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1.
Medicine (Baltimore) ; 98(41): e17523, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593125

RESUMO

Therapeutic drug monitoring has been employed in anti-tuberculosis (TB) drugs to assess optimal dose for maximum therapeutic effects and minimal toxicity. But the determinants of serum concentration need further evidences.In a retrospective case-control study, clinical and laboratory data were collected from 717 in-patients with TB at Xi'an Chest Hospital, China. Two hours serum concentrations of isoniazid, rifampicin, pyrazinamide as well as ethambutol were obtained and analyzed by liquid chromatography-tandem mass spectrometry.The month 2 culture conversion group had lower concentration of isoniazid, pyrazinamide, and ethambutol than month 1 group. Statistical analysis showed that serum concentrations of isoniazid, rifampicin, pyrazinamide, and ethambutol revealed a positive relationship with dose (mg/kg) (P < .001, P < .001, P < .001, and P = .003, respectively). Furthermore, isoniazid concentration was related to smoking (P = .009) and prior TB (P = .011), while rifampicin and pyrazinamide concentrations were correlated to sex (P = .004 and 0.025, respectively). Ethambutol concentration was associated with creatinine clearance (Ccr, P = .002).It is necessary to optimize drug doses using therapeutic drug monitoring while considering the following determinants: weight, smoking status, prior TB, sex, and Ccr. Furthermore, low 2 hours serum concentrations can be associated with longer culture conversion.


Assuntos
Etambutol/sangue , Isoniazida/sangue , Pirazinamida/sangue , Rifampina/sangue , Tuberculose/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antituberculosos/sangue , Antituberculosos/metabolismo , Antituberculosos/uso terapêutico , Estudos de Casos e Controles , China/epidemiologia , Cromatografia Líquida/instrumentação , Creatinina/metabolismo , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Etambutol/metabolismo , Etambutol/uso terapêutico , Feminino , Humanos , Isoniazida/metabolismo , Isoniazida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pirazinamida/metabolismo , Pirazinamida/uso terapêutico , Estudos Retrospectivos , Rifampina/metabolismo , Rifampina/uso terapêutico , Fatores Sexuais , Fumar/efeitos adversos , Tuberculose/sangue , Adulto Jovem
2.
Expert Opin Drug Saf ; 18(11): 1009-1015, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31478396

RESUMO

Introduction: Therapeutic drug monitoring in oncology is used to prevent major toxicities of selected anticancer agents due to overexposure by individualizing the dose based on a pharmacokinetic target. Areas covered: Numerous studies relating a relation between pharmacokinetic variability and toxicity have been reported since the eighties but very few have been implemented in clinical practice due to a lack of validation and harmonization, logistical constraints and reluctance from oncologists. Following recent recommendations, this paper highlights the current-validated applications of pharmacokinetic monitoring in oncology focusing on the safety of anticancer therapies. Expert opinion: Paradoxically given the oldness of the agents, guidelines of dose adjustment have been recently available for intravenous busulfan, 5-fluorouracil, and high-dose methotrexate. Interestingly, besides the enhancement of tolerability, it applies to potential curative clinical situations. In an era of personalized oncology that integrates complex molecular factors in the treatment of cancer, education is needed for oncologists to show the benefits of this valuable (even old) resource for the safety of patients. Therapeutic drug monitoring for busulfan, 5-fluorouracil and methotrexate will still hold in the future unless more active agents are available in the concerned indications.


Assuntos
Antineoplásicos/administração & dosagem , Monitoramento de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Bussulfano/farmacocinética , Relação Dose-Resposta a Droga , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/farmacocinética , Humanos , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Metotrexato/farmacocinética , Guias de Prática Clínica como Assunto , Medicina de Precisão/métodos
3.
Expert Opin Drug Metab Toxicol ; 15(10): 831-847, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31526279

RESUMO

Introduction: Nowadays, the first-line medications in depression include SSRIs, SNRIs, NDRIs, NaSSAs, SMSs, or a melatonin (M1/M2) receptor agonist and a 5-HT2C receptor antagonist. These drugs have quite similar antidepressant efficacy and safety profiles, but they differ in chemical structure, receptor affinity, and pharmacokinetics. Areas covered: Pharmacokinetic properties of first-line antidepressant drugs and factors influencing their pharmacokinetic processes are presented. Alterations in pharmacokinetics of newer antidepressants in special populations are summarized. In addition, the significance of therapeutic drug monitoring (TDM) and pharmacogenetic testing in dose optimization for the treatment of depressive disorders using newer antidepressants is discussed. Expert opinion: Due to the fact that 30-40% of depressive patients do not respond to the therapy and that the incidence of depression is constantly growing, the search for new more effective and safer antidepressant therapies is becoming an urgent need. More well-designed clinical studies under naturalistic conditions are needed to establish/refine therapeutic ranges for older and current state-of-the-art antidepressant drugs. The pharmacogenetic testing with concomitant application of TDM seems to be the best way for implementing personalized dosing of current state-of-the-art antidepressants metabolized by polymorphic CYPs, especially when co-administered with strong inhibitors or other substrates of CYP2D6 or CYP2C19.


