Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 9.932
Filtrar
1.
Isr Med Assoc J ; 23(7): 412-415, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34251122

RESUMO

BACKGROUND: Psoriatic arthritis (PsA) is an inflammatory rheumatic disease characterized by different phenotypes in terms of joint involvement. The so-called oligoarticular pattern involves fewer than five active joints at a different time points. The evaluation of disease activity in this subset of patients is an unmet need due to the lack of specific indices able to capture modifications over time. OBJECTIVES: To evaluate the ability of musculoskeletal ultrasound to monitor the response to apremilast treatment in oligoarticular PsA patients. METHODS: We evaluated 24 oligoarticular patients (19 women, 5 men; median age 56 years, interquartile range (IQR) 19; median disease duration 5 years, IQR 5.75). All patients were assessed at baseline (T0), and after 6 (T1), 12 (T2), and 24 (T3) weeks. Clinical assessment included evaluation of 66 swollen joints and patient global health assessment. All the patients underwent ultrasound assessment of the clinically involved joints. Synovial effusion/hypertrophy and power Doppler were scored with a semi-quantitative scale (0-3). The total inflammatory score was the sum of the scores. RESULTS: We found a reduction in the ultrasound inflammatory score at all time points, with a significant improvement at 6 and 12 weeks of treatment compared with baseline: T0 median 8.5 (IQR 5.0); T1 3.5 (3.0); T2 2.0 (3.5); P = 0.01. We observed a significant reduction of patient global health assessment after 24 weeks (T0 median 50 (32.5); T3 40 (57.5); P = 0.01). CONCLUSIONS: Musculoskeletal ultrasound could be useful in the assessment of treatment response in PsA patients with oligoarticular subset.


Assuntos
Artrite Psoriásica , Monitoramento de Medicamentos/métodos , Membrana Sinovial , Talidomida/análogos & derivados , Ultrassonografia/métodos , Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Psoriásica/diagnóstico por imagem , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/fisiopatologia , Feminino , Humanos , Inflamação/diagnóstico , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Tamanho do Órgão , Gravidade do Paciente , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Líquido Sinovial/diagnóstico por imagem , Membrana Sinovial/diagnóstico por imagem , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Talidomida/administração & dosagem
3.
Isr Med Assoc J ; 23(6): 344-349, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34155846

RESUMO

BACKGROUND: There is a lack of real-life clinical data for biosimilar etanercept, an anti-TNF blocking fusion protein. We describe the comparable efficacy and safety of originator and biosimilar etanercept in rheumatoid arthritis (RA) patients in a real-life clinical setting. Our data confirm that a biosimilar etanercept can be safely used as first-line treatment as well as in patients switched from a previous originator compound. OBJECTIVES: To compare the efficacy and safety of originator and biosimilar etanercept in a cohort of RA patients attending two Italian hospitals. METHODS: The study involved 81 consecutive adult RA patients treated for at least 6 months with originator or biosimilar etanercept and considered their clinical and laboratory data, concomitant medications, and adverse events at baseline, and after 3 and 6 months of treatment. RESULTS: Group 1 included 51 patients taking originator etanercept; group 2 included 30 taking biosimilar etanercept, including 19 who had been switched from the reference product. Despite a significant baseline difference in clinical disease activity, one-way analysis of variance showed that the two groups were clinically comparable after 6 months of treatment, and the same was true when only those receiving etanercept as first-line biological treatment were considered. Nine patients discontinued the treatment due to inefficacy or adverse events, which were never serious and were only reported in group 1. CONCLUSIONS: The efficacy and safety profiles of originator and biosimilar etanercept are comparable in RA patients in a real-life clinical setting. Further studies are needed to confirm these preliminary findings.


Assuntos
Artrite Reumatoide , Medicamentos Biossimilares , Substituição de Medicamentos/métodos , Etanercepte , Preferência do Paciente , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/administração & dosagem , Medicamentos Biossimilares/efeitos adversos , Sedimentação Sanguínea/efeitos dos fármacos , Proteína C-Reativa/análise , Pesquisa Comparativa da Efetividade , Análise Custo-Benefício , Monitoramento de Medicamentos/métodos , Etanercepte/administração & dosagem , Etanercepte/efeitos adversos , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Avaliação de Processos e Resultados em Cuidados de Saúde , Gravidade do Paciente , Segurança do Paciente , Resultado do Tratamento
4.
Isr Med Assoc J ; 23(6): 353-358, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34155848

