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1.
Br J Clin Pharmacol ; 2020 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-32497307

RESUMO

AIMS: The aim of this study was to evaluate the population pharmacokinetics (PopPK) of olanzapine in children and devise a model-informed paediatric dosing scheme. METHODS: The PopPK of olanzapine was characterized using opportunistically collected plasma samples from children receiving olanzapine per standard of care for any indication. A nonlinear mixed effect modelling approach was employed for model development using the software NONMEM (v7.4). Simulations from the developed PopPK model were used to devise a paediatric dosing scheme that targeted comparable plasma exposures to adolescents and adults. RESULTS: Forty-five participants contributed 83 plasma samples towards the analysis. The median (range) postnatal age and body weight of participants were 3.8 years (0.2-19.2) and 14.1 kg (4.2-111.7), respectively. The analysis was restricted to pharmacokinetic (PK) samples collected following enteral administration (oral and feeding tube). A one-compartment model with linear elimination provided an appropriate fit to the data. The final model included the covariates body weight and postmenstrual age (PMA) on apparent olanzapine clearance (CL/F). Typical CL/F and apparent volume of distribution (scaled to 70 kg) were 16.8 L/h (21% RSE) and 663 L (13% RSE), respectively. Developed dosing schemes used weight-normalized doses for children ≤6 months postnatal age or <15 kg and fixed doses for children ≥15 kg. CONCLUSION: We developed a paediatric PopPK model for enterally-administered olanzapine. To our knowledge, this analysis is the first study to characterize the PK of olanzapine in participants ranging from infants to adolescents. Body weight and PMA were identified as influential covariates for characterizing developmental changes in olanzapine apparent clearance.

3.
Leuk Lymphoma ; : 1-12, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32264729

RESUMO

Pharmacokinetic (PK) conflicts can arise between supportive care medications (SCM) and chemotherapy in children with hematologic malignancy (HM). In this retrospective study, medical records for children (28 days-18 years) diagnosed with HM and receiving an SCM antimicrobial were collected from a hospital network between 1 May 2000 and 31 December 2014. PK drug-gene associations were obtained from a curated pharmacogenomics database. Among 730 patients (median age of 7.5 (IQR 3.7-13.9) years), primarily diagnosed with lymphoid leukemia (52%), lymphoma (28%), or acute myeloid leukemia (16%), chemotherapy was administered in 2846 hospitalizations. SCM accounted for 90.5% (n = 448) of distinct drugs with 93% (n = 679) of children, receiving ≥5 different SCM/hospitalization. Same-day SCM/chemotherapeutic PK gene overlap occurred in 48.3% of hospitalizations and was associated with age (p = 0.026), number of SCM, HM subtype, surgery, and hematopoietic stem cell transplant (p < 0.0001). A high and variable SCM burden among children with HM receiving chemotherapy poses a risk for unanticipated PK conflicts.

4.
Paediatr Drugs ; 22(3): 279-293, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32140997

RESUMO

Supplemental arginine has shown promise as a safe therapeutic option to improve endogenous nitric oxide (NO) regulation in cardiovascular diseases associated with endothelial dysfunction. In clinical studies in adults, L-arginine, an endogenous amino acid, was reported to improve cardiovascular function in hypertension, pulmonary hypertension, preeclampsia, angina, and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome. L-citrulline, a natural precursor of L-arginine, is more bioavailable than L-arginine because it avoids hepatic first-pass metabolism and has a longer circulation time. Although not yet well-studied, arginine/citrulline has immense therapeutic potential in some life-threatening diseases in children. However, the optimal clinical development of arginine or citrulline in children requires more information about pharmacokinetics and exposure-response relationships at appropriate ages and under relevant disease states. This article summarizes the preclinical and clinical studies of arginine/citrulline in both adults and children, including currently available pharmacokinetic information. The pharmacology of arginine/citrulline is confounded by several patient-specific factors such as variations in baseline arginine/citrulline due to developmental ages and disease states. Currently available pharmacokinetic studies are insufficient to inform the optimal design of clinical studies, especially in children. Successful bench-to-bedside clinical translation of arginine supplementation awaits information from well-designed pharmacokinetic/pharmacodynamic studies, along with pharmacometric approaches.

