Rapid and simultaneous determination of ten anti-tuberculosis drugs in human plasma by UPLC-MS/MS with applications in therapeutic drug monitoring.

Tuberculosis remains a global challenge, particularly with a growing number of resistant cases, which may become an obstacle to eliminating this disease. Standardized short-course therapy composed of first-line anti-tuberculosis drugs isoniazid (INH), rifampicin (RIF), ethambutol (EMB), and pyrazinamide (PZA) is playing vital roles for curbing the rapid spread of tuberculosis. However, some patients have poor responses to standardized short-course therapy. As the number of drug-resistant tuberculosis increase, some other anti-tuberculous drugs are needed to achieve better treatment outcomes. In this study, we established a UPLC-MS/MS method for simultaneous detection of ten anti-tuberculosis drugs in human plasma including INH, EMB, PZA, RIF, rifampin, rifapentine as well as four second-line antituberculosis drugs, i.e. ethionamide, protionamide, thiosemicarbazone and clofazimine. This study contains almost all the commonly used anti-tuberculosis drugs. The plasma samples were treated with acetonitrile to precipitate proteins, and doped with the isotope internal standard. A Shiseido CAPCELL RAK-ADME (2.1 mm × 50 mm, 3 µm) column was used for chromatographic separation, and acetonitrile-water (containing 0.1% formic acid) was the mobile phase. The separation used gradient elution with a flow rate of 0.4 mL/min. The column temperature was 40 °C, and the sample volume was 1 µL. The electrospray ionization source (ESI) and the positive ion multiple reaction monitoring (MRM) mode were used for the detection. The analysis time was as short as 7 min. The results show a good linear relationship under optimized conditions in the range of 5.00-7.50 × 103, 1.00-1.50 × 103, 5.00-5.00 × 104, 5.00-7.50 × 103, 1.00-3.00 × 103, 1.00 × 101-1.00 × 104, 1.00-3.00 × 103, 1.00-3.00 × 103, 2.00-4.00 × 103, and 1.00 × 10-1-2.00 × 102 ng/mL for INH, EMB PZA, RIF, rifabutin, rifapentine, ethionamide, protionamide, thiosemicarbazone, and clofazimine, respectively, with a linear correlation coefficient of R > 0.99. Finally, 34 patients with pulmonary TB were tested for therapeutic drug monitoring. The results showed that the presented method have significant advances in sensitivity, separation efficiency and simplicity.

Clinical Applicability of Monitoring Antihypertensive Drug Levels in Blood.

Dried blood spot (DBS) analysis is a novel analytical method for therapeutic drug monitoring to identify nonadherence to antihypertensive drugs. This study was conducted to evaluate the clinical applicability of measuring drug concentrations of 8 antihypertensive drugs, using DBS and venipuncture. Furthermore, this study aimed to provide more insight into the between-patient variability in drug concentrations. False-negative values from DBS compared with a venipuncture were determined to assess drug adherence. A generalized estimating equation was used to estimate the model parameters, including sex, dose, age, weight, and the time interval, between drug intake and sampling, on the Cplasma (drug concentration in plasma). No false-negative values were found when measuring nonadherence using DBS compared with venipuncture. A high variability in Cplasma between patients was observed, especially at peak concentrations with a fold change reaching from 2.3 to 35.2. The time of intake was significantly related to the height of the Cplasma in 7 of the 8 measured drugs with a P<0.05, but the influence of dose, weight, age, and sex on drug levels differed largely between the measured drugs. DBS is a reliable and convenient method to assess nonadherence to antihypertensive drugs in clinical practice. The Cplasma of the 8 antihypertensive drugs in this study show a large interindividual difference, and therefore, low plasma concentrations do not necessarily mean nonadherence. Nonadherence can only be confirmed if drug levels are undetectable, that is, values below the lower limit of detection.

Monitoring evidence on overall survival benefits of anticancer drugs approved by the European Medicines Agency between 2009 and 2015.