Assuntos
Antidepressivos/administração & dosagem , Depressão/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Animais , Antidepressivos/farmacocinética , Antidepressivos/farmacologia , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Humanos , Farmacogenética
4.
Expert Opin Drug Metab Toxicol ; 15(11): 881-895, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31550939

RESUMO

Introduction: Therapeutic drug monitoring (TDM) has been shown to optimize the management of invasive fungal infections (IFIs), particularly for select antifungal agents with a well-defined exposure-response relationship and an unpredictable pharmacokinetic profile or a narrow therapeutic index. Select triazoles (itraconazole, voriconazole, and posaconazole) and flucytosine fulfill these criteria, while the echinocandins, fluconazole, isavuconazole, and amphotericin B generally do not do so. Given the morbidity and mortality associated with IFIs and the challenges surrounding the use of currently available antifungal agents, TDM plays an important role in therapy.Areas covered: This review seeks to describe the rationale for TDM of antifungal agents, summarize their pharmacokinetic and pharmacodynamic properties, identify treatment goals for efficacy and safety, and provide recommendations for optimal dosing and therapeutic monitoring strategies.Expert opinion: Several new antifungal agents are currently in development, including compounds from existing antifungal classes with enhanced pharmacokinetic or safety profiles as well as agents with novel targets for the treatment of IFIs. Given the predictable pharmacokinetics of these newly developed agents, use of routine TDM is not anticipated. However, expanded knowledge of exposure-response relationships of these compounds may yield a role for TDM to improve outcomes for adult and pediatric patients.


Assuntos
Antifúngicos/administração & dosagem , Monitoramento de Medicamentos/métodos , Infecções Fúngicas Invasivas/tratamento farmacológico , Adulto , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Criança , Desenvolvimento de Medicamentos , Humanos , Infecções Fúngicas Invasivas/microbiologia
5.
Expert Opin Drug Metab Toxicol ; 15(9): 735-749, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31402708

RESUMO

Introduction: Vancomycin is commonly administered to neonates, while observational data on therapeutic drug monitoring (TDM, trough levels) suggest that vancomycin exposure and dosage remain substandard. Area covered: Data on vancomycin pharmacokinetics (PK) and its covariates are abundant. Consequently, modeling is an obvious tool to improve targeted exposure, with a shift from TDM trough levels to area under the curve (AUC24h) targets, as in adults. Continuous administration appeared as a practice to facilitate AUC24h target attainment, while Bayesian model-supported targeting emerged as a novel tool. However, the AUC24h/MIC (minimal inhibitory concentration) target itself should consider neonate-specific aspects (bloodstream infections, coagulase-negative staphylococci, protein binding, underexplored causes of variability, like assays, preparation and administration inaccuracies, or missing covariates). Expert opinion: To improve targeted exposure in neonates, initial vancomycin prescription should be based on 'a priori model-based individual dosing' using validated dosing regimens, followed by further tailoring by dosing optimization applying Bayesian estimation-assisted TDM. Future research should focus on the feasibility to integrate these tools (individualized dosing, Bayesian models) in clinical practice, and to perform PK/PD studies in the relevant animal models and human neonatal setting (coagulase-negative staphylococci, bloodstream infections).


Assuntos
Antibacterianos/administração & dosagem , Modelos Biológicos , Vancomicina/administração & dosagem , Animais , Antibacterianos/farmacocinética , Área Sob a Curva , Teorema de Bayes , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Humanos , Recém-Nascido , Testes de Sensibilidade Microbiana , Vancomicina/farmacocinética
6.
Crit Rev Oncol Hematol ; 141: 112-124, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31276964

RESUMO

Protein kinase inhibitors (PKI) are a growing class of anticancer agents. They are prescribed with flat doses, and their oral administration is associated with interindividual variability in exposure. Patients can be over- or underexposed, due to numerous factors. We reviewed key pharmacokinetic concepts and mechanisms by which PKIs prescription could be altered. Challenging situations that could lead to increased toxicity or to therapeutic failure are described and recommendation for clinicians are proposed. Finally, the interest of therapeutic drug monitoring and indications for its use in daily practice is discussed.


