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1.
Am Heart J ; 228: 81-90, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32866928

RESUMO

Recurrent pericarditis (RP) occurs in 15% to 30% of patients following a first episode, despite standard treatment with nonsteroidal anti-inflammatory drugs, colchicine, and corticosteroids; many patients become dependent on corticosteroids. Rilonacept (KPL-914), an interleukin-1α and ß inhibitor, is in development for the treatment of RP. RHAPSODY, a double-blind, placebo-controlled, randomized-withdrawal (RW) pivotal Phase 3 trial (NCT03737110), enrolls patients 12 years or older presenting with at least a third pericarditis episode, pericarditis pain score ≥4 (11-point numeric rating scale [NRS]), and C-reactive protein ≥1 mg/dL at screening. After a subcutaneous loading dose (adults, 320 mg; children, 4.4 mg/kg), all patients receive blinded weekly subcutaneous rilonacept (adults, 160 mg; children, 2.2 mg/kg) during the run-in period. Patients must taper and discontinue concomitant pericarditis medications during the blinded run-in period and achieve clinical response (C-reactive protein ≤0.5 mg/dL and weekly average NRS ≤2.0 during the 7 days prior to and including the day of randomization) by end of the run-in (while on rilonacept monotherapy) to be randomized to either continued rilonacept or placebo in the RW period. Primary efficacy end point was time to adjudicated pericarditis recurrence during the RW period; secondary efficacy end points were proportion of patients maintaining clinical response, percentage of days with NRS ≤2, and percentage of patients with no-to-minimal pericarditis symptoms at week 16 of the RW period. Safety evaluations include adverse event monitoring, physical examinations, and laboratory tests. The RHAPSODY trial will evaluate the efficacy and safety of rilonacept in the treatment of RP to improve outcomes and patient health-related quality of life.


Assuntos
Monitoramento de Medicamentos/métodos , Pericardite , Qualidade de Vida , Proteínas Recombinantes de Fusão , Prevenção Secundária/métodos , Adolescente , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Interleucina-1alfa/antagonistas & inibidores , Interleucina-1beta/antagonistas & inibidores , Masculino , Pericardite/diagnóstico , Pericardite/tratamento farmacológico , Pericardite/fisiopatologia , Pericardite/psicologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos
2.
Trials ; 21(1): 790, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32933552

RESUMO

OBJECTIVES: We investigate the effects of Licorice (Glycyrrhiza glabra L.) root extract, an anti-inflammatory natural medicine, compared to the usual therapeutic regimen on clinical symptoms and laboratory signs in patients with confirmed COVID-19 that are moderately ill. TRIAL DESIGN: This is a single-center, open-label, randomized, clinical trial with parallel-group design. This study is being conducted at Shahid Mohammadi Hospital, Bandar Abbas, Iran. PARTICIPANTS: Both male and female patients with ≥18 years of age (≥ 35 kg of weight), admitted at the Shahid Mohammadi Hospital, Hormozgan University of Medical Sciences, Bandar Abbas for treatment, screened for the following criteria. INCLUSION CRITERIA: 1. Confirmed diagnosis of SARS-CoV-2 infection (via polymerase chain reaction [PCR] and/or antibody test). 2. Presenting as moderate COVID-19 pneumonia (via chest computed tomography (CT) and/or X-ray) requiring hospitalization. 3. Hospitalized ≤48 hours. 4. Signing informed consent and willingness of study participant to accept randomization to any assigned treatment arm. EXCLUSION CRITERIA: 1. Underlying diseases, including chronic heart disease, chronic hypertension, severe renal failure, severe liver failure, and thyroid disorders. 2. Severe and critical COVID-19 pneumonia. 3. Use of warfarin, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), diuretics, corticosteroids, and antiarrhythmic drugs. 4. Treatment with Investigational and antiviral therapy in a clinical study within one month before randomization. 5. History of allergy to Licorice. 6. Pregnancy and breastfeeding. INTERVENTION AND COMPARATOR: Intervention group: The standard treatment regimen for COVID-19 along with a Licorice-based herbal preparation (D-Reglis ®, Irandarouk Pharmaceutical Company, Iran) at a dose of 760 mg three times a day for a period of seven days. CONTROL GROUP: The standard treatment for COVID-19 based on the Iranian Ministry of Health and Medical Education's protocol for a period of seven days. MAIN OUTCOMES: The recovery rate of clinical symptoms, including fever, dry cough, and tiredness, as well as paraclinical features, including thrombocytopenia, lymphocytopenia, and C-reactive protein, are evaluated as primary outcomes within seven days of randomization. Time to improvement of clinical and paraclinical features and length of stay in a hospital, along with the incidence of adverse reactions are also evaluated as the secondary outcomes within seven days of randomization. RANDOMIZATION: An electronic table of random numbers will be used to allocate the included participants into either control or intervention groups (in a 1:1 ratio) using the simple randomization method. BLINDING (MASKING): This is an open-label trial without blinding and placebo control. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): A total of 60 participants randomizes (30 patients allocated to the intervention group and 30 patients allocated to the control group). TRIAL STATUS: The protocol is Version 1.0, May 31, 2020. Recruitment began July 30, 2020, and is anticipated to be completed by October 30, 2020. TRIAL REGISTRATION: This clinical trial has been registered in the Iranian Registry of Clinical Trials (IRCT). The registration number is "IRCT20200506047323N2", https://www.irct.ir/trial/47990 . The registration date is 31 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Infecções por Coronavirus , Glycyrrhiza , Pandemias , Extratos Vegetais , Raízes de Plantas , Pneumonia Viral , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Monitoramento de Medicamentos/métodos , Feminino , Hospitalização , Humanos , Masculino , Extratos Vegetais/administração & dosagem , Extratos Vegetais/efeitos adversos , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/etiologia , Pneumonia Viral/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Resultado do Tratamento
3.
J Chromatogr A ; 1628: 461445, 2020 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-32822984