OBJECTIVE: The introduction provisional approval strategies increases the approval of anticancer drugs with ambiguous benefit-risk profiles. Thus, in many instances, there is lacking evidence about overall survival (OS) at the time of marketing authorisation. Our objective was to monitor and characterise therapies with ambiguous benefit-risk profiles and identify any postapproval updates on median OS after at least 3 years of approval by the European Medicines Agency (EMA). METHODS: We included all originator anticancer drugs with initially ambiguous benefit-risk profiles that received marketing authorisation by the EMA between January 1, 2009 and May 31, 2015. Our monitoring timeframe was at least 3 years after EMA approval. To identify study updates, the following three sources were included: clinicaltrials.gov, European Public Assessments Reports and PubMed. RESULTS: In total, we identified 102 eligible approval studies. Out of these, a negative difference in median OS or no information was available in 43 (42.2%) instances. During monitoring, 14 updates with accessible positive information on OS could be identified. Including monitoring results, there are still 29 remaining therapies (28.4%) where no or negative information (n = 24 [23.5%] and n = 5 [4.9%], respectively) regarding OS is present at least 3 years after EMA approval. CONCLUSION: One-third of oncology drugs with ambiguous benefit-risk profiles at the time of approval fail to demonstrate a survival benefit even after several years of marketing authorisation. Systematic and transparent postapproval monitoring mechanisms will be of high relevance to assure a clinically relevant patient benefit, since the trend towards faster access to medicines with uncertain benefit is increasing rather than declining.

Bioelectrical impedance analysis for monitoring cancer patients receiving chemotherapy and home parenteral nutrition.

BACKGROUND: Home parenteral nutrition (HPN) can improve survival, quality of life, nutritional and functional status in cancer patients. Bioelectrical impedance analysis (BIA) is a non-invasive, validated method to assess body composition. The objective of this prospective single-arm study was to investigate the impact of HPN in advanced cancer patients receiving chemotherapy assessed by BIA, clinical and laboratory measures. METHODS: Adult malnourished cancer outpatients with solid tumors receiving anticancer treatments who were candidates for daily HPN were enrolled. Patients were assessed at baseline (T0), 60 (T1) and 90 days (T2) after HPN start. Assessments included anthropometric and clinical-oncological characteristics, performance status, inflammatory response and Patient-Generated Subjective Global Assessment (PG-SGA). RESULTS: Sixty-five advanced cancer patients were enrolled. Median overall survival was 317 days. Body weight, BMI, oral calorie and protein intake increased over time (P < 0.01). At T2 the proportion of well-nourished patients, Karnofsky performance status and modified Glasgow prognostic score were improved (P < 0.01), total body water was reduced (P = 0.04), and fat mass increased (P = 0.04). Reactance, resistance and phase angle were significantly associated with survival at T0, T1, and T2, respectively. At T2, PG-SGA category A was a predictor of survival (P < 0.0001). CONCLUSIONS: After 90 days of HPN, patients experienced significantly improved nutritional status, performance status, prognostic score and some BIA measures. HPN may be an important therapy in oncology patients receiving chemotherapy. Longitudinal use of BIA may help track the effects of HPN and disease progression, potentially contributing to optimal global patient management.

Implementation Of Prescription Drug Monitoring Programs Associated With Reductions In Opioid-Related Death Rates.

Over the past two decades the number of opioid pain relievers sold in the United States rose dramatically. This rise in sales was accompanied by an increase in opioid-related overdose deaths. In response, forty-nine states (all but Missouri) created prescription drug monitoring programs to detect high-risk prescribing and patient behaviors. Our objectives were to determine whether the implementation or particular characteristics of the programs were effective in reducing opioid-related overdose deaths. In adjusted analyses we found that a state's implementation of a program was associated with an average reduction of 1.12 opioid-related overdose deaths per 100,000 population in the year after implementation. Additionally, states whose programs had robust characteristics-including monitoring greater numbers of drugs with abuse potential and updating their data at least weekly-had greater reductions in deaths, compared to states whose programs did not have these characteristics. We estimate that if Missouri adopted a prescription drug monitoring program and other states enhanced their programs with robust features, there would be more than 600 fewer overdose deaths nationwide in 2016, preventing approximately two deaths each day.

Monitorización y biopsia / Monitoring and biopsy

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