RESUMO

BACKGROUND: Real-world information regarding the use of direct oral anticoagulants therapy and the outcome in patients with renal dysfunction is limited. OBJECTIVES: To evaluate the clinical characteristics and outcomes of patients with atrial fibrillation (AF) and severe renal dysfunction who are treated with apixaban. METHODS: A sub-analysis was conducted within a multicenter prospective cohort study. The study included consecutive eligible apixaban- or warfarin-treated patients with non-valvular AF and renal impairment (estimated glomerular filtration rate [eGFR] modification of diet in renal disease [MDRD] < 60 ml/min/BSA) were registered. All patients were prospectively followed for clinical events and over a mean period of 1 year. Our sub-analysis included the patients with 15 < eGFR MDRD < 30 ml/min/BSA. The primary outcomes at 1 year were recorded. They included mortality, stroke or systemic embolism, major bleeding, and myocardial infarction as well as their composite occurrence. RESULTS: The sub-analysis included 155 warfarin-treated patients and 97 apixaban-treated ones. All had 15 < eGFR MDRD < 30 ml/min/BSA. When comparing outcomes for propensity matched groups (n=76 per group) of patients treated by reduced dose apixaban or warfarin, the rates of the 1-year composite endpoint as well as mortality alone were higher among the warfarin group (30 [39.5%] vs. 14 [18.4%], P = 0.007 and 28 [36.8%] vs.12 [15.8%], P = 0.006), respectively. There was no significant difference in the rates of stroke, systemic embolism, or major bleeding. CONCLUSIONS: Apixaban might be a reasonable alternative to warfarin in patients with severe renal impairment.


Assuntos
Fibrilação Atrial , Hemorragia , Infarto do Miocárdio , Insuficiência Renal , Acidente Vascular Cerebral , Varfarina , Idoso , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/mortalidade , Estudos de Coortes , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Humanos , Israel/epidemiologia , Testes de Função Renal/métodos , Testes de Função Renal/estatística & dados numéricos , Masculino , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Avaliação de Resultados em Cuidados de Saúde , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Insuficiência Renal/complicações , Insuficiência Renal/diagnóstico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Análise de Sobrevida , Varfarina/administração & dosagem , Varfarina/efeitos adversos
5.
Medicine (Baltimore) ; 100(26): e26478, 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34190172

RESUMO

ABSTRACT: This study aims to evaluate the effect of dose titration for different oral antiepileptic medications among children with epilepsy in Riyadh, Saudi Arabia.A single-center prospective pilot, cohort study was undertaken at a tertiary hospital in Riyadh, Saudi Arabia. All medical records of pediatric patients below the age of 14 years of age who has been newly diagnosed with epilepsy by attending a medical specialist or on a new epileptic treatment plans were enrolled in the study.A total of 76 epileptic patients were screened for 3 months' period and 48 patients were included in this study. Out of the 48 patients, 31 patients followed the regular practice in the titration processes and 17 patients were in the British national formulary (BNF) guideline. Fifteen children who were on monotherapy of levetiracetam were in regular practice guideline experienced poor seizure control with a recorded number of seizure incidence (n = 10). The patient in regular practice guidelines using a combination therapy of phenytoin and levetiracetam were experiencing some behavioral disturbance and sedation effect. Seventeen patients followed in the BNF guideline who were on levetiracetam were experienced less adverse effect (n = 2) with no behavioral changes.The group who followed the regular practice found having a greater incidence of documented adverse effects compared to the patients following the BNF guideline. The titrating antiepileptic medication has a detrimental effect on the pediatric population as observed in this study.


Assuntos
Anticonvulsivantes , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Epilepsia , Conduta do Tratamento Medicamentoso , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/classificação , Criança , Saúde da Criança , Estudos de Coortes , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Epilepsia/fisiopatologia , Feminino , Humanos , Masculino , Conduta do Tratamento Medicamentoso/organização & administração , Conduta do Tratamento Medicamentoso/normas , Guias de Prática Clínica como Assunto , Padrões de Prática Médica/normas , Estudos Prospectivos , Arábia Saudita/epidemiologia
7.
Am Fam Physician ; 103(10): 605-613, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33983002

RESUMO

Clinical hypothyroidism affects one in 300 people in the United States, with a higher prevalence among female and older patients. Symptoms range from minimal to life-threatening (myxedema coma); more common symptoms include cold intolerance, fatigue, weight gain, dry skin, constipation, and voice changes. The signs and symptoms that suggest thyroid dysfunction are nonspecific and nondiagnostic, especially early in disease presentation; therefore, a diagnosis is based on blood levels of thyroid-stimulating hormone and free thyroxine. There is no evidence that population screening is beneficial. Symptom relief and normalized thyroid-stimulating hormone levels are achieved with levothyroxine replacement therapy, started at 1.5 to 1.8 mcg per kg per day. Adding triiodothyronine is not recommended, even in patients with persistent symptoms and normal levels of thyroid-stimulating hormone. Patients older than 60 years or with known or suspected ischemic heart disease should start at a lower dosage of levothyroxine (12.5 to 50 mcg per day). Women with hypothyroidism who become pregnant should increase their weekly dosage by 30% up to nine doses per week (i.e., take one extra dose twice per week), followed by monthly evaluation and management. Patients with persistent symptoms after adequate levothyroxine dosing should be reassessed for other causes or the need for referral. Early recognition of myxedema coma and appropriate treatment is essential. Most patients with subclinical hypothyroidism do not benefit from treatment unless the thyroid-stimulating hormone level is greater than 10 mIU per L or the thyroid peroxidase antibody is elevated.


