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1.
Expert Rev Clin Pharmacol ; : 1-10, 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32730191

RESUMO

INTRODUCTION: Three major classes of natural products (NPs) for medicinal purposes or improving wellbeing are generally available in the US: conventional drugs of herbal origin, botanical drugs, and dietary supplements (DSs). Consumer consumption of DSs is growing annually. The U.S. FDA regulates conventional and botanical drugs for safety and efficacy; however, DSs are minimally regulated. AREAS COVERED: This article will: i) highlight the importance of NP as a significant source of prescription drugs; ii) discuss differences in the regulation of conventional drugs of NP product, botanical drugs, and DSs; iii) discuss the safety and efficacy of DSs and iv) make recommendations for improvement of safety for minimally regulated NPs. EXPERT OPINION: Toxicities associated with the use of NPs, including vitamins and DSs, are mainly due to excessive use and interactions with conventional drug(s) and may represent challenges for clinicians. Conventional and botanical-based prescription drugs are rarely associated with unknown toxicities. However, DSs are minimally regulated and can produce severe adverse effects. We believe that clinical pharmacologists can have a role in developing criteria for DS safety analysis. There is also the potential for a standardized NP stewardship program(s) and the development of NP policies and practices nationally and globally.

2.
J Clin Pharmacol ; 58 Suppl 10: S10-S25, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30248190

RESUMO

Effective drug therapy to optimally influence disease requires an understanding of a drug's pharmacokinetic, pharmacodynamic, and pharmacogenomic interrelationships. In pediatrics, age is a continuum that can and does add variability in drug disposition and effect. This article addresses the many important factors that influence drug disposition and effect relative to age. What is known about the influence of maturation on the processes of drug absorption, distribution, metabolism, excretion, and drug receptor dynamics are outlined. Our state of understanding of many of these factors remains in flux, however, and only with additional study will we be able to better anticipate and model drug-response relationships across the age continuum. Being able to continuously improve our care of the ill pediatric patient while simultaneously being able to accurately determine the utility of new drugs and chemical entities in this population requires our enhanced understanding of these disposition characteristics.


Assuntos
Envelhecimento/metabolismo , Desenvolvimento Infantil , Farmacocinética , Fenômenos Farmacológicos , Criança , Humanos , Absorção Intestinal , Rim/metabolismo , Preparações Farmacêuticas/metabolismo , Distribuição Tecidual
4.
Artigo em Inglês | MEDLINE | ID: mdl-28137820

RESUMO

Although obesity is prevalent among children in the United States, pharmacokinetic (PK) data for obese children are limited. Clindamycin is a commonly used antibiotic that may require dose adjustment in obese children due to its lipophilic properties. We performed a clindamycin population PK analysis using data from three separate trials. A total of 420 samples from 220 children, 76 of whom had a body mass index greater than or equal to the 95th percentile for age, were included in the analysis. Compared to other metrics, total body weight (TBW) was the most robust measure of body size. The final model included TBW and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (liters/hour) = 13.8 × (TBW/70)0.75 × [PMA2.83/(39.52.83+PMA2.83)]; volume of distribution (V) was associated with TBW, albumin (ALB), and alpha-1 acid glycoprotein (AAG): V (liters) = 63.6 × (TBW/70) × (ALB/3.3)-0.83 × (AAG/2.4)-0.25 After accounting for differences in TBW, obesity status did not explain additional interindividual variability in model parameters. Our findings support TBW-based dosing for obese and nonobese children.


Assuntos
Antibacterianos/farmacocinética , Clindamicina/farmacocinética , Modelos Estatísticos , Obesidade/metabolismo , Adolescente , Antibacterianos/sangue , Área Sob a Curva , Teorema de Bayes , Disponibilidade Biológica , Índice de Massa Corporal , Peso Corporal , Criança , Clindamicina/sangue , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Injeções Intravenosas , Masculino , Obesidade/fisiopatologia , Orosomucoide/metabolismo , Albumina Sérica/metabolismo
5.
J Clin Pharmacol ; 56(12): 1461-1473, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27539787

RESUMO

Differences in physiology related to young or old age and/or organ system impairment alter the absorption, distribution, metabolism, and excretion of many medications and consequently their effectiveness and toxicity. This module discusses common alterations in medication use and dosage that are required in the pediatric age group, in the elderly, and in patients with renal or hepatic disease.