Assuntos
Padrões de Prática Médica/normas , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Área Sob a Curva , Biomarcadores Farmacológicos/análise , Relação Dose-Resposta a Droga , Interações de Medicamentos , Monitoramento de Medicamentos/métodos , Humanos , Inativação Metabólica/fisiologia , Farmacologia Clínica , Padrões de Prática Médica/estatística & dados numéricos , Inibidores de Proteínas Quinases/farmacologia , Distribuição Tecidual
7.
Crit Rev Oncol Hematol ; 141: 153-162, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31302407

RESUMO

Failure of systemic cancer treatment can be, at least in part, due to the drug not being delivered to the tumour at sufficiently high concentration and/or sufficiently homogeneous distribution; this is termed as "pharmacokinetic drug resistance". To understand whether a drug is being adequately delivered to the tumour, "precision pharmacology" techniques are needed. Mass spectrometry imaging (MSI) is a relatively new and complex technique that allows imaging of drug distribution within tissues. In this review we address the applicability of MSI to the study of cancer drug distribution from the bench to the bedside. We address: (i) the role of MSI in pre-clinical studies to characterize anti-cancer drug distribution within the body and the tumour, (ii) the application of MSI in pre-clinical studies to define optimal drug dose or schedule, combinations or new drug delivery systems, and finally (iii) the emerging role of MSI in clinical research.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Resistencia a Medicamentos Antineoplásicos , Espectrometria de Massas/métodos , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Disponibilidade Biológica , Diagnóstico por Imagem/métodos , Relação Dose-Resposta a Droga , Esquema de Medicação , Sistemas de Liberação de Medicamentos , Monitoramento de Medicamentos/métodos , Humanos , Neoplasias/metabolismo , Medicina de Precisão/métodos , Distribuição Tecidual
8.
Expert Rev Clin Pharmacol ; 12(9): 885-891, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31305158

RESUMO

Introduction: Secondary loss of response to anti-tumor necrosis factor (TNF) therapy remains a challenge in the clinical management of inflammatory bowel disease (IBD) patients. A frequently observed reason for secondary loss of response to TNF blockers is inadequate drug exposure and sub-therapeutic serum drug concentrations. Areas covered: This review presents an overview of recent research on therapeutic drug monitoring (TDM)-based dosing with anti-TNF agents in IBD. The role of reactive and proactive TDM and different approaches on how to optimize anti-TNF treatment are discussed. Expert opinion: Due to variations within and between patients, the 'one size fits all' theory does not apply to all IBD patients receiving anti-TNF agents. Timing of TDM (i.e. reactive versus proactive) is a matter of debate. Both strategies might optimize anti-TNF treatment, although most trials did not show a clinical benefit compared to conventional dosing up to now. So-called dashboard systems might have an additive value in the optimization of anti-TNF treatment, since these tools enable clinicians to really personalize anti-TNF treatment.


Assuntos
Monitoramento de Medicamentos/métodos , Fármacos Gastrointestinais/administração & dosagem , Doenças Inflamatórias Intestinais/tratamento farmacológico , Relação Dose-Resposta a Droga , Fármacos Gastrointestinais/farmacologia , Humanos , Medicina de Precisão/métodos , Fatores de Tempo , Fator de Necrose Tumoral alfa/antagonistas & inibidores
9.
BMJ ; 365: l1800, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31335316

RESUMO

OBJECTIVE: To determine whether extending initial prednisolone treatment from eight to 16 weeks in children with idiopathic steroid sensitive nephrotic syndrome improves the pattern of disease relapse. DESIGN: Double blind, parallel group, phase III randomised placebo controlled trial, including a cost effectiveness analysis. SETTING: 125 UK National Health Service district general hospitals and tertiary paediatric nephrology centres. PARTICIPANTS: 237 children aged 1-14 years with a first episode of steroid sensitive nephrotic syndrome. INTERVENTIONS: Children were randomised to receive an extended 16 week course of prednisolone (total dose 3150 mg/m2) or a standard eight week course of prednisolone (total dose 2240 mg/m2). The drug was supplied as 5 mg tablets alongside matching placebo so that participants in both groups received the same number of tablets at any time point in the study. A minimisation algorithm ensured balanced treatment allocation by ethnicity (South Asian, white, or other) and age (5 years or less, 6 years or more). MAIN OUTCOME MEASURES: The primary outcome measure was time to first relapse over a minimum follow-up of 24 months. Secondary outcome measures were relapse rate, incidence of frequently relapsing nephrotic syndrome and steroid dependent nephrotic syndrome, use of alternative immunosuppressive treatment, rates of adverse events, behavioural change using the Achenbach child behaviour checklist, quality adjusted life years, and cost effectiveness from a healthcare perspective. Analysis was by intention to treat. RESULTS: No significant difference was found in time to first relapse (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17, log rank P=0.28) or in the incidence of frequently relapsing nephrotic syndrome (extended course 60/114 (53%) v standard course 55/109 (50%), P=0.75), steroid dependent nephrotic syndrome (48/114 (42%) v 48/109 (44%), P=0.77), or requirement for alternative immunosuppressive treatment (62/114 (54%) v 61/109 (56%), P=0.81). Total prednisolone dose after completion of the trial drug was 6674 mg for the extended course versus 5475 mg for the standard course (P=0.07). There were no statistically significant differences in serious adverse event rates (extended course 19/114 (17%) v standard course 27/109 (25%), P=0.13) or adverse event rates, with the exception of behaviour, which was poorer in the standard course group. Scores on the Achenbach child behaviour checklist did not, however, differ. Extended course treatment was associated with a mean increase in generic quality of life (0.0162 additional quality adjusted life years, 95% confidence interval -0.005 to 0.037) and cost savings (difference -£1673 ($2160; €1930), 95% confidence interval -£3455 to £109). CONCLUSIONS: Clinical outcomes did not improve when the initial course of prednisolone treatment was extended from eight to 16 weeks in UK children with steroid sensitive nephrotic syndrome. However, evidence was found of a short term health economic benefit through reduced resource use and increased quality of life. TRIAL REGISTRATION: ISRCTN16645249; EudraCT 2010-022489-29.