Assuntos
Monitoramento de Medicamentos/métodos , Hipotireoidismo , Complicações na Gravidez , Avaliação de Sintomas/métodos , Testes de Função Tireóidea/métodos , Tiroxina , Adulto , Fatores Etários , Idoso , Relação Dose-Resposta a Droga , Feminino , Terapia de Reposição Hormonal/métodos , Humanos , Hipotireoidismo/complicações , Hipotireoidismo/diagnóstico , Hipotireoidismo/fisiopatologia , Hipotireoidismo/terapia , Masculino , Gravidade do Paciente , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/terapia , Hormônios Tireóideos/sangue , Tireotropina/sangue , Tiroxina/administração & dosagem , Tiroxina/efeitos adversos
8.
Artigo em Inglês | MEDLINE | ID: mdl-33991955

RESUMO

In recent years, more than 50 tyrosine kinase inhibitors (TKIs) was indicated against numerous cancers, especially outstanding advantages in the treatment of non-small cell lung cancer (NSCLC), and several studies have shown that therapeutic drug monitoring (TDM) of TKIs can improve treatment efficacy and safety. The present study aimed to develop and validate a LC-MS/MS method for the TDM of 12 TKIs (gefitinib, erlotinib, afatinib, dacomitinib, icotinib, osimertinib, crizotinib, ceritinib, alectinib, dabrafenib, trametinib, anlotinib) in patients with NSCLC. The analytes of interest and internal standard were extracted from human plasma. Salting-out assisted liquid-liquid extraction (SALLE) with 5 M ammonium acetate solution was optimized for method validation and compared to simple protein precipitation (PPT). Chromatographic separation was conducted on Waters X bridge C18 column (100 × 4.6 mm, 3.5 µm) using a gradient elution of acetonitrile/5mM ammonium acetate in pure water with 0.1% (v/v) formic acid at 40 °C within 6 min. The total flow was maintained at 1 mL/min, 30% of the post column flow was split into the mass spectrometer and the rest to waste via a 3-way tee. The mass analysis was performed by positive ion electrospray ionization (ESI) in multiple-reaction monitoring (MRM) mode. The assay was validated based on the guidelines on bioanalytical methods by FDA. This quantification method was proved to be satisfactory in selectivity, accuracy, precision, linearity (r2 > 0.995), recovery, matrix effect and stability and the accuracy was further assessed in plasma with a degree of hemolysis of 4%. The described method to simultaneously quantify the 12 selected anticancer drugs in human plasma was successfully validated and applied to routine TDM of gefitinib, erlotinib, icotinib, osimertinib, crizotinib and anlotinib in cancer patients. TKIs plasma monitoring helps to individualize dose adjustment and manage adverse effects in NSCLC patients.


Assuntos
Antineoplásicos/sangue , Carcinoma Pulmonar de Células não Pequenas , Monitoramento de Medicamentos/métodos , Neoplasias Pulmonares , Inibidores de Proteínas Quinases/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cromatografia Líquida de Alta Pressão , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Espectrometria de Massas em Tandem
9.
Molecules ; 26(5)2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33801290

RESUMO

The antihyerlipidemic drug atorvastatin (ATR) is used worldwide as part of the strategy to prevent cardiovascular events. The high prevalence of patient nonadherence remains an important challenge which could be addressed efficiently by precision pharmacotherapy based on therapeutic drug monitoring (TDM). ATR is metabolized to pharmacologically active metabolites, and evidence shows that the sums of ATR acid and lactone form concentrations (ATR + ATRL), or of ATR and hydroxylated metabolites (ATR + MET) should be assayed. A method is presented for the analysis of these substances in serum. Method validation included the estimation of the quantitative relationship between the concentrations and the standard deviations (SD), which supports the optimal incorporation of TDM results into nonparametric pharmacokinetic models. The concentrations of the analytes were evaluated in human subjects receiving ATR. The method's performance improved by taking the sums of acid and lactone concentrations into account. The concentration-SD relationship was linear, and we recommend applying Theil's regression for estimating the assay error. All analytes could be detected by 2 h post dose in the samples of human subjects. The changes in metabolite/parent drug concentration ratios in time depended on the dose. The method is suitable for the TDM of ATR with a focus on precision pharmacotherapy.