Assuntos
Cálculos da Dosagem de Medicamento , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Preparações Farmacêuticas/administração & dosagem , Adolescente , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Formas de Dosagem/normas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Humanos , Lactente , Recém-Nascido , Rim/metabolismo , Fígado/metabolismo , Pediatria/métodos , Preparações Farmacêuticas/metabolismo
7.
Antimicrob Agents Chemother ; 60(4): 2150-6, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26810655

RESUMO

The Clinical and Laboratory Standards Institute (CLSI) revised cefepime (CFP) breakpoints forEnterobacteriaceaein 2014, and MICs of 4 and 8 µg/ml were reclassified as susceptible-dose dependent (SDD). Pediatric dosing to provide therapeutic concentrations against SDD organisms has not been defined. CFP pharmacokinetics (PK) data from published pediatric studies were analyzed. Population PK parameters were determined using NONMEM, and Monte Carlo simulation was performed to determine an appropriate CFP dosage regimen for SDD organisms in children. A total of 664 CFP plasma concentrations from 91 neonates, infants, and children were included in this analysis. The median patient age was 1.0 month (interquartile range [IQR], 0.2 to 11.2 months). Serum creatinine (SCR) and postmenstrual age (PMA) were covariates in the final PK model. Simulations indicated that CFP dosing at 50 mg/kg every 8 h (q8h) (as 0.5-h intravenous [i.v.] infusions) will maintain free-CFP concentrations in serum of >4 and 8 µg/ml for >60% of the dose interval in 87.1% and 68.6% of pediatric patients (age, ≥30 days), respectively, and extending the i.v. infusion duration to 3 h results in 92.3% of patients with free-CFP levels above 8 µg/ml for >60% of the dose interval. CFP clearance (CL) is significantly correlated with PMA and SCR. A dose of 50 mg/kg of CFP every 8 to 12 h does not achieve adequate serum exposure for older children with serious infections caused by Gram-negative bacilli with a MIC of 8 µg/ml. Prolonged i.v. infusions may be useful for this population.


Assuntos
Antibacterianos/farmacocinética , Cefalosporinas/farmacocinética , Infecções por Enterobacteriaceae/tratamento farmacológico , Modelos Estatísticos , Infecções por Pseudomonas/tratamento farmacológico , Antibacterianos/sangue , Antibacterianos/uso terapêutico , Cefepima , Cefalosporinas/sangue , Cefalosporinas/uso terapêutico , Simulação por Computador , Creatinina/sangue , Cálculos da Dosagem de Medicamento , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/crescimento & desenvolvimento , Infecções por Enterobacteriaceae/sangue , Infecções por Enterobacteriaceae/microbiologia , Feminino , Humanos , Lactente , Recém-Nascido , Infusões Intravenosas , Masculino , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Infecções por Pseudomonas/sangue , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento
9.
Contraception ; 92(4): 298-300, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26071674

RESUMO

OBJECTIVE: To evaluate whether serum adipocytokine concentrations, controlling for baseline adiposity, are predictive of adipose weight gain in adolescents initiating depot medroxyprogesterone acetate (DMPA). METHODS: Percent body fat was measured at baseline and 6 months. Baseline serum adipocytokine concentrations were quantified. RESULTS: Mean percent body fat was 31.6% (±7.6) at baseline and 33.5% (±7.6) at 6 months. In multivariable linear regression modeling (adjusted for baseline percent body fat), Hispanic ethnicity and baseline serum adiponectin concentration were inversely associated (p≤.05) with absolute change in percent body fat at 6 months. CONCLUSIONS: Serum adiponectin concentration may be useful for assessing risk of DMPA-associated adipose gains.


Assuntos
Adipocinas/sangue , Adiposidade/efeitos dos fármacos , Anticoncepcionais Femininos/efeitos adversos , Acetato de Medroxiprogesterona/efeitos adversos , Ganho de Peso/efeitos dos fármacos , Adolescente , Biomarcadores/sangue , Criança , Preparações de Ação Retardada , Feminino , Humanos , Projetos Piloto , Estudos Prospectivos , Adulto Jovem
10.
Drug Alcohol Depend ; 153: 369-73, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26048642