RESUMO

Anabolic androgenic steroids (AAS) have been the most commonly abused substances taken by not only professional sportsmen but also recreational bodybuilders. The detection of micro-dose testosterone (T) misuse is particularly challenging as it possesses pseudo-endogenous origin and is sometimes impossible to be identified in urine samples. Dried blood (DB) obtained by finger pricking has been proven to be an alternative matrix for better correlating to physiological responses. Moreover, the introduction of the volumetric absorptive microsampling (VAMS) technology allows overcoming some major limitations of spotting blood onto a filter paper card. In this work, a fast and sensitive GC-MS/MS method was developed and validated for the quantification of AAS in DB collected by means of VAMS. T and the eight top abused synthetic AAS, namely nandrolone, boldenone, mesterolone, drostanolone, metenolone, metandienone, oxandrolone, and dehydrochloromethyl T were selected as the target analytes. The method based on VAMS exhibited good precision, accuracy as well as stability, and superior extraction recoveries over the punched DB spots reported in the literature. The chromatographic separation was achieved within 6.4 min and the detection limit is as little as 50 fg (i.e. able to detect 0.10 ng mL-1 in 20 µL of DB). Confirmed by forty real blood samples, the Deming regression and Bland-Altman analysis revealed that the VAMS DB could be employed for quantifying blood T level in agreement with using the serum specimen. The feasibility of the method was then successfully proven by the analysis of samples collected from a three-arm T administration trial. Our results highlighted that DB total T was a sensitive indicator for identifying transdermal micro-dosing of T. In the groups of receiving T gel administration, T concentrations could rise up to ten times higher than the baseline at 9 h after the application. As a future step, this approach is being expanded to a large cohort screening of bodybuilders at gym and ultimately may allow universal applications on monitoring sports drug misuse.


Assuntos
Androgênios/sangue , Teste em Amostras de Sangue Seco/métodos , Monitoramento de Medicamentos/métodos , Cromatografia Gasosa-Espectrometria de Massas , Espectrometria de Massas em Tandem , Congêneres da Testosterona/sangue , Testosterona/análise , Humanos
4.
Yakugaku Zasshi ; 140(8): 1035-1040, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741861

RESUMO

For many of the novel antiepileptics, immunoassays, used for routine therapeutic drug monitoring (TDM), cannot be used. We could monitor eight novel antiepileptics using an LC/MS method since July 2017. The purpose of this study was to evaluate the significant changes associated with the transition from outsourcing to in-hospital monitoring of novel antiepileptics. The number of measurements of novel antiepileptics was significantly increased during the first (p<0.01) and second (p<0.001) years of in-hospital monitoring as compared to that one year prior to in-hospital monitoring which was outsourced. The proportion of measurements of novel antiepileptics to all antiepileptics was 19.7%, 31.1%, and 38.4% during outsourcing, and first, and second years of in-hospital monitoring, respectively. The measurement cost was significantly reduced during the first (p<0.001) and second (p<0.001) years of in-hospital monitoring as compared to that during outsourcing. In addition, the revenue from TDM of antiepileptic drugs was significantly increased during the first (p<0.05) and second (p<0.01) years of in-hospital monitoring as compared with that during outsourcing. In conclusion, the switch from outsourcing to in-hospital monitoring led to an increase in the number of orders, a reduction in the measurement-related expenses of novel antiepileptics, and an increase in the revenue from TDM of antiepileptic drugs, which could promote the proper use of novel antiepileptics through TDM.