Assuntos
Assistência de Longa Duração , Síndrome Nefrótica , Prednisolona , Qualidade de Vida , Prevenção Secundária , Adolescente , Criança , Pré-Escolar , Análise Custo-Benefício , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Monitoramento de Medicamentos/métodos , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Glucocorticoides/economia , Humanos , Imunossupressores/uso terapêutico , Lactente , Análise de Intenção de Tratamento , Assistência de Longa Duração/economia , Assistência de Longa Duração/métodos , Masculino , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/economia , Síndrome Nefrótica/psicologia , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Prednisolona/economia , Prevenção Secundária/economia , Prevenção Secundária/métodos , Resultado do Tratamento
10.
Medicine (Baltimore) ; 98(29): e15404, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335666

RESUMO

This study retrospectively evaluated the effect of lutein supplement (LS) on patients with non-proliferative diabetic retinopathy (NPDR).A total of 72 patients with NPDR were included in this study. All patients received Zeaxanthin during the study period. In addition, 36 patients also received LS and were assigned to the treatment group, while the other 36 patients did not receive LS and were assigned to the control group. All patients were treated for a total of 4 months. The endpoints included visual acuity (VA), contrast sensitivity (CS), and glare sensitivity (GS). In addition, any adverse events were also assessed. All endpoints were measured before and after 4-month treatment.Before treatment, there were no significant differences in VA (P = .75), CS (P = .71), and GS (P = .73) between two groups. After 4-month treatment, there were still no significant differences in all endpoints of VA (P = .66), CS (P = .58), and GS (P = .61) between two groups. No adverse events were recorded in either group.The results of this retrospective study showed that LS may not benefit for patients with NPDR after 4-month treatment. More high quality randomized controlled trials should still be needed to warrant the results of this study.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/metabolismo , Luteína , Antioxidantes/administração & dosagem , Antioxidantes/efeitos adversos , Sensibilidades de Contraste , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/fisiopatologia , Suplementos Nutricionais , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Luteína/administração & dosagem , Luteína/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Estudos Retrospectivos , Resultado do Tratamento , Acuidade Visual/efeitos dos fármacos
11.
Expert Opin Drug Saf ; 18(9): 861-868, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31282227

RESUMO

Objectives: Although the safety profile of oral antineoplastic agents (OAAs) is better than that of classic chemotherapy, the rate of severe adverse events (AEs) is high. The objective was to assess the reasons for adjustments to treatment with OAAs during the first 100 days of treatment. Methods: The authors performed a prospective observational study of cancer outpatients who initiated OAAs between November 2015 and October 2017. Dose reductions and treatment interruptions were closely followed-up during the first 100 days after the beginning of treatment with an OAA. The authors described the different safety profile of different OAA classes. Results: The authors included 443 patients (31 different OAA assessed), of whom 53.0% required their OAA to be adjusted during the first 100 days of treatment. A total of 151 patients required dose reductions and/or interruptions of OAAs owing to AEs. The authors identified 203 AEs in these patients. Treatment with sorafenib, lower ECOG performance status, and first-line treatment were associated with a higher proportion of treatment adjustments due to AEs. Conclusion: These results in clinical practice could be a first approach to help healthcare professionals to design patient monitoring programs by identifying priority patients and drugs, and remarks the importance of pharmacovigilance in OAAs.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Farmacovigilância , Administração Oral , Idoso , Antineoplásicos/efeitos adversos , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sorafenibe/administração & dosagem
12.
Expert Opin Drug Metab Toxicol ; 15(7): 527-539, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31177858