Assuntos
Atorvastatina/sangue , Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Ácidos Heptanoicos/sangue , Lactonas/sangue , Medicina de Precisão , Espectrometria de Massas em Tandem/métodos , Humanos
10.
Medicine (Baltimore) ; 100(17): e25710, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33907154

RESUMO

BACKGROUND: Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes. As apelin is an adipocytokine closely associated with diabetes, this study explored the clinical significance of serum apelin levels in patients with type 2 DPN before and after treatment. METHODS: In total, 44 patients with T2DM without DPN (non-DPN group), 41 patients with DPN who received antihyperglycemic treatment (DPN-A group), 44 patients with DPN who received antihyperglycemic treatment combined with nutritional neurotherapy (DPN-B group), and 40 healthy control individuals (NC group) were selected continuously enrolled in the present study. Enzyme-linked immunosorbent assays (ELISA) were performed to determine serum levels of apelin and tumor necrosis factor-α (TNF-α). Related apelin, fasting blood glucose (FBG), glycosylated hemoglobin A1c, TNF-α, body mass index, fasting C peptide, and nerve conduction velocity (NCV) were recorded in each group before and after treatment. RESULTS: Serum levels of apelin and TNF-α were higher in patients with diabetes than those in the NC group, as well as in the DPN group as compared to the non-DPN group; furthermore, some NCV values were significantly reduced in the DPN group. After treatment, the serum levels of apelin, TNF-α, and FBG reduced in patients with diabetes; moreover, apelin levels were found significantly lower in the DPN-B group as compared to the DPN-A group, while some NCV values significantly increased in the DPN-B group. Apelin was negatively correlated with part of NCV values and positively correlated with TNF-α and FBG (P < .01). CONCLUSION: Our results show that the increase in serum apelin levels is an important clinical reference index for DPN, while a decrease indicates that the DPN treatment is effective.


Assuntos
Apelina/sangue , Diabetes Mellitus Tipo 2 , Neuropatias Diabéticas , Monitoramento de Medicamentos , Insulina , Condução Nervosa/efeitos dos fármacos , Glicemia/análise , Índice de Massa Corporal , China/epidemiologia , Correlação de Dados , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/terapia , Neuropatias Diabéticas/diagnóstico , Neuropatias Diabéticas/epidemiologia , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/terapia , Dietoterapia/métodos , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/estatística & dados numéricos , Eletromiografia/métodos , Feminino , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Insulina/administração & dosagem , Insulina/farmacocinética , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/sangue
11.
JAMA Netw Open ; 4(4): e216468, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33885775

RESUMO

Importance: Data on the efficacy of hydroxychloroquine or lopinavir-ritonavir for the treatment of high-risk outpatients with COVID-19 in developing countries are needed. Objective: To determine whether hydroxychloroquine or lopinavir-ritonavir reduces hospitalization among high-risk patients with early symptomatic COVID-19 in an outpatient setting. Design, Setting, and Participants: This randomized clinical trial was conducted in Brazil. Recently symptomatic adults diagnosed with respiratory symptoms from SARS-CoV-2 infection were enrolled between June 2 and September 30, 2020. The planned sample size was 1476 patients, with interim analyses planned after 500 patients were enrolled. The trial was stopped after the interim analysis for futility with a sample size of 685 patients. Statistical analysis was performed in December 2020. Interventions: Patients were randomly assigned to hydroxychloroquine (800 mg loading dose, then 400 mg daily for 9 days), lopinavir-ritonavir (loading dose of 800 mg and 200 mg, respectively, every 12 hours followed by 400 mg and 100 mg, respectively, every 12 hours for the next 9 days), or placebo. Main Outcomes and Measures: The primary outcomes were COVID-19-associated hospitalization and death assessed at 90 days after randomization. COVID-19-associated hospitalization was analyzed with a Cox proportional hazards model. The trial included the following secondary outcomes: all-cause hospitalization, viral clearance, symptom resolution, and adverse events. Results: Of 685 participants, 632 (92.3%) self-identified as mixed-race, 377 (55.0%) were women, and the median (range) age was 53 (18-94) years. A total of 214 participants were randomized to hydroxychloroquine; 244, lopinavir-ritonavir; and 227, placebo. At first interim analysis, the data safety monitoring board recommended stopping enrollment of both hydroxychloroquine and lopinavir-ritonavir groups because of futility. The proportion of patients hospitalized for COVID-19 was 3.7% (8 participants) in the hydroxychloroquine group, 5.7% (14 participants) in the lopinavir-ritonavir group, and 4.8% (11 participants) in the placebo group. We found no significant differences between interventions for COVID-19-associated hospitalization (hydroxychloroquine: hazard ratio [HR], 0.76 [95% CI, 0.30-1.88]; lopinavir-ritonavir: HR, 1.16 [95% CI, 0.53-2.56] as well as for the secondary outcome of viral clearance through day 14 (hydroxychloroquine: odds ratio [OR], 0.91 [95% CI, 0.82-1.02]; lopinavir-ritonavir: OR, 1.04 [95% CI, 0.94-1.16]). At the end of the trial, there were 3 fatalities recorded, 1 in the placebo group and 2 in the lopinavir-ritonavir intervention group. Conclusions and Relevance: In this randomized clinical trial, neither hydroxychloroquine nor lopinavir-ritonavir showed any significant benefit for decreasing COVID-19-associated hospitalization or other secondary clinical outcomes. This trial suggests that expedient clinical trials can be implemented in low-income settings even during the COVID-19 pandemic. Trial Registration: ClinicalTrials.gov Identifier: NCT04403100.