RESUMO

BACKGROUND: The nucleus accumbens (NAc) plays a key role in brain reward processes including drug seeking and reinstatement. Several anatomical, behavioral, and neurochemical studies discriminate between the limbic-associated shell and the motor-associated core regions. Less studied is the fact that the shell can be further subdivided into a dorsomedial shell (NAcDMS) and an intermediate zone (NAcINT) based on differential expression of transient c-Fos and long-acting immediate-early gene ΔFosB upon cocaine sensitization. These disparate expression patterns suggest that NAc shell subregions may play distinct roles in reward-seeking behavior. In this study, we examined potential differences in the contributions of the NAcDMS and the NAcINT to reinstatement of reward-seeking behavior after extinction. METHODS: Rats were trained to intravenously self-administer cocaine, extinguished, and subjected to a reinstatement test session consisting of an intracranial microinfusion of either amphetamine or vehicle targeted to the NAcDMS or the NAcINT. RESULTS: Small amphetamine microinfusions targeted to the NAcDMS resulted in statistically significant reinstatement of lever pressing, whereas no significant difference was observed for microinfusions targeted to the NAcINT. No significant difference was found for vehicle microinfusions in either case. CONCLUSION: These results suggest heterogeneity in the behavioral relevance of NAc shell subregions, a possibility that can be tested in specific neuronal populations in the future with recently developed techniques including optogenetics.


Assuntos
Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Núcleo Accumbens/fisiologia , Recompensa , Anfetamina/administração & dosagem , Anfetamina/farmacologia , Animais , Cocaína/administração & dosagem , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Masculino , Microinjeções , Núcleo Accumbens/anatomia & histologia , Ratos , Ratos Sprague-Dawley , Autoadministração
11.
Dev Med Child Neurol ; 57(11): 1064-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25951240

RESUMO

AIM: Osteoporosis is a significant clinical problem in persons with moderate to severe cerebral palsy (CP), causing fractures with minimal trauma. Over the past decade, most studies examining osteoporosis and CP have been cross-sectional in nature, focused exclusively on children and adolescents and only involving one evaluation of bone mineral density (BMD). The purpose of this study was to assess BMD in a group including adults with CP, and changes in each individual's BMD over a 5- to 6-year period. METHOD: The study group included 40 residents of a long-term care facility aged 6 to 26 years at the time of their initial evaluation. Twenty-one patients (52.5%) were male, 35 (88%) were white, and 38 (95%) were in Gross Motor Function Classification System level V. BMD was assessed by dual-energy X-ray absorptiometry on the right and left distal femurs for three distinct regions of interest. RESULTS: Five residents had a fracture that occurred during the study period; this represented a fracture rate of 2.1% per year in the study group. Longitudinally, annualized change in the median BMD was 0.7% to 1.0% per year in the different regions of the distal femur, but ranged widely among the study group, with both increases and decreases in BMD. Increase in BMD over time was negatively correlated with age and positively correlated with change in weight. INTERPRETATION: Changes in BMD over time in profoundly involved persons with CP can range widely, which is important to recognize when evaluating potential interventions to improve BMD. Age and changes in body weight appear the most relevant factors.


Assuntos
Densidade Óssea/fisiologia , Paralisia Cerebral/fisiopatologia , Assistência de Longa Duração/estatística & dados numéricos , Absorciometria de Fóton , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Fatores de Risco , Adulto Jovem
12.
J Clin Pharmacol ; 55(7): 731-8, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25781151

RESUMO

Considerable progress has been made in pediatric drug development. Despite these gains there remain certain therapeutic areas where a high percentage of drugs approved for use in adults do not gain approval for use in children. Lack of sufficient US Food and Drug Administration (FDA)-approved labeling correlates with diminished therapeutic efficacy and increased risk for adverse drug reactions. Despite the increasing prevalence and important clinical challenge with pediatric type 2 diabetes mellitus (T2DM), only 1 drug (metformin) of the first 4 T2DM drugs to complete testing in children gained FDA approval. This analysis reviews 4 pediatric drug development programs for orally administered antidiabetic agents that have undergone FDA review and discusses factors influencing failure to meet specified end points for approval. Recommendations to guide future study are also provided.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Hipoglicemiantes/uso terapêutico , Criança , Aprovação de Drogas , Rotulagem de Medicamentos , Humanos , Hipoglicemiantes/efeitos adversos , Estados Unidos , United States Food and Drug Administration
13.
Contraception ; 89(5): 357-60, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24582292

RESUMO

OBJECTIVE: To explore the relationship between medroxyprogesterone acetate (MPA) pharmacokinetic (PK) parameter estimates and weight gain. STUDY DESIGN: Prospective study of adolescents (N=40; age 12-21 years) initiating DMPA. PK parameters were calculated: maximum MPA concentration (Cmax, ng/mL), time to Cmax (Tmax, days) and elimination rate constant (ng/mL/day). Optimal PK cut points were determined for predicting body mass index (BMI) increase ≥10%. RESULTS: Cmax <2.88 ng/mL and elimination rate constant <0.021 ng/mL/day were associated (p<.05) with BMI increase ≥10%. Elimination rate constant was most predictive of weight gain. CONCLUSIONS: PK evaluation may help identify adolescents at risk of excessive DMPA-associated weight gain.