5.
Front Pharmacol ; 10: 1191, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31680968

RESUMO

Neonatal sepsis causes significant mortality and morbidity worldwide. Diagnosis is usually confirmed via blood culture results. Blood culture sepsis confirmation can take days and suffer from contamination and false negatives. Empiric therapy with antibiotics is common. This study aims to retrospectively describe and compare treatments of blood culture-confirmed and unconfirmed, but suspected, sepsis within the University of Utah Hospital system. Electronic health records were obtained from 1,248 neonates from January 1, 2006, to December 31, 2017. Sepsis was categorized into early-onset (≤3 days of birth, EOS) and late-onset (>3 and ≤28 days of birth, LOS) and categorized as culture-confirmed sepsis if a pathogen was cultured from the blood and unconfirmed if all blood cultures were negative with no potentially contaminated blood cultures. Of 1,010 neonates in the EOS cohort, 23 (2.3%) were culture-confirmed, most with Escherichia coli (42%). Treatment for unconfirmed EOS lasted an average of 6.1 days with primarily gentamicin and ampicillin while confirmed patients were treated for an average of 12.3 days with increased administration of cefotaxime. Of 311 neonates in the LOS cohort, 62 (20%) were culture-confirmed, most culturing coagulase negative staphylococci (46%). Treatment courses for unconfirmed LOS lasted an average of 7.8 days while confirmed patients were treated for an average of 11.4 days, these patients were primarily treated with vancomycin and gentamicin. The use of cefotaxime for unconfirmed EOS and LOS increased throughout the study period. Cefotaxime administration was associated with an increase in neonatal mortality, even when potential confounding factors were added to the logistic regression model (adjusted odds ratio 2.8, 95%CI [1.21, 6.88], p = 0.02). These results may not be generalized to all hospitals and the use of cefotaxime may be a surrogate for other factors. Given the low rate of blood culture positive diagnosis and the high exposure rate of empiric antibiotics, this patient population might benefit from improved diagnostics with reevaluation of antibiotic use guidelines.

6.
Int Immunopharmacol ; 76: 105868, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31487613

RESUMO

The use of immunoglobulins is gradually increasing. Intravenous immunoglobulins (IVIG) are used as replacement therapy for primary and secondary immune deficiencies, and as an anti-inflammatory and immunomodulatory medication for the treatment of neurologic, dermatologic, and rheumatologic diseases. The objective of this study was to analyze trends in the IVIG use in pediatric patients hospitalized to 47 US-based children's hospitals from 2007 to 2014. IVIG was used for the treatment of >2300 primary diagnoses in 53,648 unique patients. The number of IVIG admissions increased by 30.2% during the study period, while the mean rate of IVIG admissions/100,000 admissions increased only 5.8%. Most patients receiving IVIG were children and adolescents. IVIG was frequently used off-label or for the treatment of FDA-approved indications in children under two years of age and BMT patients <20 years of age. Primary immune deficiencies represented only 1.2% of all IVIG admissions. Pediatric patients with mucocutaneous lymph node syndrome (Kawasaki disease, KD) and idiopathic thrombocytopenic purpura (ITP) were two primary consumers of the IVIG. Another top-ranked indications were acute infectious polyneuritis (Guillain-Barré syndrome, GBS) and prophylaxis of infections in patients receiving antineoplastic chemotherapy. IVIG usage is a dynamic process guided by emerging evidence and FDA approval for new indications. IVIG was mostly prescribed for treatment of diseases with pathologic immune responses to foreign of self-antigens. These indications usually, require higher amounts of IVIG per admission. More studies are needed to understand whether IVIG treatments of off-label indications are effective and cost-efficient.