Assuntos
COVID-19 , Intervenção Médica Precoce , Hidroxicloroquina/administração & dosagem , Lopinavir/administração & dosagem , Ritonavir/administração & dosagem , Antivirais/administração & dosagem , Brasil/epidemiologia , COVID-19/epidemiologia , COVID-19/terapia , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/estatística & dados numéricos , Quimioterapia Combinada/métodos , Intervenção Médica Precoce/métodos , Intervenção Médica Precoce/estatística & dados numéricos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Futilidade Médica , Pessoa de Meia-Idade , Risco Ajustado/métodos , Avaliação de Sintomas/métodos , Resultado do Tratamento
12.
Lancet Respir Med ; 9(5): 476-486, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33798455

RESUMO

BACKGROUND: Pirfenidone has been shown to slow disease progression in patients with idiopathic pulmonary fibrosis (IPF). However, there are few treatment options for progressive fibrotic interstitial lung diseases (ILDs)) other than IPF. In view of the pathomechanistic and clinical similarities between IPF and other progressive fibrotic ILDs, we aimed to assess the efficacy and safety of pirfenidone in patients with four non-IPF progressive fibrotic ILDs. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18-80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40-90% predicted, a diffusing capacity of the lung for carbon monoxide of 10-90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6-24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebo-controlled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32; DRKS00009822 and is no longer recruiting. FINDINGS: Between April 5, 2016, and Oct 4, 2018, we randomly assigned 127 patients to treatment: 64 to pirfenidone, 63 to placebo. After 127 patients had been randomised, the study was prematurely terminated on the basis of an interim analysis for futility triggered by slow recruitment. After 48 weeks and in the overall population of 127 patients, rank ANCOVA with diagnostic group included as a factor showed a significantly lower decline in FVC % predicted in the pirfenidone group compared with placebo (p=0·043); the result was similar when the model was stratified by diagnostic group (p=0·042). A significant treatment effect was also observed when applying the LOCF and multiple imputation methods to analyses of the primary endpoint. The median difference (Hodges-Lehmann estimate) between pirfenidone and placebo groups for the primary endpoint was 1·69 FVC % predicted (95% CI -0·65 to 4·03). In the linear mixed-model repeated measures slope analysis of FVC % predicted, the estimated difference between treatment and placebo groups from baseline to week 48 was 3·53 FVC % predicted (95% CI 0·21 to 6·86) with imputation of deaths as prespecified, or 2·79 FVC % predicted (95% CI 0·03 to 5·54) without imputation. One death (non-respiratory) occurred in the pirfenidone group (2%) and five deaths (three of which were respiratory) occurred in the placebo group (8%). The most frequent serious adverse events in both groups were infections and infestations (five [8%] in the pirfenidone group, ten [16%] in the placebo group); general disorders including disease worsening (two [3%] in the pirfenidone group, seven [11%] in the placebo group); and cardiac disorders (one ([2%] in the pirfenidone group, 5 [8%] in the placebo group). Adverse events (grade 3-4) of nausea (two patients on pirfenidone, two on placebo), dyspnoea (one patient on pirfenidone, one on placebo), and diarrhoea (one patient on pirfenidone) were also observed. INTERPRETATION: In view of the premature study termination, results should be interpreted with care. Nevertheless, our data suggest that in patients with fibrotic ILDs other than IPF who deteriorate despite conventional therapy, adding pirfenidone to existing treatment might attenuate disease progression as measured by decline in FVC. FUNDING: German Center for Lung Research, Roche Pharma.