Assuntos
Anticonvulsivantes , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/estatística & dados numéricos , Serviços Terceirizados/estatística & dados numéricos , Serviço de Farmácia Hospitalar/estatística & dados numéricos , Cromatografia Líquida , Monitoramento de Medicamentos/economia , Humanos , Renda/estatística & dados numéricos , Espectrometria de Massas , Fatores de Tempo
5.
Obstet Gynecol ; 136(4): 823-826, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32769659

RESUMO

Recent evidence supports the use of an early, short course of glucocorticoids in patients with COVID-19 who require mechanical ventilation or oxygen support. As the number of coronavirus disease 2019 (COVID-19) cases continues to increase, the number of pregnant women with the disease is very likely to increase as well. Because pregnant women are at increased risk for hospitalization, intensive care unit admission, and mechanical ventilation support, obstetricians will be facing the dilemma of initiating maternal corticosteroid therapy while weighing its potential adverse effects on the fetus (or neonate if the patient is postpartum and breastfeeding). Our objective is to summarize the current evidence supporting steroid therapy in the management of patients with acute respiratory distress syndrome and COVID-19 and to elaborate on key modifications for the pregnant patient.


Assuntos
Infecções por Coronavirus , Cuidados Críticos/métodos , Glucocorticoides , Conduta do Tratamento Medicamentoso/normas , Pandemias , Pneumonia Viral , Complicações Infecciosas na Gravidez , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/terapia , Monitoramento de Medicamentos/métodos , Feminino , Maturidade dos Órgãos Fetais/efeitos dos fármacos , Glucocorticoides/classificação , Glucocorticoides/farmacologia , Humanos , Recém-Nascido , Oxigenoterapia/métodos , Pneumonia Viral/epidemiologia , Pneumonia Viral/terapia , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/terapia , Complicações Infecciosas na Gravidez/virologia , Respiração Artificial/métodos , Medição de Risco
6.
PLoS One ; 15(8): e0236297, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32780750

RESUMO

Naproxen is a widely used non-steroidal anti-inflammatory drug for the control of postoperative inflammatory signs and symptoms in dentistry. Its association with esomeprazole has been widely studied and has yielded good results for the control of acute pain, even with the delayed absorption of naproxen owing to the presence of esomeprazole. To further understand the absorption, distribution, and metabolism of this drug alone and in combination with esomeprazole, we will analyze the pharmacokinetic parameters of naproxen and its major metabolite, 6-O-desmethylnaproxen, in saliva samples. A rapid, sensitive, and selective liquid chromatography-tandem mass spectrometric method for the simultaneous determination of naproxen and 6-O-desmethylnaproxen in saliva will be developed and validated. Sequential saliva samples from six patients will be analyzed before and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6 8, 11, 24, 48, 72, and 96 h after the ingestion of one naproxen tablet (500 mg) and esomeprazole-associated naproxen tablets (500 + 20 mg), at two different times. After liquid-liquid extraction with ethyl acetate and HCl, the samples will be analyzed using an 8040 Triple Quadrupole Mass Spectrometer (Shimadzu, Kyoto, Japan). Separation of naproxen and its major metabolic products will be performed using a Shim-Pack XR-ODS 75Lx2.0 column and C18 pre-column (Shimadzu, Kyoto, Japan) at 40°C using a mixture of methanol and 10 mM ammonium acetate (70:30, v/v) with an injection flow of 0.3 mL/min. The total analytical run time will be 5 min. The detection and quantification of naproxen and its metabolite will be validated, which elucidate the pharmacokinetics of this drug, thereby contributing to its proper prescription for the medical and dental interventions that cause acute pain.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Monitoramento de Medicamentos/métodos , Esomeprazol/farmacocinética , Naproxeno/análogos & derivados , Saliva/química , Administração Oral , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/isolamento & purificação , Cromatografia Líquida de Alta Pressão/métodos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Esomeprazol/administração & dosagem , Esomeprazol/isolamento & purificação , Feminino , Absorção Gastrointestinal , Humanos , Masculino , Metanol/química , Pessoa de Meia-Idade , Naproxeno/administração & dosagem , Naproxeno/isolamento & purificação , Naproxeno/farmacocinética , Dor Processual/tratamento farmacológico , Reprodutibilidade dos Testes , Comprimidos , Espectrometria de Massas em Tandem/métodos , Adulto Jovem
7.
J Gastrointestin Liver Dis ; 29(3): 470, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32830825
8.
BMC Infect Dis ; 20(1): 572, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32758158