Assuntos
Uso de Medicamentos/tendências , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Síndrome de Guillain-Barré/tratamento farmacológico , Hospitais Pediátricos , Humanos , Síndrome do Coração Esquerdo Hipoplásico/tratamento farmacológico , Lactente , Recém-Nascido , Controle de Infecções , Masculino , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Uso Off-Label/estatística & dados numéricos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Estudos Retrospectivos , Estados Unidos
7.
AAPS J ; 21(4): 68, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31140019

RESUMO

Body weight is the primary covariate in pharmacokinetics of many drugs and dramatically changes during the first weeks of life of neonates. The objective of this study is to determine if missing body weights in preterm and term neonates affect estimates of model parameters and which methods can be used to improve performance of a population pharmacokinetic model of paracetamol. Data for our analysis were obtained from previously published studies on the pharmacokinetics of intravenous paracetamol in neonates. We adopted a population model of body weight change in neonates to implement three previously introduced methods of handling missing covariates based on data imputation, likelihood function modification, and full random effects modeling. All models were implemented in NONMEM 7.4, and population parameters were estimated using the FOCE method. Our major finding was that missing body weights minimally affect population estimates of pharmacokinetic parameters but do affect the covariate relationship parameters, particularly the one describing dependence of clearance on body weight. None of the tested methods changed estimates of between-subject variability nor impacted the predictive performance of the model. Our analysis shows that a modeling approach towards handling missing covariates allows borrowing information gathered in various studies as long as they target the same population. This approach is particularly useful for handling time-dependent missing covariates.


Assuntos
Acetaminofen/farmacocinética , Analgésicos não Entorpecentes/farmacocinética , Peso Corporal , Modelos Biológicos , Acetaminofen/administração & dosagem , Acetaminofen/sangue , Analgésicos não Entorpecentes/administração & dosagem , Analgésicos não Entorpecentes/sangue , Cálculos da Dosagem de Medicamento , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Injeções Intravenosas , Funções Verossimilhança , Dinâmica não Linear , Fatores de Tempo
8.
Pediatr Blood Cancer ; 66(5): e27629, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30719841

RESUMO

INTRODUCTION: Patients with germline TP53 pathogenic variants (Li-Fraumeni syndrome [LFS]) are at extremely high lifetime risk of developing cancer. Recent data suggest that tumor surveillance for patients with LFS may improve survival through early cancer detection. The objective of this study was to assess the cost-effectiveness of a cancer surveillance strategy for patients with LFS compared with those whose tumors present clinically. METHODS: A Markov decision analytic model was developed from a third-party payer perspective to estimate cost-effectiveness of routine cancer surveillance over a patient's lifetime. The model consisted of four possible health states: no cancer, cancer, post-cancer survivorship, and death. Model outcomes were costs (2015 United States Dollars [USD]), effectiveness (life years [LY] gained), and incremental cost-effectiveness ratio (ICER; change in cost/LY gained). One-way sensitivity analyses and probabilistic sensitivity analyses examined parameter uncertainty. RESULTS: The model showed a mean cost of $46 496 and $117 102 and yielded 23 and 27 LY for the nonsurveillance and surveillance strategies, respectively. The ICER for early cancer surveillance versus no surveillance was $17 125 per additional LY gained. At the commonly accepted willingness to pay threshold of $100 000/life-year gained, surveillance had a 98% probability of being the most cost-effective strategy for early cancer detection in this high-risk population. CONCLUSIONS: Presymptomatic cancer surveillance is cost-effective for patients with germline pathogenic variants in TP53. Lack of insurance coverage or reimbursement in this population may have significant consequences and leads to undetected cancers presenting in later stages of disease with worse clinical outcomes.


Assuntos
Análise Custo-Benefício , Detecção Precoce de Câncer/economia , Síndrome de Li-Fraumeni/diagnóstico , Síndrome de Li-Fraumeni/economia , Cadeias de Markov , Anos de Vida Ajustados por Qualidade de Vida , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Síndrome de Li-Fraumeni/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estados Unidos/epidemiologia , Adulto Jovem
9.
J Clin Pharmacol ; 59(2): 198-205, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30371946