Assuntos
Doenças Pulmonares Intersticiais , Fibrose Pulmonar , Piridonas/farmacologia , Testes de Função Respiratória/métodos , Anti-Inflamatórios não Esteroides/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Monitoramento de Medicamentos/métodos , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Análise de Intenção de Tratamento , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fibrose Pulmonar/diagnóstico , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/fisiopatologia , Avaliação de Sintomas/estatística & dados numéricos
13.
Molecules ; 26(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803489

RESUMO

Poor adherence to antihypertensive drug therapy is a well-recognized problem and can be assessed by mass spectrometry-based analyses of body fluids. However, contrary statements exist whether drug quantification in blood or qualitative screening in urine is more suitable. The present pilot study aimed to further elucidate the power of blood plasma drug concentrations for adherence monitoring by developing and validating a quantification procedure for nine antihypertensive drugs (amlodipine, bisoprolol, candesartan, canrenone, carvedilol, metoprolol, olmesartan, torasemide, and valsartan) in blood plasma using liquid-liquid extraction and an ultra-high-performance liquid chromatography-ion trap mass spectrometry analysis. The procedure should then be used for an adherence assessment and compared with the results of an established qualitative urine screening. Selectivity, carryover, matrix effect, accuracy, precision, dilution integrity, and stability were successfully validated, except for amlodipine. The applicability was demonstrated by analyzing 19 plasma samples containing 28 antihypertensive drugs and comparing the measured concentrations with calculated dose-dependent reference plasma concentration ranges. The interpretation of plasma concentrations was found to be more sophisticated and time-consuming than that of urine screening results, and adherence could not be assessed in two cases (10%) due to measured plasma concentrations below the lower limit of quantification. However, 14 out of 19 subjects were classified as adherent (75%) and three as nonadherent (15%), in contrast to 19 (100%) that were claimed to be adherent based on the results of the qualitative urine screening. Nevertheless, further data is needed to estimate whether plasma quantification is superior in terms of assessing adherence to antihypertensive medication.


Assuntos
Anti-Hipertensivos/análise , Anti-Hipertensivos/uso terapêutico , Monitoramento de Medicamentos/métodos , Anlodipino/uso terapêutico , Anti-Hipertensivos/sangue , Benzimidazóis/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Líquidos Corporais/química , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Hipertensão/tratamento farmacológico , Imidazóis/uso terapêutico , Extração Líquido-Líquido/métodos , Metoprolol/uso terapêutico , Cooperação do Paciente/estatística & dados numéricos , Projetos Piloto , Plasma/química , Valores de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Tetrazóis/uso terapêutico
14.
J Chromatogr Sci ; 59(6): 502-509, 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-33884406

RESUMO

For the quantification of flurbiprofen in rat plasma, a simple UPLC-MS/MS method with high sensitivity and short retention time for flurbiprofen was developed and validated using specific parameters. Etodolac was used as internal standard. The transitions (precursor to the product) of flurbiprofen and internal standard were obtained using the electrospray ionization in the negative ion multiple reaction monitoring mode, 243.2 â†’ 199.2, 286.2 â†’ 212.1, respectively. For chromatographic separation, C18 column was used for the stationary phase and gradient elution was used for the mobile phase. This mobile phase consisted of a methanol (A) and a 5 mM ammonium formate solution (B), which varied at a flow rate of 0.4 mL/min. For flurbiprofen, LLOQ was determined as 5 ng/mL. Quantification of flurbiprofen in the rat plasma with a linear calibration curve of 5-5000 ng/mL (r > 0.9991 for plasma) is possible with a retention time of 1.89 min. The total analysis time of the method was 3 min. The proposed method was validated. The intraday and inter-day precision (RSD%) and accuracy (RE%) were within 10% in all cases for flurbiprofen. The stability of flurbiprofen was evaluated under conditions such as short-term, long-term, autosampler and freeze/thaw. After method validation, flurbiprofen was succesfully quantified in real rat plasma samples.


Assuntos
Anti-Inflamatórios não Esteroides/sangue , Cromatografia Líquida de Alta Pressão/métodos , Flurbiprofeno/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Monitoramento de Medicamentos/métodos , Limite de Detecção , Masculino , Ratos , Ratos Wistar
15.
Medicine (Baltimore) ; 100(16): e25601, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33879725

RESUMO

ABSTRACT: There is controversy in clinical application of antiplatelet drugs by monitoring platelet function. Therefore, we explored whether early and dynamic medication could bring better clinical outcomes for patients under the guidance of platelet function tests (PFT).In this retrospective cohort study, we analyzed the prognostic events of 1550 patients with acute coronary syndrome (ACS) at Tianjin People's Hospital in China. They received dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) from January 2017 to December 2018. The primary endpoint was based on the Bleeding Academic Research Consortium (BARC) 3 or 5 major bleeding. Secondary endpoints included MACCE (all-cause death, nonfatal myocardial infarction, stroke, stent thrombosis, and unplanned target vessel reconstruction) and BARC 1 to 2 minor bleeding. The endpoint events within 1 year after PCI were recorded. Patients were divided into a guided group and a control group according to the drug adjustment by PFT results. After the propensity scores matched, the end points of 2 groups were compared, and subgroup analysis was performed on major bleeding events.After propensity score matching, there were 511 cases in the guided group and the control group, respectively. The primary endpoint events occurred in 10 patients (1.96%) in the guided group and 23 patients (4.5%) in the control group (HR: 0.45; 95% CI, 0.21-0.95; P = .037). After the guided group adjusted drug doses, the risk of major bleeding was lower than standard DAPT of the control group. Although some patients in the guided group reduced doses earlier, the incidence of MACCE events did not increase in the guided group compared with the control group (4.89% vs 6.07%; P = .41). There was no statistical difference in BARC 1 to 2 minor bleeding (P = .22). Subgroup analysis showed that PFT was more effective in patients with diabetes and multivessel disease.Early observation of dynamic PFT in ACS patients after PCI can guide individualized antiplatelet therapy to reduce the risk of major bleeding without increasing the risk of ischemia.