RESUMO

Introduction: Medical treatment of pediatric inflammatory bowel diseases (IBD) has been greatly changed by the introduction of a number of biologic agents that are able to target various players of the immune response. In particular, monoclonal antibodies against the pro-inflammatory cytokine TNF-alpha (TNF) such as infliximab, adalimumab, and golimumab are now in the clinics both in induction and maintenance therapy, and several efforts are currently ongoing to optimize the use of these drugs in children. Areas covered: This review focuses on therapeutic drug monitoring (TDM) of anti-TNF levels and antidrug antibodies (ADAs), in IBD children. A revision of the analytical assays used for assessing anti-TNF plasma levels is also provided. Expert opinion: Although there is a consensus across studies that higher anti-TNF trough levels are associated with a better clinical outcome, and that early anti-TNF serum measurements could be predictive of long-term response, it is still not clear what the best predictive time of sampling is and what the ideal target drug plasma concentration to achieve. Indeed, there are a number of published studies, particularly in pediatric cohorts, limited by the population size analyzed and more prospective large studies are needed to examine the value of these predictive markers.


Assuntos
Monitoramento de Medicamentos/métodos , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Adalimumab/farmacocinética , Adalimumab/uso terapêutico , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Criança , Fármacos Gastrointestinais/farmacocinética , Humanos , Infliximab/farmacocinética , Infliximab/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores
13.
J Chromatogr A ; 1602: 30-40, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31164227

RESUMO

Herein we describe a methodology to synthesis polyurethane foam molecularly imprinted polymer (PUF-MIP) by using functional monomer for selective extraction of alprazolam. For this purpose, the various percentages of functional monomer are used to synthesis PUF-MIP of alprazolam. To evaluate the selectivity of synthesized PUF-MIP HPLC analysis is applied by introducing caffeine and methadone as an interference. To optimize the proposed technique, effective parameters in the SPE procedure including pH, flow, and salt present is investigated by experimental design. Finally, this method is evaluated in urine sample to monitor alprazolam dosage. In the optimized condition, the synthesized polymer indicates high selectivity value about 71% for alprazolam and 96.8% recovery for MIPUF compared with non-imprinted polyurethane foam (NIPUF). The linear dynamic range (LDR) of 0.03-60 mg L-1, the limit of detection of 8-10 µg L-1, the relative standard deviation (RSD, n = 3) of 2.88-3.65 % and quantification of 25-30 µg L-1 is obtained for HPLC analysis based on PUF-MIP extraction.


Assuntos
Alprazolam/isolamento & purificação , Monitoramento de Medicamentos/métodos , Poliuretanos/química , Alprazolam/química , Alprazolam/urina , Cafeína/química , Cromatografia Líquida de Alta Pressão , Concentração de Íons de Hidrogênio , Metadona/química , Impressão Molecular , Polímeros/química , Sais/química , Extração em Fase Sólida
14.
Gastroenterology ; 157(4): 985-996.e2, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31194979

RESUMO

BACKGROUND & AIMS: Proactive monitoring of drug trough concentrations and antibodies against drugs might help determine whether patients are likely to respond to treatment and increase efficacy. We investigated whether proactive drug monitoring is associated with higher rates of clinical remission in pediatric patients with Crohn's disease (CD). METHODS: We performed a nonblinded, randomized controlled trial of 78 children with CD (6-18 years old; 29% female; mean age, 14.3 ± 2.6 years) who had not received prior treatment with a biologic agent but had responded to adalimumab induction therapy, under scheduled monitoring of clinical and biologic measures (based on clinical factors and levels of C-reactive protein and fecal calprotectin), at pediatric gastroenterology units in Israel from July 2015 through December 2018. The patients were randomly assigned to groups that received proactive monitoring (trough concentrations measured at weeks 4 and 8 and then every 8 weeks until week 72, n = 38) or reactive monitoring (physicians were informed of trough concentrations after loss of response, n = 40). In both groups, doses and intervals of adalimumab were adjusted to achieve trough concentrations of 5 µg/mL. The primary endpoint was sustained corticosteroid-free clinical remission at all visits (week 8 through week 72). RESULTS: The primary endpoint was achieved by 31 children (82%) in the proactive group and 19 children (48%) in the reactive group (P = .002). Sixteen patients in the proactive monitoring group (42%) achieved a composite outcome of sustained corticosteroid-free remission, C-reactive protein ≤0.5 mg/dL, and level of fecal calprotectin ≤150 µg/g compared with 5 patients in the reactive monitoring group (12%) (P = .003). By week 72 of treatment, 33 patients in the proactive monitoring group had received adalimumab intensification (87%) compared with 24 patients in the reactive monitoring group (60%) (P = .001). CONCLUSIONS: In a randomized controlled trial of pediatric patients with CD, we found that proactive monitoring of adalimumab trough concentrations and adjustment of doses and intervals resulted in significantly higher rates corticosteroid-free clinical remission than reactive monitoring (measuring trough concentration after loss of response). Clinicaltrials.gov no.: NCT02256462.