RESUMO

BACKGROUND: Management of co-infections including cryptococcal meningitis, tuberculosis and other opportunistic infections in persons living with HIV can lead to complex polypharmacotherapy and increased susceptibility to drug-drug interactions (DDIs). Here we characterize the frequency and types of potential DDIs (pDDIs) in hospitalized HIV patients presenting with suspected cryptococcal or tuberculous meningitis. METHODS: In a retrospective review of three cryptococcal meningitis trials between 2010 and 2017 in Kampala, Uganda, medications received over hospitalization were documented and pDDI events were assessed. IBM Micromedex DRUGDEX® online drug reference system was used to identify and describe potential interactions as either contraindicated, major, moderate or minor. For antiretroviral DDIs, the Liverpool Drug Interactions Checker from the University of Liverpool was also used to further describe interactions observed. RESULTS: In 1074 patients with suspected meningitis, pDDIs were present in 959 (overall prevalence = 89.3%) during the analyzed 30 day window. In total, 278 unique interacting drug pairs were identified resulting in 4582 pDDI events. Of all patients included in this study there was a mean frequency of 4.27 pDDIs per patient. Of the 4582 pDDI events, 11.3% contraindicated, 66.4% major, 17.4% moderate and 5% minor pDDIs were observed. Among all pDDIs identified, the most prevalent drugs implicated were fluconazole (58.4%), co-trimoxazole (25.7%), efavirenz (15.6%) and rifampin (10.2%). Twenty-one percent of the contraindicated pDDIs and 27% of the major ones involved an antiretroviral drug. Increased likelihood of QT interval prolongation was the most frequent potential clinical outcome. Dissonance in drug interaction checkers was noted requiring clinicians to consult more than one database in making clinical decisions about drug combinations. CONCLUSIONS: The overall prevalence of pDDIs in this population is high. An understanding of drug combinations likely to result in undesired clinical outcomes, such as QT interval prolongation, is paramount. This is especially important in resource limited settings where availability of therapeutic drug monitoring and laboratory follow-up are inconsistent. Adequate quantification of the increased likelihood of adverse clinical outcomes from multiple drug-drug interactions of the same kind in a single patient is needed to aid clinical decisions in this setting.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Antirretrovirais/uso terapêutico , Antifúngicos/uso terapêutico , Coinfecção/tratamento farmacológico , Cryptococcus neoformans , HIV-1 , Hospitalização , Meningite Criptocócica/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/virologia , Adolescente , Adulto , Coinfecção/virologia , Interações Medicamentosas , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Meningite Criptocócica/diagnóstico , Meningite Criptocócica/microbiologia , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Uganda/epidemiologia , Adulto Jovem
9.
PLoS One ; 15(8): e0237383, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32776967

RESUMO

With obesity having doubled in the last decade, hypertension is on the rise. In one-third of hypertensive patients the metabolic syndrome is present. This might be one factor for the increasing number of prescriptions for angiotensin receptor blockers and calcium-channel blockers besides a more favorable risk-to-benefit ratio. The aim of the present study was to evaluate a therapeutic drug monitoring (TDM) method for assessment of adherence based on cut-offs in inpatients and to compare it to an established urine drug screening in outpatients. A method for quantification of calcium-channel blockers and angiotensin receptor blockers using high-performance liquid chromatography-tandem mass spectrometric analysis (LC-MS/MS) was developed and validated. The method was applied to serum samples of 32 patients under supervised medication to establish cut-off values for adherence assessment based on dose-related concentrations (DRC, calculated from pharmacokinetic data). Furthermore, corresponding urine and blood samples of 42 outpatients without supervised medication were analysed and the results compared with regard to adherence assessment. All serum concentrations measured for amlodipine (n = 40), lercanidipine (n = 14), candesartan (n = 10), telmisartan (n = 4) and valsartan (n = 10) in inpatients were above the patient specific lower DRC confirming adherence. Of 42 outpatients the identification of analytes in urine as well as the quantification in serum exhibited differing results. According to urinalysis, adherence was demonstrated in only 87.0% of prescriptions, compared to 91.3% for serum analyses. Differences were observed for amlodipine, lercanidipine and candesartan which can be explained by a higher specificity of the serum analysis approach due to pharmacokinetics. The present study confirms that assessing adherence based on serum drug concentrations with individually calculated lower DRCs is more accurate than using qualitative urine analysis. In particular, drugs with low bioavailability, low renal excretion or high metabolism rate such as lercanidipine and candesartan may lead to underestimation of adherence via urine analysis.


Assuntos
Anti-Hipertensivos/sangue , Anti-Hipertensivos/urina , Monitoramento de Medicamentos/métodos , Cooperação do Paciente/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/uso terapêutico , Feminino , Humanos , Pacientes Internados/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais/estatística & dados numéricos
10.
Proc Natl Acad Sci U S A ; 117(32): 19017-19025, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719130