RESUMO

The prevalence of pulmonary methicillin-resistant Staphylococcus aureus infections in patients with cystic fibrosis (CF) has increased over the last 2 decades. Two concentrations-a postdistributive and a trough-are currently used to estimate the area under the curve (AUC) of vancomycin, an antibiotic routinely used to treat these infections, to achieve the target AUC/minimum inhibitory concentration of ≥400 mg·h/L in ensuring optimal dosing of this drug. This study evaluated precision and bias in estimating vancomycin AUCs obtained either from a population pharmacokinetic (PK) model by using a single trough concentration or from standard PK equation-based 2-point monitoring approach. AUCs were either obtained from a single trough concentration-fitted model or derived from a model fitted by 2 concentration points. Children ≥2 years of age with CF received intravenous vancomycin at 2 centers from June 2012 to December 2014. A population PK model was developed in Pmetrics to quantify the between-subject variability in vancomycin PK parameters, define the sources of PK variability, and leverage information from the population to improve individual AUC estimates. Twenty-three children with CF received 27 courses of vancomycin. The median age was 12.3 (interquartile range [IQR] 8.5-16.6) years. From the individual vancomycin PK parameter estimates from the population PK model, median AUC was 622 (IQR 529-680) mg·h/L. Values were not significantly different from the AUC calculated using the standard PK equation-based approach (median 616 [IQR 540-663] mg·h/L) (P = .89). A standard PK equation-based approach using 2 concentrations and a population PK model-based approach using a single trough concentration yielded unbiased and precise AUC estimates. Findings suggest that options exist to implement AUC-based pediatric vancomycin dosing in patients with CF. The findings of this study reveal that several excellent options exist for centers to implement AUC-based pediatric vancomycin dosing for patients with CF.

10.
Ther Drug Monit ; 41(1): 44-52, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30299427

RESUMO

BACKGROUND: Amikacin is widely used to treat severe Gram-negative bacterial infections. Its peak concentration in plasma is associated with treatment efficacy. Amikacin pharmacokinetics (PK) is influenced by disease conditions, in addition to other patient characteristics. In this retrospective study, we evaluated the impact of clinical characteristics and disease condition on amikacin PK in children with burn injuries and those with cancer. METHODS: Amikacin PK data from 66 children with burn injuries and 112 children with cancer were analyzed. A population PK model was developed using the nonlinear mixed-effects modeling approach. Models were developed using NONMEM 7.3 (ICON Development Solutions, LLC, Ellicott City, MD). Data processing and visualization was performed using R packages. RESULTS: The amikacin PK data were best described by a 2-compartment model. The parameters were estimated with mean values (95% confidence intervals) as follows: central volume of distribution (V1), 5.70 L (4.64-6.76 L); central clearance, 2.12 L/h (1.79-2.46 L/h); peripheral volume of distribution (V2), 4.79 L (2.36-7.22 L); and distribution clearance (Q), 0.71 L/h (0.25-1.16 L/h). The final model identified the disease condition as a significant covariate and indicated 55% (28%-82%) higher central clearance and 17% (1%-34%) higher V1 in burn patients compared with cancer patients. Volume of distribution was significantly influenced by age and body weight. Clearance was significantly influenced by age, body weight, and creatinine clearance. Using the final PK model, we developed a workflow for selecting optimal dosing strategies for 3 representative pediatric patient profiles. CONCLUSIONS: Disease condition was significant in influencing amikacin PK in children. To reach the same target concentrations (64 mg/L peak concentration) with a daily-dose plan, burn patients need higher doses than cancer patients. Future investigations are needed to explore the impact of other diseases on amikacin disposition in children, and to prospectively validate the proposed dosing strategy.


Assuntos
Amicacina/farmacocinética , Antibacterianos/farmacocinética , Queimaduras/metabolismo , Neoplasias/metabolismo , Adolescente , Amicacina/uso terapêutico , Queimaduras/sangue , Criança , Pré-Escolar , Feminino , Infecções por Bactérias Gram-Negativas/sangue , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/metabolismo , Humanos , Lactente , Masculino , Neoplasias/sangue , Estudos Retrospectivos
11.
Clin Pharmacokinet ; 58(1): 1-13, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29777528