Assuntos
Adalimumab/sangue , Adalimumab/uso terapêutico , Anti-Inflamatórios/sangue , Anti-Inflamatórios/uso terapêutico , Anticorpos/sangue , Doença de Crohn/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Fármacos Gastrointestinais/sangue , Fármacos Gastrointestinais/uso terapêutico , Adalimumab/imunologia , Adalimumab/farmacocinética , Adolescente , Corticosteroides/uso terapêutico , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/farmacocinética , Biomarcadores/sangue , Criança , Doença de Crohn/sangue , Doença de Crohn/diagnóstico , Doença de Crohn/imunologia , Feminino , Fármacos Gastrointestinais/imunologia , Fármacos Gastrointestinais/farmacocinética , Humanos , Israel , Masculino , Modelos Biológicos , Valor Preditivo dos Testes , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento
15.
Clin Biochem ; 70: 14-17, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31175859

RESUMO

Therapeutic drug monitoring (TDM) of voriconazole, itraconazole, and posaconazole is a useful tool for treatment of fungal infections. We validated a simple and reliable LC-MS/MS method using simple protein precipitation for simultaneous determination of voriconazole, itraconazole, and posaconazole. The linearity, accuracy, precision, carryover, and matrix effects were validated. Total sample preparation time was <30 min per batch, and analytical run time was 3.8 min per sample. We also presented clinical experience of TDM at 1183 serum concentrations over one year using this validated assay method. About 77%, 85%, and 96% of measured voriconazole, itraconazole, and posaconazole concentrations were within the therapeutic range, respectively. The number of respective measurements per patient was 1-63, 1-8, and 1-4 for voriconazole, itraconazole, and posaconazole. All three antifungal agents showed large intra-individual variability (2 to 181% CV) and drug-drug interaction with proton pump inhibitors or rifampin. In conclusion, we developed and validated a simple and fast method that was successfully applied in a routine clinical setting.


Assuntos
Antifúngicos/uso terapêutico , Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Espectrometria de Massas em Tandem/métodos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
Clin Biochem ; 70: 39-45, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31228434

RESUMO

BACKGROUND: Amikacin (AMI) and vancomycin (VAN) are antibiotics largely used in intensive care in the empiric treatment of severe infections by multi-resistant gram-negative and gram-positive bacteria. AMI and VAN are eliminated untransformed by glomerular filtration, showing depuration ratio highly correlated with creatinine (CRE) clearance. AMI, VAN and CRE are highly polar structures, presenting poor retention in reversed-phase liquid chromatography when using conventional stationary phases. OBJECTIVE: This study aimed to develop and validate a simple UPLC-MS/MS method for simultaneous determination of AMI, VAN, and CRE in human plasma for therapeutic drug monitoring. RESULTS: Samples were prepared by protein precipitation, followed by dilution. Heptafluorobutyric acid (HFBA) was added to the mobile phase at low concentration (0.01%), and separation was performed in an ultra-performance reversed-phase column (particle diameter of 1.8 µm). These conditions allowed retention times of 0.92, 0.93, 2.12, 2.17 and 2.27 min for CRE, CRE-D3, AMI, KAN and VAN, respectively. The assay was linear from 0.5 to 100 mg L-1 for AMI and VAN and 5 to 100 mg L-1. Precision, accuracy and stability assays were acceptable according to bioanalytical validation guidelines. Suitable results. Matrix effects were in the range of +10.5 to +11.6% for AMI, -4.3 to -4.5% for VAN, and - 1.7 to +0.7 for CRE. CONCLUSION: The first assay for the simultaneous determination of AMI, VAN and CRE in plasma by liquid chromatography-tandem mass spectrometry was reported. This assay allows the obtention of the necessary analytical data for the clinical application of population pharmacokinetic methods for therapeutic drug monitoring of AMI and VAN.