RESUMO

To achieve the mission of personalized medicine, centering on delivering the right drug to the right patient at the right dose, therapeutic drug monitoring solutions are necessary. In that regard, wearable biosensing technologies, capable of tracking drug pharmacokinetics in noninvasively retrievable biofluids (e.g., sweat), play a critical role, because they can be deployed at a large scale to monitor the individuals' drug transcourse profiles (semi)continuously and longitudinally. To this end, voltammetry-based sensing modalities are suitable, as in principle they can detect and quantify electroactive drugs on the basis of the target's redox signature. However, the target's redox signature in complex biofluid matrices can be confounded by the immediate biofouling effects and distorted/buried by the interfering voltammetric responses of endogenous electroactive species. Here, we devise a wearable voltammetric sensor development strategy-centering on engineering the molecule-surface interactions-to simultaneously mitigate biofouling and create an "undistorted potential window" within which the target drug's voltammetric response is dominant and interference is eliminated. To inform its clinical utility, our strategy was adopted to track the temporal profile of circulating acetaminophen (a widely used analgesic and antipyretic) in saliva and sweat, using a surface-modified boron-doped diamond sensing interface (cross-validated with laboratory-based assays, R 2 ∼ 0.94). Through integration of the engineered sensing interface within a custom-developed smartwatch, and augmentation with a dedicated analytical framework (for redox peak extraction), we realized a wearable solution to seamlessly render drug readouts with minute-level temporal resolution. Leveraging this solution, we demonstrated the pharmacokinetic correlation and significance of sweat readings.


Assuntos
Acetaminofen/análise , Monitoramento de Medicamentos/métodos , Saliva/química , Suor/química , Acetaminofen/administração & dosagem , Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/métodos , Monitoramento de Medicamentos/instrumentação , Humanos , Medicina de Precisão , Dispositivos Eletrônicos Vestíveis
11.
Anticancer Res ; 40(8): 4655-4661, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727789

RESUMO

In recent years, therapeutic drug monitoring (TDM) of intravenous administration of 5-fluorouracil (5-FU) has resulted in reduced toxicity and improved efficacy. Prodrugs of 5-FU were developed to reduce toxicity, extend the duration of action, and increase tumour selectivity of 5-FU. These drugs are important in daily practice because of their ease of administration. Dose adjustment of 5-FU prodrugs by TDM is expected to reduce its toxicity and improve its efficacy. This review focuses on data from a recent study of personalized treatment using TDM of 5-FU and its prodrugs.


Assuntos
Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Monitoramento de Medicamentos/métodos , Humanos , Neoplasias/tratamento farmacológico
13.
Arthritis Res Ther ; 22(1): 125, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: covidwho-457521

RESUMO

BACKGROUND: Hydroxychloroquine (HCQ) is the standard of care in the treatment of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and other inflammatory rheumatic diseases and potentially for the treatment in COVID-19 patients. Determination of HCQ for therapeutic drug monitoring (TDM) can be performed in whole blood (WB), serum, and plasma. Direct comparisons of WB, serum, and plasma levels of HCQ in patients with SLE have not previously been reported. We describe a method for the determination of HCQ in human blood using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) and compare the suitability of the three sample matrices. METHODS: A method for the determination of HCQ in human blood using LC-HRMS was developed, validated, and applied for the determination of HCQ levels in WB, serum, and plasma from 26 SLE patients. The reproducibility of the method, in the three matrices, was evaluated using quality control samples and repeated preparations and measurements of patient samples. The performance of the developed method for HCQ measurement in serum was further evaluated by comparison with two previously reported extraction methods. RESULTS: The performance of the presented method demonstrated high accuracy and precision. A large range of HCQ concentrations was observed for the SLE patients in all three matrices (WB, serum, and plasma). The mean levels in WB were approximately two-fold the levels in serum and plasma (813 ng/mL compared to 436 ng/mL and 362 ng/mL, respectively). Spiked quality controls showed high reproducibility for all matrices (coefficient of variation, CV, approx. 5%), whereas in patient samples, equally high-precision was only found using WB as the matrix (CV 3%). The CV for serum and plasma was 14% and 39%, respectively. Two alternative methods applied to serum samples did not demonstrate improved precision. CONCLUSIONS: A LC-HRMS method for the measurement of HCQ in human blood was developed and validated. Whole blood was found to be the superior sample matrix in terms of sample reproducibility. Thus, whole blood samples should be used for HCQ analysis when patients are monitored for HCQ treatment effects. The assay is in clinical use to monitor levels of HCQ in patients.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Monitoramento de Medicamentos/normas , Hidroxicloroquina/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Pandemias , Pneumonia Viral , Adulto , Idoso , Cromatografia Líquida/métodos , Cromatografia Líquida/normas , Infecções por Coronavirus/sangue , Infecções por Coronavirus/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Masculino , Espectrometria de Massas/métodos , Espectrometria de Massas/normas , Pessoa de Meia-Idade , Plasma , Pneumonia Viral/sangue , Pneumonia Viral/tratamento farmacológico , Soro , Adulto Jovem
14.
Medicine (Baltimore) ; 99(26): e20719, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590747

