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1.
South Med J ; 110(5): 347-352, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28464176

RESUMO

OBJECTIVES: Increased adiposity increases leptin and decreases adiponectin concentrations, resulting in an increased leptin:adiponectin ratio (LAR). In adults, components of the metabolic syndrome and other cardiometabolic risk factors, what we classify here as "metabolic dysfunction," are associated with both a high LAR and a history of being breast-fed. The relation among breast-feeding, LAR, and degree of metabolic dysfunction in obese youth is unknown. The purpose of our pilot study was to explore this relation and estimate the effect size of the relations to determine the sample size needed to power future prospective studies. METHODS: We obtained fasting levels of leptin, adiponectin, lipids, insulin, and glucose from obese youth (aged 8-17 years). Weight, height, waist circumference, blood pressure, and breast-feeding history also were assessed. RESULTS: Of 96 participants, 78 were breast-fed as infants, 54% of whom were breast-fed for >6 months. Wide variation was observed in LARs among children who were and were not breast-fed (>100% coefficient of variation). Overall, prevalence of metabolic dysfunction in the cohort was 94% and was not proven to be associated with higher LAR. CONCLUSIONS: In this cohort of obese youth, we found a high prevalence of breast-feeding, metabolic dysfunction, and wide variation in the LARs. Based on the effect size estimated, future studies would need to enroll >1500 patients or identify, stratify, and selectively enroll obese patients without metabolic dysfunction to accurately determine whether breast-feeding in infancy influences LARs or metabolic dysfunction among obese youth.


Assuntos
Adiponectina/sangue , Aleitamento Materno , Leptina/sangue , Obesidade Pediátrica/metabolismo , Adolescente , Biomarcadores/sangue , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Obesidade Pediátrica/sangue , Projetos Piloto
2.
J Clin Pharmacol ; 57(1): 77-84, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27291466

RESUMO

Vancomycin is a first-line treatment for ß-lactam-resistant Gram-positive bacterial infections. Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of vancomycin in an adolescent population is of clinical importance in this often overlooked pediatric population. This retrospective study investigated vancomycin PK-PD in an adolescent cohort (12 to 18 years of age) of 463 patients (57% male, 81% white) admitted to the Intermountain Healthcare System between January 2006 and December 2013. Population PK modeling was performed in NONMEM 7.3. Vancomycin PK was well described with a 1-compartment model that identified both body weight (WT) and creatinine clearance (CRCL) as covariates significantly impacting vancomycin disposition. The model was then utilized to determine dosing strategies that achieved the targeted area under the 24-hour time curve vs minimum inhibitory concentration (AUC0-24 /MIC) ratio of ≥400. Additionally, these data were correlated with minimum steady-state concentrations (Css,min ) to find an acceptable target trough concentration range in adolescents. This analysis demonstrated that Css,min ranging from 10 to 12.5 mg/L were highly predictive of achieving an AUC0-24 /MIC ≥400 when the MIC was ≤1 mg/L. These results suggest that the target trough concentration for adolescents may be lower than that for adults.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/sangue , Área Sob a Curva , Sepse/sangue , Vancomicina/administração & dosagem , Vancomicina/sangue , Adolescente , Criança , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Estudos Retrospectivos , Sepse/diagnóstico , Sepse/tratamento farmacológico
3.
Expert Rev Anti Infect Ther ; 14(8): 731-46, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27355512

RESUMO

INTRODUCTION: Voriconazole is a broad-spectrum antifungal agent commonly used to treat invasive fungal infections (IFI), including aspergillosis, candidiasis, Scedosporium infection, and Fusarium infection. IFI often occur in immunocompromised patients, leading to increased morbidity and mortality. AREAS COVERED: The objective of this review is to summarize the pharmacodynamic properties of voriconazole and to provide considerations for potential optimal dosing strategies. Studies have demonstrated superior clinical response when an AUC/MIC >25 or Cmin/MIC >1 is attained in adult patients, correlating to a trough concentration range as narrow as 2-4.5 mg/L; however, these targets are poorly established in the pediatric population. Topics in this discussion include voriconazole use in multiple age groups, predisposing patient factors for IFI, and considerations for clinicians managing IFI. Expert commentary: The relationship between voriconazole dosing and exposure is not well defined due to the large inter- and intra-subject variability. Development of comprehensive decision support tools for individualizing dosing, particularly in children who require higher dosing, will help to increase the probability of achieving therapeutic efficacy and decrease sub-therapeutic dosing and adverse events.