Assuntos
Amicacina/sangue , Cromatografia Líquida/métodos , Creatinina/sangue , Monitoramento de Medicamentos/métodos , Espectrometria de Massas em Tandem/métodos , Vancomicina/sangue , Antibacterianos/sangue , Humanos , Limite de Detecção , Reprodutibilidade dos Testes
17.
J Chromatogr A ; 1601: 95-103, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31208795

RESUMO

Fully automated dried blood spot (DBS) extraction systems, online coupled to standard liquid chromatography-tandem mass spectrometry (LC-MS/MS) configurations, decrease the hands-on time associated with conventional DBS analysis, resulting in a higher sample throughput, making the technique more compatible with a high-capacity bioanalytical workflow. The aim of this study was to develop and validate an LC-MS/MS method, using a DBS-MS 500 autosampler, for the determination and quantification of four anti-epileptic drugs (carbamazepine, valproic acid, phenobarbital and phenytoin) and one active metabolite (carbamazepine-10,11-epoxide) in DBS samples. Method development included thorough optimization of the fully automated extraction procedure (i.e. extraction solvent, extraction (loop) volume, internal standard application, internal standard drying time, etc.). The method was fully validated based on international guidelines. Accuracy (%bias), as well as precision (%RSD) (with a single exception) were below 13%. Neither carry-over nor unacceptable interferences were observed. All compounds were stable in DBS for at least 1 month when stored at room temperature, 4 °C and -20 °C and for at least 4 days when stored at 60 °C. Internal standard-corrected matrix effects were below 8%, with %RSDs below 9.1%. Reproducible relative recovery values (around 60% for all analytes) were obtained and the effect of the hematocrit on the relative recovery was overall limited. Successful application on capillary patient samples originating from developing countries demonstrated the applicability of the developed procedure in a remote setting.


Assuntos
Anticonvulsivantes/análise , Teste em Amostras de Sangue Seco , Monitoramento de Medicamentos/métodos , Anticonvulsivantes/sangue , Automação , Cromatografia Líquida , Teste em Amostras de Sangue Seco/normas , Monitoramento de Medicamentos/instrumentação , Humanos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
18.
Eur Arch Otorhinolaryngol ; 276(7): 1995-1999, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31161361

RESUMO

BACKGROUND: Bleeding during functional endoscopic sinus surgery always been a challenge for the quality of surgical field for surgeons. This study aimed to evaluate the effect of local nasal desmopressin premedication on blood loss and the quality of surgical field in functional endoscopic sinus surgery. METHODS: This study was conducted on 90 patients with chronic rhinosinusitis who were candidate for endoscopic sinus surgery. They were randomly assigned to two study groups. One group received a single puff of local desmopressin (10 µg) in each side of nasal cavity 30 min before the surgery and the other received normal saline instead. Blood loss and the quality surgical field were determined in 15, 30, 60 and 90 min during the surgery (scoring by BOEZAART grading system). All data were analyzed. RESULTS: Blood loss was significantly lesser in the desmopressin group (mean ± SD, 16.289 ± 5.605 ml) than in the control group (24.289 ± 5.2722 ml, P < 0.001).Surgeons were more satisfied with the surgical field in the desmopressin group than control group in all cutoff points (15, 30, 60, and 90 min during the surgery, P < 0.001). No side effects were observed using local desmopressin. CONCLUSIONS: Premedication with local desmopressin can reduce bleeding effectively and clear the surgical field during functional endoscopic sinus surgery.


Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Desamino Arginina Vasopressina/administração & dosagem , Endoscopia , Rinite/cirurgia , Sinusite/cirurgia , Adulto , Doença Crônica , Monitoramento de Medicamentos/métodos , Endoscopia/efeitos adversos , Endoscopia/métodos , Feminino , Hemostáticos/administração & dosagem , Humanos , Cuidados Intraoperatórios/métodos , Masculino , Pessoa de Meia-Idade , Pré-Medicação/métodos , Resultado do Tratamento
19.
BMC Infect Dis ; 19(1): 559, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31242863