RESUMO

BACKGROUND: Regorafenib, a multitargeted tyrosine kinase inhibitor, proved to be active in patients with soft tissue sarcomas (STS). METHODS: We conducted an open-label, non-randomized, single-center phase II study in advanced pretreated STS patients. Patients received regorafenib 160 mg daily on days 1 enrule 21 of a 28-day cycle. The primary endpoint was the progression-free survival (PFS) at 8 weeks. Toxicity was registered. RESULTS: Between April 2015 and November 2016, 21 patients were enrolled in the trial. A total of 13 out of 21 evaluable patients (61.9%) were progression-free at 8 weeks. Median PFS was 3.8 months (95% CI: 2.1-9.4). Median overall survival was 14.8 months (95% CI: 7.7-27.8). In the intention-to-treat population, we reported a PFS of 66.7% at 3 months (95% CI: 40.4-83.4) and 16.7% at 12 months (95% CI: 4.1-36.5). As per the RECIST criteria, the response rate was 4.7% (1 partial response out of 21 evaluable patients) with a clinical benefit rate of 61.9%; no complete response was observed. Treatment was well tolerated. CONCLUSION: Regorafenib shows signs of clinical activity in patients with advanced STS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02307500.


Assuntos
Neoplasias Ovarianas , Neoplasias Pancreáticas , Compostos de Fenilureia , Piridinas , Sarcoma , Timoma , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Monitoramento de Medicamentos/métodos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Timoma/tratamento farmacológico , Timoma/patologia , Resultado do Tratamento
15.
Farm. hosp ; 44(3): 81-86, mayo-jun. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-192338

RESUMO

OBJETIVO: Una revisión de la literatura sobre nivolumab permite verificar la existencia de diversos aspectos sin resolver sobre su intervalo de dosificación. El objetivo del presente estudio ha sido explorar las posibilidades de personalización del tratamiento con nivolumab mediante la monitorización terapéutica de sus concentraciones séricas para mejorar su efectividad y eficiencia. MÉTODO: Estudio observacional, prospectivo, realizado entre mayo de 2017 y junio de 2019 en pacientes tratados con nivolumab que estaban diagnosticados de diferentes tumores. Se obtuvieron muestras de sangre en la práctica clínica habitual, una vez alcanzado el estado de equilibrio de nivolumab. Las concentraciones séricas de nivolumab fueron determinadas mediante ELISA cuantitativo. La pauta posológica habitual de 3 mg/kg cada dos semanas tuvo que ser modificada en algunos pacientes debido a diferentes circunstancias, y las concentraciones séricas resultantes se compararon con las correspondientes a los pacientes en los que no se modificó y con datos publicados. RESULTADOS: Se analizaron muestras de 19 pacientes que recibieron inicialmente 3 mg/kg de nivolumab cada dos semanas. Se analizó un total de 39 muestras, entre los ciclos 6 y 27. La pauta habitual se modificó, una vez alcanzado el estado de equilibrio, en 12/19 (60%) pacientes, en los que se amplió el intervalo a 3, 4, 5, 6 o 7 semanas. No se encontraron diferencias estadísticamente significativas al comparar la administración cada dos semanas y cada cuatro semanas. Cuando los intervalos fueron de seis o siete semanas, la concentración sérica media mostró una diferencia estadísticamente significativa en comparación con la administración cada dos semanas. CONCLUSIONES: La información recogida parece confirmar la necesidad de explorar nuevos escenarios para personalizar la dosificación de nivolumab. Se necesitan estudios adicionales en series de mayor tamaño para confirmar esta información, correlacionarla con los resultados clínicos y definir mejor el papel de la monitorización terapéutica, no solo por motivos económicos, sino también para mejorar la calidad de vida de los pacientes y facilitar la administración clínica del tratamiento


OBJECTIVE: A review of the literature about the anti-programmed death 1 monoclonal antibody nivolumab permits to verify the existence of several issues still unresolved about their dosing schedule. The aim of the present work was to explore possibilities of nivolumab treatment perso-nalization through therapeutic drug monitoring, in order to improve their effectiveness and efficiency. METHOD: Observational, prospective study carried out from May 2017 through June 2019 in patients with different tumor diagnoses treated with nivolumab. Blood samples were obtained in the routine clinical practice, once nivolumab steady state was reached. Serum nivolumab levels were determined by means of quantitative ELISA. The standard schedule of 3 mg/kg every two weeks (Q2W) was modified in some patients due to different circumstances, and resulting serum concentrations were compared with those from the non-modified patients and the published data.RESULTS: Blood samples from 19 patients in treatment with nivolumab were analyzed. A total of 39 samples of nivolumab were analyzed bet-ween 6th and 27th cycles. The standard schedule of 3 mg/kg every two weeks was modified in 12/19 (60%) patients, with intervals of 3, 4, 5, 6 or 7 weeks, once the steady state was reached. No statistically significant differences were detected when comparing every two weeks and every four week intervals. When the intervals were six or seven weeks, mean plasma concentration showed a statistically significant difference compared with every two weeks.CONCLUSIONS: Current data contribute to confirm former suspects about the possibilities of exploring new scenarios to improve and personalize nivolumab dosage. Additional studies to confirm it in bigger series and correlate it with clinical results, and to better define the role of therapeutic drug monitoring in the treatment, are warranted, not only by financial concerns but also for improving quality of life of patients and clinical management aspects