RESUMO

Physiologically based pharmacokinetic modeling and simulation is an important tool for predicting the pharmacokinetics, pharmacodynamics, and safety of drugs in pediatrics. Physiologically based pharmacokinetic modeling is applied in pediatric drug development for first-time-in-pediatric dose selection, simulation-based trial design, correlation with target organ toxicities, risk assessment by investigating possible drug-drug interactions, real-time assessment of pharmacokinetic-safety relationships, and assessment of non-systemic biodistribution targets. This review summarizes the details of a physiologically based pharmacokinetic modeling approach in pediatric drug research, emphasizing reports on pediatric physiologically based pharmacokinetic models of individual drugs. We also compare and contrast the strategies employed by various researchers in pediatric physiologically based pharmacokinetic modeling and provide a comprehensive overview of physiologically based pharmacokinetic modeling strategies and approaches in pediatrics. We discuss the impact of physiologically based pharmacokinetic models on regulatory reviews and product labels in the field of pediatric pharmacotherapy. Additionally, we examine in detail the current limitations and future directions of physiologically based pharmacokinetic modeling in pediatrics with regard to the ability to predict plasma concentrations and pharmacokinetic parameters. Despite the skepticism and concern in the pediatric community about the reliability of physiologically based pharmacokinetic models, there is substantial evidence that pediatric physiologically based pharmacokinetic models have been used successfully to predict differences in pharmacokinetics between adults and children for several drugs. It is obvious that the use of physiologically based pharmacokinetic modeling to support various stages of pediatric drug development is highly attractive and will rapidly increase, provided the robustness and reliability of these techniques are well established.


Assuntos
Desenvolvimento de Medicamentos , Modelos Biológicos , Farmacocinética , Criança , Desenvolvimento de Medicamentos/legislação & jurisprudência , Humanos , Legislação de Medicamentos
13.
Clin Pharmacokinet ; 57(10): 1325-1336, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29654492

RESUMO

INTRODUCTION: Acetaminophen (paracetamol, APAP) is widely used as an analgesic and antipyretic drug in children and neonates. A number of enzymes contribute to the metabolism of acetaminophen, and genetic factors might be important to explain variability in acetaminophen metabolism among individuals. METHODS: The current investigation utilized a previously published parent-metabolite population pharmacokinetic model describing acetaminophen glucuronidation, sulfation, and oxidation to examine the potential role of genetic variability on the relevant metabolic pathways. Neonates were administered 30-min intravenous infusions of acetaminophen 15 mg/kg every 12 h (< 28 weeks' gestational age [GA]) or every 8 h (≥ 28 weeks GA) for 48 h. A total of 18 sequence variations (SVs) in UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), and cytochrome P450 (CYP) genes from 33 neonates (aged 1-26 days) were examined in a stepwise manner for an effect on the metabolic formation clearance of acetaminophen by glucuronidation (UGT), sulfation (SULT), and oxidation (CYP). The stepwise covariate modeling procedure was performed using NONMEM® version 7.3. RESULTS: Incorporation of genotype as a covariate for one SV located in the UGT1A9 gene promoter region (rs3832043, - 118 > insT, T9 > T10) significantly improved model fit (likelihood ratio test, p < 0.001) and reduced between-subject variability in glucuronide formation clearance. Individuals with the UGT1A9 T10 polymorphism, indicating insertion of an additional thymidine nucleotide, had a 42% reduction in clearance to APAP-glucuronide as compared to their wild-type counterparts. CONCLUSION: This study shows a pharmacogenetic effect of an SV in the UGT1A9 promoter region on the metabolism of acetaminophen in neonates.


Assuntos
Acetaminofen/farmacocinética , Glucuronídeos/metabolismo , Glucuronosiltransferase/genética , Modelos Biológicos , Polimorfismo Genético , Feminino , Humanos , Recém-Nascido , Masculino , Regiões Promotoras Genéticas , Estudos Prospectivos
15.
BMJ Paediatr Open ; 1: e000147, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29177199