Assuntos
Antifúngicos/uso terapêutico , Infecções Fúngicas Invasivas/tratamento farmacológico , Voriconazol/uso terapêutico , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Área Sob a Curva , Relação Dose-Resposta a Droga , Predisposição Genética para Doença , Humanos , Infecções Fúngicas Invasivas/genética , Infecções Fúngicas Invasivas/imunologia , Infecções Fúngicas Invasivas/microbiologia , Testes de Sensibilidade Microbiana , Modelos Biológicos , Voriconazol/administração & dosagem , Voriconazol/farmacocinética , Voriconazol/farmacologia
4.
BMC Pharmacol Toxicol ; 17(1): 22, 2016 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-27266401

RESUMO

BACKGROUND: This study sought to assess the pharmacokinetic and pharmacodynamic relationships of caffeine citrate therapy in preterm neonates who had therapeutic drug monitoring (TDM) in the post-extubation period. METHODS: A retrospective observational study was conducted in preterm neonates who received caffeine citrate therapy for apnea of prematurity and had TDM done in the post-extubation period between January 2006 and October 2011. The relationships between pharmacodynamic effects (heart rate, respiratory rate, episodes of apnea, adverse events) and caffeine serum concentrations were explored. RESULTS: A total of 177 blood samples were obtained from 115 preterm neonates with a median (range) gestational age of 29 (24 - 33) weeks and birth weight of 1230 (607 - 2304) kg. Caffeine citrate therapy was initiated at a median (interquartile range) postnatal age of 1 (1 - 3) day and TDM was performed at a postnatal age of 15 (10 - 24) days. No direct correlations were found between respiratory rate or apneic episodes and caffeine serum concentrations; however, heart rate and caffeine serum concentrations were significantly correlated (p < 0.05). Dosing regimen of 40/5 mg/kg q12h (loading dose/maintenance dose, time interval) led to similar endotracheal re-intubation rate but increased percentage of patients experiencing tachycardia compared to the standard regimen of 20/5 mg/kg q24h (44.7 % vs 10.2 %, p < 0.001). CONCLUSION: Based on this retrospective study, no correlation between episodes of apnea and caffeine serum concentrations was found in neonates who had TDM of caffeine citrate therapy in the post-extubation period, whereas a significant association between tachycardia and concentrations existed. Notwithstanding the absence of severe adverse reactions, TDM should be considered in critically ill neonates with unexplained adverse effects, such as tachycardia.


Assuntos
Cafeína/sangue , Citratos/administração & dosagem , Monitoramento de Medicamentos/métodos , Recém-Nascido Prematuro/sangue , Apneia/sangue , Apneia/tratamento farmacológico , Cafeína/administração & dosagem , Feminino , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Recém-Nascido , Infusões Intravenosas , Masculino , Estudos Retrospectivos
5.
Arch Dis Child Fetal Neonatal Ed ; 101(3): F236-43, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26400103

RESUMO

BACKGROUND: The incidence of nephrotoxicity among vancomycin-treated neonates has been reported to range from 2% to 20%. These widely varying estimates have led to confusion and controversy regarding the safety of vancomycin among neonates. OBJECTIVE: Evaluate the incidence of nephrotoxicity among neonates receiving vancomycin concomitantly with gentamicin. DESIGN: Retrospective observational cohort study using propensity score matching to provide covariate balance between neonates who did or did not receive vancomycin based on factors known to be related to the development of renal dysfunction. SETTING: Hospitals (n=22) throughout the Intermountain West, including a quaternary care children's hospital. PATIENTS: Neonates ≤44 postmenstrual weeks (median gestational age: 31 (IQR 28-36) weeks) receiving intravenous gentamicin with or without exposure to vancomycin from January 2006 to December 2012. MAIN OUTCOME MEASURES: Nephrotoxicity based on the modified Acute Kidney Injury Network criteria for acute kidney injury (AKI) or serum creatinine concentration ≥1.5 mg/dL persisting for ≥48 h. RESULTS: The final cohort was comprised of 1066 neonates (533 receiving vancomycin and gentamicin vs 533 receiving gentamicin). In a propensity score-matched cohort that was well balanced across 16 covariates, AKI was not associated with vancomycin use (16 neonates receiving vancomycin vs 7 controls experienced AKI; OR 1.5; 95% CI 0.6 to 4.0). However, the presence of a patent ductus arteriosus, concomitant non-steroidal anti-inflammatory drug use, ≥1 positive blood cultures, low birth weight and higher severity of illness and risk of mortality scores were associated with an increased risk of nephrotoxicity. CONCLUSIONS: These results corroborate several earlier reports and much anecdotal evidence describing the infrequent occurrence of nephrotoxicity in neonates receiving concomitant vancomycin and gentamicin.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Antibacterianos/efeitos adversos , Vancomicina/efeitos adversos , Lesão Renal Aguda/epidemiologia , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Bacteriemia/epidemiologia , Estudos de Coortes , Creatinina/sangue , Quimioterapia Combinada , Permeabilidade do Canal Arterial/epidemiologia , Feminino , Gentamicinas/administração & dosagem , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Masculino , Pontuação de Propensão , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Estados Unidos/epidemiologia
6.
Expert Opin Drug Metab Toxicol ; 11(12): 1861-78, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26535960