Assuntos
Anticoncepcionais Femininos/efeitos adversos , Acetato de Medroxiprogesterona/efeitos adversos , Ganho de Peso/efeitos dos fármacos , Adolescente , Criança , Anticoncepcionais Femininos/farmacocinética , Feminino , Voluntários Saudáveis , Humanos , Acetato de Medroxiprogesterona/farmacocinética , Projetos Piloto , Estudos Prospectivos , Adulto Jovem
14.
Biomark Med ; 8(2): 147-59, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24521011

RESUMO

AIM: Long-chain acylcarnitines have been postulated to be sensitive biomarkers of acetaminophen (APAP)-induced hepatotoxicity in mouse models. In the following study, the relationship of acylcarnitines with other known indicators of APAP toxicity was examined in children receiving low-dose (therapeutic) and high-dose ('overdose' or toxic ingestion) exposure to APAP. MATERIALS & METHODS: The study included three subject groups: group A (therapeutic dose, n = 187); group B (healthy controls, n = 23); and group C (overdose, n = 62). Demographic, clinical and laboratory data were collected for each subject. Serum samples were used for measurement of APAP protein adducts, a biomarker of the oxidative metabolism of APAP and for targeted metabolomics analysis of serum acylcarnitines using ultra performance liquid chromatography-triple-quadrupole mass spectrometry. RESULTS: Significant increases in oleoyl- and palmitoyl-carnitines were observed with APAP exposure (low dose and overdose) compared with controls. Significant increases in serum ALT, APAP protein adducts and acylcarnitines were observed in overdose children that received delayed treatment (time to treatment from overdose >24 h) with the antidote N-acetylcysteine. Time to peak APAP protein adducts in serum was shorter than that of the acylcarnitines and serum ALT. CONCLUSION: Perturbations in long-chain acylcarnitines in children with APAP toxicity suggest that mitochrondrial injury and associated impairment in the ß-oxidation of fatty acids are clinically relevant as biomarkers of APAP toxicity.


Assuntos
Acetaminofen/efeitos adversos , Carnitina/análogos & derivados , Doença Hepática Induzida por Substâncias e Drogas/sangue , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas , Acetilcisteína/uso terapêutico , Adolescente , Fatores Etários , Alanina Transaminase/sangue , Biomarcadores/sangue , Carnitina/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Criança , Pré-Escolar , Análise Discriminante , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Metabolômica , Fatores Sexuais
16.
J Pediatr Pharmacol Ther ; 18(2): 128-36, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23798907

RESUMO

A 17-year-old female developed hyperammonemic encephalopathy 2 weeks after valproic acid (VPA), 500 mg twice a day, was added to her regimen of topiramate (TPM), 200 mg twice a day. She presented to the emergency department (ED) with altered mental status, hypotension, bradycardia, and lethargy. Laboratory analysis showed mild non-anion gap hyperchloremic acidosis, serum VPA concentration of 86 mg/L, and urine drug screen result that was positive for marijuana. She was admitted to the pediatric intensive care unit for persistent symptoms, prolonged QTc, and medical history. Blood ammonia concentrations were obtained because of her persistent altered mental status, initially 94 µmol/L and a peak of 252 µmol/L. A serum carnitine profile was obtained at the time of hyperammonemia and was found to be normal (results were available postdischarge). VPA and TPM were discontinued on day 1 and day 2, respectively, as the patient's blood ammonia concentration remained elevated. On day 3, her mental status had returned to baseline, and blood ammonia concentrations trended downward; by day 4 her blood ammonia concentration was 23 µmol/L. VPA has been associated with numerous side effects including hyperammonemia and encephalopathy. Recently, drug interactions with TPM and VPA have been reported; however, serum carnitine concentrations have not been available. We discuss the possible mechanisms that VPA and TPM may affect serum ammonia and carnitine concentrations and the use of levocarnitine for patients or treating toxicity.