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Projetos Piloto , Monitoramento de Medicamentos/métodos , Nivolumabe/administração & dosagem , Resultado do Tratamento , Neoplasias/tratamento farmacológico , Estudos Prospectivos , Ensaio de Imunoadsorção Enzimática , Imunoterapia , Nivolumabe/farmacocinética , Nivolumabe/metabolismo
16.
Gut ; 69(9): 1592-1597, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32499303

RESUMO

OBJECTIVE: Treatment options for non-hospitalised patients with coronavirus disease 2019 (COVID-19) to reduce morbidity, mortality and spread of the disease are an urgent global need. The over-the-counter histamine-2 receptor antagonist famotidine is a putative therapy for COVID-19. We quantitively assessed longitudinal changes in patient reported outcome measures in non-hospitalised patients with COVID-19 who self-administered high-dose famotidine orally. DESIGN: Patients were enrolled consecutively after signing written informed consent. Data on demographics, COVID-19 diagnosis, famotidine use, drug-related side effects, temperature measurements, oxygen saturations and symptom scores were obtained using questionnaires and telephone interviews. Based on a National Institute of Health (NIH)-endorsed Protocol to research Patient Experience of COVID-19, we collected longitudinal severity scores of five symptoms (cough, shortness of breath, fatigue, headaches and anosmia) and general unwellness on a four-point ordinal scale modelled on performance status scoring. All data are reported at the patient level. Longitudinal combined normalised symptom scores were statistically compared. RESULTS: Ten consecutive patients with COVID-19 who self-administered high-dose oral famotidine were identified. The most frequently used famotidine regimen was 80 mg three times daily (n=6) for a median of 11 days (range: 5-21 days). Famotidine was well tolerated. All patients reported marked improvements of disease related symptoms after starting famotidine. The combined symptom score improved significantly within 24 hours of starting famotidine and peripheral oxygen saturation (n=2) and device recorded activity (n=1) increased. CONCLUSIONS: The results of this case series suggest that high-dose oral famotidine is well tolerated and associated with improved patient-reported outcomes in non-hospitalised patients with COVID-19.


Assuntos
Infecções por Coronavirus , Monitoramento de Medicamentos/métodos , Famotidina/administração & dosagem , Pandemias , Pneumonia Viral , Avaliação de Sintomas/métodos , Adulto , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Relação Dose-Resposta a Droga , Feminino , Antagonistas dos Receptores Histamínicos H2/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Oximetria/métodos , Medidas de Resultados Relatados pelo Paciente , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Estudos Retrospectivos , Autoadministração , Resultado do Tratamento
17.
Clin Chem Lab Med ; 58(9): 1461-1468, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32573468

RESUMO

Objectives: A method based on liquid chromatography coupled to triple quadrupole mass spectrometry detection using 50 µL of plasma was developed and fully validated for quantification of remdesivir and its active metabolites GS-441524. Methods: A simple protein precipitation was carried out using 75 µL of methanol containing the internal standard (IS) remdesivir-13C6 and 5 µL ZnSO4 1 M. After separation on Kinetex® 2.6 µm Polar C18 100A LC column (100 × 2.1 mm i.d.), both compounds were detected by a mass spectrometer with electrospray ionization in positive mode. The ion transitions used were m/z 603.3 â†’ m/z 200.0 and m/z 229.0 for remdesivir, m/z 292.2 â†’ m/z 173.1 and m/z 147.1 for GS-441524 and m/z 609.3 â†’ m/z 206.0 for remdesivir-13C6. Results: Calibration curves were linear in the 1-5000 µg/L range for remdesivir and 5-2500 for GS-441524, with limit of detection set at 0.5 and 2 µg/L and limit of quantification at 1 and 5 µg/L, respectively. Precisions evaluated at 2.5, 400 and 4000 µg/L for remdesivir and 12.5, 125, 2000 µg/L for GS-441524 were lower than 14.7% and accuracy was in the [89.6-110.2%] range. A slight matrix effect was observed, compensated by IS. Higher stability of remdesivir and metabolite was observed on NaF-plasma. After 200 mg IV single administration, remdesivir concentration decrease rapidly with a half-life less than 1 h while GS-441524 appeared rapidly and decreased slowly until H24 with a half-life around 12 h. Conclusions: This method would be useful for therapeutic drug monitoring of these compounds in Covid-19 pandemic.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/sangue , Betacoronavirus , Cromatografia Líquida/métodos , Infecções por Coronavirus/sangue , Monitoramento de Medicamentos/métodos , Pneumonia Viral/sangue , Espectrometria de Massas em Tandem/métodos , Monofosfato de Adenosina/sangue , Monofosfato de Adenosina/farmacocinética , Alanina/sangue , Alanina/farmacocinética , Antivirais/farmacocinética , Estabilidade de Medicamentos , Feminino , Humanos , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Pandemias , Reprodutibilidade dos Testes
18.
Arthritis Res Ther ; 22(1): 125, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32475347

