higher in women. These data underscore the importance of applying effective strategies to limit post-PCI bleeding, especially in women.


Asunto(s)
Pérdida de Sangre Quirúrgica/prevención & control , Hemostasis Quirúrgica/estadística & datos numéricos , Isquemia Miocárdica/terapia , Intervención Coronaria Percutánea/efectos adversos , Hemorragia Posoperatoria/prevención & control , Factores Sexuales , Anciano , Antitrombinas/uso terapéutico , Femenino , Hirudinas , Humanos , Masculino , Persona de Mediana Edad , Selección de Paciente , Fragmentos de Péptidos/uso terapéutico , Hemorragia Posoperatoria/epidemiología , Pautas de la Práctica en Medicina/estadística & datos numéricos , Proteínas Recombinantes/uso terapéutico , Sistema de Registros , Estudios Retrospectivos , Medición de Riesgo , Resultado del Tratamiento , Estados Unidos/epidemiología
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