Assuntos
Síndrome Coronariana Aguda/terapia , Monitoramento de Medicamentos/métodos , Hemorragia/prevenção & controle , Inibidores da Agregação Plaquetária/uso terapêutico , Testes de Função Plaquetária/estatística & dados numéricos , Síndrome Coronariana Aguda/complicações , Idoso , China , Terapia Antiplaquetária Dupla , Feminino , Hemorragia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Período Pós-Operatório , Prognóstico , Pontuação de Propensão , Estudos Retrospectivos , Resultado do Tratamento
16.
Ther Drug Monit ; 43(4): 455-458, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33908408

RESUMO

ABSTRACT: In this article, we present a case of apixaban elimination prolonged by 450% in a patient with coronavirus disease 2019 because of multiple conditions, including drug-drug interaction, severe inflammation, and acute kidney injury. Therapeutic drug monitoring was used to explain unusual routine coagulation assays. This grand round highlights the importance of dialog between the clinician and a therapeutic drug monitoring consultant for optimal patient care.


Assuntos
Injúria Renal Aguda/metabolismo , COVID-19/metabolismo , Monitoramento de Medicamentos/métodos , Pirazóis/metabolismo , Piridonas/metabolismo , Eliminação Renal/efeitos dos fármacos , Visitas com Preceptor/métodos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Idoso de 80 Anos ou mais , Antivirais/efeitos adversos , Antivirais/metabolismo , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Interações Medicamentosas/fisiologia , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/metabolismo , Inibidores do Fator Xa/uso terapêutico , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/prevenção & controle , Masculino , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Piridonas/efeitos adversos , Piridonas/uso terapêutico , Eliminação Renal/fisiologia , Índice de Gravidade de Doença , Fatores de Tempo
17.
Artigo em Inglês | MEDLINE | ID: mdl-33756448

RESUMO

Remdesivir, formerly GS-5734, has recently become the first antiviral drug approved by the U.S. Food and Drug Administration (FDA) to treat COVID-19, the disease caused by SARS-CoV-2. Therapeutic dosing and pharmacokinetic studies require a simple, sensitive, and selective validated assay to quantify drug concentrations in clinical samples. Therefore, we developed a rapid and sensitive LC-MS/MS assay for the quantification of remdesivir in human plasma with its deuterium-labeled analog, remdesivir-2H5, as the internal standard. Chromatographic separation was achieved on a Phenomenex® Synergi™ HPLC Fusion-RP (100 × 2 mm, 4 µm) column by gradient elution. Excellent accuracy and precision (<5.2% within-run variations and. <9.8% between-run variations) were obtained over the range of 0.5-5000 ng/mL. The assay met the FDA Bioanalytical Guidelines for selectivity and specificity, and low inter-matrix lot variability (<2.7%) was observed for extraction efficiency (77%) and matrix effect (123%) studies. Further, stability tests showed that the analyte does not degrade under working conditions, nor during freezing and thawing processes.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/sangue , COVID-19/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Espectrometria de Massas em Tandem/métodos , Monofosfato de Adenosina/sangue , Alanina/sangue , Cromatografia Líquida de Alta Pressão/economia , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/economia , Feminino , Humanos , Limite de Detecção , Masculino , Espectrometria de Massas em Tandem/economia
18.
Molecules ; 26(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652935

RESUMO

Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has rarely been used in the field of therapeutic drug monitoring, partly because of the complexity of the ionization processes between the compounds to be quantified and the many MALDI matrices available. The development of a viable MALDI-MS method that meets regulatory guidelines for bioanalytical method validation requires prior knowledge of the suitability of (i) the MALDI matrix with the analyte class and properties for ionization, (ii) the crystallization properties of the MALDI matrix with automation features, and (iii) the MS instrumentation used to achieve sensitive and specific measurements in order to determine low pharmacological drug concentrations in biological matrices. In the present hybrid article/white paper, we review the developments required for the establishment of MALDI-MS assays for the quantification of drugs in tissues and plasma, illustrated with concrete results for the different steps. We summarize the necessary parameters that need to be controlled for the successful development of fully validated MALDI-MS methods according to regulatory authorities, as well as currently unsolved problems and promising ways to address them. Finally, we propose an expert opinion on future perspectives and needs in order to establish MALDI-MS as a universal method for therapeutic drug monitoring.