17.
J Neurosci Methods ; 217(1-2): 63-6, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23562621

RESUMO

Functional MRI in awake rats involves acclimatization to restraint to minimize motion. We designed a study to examine the effects of an acclimatization protocol (5 days of restraint, 60 min per day) on the emission of 22-kHz ultrasonic vocalizations and performance in a forced swim test (FST). Our results showed that USV calls are reduced significantly by days 3, 4 and 5 of acclimatization. Although the rats showed less climbing activity (and more immobility) in FST on day 5 compared to the 1st day of restraint acclimatization, the difference was not detected once the animals were given a 2-week hiatus. Overall, we showed that animals adapt to the restraint over a five-day period; however, restraint may introduce confounding behavioral outcomes that may hinder the interpretation of results derived from awake rat imaging. The present data warrants further testing of the effects of MRI restraint on behavior.


Assuntos
Aclimatação/fisiologia , Comportamento Animal/fisiologia , Encéfalo/fisiologia , Imagem por Ressonância Magnética/métodos , Atividade Motora/fisiologia , Vigília/fisiologia , Animais , Masculino , Ratos , Ratos Long-Evans , Restrição Física
18.
Pediatr Emerg Care ; 29(1): 13-6, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23283255

RESUMO

BACKGROUND: Research suggests that young children experience an increased incidence and severity of discomfort during propofol infusion. Evaluations of varied interventions to reduce or eliminate this discomfort with adult subjects suggest that premedication with intravenously administered lidocaine (0.5 mg/kg) offers the best overall effectiveness. OBJECTIVE: Because this regimen's efficacy in a pediatric population is undocumented, we conducted a randomized, double-blind, placebo-controlled study to determine the effectiveness of intravenous lidocaine pretreatment to alleviate pain in pediatric subjects before propofol infusion. METHODS: Subjects (aged 2-7 years) scheduled for painless diagnostic procedures received either a saline placebo or 1 of 2 lidocaine doses before administering propofol. To capture the patient's baseline behavioral state, a trained observer administered the validated face, legs, activity, cry, consolability pain assessment scale before propofol infusion. During deep sedation induction, the sedating physician, a trained research assistant, and the patient's parent documented maximum distress using a 100-mm visual analog scale (VAS). RESULTS: Ninety-one subjects participated. We found no difference in VAS pain scores between groups pretreated with lidocaine 0.25 mg/kg, lidocaine 0.5 mg/kg, and placebo. Statistical analysis also found no interrater differences between parents, physician, or observer VAS scores. CONCLUSIONS: Our data do not support using lidocaine pretreatment to alleviate pain/discomfort in pediatric patients during propofol infusion.


Assuntos
Anestésicos Locais/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Lidocaína/administração & dosagem , Propofol/administração & dosagem , Análise de Variância , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Lactente , Injeções Intravenosas , Masculino , Medição da Dor , Placebos , Estudos Prospectivos , Resultado do Tratamento
19.
Brain Res ; 1494: 70-83, 2013 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-23219972

RESUMO

Modulators of unconditioned fear are potential targets for developing treatments for anxiety disorders. We used blood oxygen level dependent (BOLD) MRI to investigate the pattern of brain activity during the presentation of a predator odor (cat fur) and a repulsive novel odor, butyric acid (BA), to awake rats. We further tested whether odor-evoked BOLD activation involved oxytocin (OT) and vasopressin V(1a) receptors. Animals were subdivided into groups either administered an intracerebroventricular injection of artificial cerebrospinal fluid (CSF), an OT receptor antagonist or a V(1a) antagonist (125 ng/10 µL each) 90 min before studies. BA odor evoked robust brain activation across olfactory, sensory, memory and limbic regions. The magnitude of BOLD activation across these regions was greater for BA than with cat fur. However, blockade of OT and V(1a) receptors differentially modulated odor evoked neural activity, particularly in the amygdala. OT and V(1a) antagonism preferentially modulated BOLD responding to BA in the cortical amygdala. While, OT and V(1a) antagonisms preferentially modulated BOLD responding to cat fur in the central amygdala. The data suggest that although OT receptors modulate BOLD activation in response to a novel and repulsive odor such as BA, vasopressin V(1a) receptors exert a modulatory influence on the neural response to a predator odor.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Reação de Fuga/fisiologia , Potenciais Evocados/fisiologia , Medo/fisiologia , Percepção Olfatória/fisiologia , Ocitocina/fisiologia , Animais , Aprendizagem da Esquiva/fisiologia , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Butiratos/farmacologia , Gatos , Reação de Fuga/efeitos dos fármacos , Potenciais Evocados/efeitos dos fármacos , Medo/efeitos dos fármacos , Neuroimagem Funcional , Imagem por Ressonância Magnética , Oxigênio/metabolismo , Ratos
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