RESUMO

INTRODUCTION: Neonatal patients, because of the inability of their immune system to properly respond to microbial challenge, are highly susceptible to viral infections. Immunoglobulins, monoclonal antibody and antiviral drugs are used for prophylaxis and treatment of viral diseases in neonates. Neonates and, especially, preterm infants differ in drug absorption, distribution, metabolism and excretion from adults and older children. AREAS COVERED: This review will evaluate deficiencies of neonatal immune responses to microbial challenge that predispose newborns to viral infections, clinical manifestations and the treatment of viral diseases in neonates. We focus on published studies describing antiviral drug pharmacokinetics in neonates and make recommendations on the dosing of these drugs, allowing achievement of maximal clinical benefits in neonates. EXPERT OPINION: While some efforts were undertaken to study pharmacokinetics and pharmacodynamics of antiviral drugs, much more needs to be done. Current data indicate that the pharmacokinetics of antiviral drugs may vary significantly depending on gestational age, maturation processes of drug-metabolizing enzymes and renal clearance. Specifics of pharmacokinetics of antiviral drugs need to be taken into consideration when they are prescribed to neonates and infants.


Assuntos
Antivirais/farmacocinética , Sistema Imunitário/fisiologia , Viroses/tratamento farmacológico , Adulto , Fatores Etários , Animais , Antivirais/administração & dosagem , Criança , Suscetibilidade a Doenças/imunologia , Relação Dose-Resposta a Droga , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Viroses/epidemiologia , Viroses/imunologia
7.
Antimicrob Agents Chemother ; 59(10): 5984-91, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26169416

RESUMO

The human immunodeficiency virus type 1 (HIV-1) latent reservoir in resting CD4(+) T cells represents a major barrier to viral eradication. Small compounds capable of latency reversal have not demonstrated uniform responses across in vitro HIV-1 latency cell models. Characterizing compounds that demonstrate latency-reversing activity in resting CD4(+) T cells from aviremic patients ex vivo will help inform pilot clinical trials aimed at HIV-1 eradication. We have optimized a rapid ex vivo assay using resting CD4(+) T cells from aviremic HIV-1(+) patients to evaluate both the bioactivity and latency-reversing potential of candidate latency-reversing agents (LRAs). Using this assay, we characterize the properties of two candidate compounds from promising LRA classes, ingenol 3,20-dibenzoate (a protein kinase C agonist) and panobinostat (a histone deacetylase inhibitor), in cells from HIV-1(+) antiretroviral therapy (ART)-treated aviremic participants, including the effects on cellular activation and cytotoxicity. Ingenol induced viral release at levels similar to those of the positive control (CD3/28 receptor stimulation) in cells from a majority of participants and represents an exciting LRA candidate, as it combines a robust viral reactivation potential with a low toxicity profile. At concentrations that blocked histone deacetylation, panobinostat displayed a wide range of potency among participant samples and consistently induced significant levels of apoptosis. The protein kinase C agonist ingenol 3,20-dibenzoate demonstrated significant promise in a rapid ex vivo assay using resting CD4(+) T cells from treated HIV-1-positive patients to measure latent HIV-1 reactivation.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Diterpenos/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Ativação Viral/efeitos dos fármacos , Latência Viral/efeitos dos fármacos , Adulto , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Estudos de Casos e Controles , DNA Viral/antagonistas & inibidores , DNA Viral/biossíntese , Ativadores de Enzimas/farmacologia , Feminino , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/enzimologia , HIV-1/genética , Inibidores de Histona Desacetilases/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Panobinostat , Cultura Primária de Células , Proteína Quinase C/metabolismo , Carga Viral/efeitos dos fármacos
8.
Biopharm Drug Dispos ; 36(6): 405-409, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25766031