Assuntos
Monitoramento de Medicamentos/métodos , Preparações Farmacêuticas , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Cristalização , Humanos
19.
JAMA Netw Open ; 4(3): e212713, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33755168

RESUMO

Importance: Acute bacterial sinusitis is common, but currently recommended antibiotic treatment provides minimal benefit. Objective: To confirm the previous finding that high-dose amoxicillin plus clavulanate (with double the amount of amoxicillin) may be superior to standard-dose amoxicillin plus clavulanate in adults. Design, Setting, and Participants: This double-blind, comparative-effectiveness randomized clinical trial was conducted from February 26, 2018, through May 10, 2020, at the academic primary care internal medicine and pediatrics practice of Albany Medical Center, located in Cohoes, New York. Participants included adults aged 18 years or older who were prescribed amoxicillin plus clavulanate for acute bacterial sinusitis diagnosed in accordance with the Infectious Diseases Society of America guidelines. Interventions: Amoxicillin 875 mg with clavulanate 125 mg plus either placebo (standard dose) or amoxicillin 875 mg (high dose) twice a day for 7 days. Main Outcomes and Measures: The primary efficacy outcome was a global rating of "a lot better" or "no symptoms" at the end of 3 days of treatment using a Global Rating of Improvement scale, with outcomes ranging from 1 (a lot worse) to 6 (no symptoms). The primary adverse effect outcome was severe diarrhea at 3 or 10 days after the start of treatment. Results: At an unplanned interim analysis prompted by COVID-19 restrictions, 157 of a projected 240 participants had been enrolled (mean age, 48.5 [range, 18.7-84.0] years; 117 women [74.5%]), with 79 randomized to the standard dose and 78 to the high dose; 9 and 12, respectively, withdrew or were lost to follow-up before the assessment of the primary outcome. At day 3, 31 of 70 participants (44.3%) in the standard-dose group reported a global rating of "a lot better" or "no symptoms," as did 24 of 66 (36.4%) in the high-dose group, for a difference of -7.9% (95% CI, -24.4% to 8.5%; P = .35). The study was, therefore, stopped for futility. Diarrhea was common in both groups by day 3, with any diarrhea reported in 29 of 71 participants (40.8%) receiving the standard dose and 28 of 65 (43.1%) receiving the high dose and severe diarrhea reported in 5 of 71 (7.0%) and 5 of 65 (7.7%), respectively. Conclusions and Relevance: The results of this randomized clinical trial suggest that adults treated for clinically diagnosed acute sinusitis did not appear to benefit from taking high-dose compared with standard-dose amoxicillin plus clavulanate. Trial Registration: ClinicalTrials.gov Identifier: NCT03431337.


Assuntos
Amoxicilina , Ácido Clavulânico , Sinusite , Doença Aguda , Amoxicilina/administração & dosagem , Amoxicilina/efeitos adversos , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Ácido Clavulânico/administração & dosagem , Ácido Clavulânico/efeitos adversos , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Método Duplo-Cego , Combinação de Medicamentos , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sinusite/diagnóstico , Sinusite/tratamento farmacológico , Resultado do Tratamento , Inibidores de beta-Lactamases/administração & dosagem , Inibidores de beta-Lactamases/efeitos adversos
20.
Expert Opin Drug Metab Toxicol ; 17(5): 543-554, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33733979

RESUMO

Introduction: Mortality due to severe infections in critically ill patients undergoing continuous renal replacement therapy (CRRT) remains high. Nevertheless, rapid administration of adequate antibiotic therapy can improve survival. Delivering optimized antibiotic therapy can be a challenge, as standard drug regimens often result in insufficient or excessive serum concentrations due to significant changes in the volume of distribution and/or drug clearance in these patients. Insufficient drug concentrations can be responsible for therapeutic failure and death, while excessive concentrations can cause toxic adverse events.Areas covered: We performed a narrative review of the impact of CRRT on the pharmacokinetics of the most frequently used antibiotics in critically ill patients. We have provided explanations for the changes in the PKs of antibiotics observed and suggestions to optimize dosage regimens in these patients.Expert opinion: Despite considerable efforts to identify optimal antibiotic dosage regimens for critically ill patients receiving CRRT, adequate target achievement remains too low for hydrophilic antibiotics in many patients. Whenever possible, individualized therapy based on results from therapeutic drug monitoring must be given to avoid undertreatment or toxicity.


Assuntos
Antibacterianos/farmacocinética , Infecções Bacterianas/tratamento farmacológico , Terapia de Substituição Renal Contínua , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Infecções Bacterianas/mortalidade , Estado Terminal , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...