RESUMO

BACKGROUND: Blood smear microscopy remains the gold-standard method to diagnose and quantify malaria parasite density. In addition, parasite genotyping of select loci is the most utilized method for distinguishing recrudescent and new infections and to determine the number of strains per sample. In research settings, blood may be obtained from capillary or venous compartments, and results from these matrices have been used interchangeably. Our aim was to compare quantitative results for parasite density and strain complexity from both compartments. METHODS: In a prospective observational study, children and adults presenting with uncomplicated Plasmodium falciparum malaria, simultaneous capillary and venous blood smears and dried blood spots were collected over 42-days following treatment with artemether-lumefantrine. Blood smears were read by two microscopists, any discrepancies resolved by a third reader. Parasite DNA fingerprinting was conducted using six microsatellites. Bland Altman analysis and paired t-test/McNemar's test were used to assess the difference in density readings and measurements. RESULTS: Two hundred twenty-three participants were included in the analysis (177 children (35 HIV-infected/142 HIV-uninfected), 21 HIV-uninfected pregnant women, and 25 HIV-uninfected non-pregnant adults). Parasite density measurements did not statistically differ between capillary and venous blood smears at the time of presentation, nor over the course of 42-day follow-up. Characterization of merozoite surface protein-2 (MSP-2) genetic polymorphism demonstrated a higher level of strain diversity at the time of presentation in venous samples, as compared with capillary specimens (p = 0.02). There was a high degree of variability in genotype-corrected outcomes when pairs of samples from each compartment were compared using MSP-2 alone, although the variability was reduced with the use of multiple markers. CONCLUSIONS: Parasite density measurements do not statistically differ between capillary and venous compartments in all studied demographic groups at the time of presentation with malaria, or over the course of follow-up. More strains were detected by MSP-2 genotyping in venous samples than in capillary samples at the time of malaria diagnosis. The use of multiple polymorphic markers reduces the impact of variability in strain detection on genotype-corrected outcomes. This study confirms that both capillary and venous compartments can be used for sampling with confidence in the clinical research setting. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov under registration no. NCT01717885 .


Assuntos
Capilares/parasitologia , Malária Falciparum/parasitologia , Carga Parasitária/métodos , Plasmodium falciparum/genética , Veias/parasitologia , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/parasitologia , Adolescente , Adulto , Idoso , Animais , Antimaláricos/farmacocinética , Antimaláricos/uso terapêutico , Combinação Arteméter e Lumefantrina/farmacocinética , Combinação Arteméter e Lumefantrina/uso terapêutico , Criança , Pré-Escolar , Monitoramento de Medicamentos/métodos , Feminino , Genótipo , Técnicas de Genotipagem/métodos , HIV , Infecções por HIV/complicações , Infecções por HIV/parasitologia , Humanos , Lactente , Malária Falciparum/sangue , Malária Falciparum/diagnóstico , Malária Falciparum/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Parasitemia/sangue , Parasitemia/complicações , Parasitemia/diagnóstico , Parasitemia/tratamento farmacológico , Plasmodium falciparum/isolamento & purificação , Uganda , Adulto Jovem
20.
Rev Fac Cien Med Univ Nac Cordoba ; 76(2): 101-106, 2019 06 19.
Artigo em Espanhol | MEDLINE | ID: mdl-31216164

RESUMO

Introduction: Vancomycin (VAN) is an antibiotic used to treat serious infections. Its use is related to adverse effects such as acute facial hyperemia, nephrotoxicity and ototoxicity. By having a very narrow therapeutic range, its monitoring is necessary to maximize efficiency and minimize toxic effects. It is estimated that its concentration in CSF is approximately 10% of the plasma level in patients who receive intravenous treatment and who have meninges inflammation. Plasma concentrations of VAN are not a reliable indicator of those present in CSF. The aim of this study was to validate an immunological method based on the kinetic interaction of microparticles in solution (KIMS) for the determination of VAN in CSF. Materials and Methods: KIMS was validated for the evaluation of VAN in CSF. For this, the parameters of linearity, precision, accuracy, limit of detection, limit of quantification, interference, selectivity and specificity were determined. Results: The method was linear in a range between 0 and 15 µg/mL, the CV% obtained oscillated between 0.7 and 2.5% on the linear range. The LOD and LOQ were 0.4 µg/mL and 1.4 µg/mL respectively. The equation of the line obtained based on the correlation of methods between KIMS and HPLC-UV was y = 0.9151x + 1.1695, R² = 0.9453. Conclusion: The KIMS method demonstrated to have an adequate sensitivity and specificity to determine VAN in CSF and being a useful tool for monitoring patients who present complicated infections at CNS level. Materials and Methods: KIMS was validated for the evaluation of VAN in CSF. For this, the parameters of linearity, precision, accuracy, limit of detection, limit of quantification, interference, selectivity and specificity were determined. Results: The method was linear in a range between 0 and 15 µg/mL, the CV% obtained oscillated between 0.7 and 2.5% on the linear range. The LOD and LOQ were 0.4 µg/mL and 1.4 µg/mL respectively. The equation of the line obtained based on the correlation of methods between KIMS and HPLC-UV was y = 0.9151x + 1.1695, R² = 0.9453. Conclusion: The KIMS method demonstrated to have an adequate sensitivity and specificity to determine VAN in CSF and being a useful tool for monitoring patients who present complicated infections at CNS level.


Assuntos
Monitoramento de Medicamentos/métodos , Imunoensaio/métodos , Vancomicina/líquido cefalorraquidiano , Cromatografia Líquida de Alta Pressão , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
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