RESUMO

Objective: Immunosuppressant therapy plays a pivotal role in transplant success and longevity. Tacrolimus, a primary immunosuppressive agent, is well known to exhibit significant pharmacological interpatient and intrapatient variability. This variability necessitates the collection of serial trough concentrations to ensure that the drug remains within therapeutic range. The objective of this study was to build a population pharmacokinetic (PK) model and use it to determine the minimum number of trough samples needed to guide the prediction of an individual's future concentrations. Design setting and patients: Retrospective data from 48 children who received tacrolimus as inpatients at Primary Children's Hospital in Salt Lake City, Utah were included in the study. Data were collected within the first 6 weeks after heart transplant. Outcome measures: Data analysis used population PK modelling techniques in NONMEM. Predictive ability of the model was determined using median prediction error (MPE, a measure of bias) and median absolute prediction error (MAPE, a measure of accuracy). Of the 48 children in the study, 30 were used in the model building dataset, and 18 in the model validation dataset. Results: Concentrations ranged between 1.5 and 37.7 µg/L across all collected data, with only 40% of those concentrations falling within the targeted concentration range (12 to 16 µg/L). The final population PK model contained the impact of age (on volume), creatinine clearance (on elimination rate) and fluconazole use (on elimination rate) as covariates. Our analysis demonstrated that as few as three concentrations could be used to predict future concentrations, with negligible bias (MPE (95% CI)=0.10% (-2.9% to 3.7%)) and good accuracy (MAPE (95% CI)=24.1% (19.7% to 27.7%)). Conclusions: The use of PK in dose guidance has the potential to provide significant benefits to clinical care, including dose optimisation during the early stages of therapy, and the potential to limit the need for frequent drug monitoring.

17.
Br J Clin Pharmacol ; 83(12): 2709-2717, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28771779

RESUMO

AIMS: Nicotine addiction is an issue faced by millions of individuals worldwide. As a result, nicotine replacement therapies, such as transdermal nicotine patches, have become widely distributed and used. While the pharmacokinetics of transdermal nicotine have been extensively described using noncompartmental methods, there are few data available describing the between-subject variability in transdermal nicotine pharmacokinetics. The aim of this investigation was to use population pharmacokinetic techniques to describe this variability, particularly as it pertains to the absorption of nicotine from the transdermal patch. METHODS: A population pharmacokinetic parent-metabolite model was developed using plasma concentrations from 25 participants treated with transdermal nicotine. Covariates tested in this model included: body weight, body mass index, body surface area (calculated using the Mosteller equation) and sex. RESULTS: Nicotine pharmacokinetics were best described with a one-compartment model with absorption based on a Weibull distribution and first-order elimination and a single compartment for the major metabolite, cotinine. Body weight was a significant covariate on apparent volume of distribution of nicotine (exponential scaling factor 1.42). After the inclusion of body weight in the model, no other covariates were significant. CONCLUSIONS: This is the first population pharmacokinetic model to describe the absorption and disposition of transdermal nicotine and its metabolism to cotinine and the pharmacokinetic variability between individuals who were administered the patch.


Assuntos
Modelos Biológicos , Nicotina/administração & dosagem , Nicotina/farmacocinética , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/farmacocinética , Dispositivos para o Abandono do Uso de Tabaco , Administração Cutânea , Adulto , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Nicotina/sangue , Agonistas Nicotínicos/sangue , Estudos Retrospectivos , Absorção Cutânea , Adesivo Transdérmico , Adulto Jovem
18.
Expert Opin Drug Metab Toxicol ; 13(9): 925-934, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28772091

RESUMO

INTRODUCTION: When in flight, pilots of high performance aircraft experience conditions unique to their profession. Training flights, performed as often as several times a week, can expose these pilots to altitudes in excess of 15 km (~50,000 ft, with a cabin pressurized to an altitude of ~20,000 ft), and the maneuvers performed in flight can exacerbate the G-forces felt by the pilot. While the pilots specifically train to withstand these extreme conditions, the physiologic stress could very likely lead to differences in the disposition of chemicals in the body, and consequently, dangerously high exposures. Unfortunately, very little is known about how the conditions experienced by fighter pilots affects chemical disposition. Areas covered: The purpose of this review is to present information about the effects of high altitude, G-forces, and other conditions experienced by fighter pilots on chemical disposition. Using this information, the expected changes in chemical exposure will be discussed, using isopropyl alcohol as an example. Expert opinion: There is a severe lack of information concerning the effects of the fighter pilot environment on the pharmacokinetics and pharmacodynamics of chemicals. Given the possibility of exposure prior to or during flight, it is important that these potential effects be investigated further.