RESUMO

BACKGROUND: Hydroxychloroquine (HCQ) is the standard of care in the treatment of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and other inflammatory rheumatic diseases and potentially for the treatment in COVID-19 patients. Determination of HCQ for therapeutic drug monitoring (TDM) can be performed in whole blood (WB), serum, and plasma. Direct comparisons of WB, serum, and plasma levels of HCQ in patients with SLE have not previously been reported. We describe a method for the determination of HCQ in human blood using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) and compare the suitability of the three sample matrices. METHODS: A method for the determination of HCQ in human blood using LC-HRMS was developed, validated, and applied for the determination of HCQ levels in WB, serum, and plasma from 26 SLE patients. The reproducibility of the method, in the three matrices, was evaluated using quality control samples and repeated preparations and measurements of patient samples. The performance of the developed method for HCQ measurement in serum was further evaluated by comparison with two previously reported extraction methods. RESULTS: The performance of the presented method demonstrated high accuracy and precision. A large range of HCQ concentrations was observed for the SLE patients in all three matrices (WB, serum, and plasma). The mean levels in WB were approximately two-fold the levels in serum and plasma (813 ng/mL compared to 436 ng/mL and 362 ng/mL, respectively). Spiked quality controls showed high reproducibility for all matrices (coefficient of variation, CV, approx. 5%), whereas in patient samples, equally high-precision was only found using WB as the matrix (CV 3%). The CV for serum and plasma was 14% and 39%, respectively. Two alternative methods applied to serum samples did not demonstrate improved precision. CONCLUSIONS: A LC-HRMS method for the measurement of HCQ in human blood was developed and validated. Whole blood was found to be the superior sample matrix in terms of sample reproducibility. Thus, whole blood samples should be used for HCQ analysis when patients are monitored for HCQ treatment effects. The assay is in clinical use to monitor levels of HCQ in patients.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Monitoramento de Medicamentos/normas , Hidroxicloroquina/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Pandemias , Pneumonia Viral , Adulto , Idoso , Cromatografia Líquida/métodos , Cromatografia Líquida/normas , Infecções por Coronavirus/sangue , Infecções por Coronavirus/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Masculino , Espectrometria de Massas/métodos , Espectrometria de Massas/normas , Pessoa de Meia-Idade , Plasma , Pneumonia Viral/sangue , Pneumonia Viral/tratamento farmacológico , Soro , Adulto Jovem
19.
Paediatr Drugs ; 22(4): 433-444, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32507958

RESUMO

BACKGROUND: The Dutch Pediatric Formulary (DPF) increasingly bases its guidelines on model-based dosing simulations from pharmacokinetic studies. This resulted in nationwide dose changes for vancomycin, gentamicin, and tobramycin in 2015. OBJECTIVE: We aimed to evaluate target attainment of these altered, model-based doses in critically ill neonates and children. METHODS: This was a retrospective cohort study in neonatal intensive care unit (NICU) and pediatric ICU (PICU) patients receiving vancomycin, gentamicin, or tobramycin between January 2015 and March 2017 in two university hospitals. The first therapeutic drug monitoring concentration for each patient was collected, as was clinical and dosing information. Vancomycin and tobramycin target trough concentrations were 10-15 and ≤ 1 mg/L, respectively. Target gentamicin trough and peak concentrations were < 1 and 8-12 mg/L, respectively. RESULTS: In total, 482 patients were included (vancomycin [PICU] n = 62, [NICU] n = 102; gentamicin [NICU] n = 97; tobramycin [NICU] n = 221). Overall, median trough concentrations were within the target range for all cohorts but showed large interindividual variability, causing nontarget attainment. Trough concentrations were outside the target range in 66.1%, 60.8%, 14.7%, and 23.1% of patients in these four cohorts, respectively. Gentamicin peak concentrations were outside the range in 69% of NICU patients (term neonates 87.1%, preterm infants 57.1%). Higher creatinine concentrations were associated with higher vancomycin and tobramycin trough concentrations. CONCLUSION: This study illustrates the need to validate model-based dosing advice in the real-world setting as both sub- and supratherapeutic concentrations of vancomycin, gentamicin, and tobramycin were very prevalent. Our data underline the necessity for further individualization by addressing the high interindividual variability to improve target attainment.


Assuntos
Antibacterianos/administração & dosagem , Gentamicinas/administração & dosagem , Vancomicina/administração & dosagem , Antibacterianos/uso terapêutico , Estado Terminal , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Unidades de Terapia Intensiva Neonatal , Masculino , Estudos Retrospectivos , Tobramicina/administração & dosagem , Tobramicina/farmacocinética
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