RESUMO

With traditional non-compartmental methods, it is challenging to deconstruct plasma concentration versus time curves to assess the influence of individual doses. This study describes the application of a mathematical approach used to deconstruct a single dose curve using data derived from the second, third, fourth or nth dosing interval. Using data from a prospective clinical trial it is demonstrated that this approach reliably estimates pharmacokinetic parameters measured following two doses of zolpidem tartrate. Additionally, the study demonstrates the application of this approach using previously published data from a single- and multiple-dose pharmacokinetic study of the antibiotic gatifloxacin. Copyright © 2015 John Wiley & Sons, Ltd.

9.
J Clin Pharmacol ; 55(2): 212-20, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25264036

RESUMO

Monitoring of vancomycin trough concentrations is recommended for pediatric patients in the product label and by several professional societies. However, among a network of freestanding children's hospitals vancomycin therapeutic drug monitoring (TDM) practices were reported to be highly variable. In this study, we sought to evaluate whether trends in vancomycin use and TDM changed across a large healthcare delivery system in Utah and Idaho from 2006 to 2012. Children ≤18 years who received ≥2 vancomycin doses were included. Overall, vancomycin TDM was performed during 5,035 (80%) of 6,259 hospital encounters, in which 85,442 doses were administered and 7,935 concentrations were obtained. Across this time period, the median trough concentration increased from 10.9 to 13.7 µg/mL (P < .001), which temporally coincided with recommendations published by the Infectious Disease Society of America that recommend targeting higher trough concentrations. Two or more abnormally low trough concentrations were accompanied by an increase in the dose 75% of the time. Similarly, ≥2 abnormally high trough concentrations were followed by a decrease in the dose 35% of the time. In aggregate, these data suggest that vancomycin TDM is commonly performed among children and the majority of abnormal trough concentrations were associated with an appropriate modification to the dosing regimen.


Assuntos
Antibacterianos/administração & dosagem , Monitoramento de Medicamentos/tendências , Uso de Medicamentos/tendências , Vancomicina/administração & dosagem , Antibacterianos/sangue , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Criança , Pré-Escolar , Feminino , Hospitais/estatística & dados numéricos , Humanos , Idaho/epidemiologia , Incidência , Lactente , Masculino , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas/epidemiologia , Utah/epidemiologia , Vancomicina/sangue , Vancomicina/farmacocinética , Vancomicina/uso terapêutico
10.
Int J Antimicrob Agents ; 43(3): 215-22, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24183801

RESUMO

Use of vancomycin has increased following the emergence of resistant Gram-positive bacterial infections. Investigation into recent vancomycin clinical studies provides insight into the optimal use of vancomycin and the development of novel antibiotics for the treatment of resistant infections. Interventional vancomycin trials registered in ClinicalTrials.gov from January 1999 to December 2012 were identified. Trial trends and characteristics were evaluated in the context of vancomycin use and new antibiotic development. Overall, 122 interventional vancomycin trials were identified, with a significant increase in the number of registered trials per year (P<0.001). The top three indications studied were skin and soft-tissue infections (28.7%), Clostridium difficile infections (13.1%) and surgical prophylaxis (12.3%). Trials testing vancomycin as an experimental agent differed from trials using vancomycin as an active comparator. Experimental agent trials commonly investigated new formulations, dosing regimen optimisation and combination therapy, which were less likely to be in phase 2 or 3 (25% vs. 70%; P<0.001), adopt a randomisation procedure (70% vs. 98%; P<0.001), report results (15% vs. 35%; P=0.02) or be funded by industry (8% vs. 76%; P<0.001). Active comparator trials mainly focused on monotherapy, which led to six FDA-approved drug products and ten investigational new drugs in late-phase development. This study demonstrated a significant increase in interventional vancomycin trials and its recent success, which resulted in several novel agents against resistant Gram-positive bacteria. Further studies are warranted to determine how these agents can best be incorporated within clinical practice.