Assuntos
Altitude , Doenças Profissionais/fisiopatologia , Pilotos , 2-Propanol/envenenamento , Aeronaves , Animais , Gravitação , Humanos , Exposição Ocupacional/efeitos adversos , Estresse Fisiológico/fisiologia
19.
Expert Rev Clin Pharmacol ; 10(11): 1203-1214, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28836870

RESUMO

INTRODUCTION: In the modern antimicrobial era, the rapid spread of resistance to antibiotics and introduction of new and mutating viruses is a global concern. Combating antimicrobial resistant microbes (AMR) requires coordinated international efforts that incorporate new conventional antibiotic development as well as development of alternative drugs with antimicrobial activity, management of existing antimicrobials, and rapid detection of AMR pathogens. Areas covered: This manuscript discusses some conventional strategies to control microbial resistance. The main purpose of the manuscript is to present information on specific herbal medicines that may serve as good treatment alternatives to conventional antimicrobials for infections sensitive to conventional as well as resistant strains of microorganisms. Expert commentary: Identification of potential new antimicrobials is challenging; however, one source for potential structurally diverse and complex antimicrobials are natural products. Natural products may have advantages over other post-germ theory antimicrobials. Many antimicrobial herbal medicines possess simultaneous antibacterial, antifungal, antiprotozoal and/or antiviral properties. Herbal products have the potential to boost host resistance to infections, particularly in immunocompromised patients. Antimicrobial broad-spectrum activity in conjunction with immunostimulatory properties may help to prevent microbial resistance to herbal medicine. As part of the efforts to broaden use of herbal medicines to treat microbial infections, pre-clinical and clinical testing guidelines of these compounds as a whole should be implemented to ensure consistency in formulation, efficacy and safety.


Assuntos
Anti-Infecciosos/administração & dosagem , Fitoterapia/métodos , Preparações de Plantas/administração & dosagem , Animais , Anti-Infecciosos/farmacologia , Desenho de Fármacos , Resistência Microbiana a Medicamentos , Humanos , Hospedeiro Imunocomprometido , Infecções/tratamento farmacológico , Infecções/microbiologia , Preparações de Plantas/farmacologia
20.
Eur J Clin Pharmacol ; 73(9): 1055-1069, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28600701

RESUMO

INTRODUCTION: Concerns with prescription antidepressant use in pregnant women have instigated the examination of potential associations between fetal exposure to antidepressant medication and outcomes including preterm delivery, congenital malformations, perinatal and post-natal adverse events, persistent pulmonary hypertension, and mortality. The retrospective cohort model is an often utilized study design. The objective of this review is to evaluate the literature on antidepressant use in pregnancy conducted as retrospective cohorts in national/regional medical, or claims databases that assess neonatal and infant outcomes for agreement between studies, ultimately providing a methodological and outcomes summary for future scientific endeavors. METHODS: PubMed was searched for literature relating to antidepressant use and infant outcomes from the earliest available date through July 15, 2016. Studies with a retrospective cohort design and conducted in national/regional medical or claims databases were included. Searched outcomes included preterm delivery, congenital malformations, low birth weight, small for gestational age, persistent pulmonary hypertension of the newborn, and other select adverse events comprising low Apgar score (5 min), convulsions/seizures, respiratory distress/problems, fetal mortality, and infant mortality. RESULTS: Of the 784 studies identified, 36 retrospective cohort studies met eligibility criteria. An increase in preterm delivery and respiratory distress/problems and no increase in congenital malformation or fetal and infant death were associated with prenatal use of prescription antidepressants by majority consensus (at least 2/3 [67%] of studies). CONCLUSIONS: While consensus indicates that perinatal prescription antidepressant use has consequences for the fetus and infant, there are notable inconsistencies in the literature. More investigations that address prenatal exposure to depression and other important covariates are needed.


Assuntos
Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Anormalidades Congênitas/epidemiologia , Bases de Dados Factuais , Feminino , Humanos , Hipertensão Pulmonar/epidemiologia , Recém-Nascido de Baixo Peso , Recém-Nascido , Trabalho de Parto Prematuro/epidemiologia , Gravidez , Transtornos Respiratórios/epidemiologia , Convulsões/epidemiologia
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