Assuntos
Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Ensaios Clínicos como Assunto/estatística & dados numéricos , Vancomicina/uso terapêutico , Uso de Medicamentos/estatística & dados numéricos , Humanos , Estados Unidos
11.
PLoS One ; 7(8): e42282, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22879929

RESUMO

BACKGROUND: Invasive candidiasis (IC) is a devastating disease. While prompt antifungal therapy improves outcomes, empiric treatment based on the presence of fever has little clinical impact. Β-D-Glucan (BDG) is a fungal cell wall component detectable in the serum of patients with early invasive fungal infection (IFI). We evaluated the utility of BDG surveillance as a guide for preemptive antifungal therapy in at-risk intensive care unit (ICU) patients. METHODS: Patients admitted to the ICU for ≥ 3 days and expected to require at least 2 additional days of intensive care were enrolled. Subjects were randomized in 3:1 fashion to receive twice weekly BDG surveillance with preemptive anidulafungin in response to a positive test or empiric antifungal treatment based on physician preference. RESULTS: Sixty-four subjects were enrolled, with 1 proven and 5 probable cases of IC identified over a 2.5 year period. BDG levels were higher in subjects with proven/probable IC as compared to those without an IFI (117 pg/ml vs. 28 pg/ml; p<0.001). Optimal assay performance required 2 sequential BDG determinations of ≥ 80 pg/ml to define a positive test (sensitivity 100%, specificity 75%, positive predictive value 30%, negative predictive value 100%). In all, 21 preemptive and 5 empiric subjects received systemic antifungal therapy. Receipt of preemptive antifungal treatment had a significant effect on BDG concentrations (p< 0.001). Preemptive anidulafungin was safe and generally well tolerated with excellent outcome. CONCLUSIONS: BDG monitoring may be useful for identifying ICU patients at highest risk to develop an IFI as well as for monitoring treatment response. Preemptive strategies based on fungal biomarkers warrant further study. TRIAL REGISTRATION: Clinical Trials.gov NCT00672841.


Assuntos
Antifúngicos/uso terapêutico , Candidíase Invasiva/tratamento farmacológico , Candidíase Invasiva/prevenção & controle , Equinocandinas/uso terapêutico , Unidades de Terapia Intensiva , beta-Glucanas , Adulto , Idoso , Idoso de 80 Anos ou mais , Anidulafungina , Antifúngicos/efeitos adversos , Demografia , Equinocandinas/efeitos adversos , Reações Falso-Positivas , Estudos de Viabilidade , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Valor Preditivo dos Testes , Fatores de Tempo , Adulto Jovem
12.
Hum Psychopharmacol ; 24(2): 145-52, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19132712

RESUMO

OBJECTIVE: To determine the effect of aripiprazole on steady-state pharmacokinetics of lamotrigine in patients with bipolar I disorder who were clinically stable on lamotrigine (100-400 mg/day) for >or=4 weeks. METHODS: In this open-label study, aripiprazole was administered at 10 mg/day for 3 days, 20 mg/day for 3 days, then 30 mg/day for 8 days. Blood samples were collected on Days -1 and 14 for determination of lamotrigine steady-state pharmacokinetic parameters. Safety and tolerability were assessed. RESULTS: Eighteen patients were administered aripiprazole in combination with lamotrigine. Geometric mean (GM) values for lamotrigine maximum plasma concentration were similar for lamotrigine alone (26 ng/mL) and with co-administered aripiprazole (23 ng/mL). GM values for plasma lamotrigine area under the concentration-time curve (AUCtau) were comparable for lamotrigine alone (434 ng/h/mL) and with co-administered aripiprazole (394 ng/h/mL). Median T(max) of lamotrigine alone and combined with aripiprazole was 1.98 and 0.77 h, respectively. No changes to lamotrigine dose-normalized plasma trough concentrations were observed with co-administered aripiprazole. Sixteen patients (88.9%) experienced >or=1 adverse event (AE), the most common of which was insomnia (n = 6). CONCLUSIONS: Aripiprazole had no meaningful effect on lamotrigine steady-state pharmacokinetics in patients with bipolar I disorder. No dosage adjustment of lamotrigine is required and the combination was generally safe and well tolerated.


Assuntos
Anticonvulsivantes/farmacocinética , Antipsicóticos/farmacologia , Piperazinas/farmacologia , Quinolonas/farmacologia , Triazinas/farmacocinética , Adulto , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Área Sob a Curva , Aripiprazol , Transtorno Bipolar/tratamento farmacológico , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Lamotrigina , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Triazinas/administração & dosagem , Triazinas/efeitos adversos
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