Switching Vancomycin Monitoring From Trough Concentration to Area Under the Curve Estimation by Bayesian Forecasting: A Short Communication on a Cost-Benefit Study in Resource-Limited Settings.

BACKGROUND: This study was conducted to evaluate the cost-benefit indicators of a vancomycin monitoring protocol based on area under the curve estimation using commercial Bayesian software. METHODS: This quasi-experimental study included patients who were aged >18 years with a vancomycin prescription for >24 hours. Patients who were terminally ill or those with acute kidney injury (AKI) ≤24 hours were excluded. During the preintervention period, doses were adjusted based on the trough concentration target of 15-20 mg/L, whereas the postintervention period target was 400-500 mg × h/L for the area under the curve. The medical team was responsible for deciding to stop the antimicrobial prescription without influence from the therapeutic drug monitoring team. The main outcomes were the incidence of AKI and length of stay. Cost-benefit simulation was performed after statistical analysis. RESULTS: There were 96 patients in the preintervention group and 110 in the postintervention group. The AKI rate decreased from 20% (n = 19) to 6% (n = 6; P = 0.003), whereas the number of vancomycin serum samples decreased from 5 (interquartile range: 2-7) to 2 (interquartile range: 1-3) examinations per patient ( P < 0.001). The mean length of hospital stay for patients was 26.19 days after vancomycin prescription, compared with 17.13 days for those without AKI ( P = 0.003). At our institution, the decrease in AKI rate and reduced length of stay boosted yearly savings of up to US$ 369,000 for 300 patients receiving vancomycin therapy. CONCLUSIONS: Even in resource-limited settings, a commercial Bayesian forecasting-based protocol for vancomycin is important for determining cost-benefit outcomes.

Evaluation of Empiric Voriconazole Dosing and Therapeutic Drug Monitoring in Hospitalized Pediatric Patients.

SUMMARY: Invasive fungal infections are a significant cause of morbidity and mortality in children with immunodeficiencies. Current dosing recommendations for voriconazole often result in subtherapeutic exposure in pediatric patients. In this single-center retrospective study, we reviewed hospitalized pediatric patients receiving voriconazole with at least one inpatient serum trough concentration measured. Patient characteristics and voriconazole dosing courses with associated trough concentrations were summarized for all patients as well as grouped by age (0 to 1 y, 2 to 11 y, and 12 to 18 y). Of 106 included patients, the median age was 9 years (range, 29 d to 18 y). Five hundred ninety courses of voriconazole were administered with 365 associated troughs. Most troughs were subtherapeutic (49%) and 30% of patients never attained a therapeutic trough. The median oral daily dose associated with a therapeutic trough was higher in younger age groups: 21.6 mg/kg 0 to 1 year, 17.9 mg/kg 2 to 11, and 9.5 mg/kg 12 to 18 years ( P <0.001). Patients younger than 2 years had the largest proportion of subtherapeutic troughs and variability in dosing. Attainment of therapeutic voriconazole concentrations was challenging across all pediatric age groups. Higher starting doses for patients younger than 2 years are likely needed.

Standardization and validation of a high-efficiency liquid chromatography with a diode-array detector (HPLC-DAD) for voriconazole blood level determination. / Estandarización y validación de un método de cromatografía líquida de alta eficiencia con detector de arreglo de diodos (HPLC-DAD) para la determinación de niveles sanguíneos de voriconazol

INTRODUCTION: A specialized service for antifungal blood level determination is not available in Colombia. This service is essential for the proper follow-up of antifungal therapies. OBJECTIVE: To standardize and validate a simple, sensitive, and specific protocol based on high-performance liquid chromatography with a diode array detector for voriconazole blood level quantification. MATERIALS AND METHODS: We used an Agilent HPLC™ series-1200 equipment with a UVdiode array detector with an analytical column Eclipse XDB-C18 and pre-column Eclipse- XDB-C18 (Agilent). We used voriconazole as the primary control and posaconazole as an internal control. We performed the validation following the Food and Drug Administration (FDA) recommendations. RESULTS: The best chromatographic conditions were: Column temperature of 25°C, UV variable wavelength detection at 256 nm for voriconazole and 261 nm for posaconazole (internal standard); 50 µl of injection volume, 0,8 ml/min volume flow, 10 minutes of run time, and mobile phase of acetonitrile:water (60:40). Finally, retention times were 3.13 for voriconazole and 5.16 minutes for posaconazole. Quantification range varied from 0.125 µg/ml to 16 µg/ml. CONCLUSION: The selectivity and chromatographic purity of the obtained signal, the detection limits, and the standardized quantification make this method an excellent tool for the therapeutic monitoring of patients treated with voriconazole.

Introducción. Hasta la fecha, Colombia no cuenta con un servicio especializado de medición de niveles séricos de antifúngicos, procedimiento esencial para el adecuado seguimiento del tratamiento de infecciones fúngicas invasoras. Objetivo. Estandarizar y validar un protocolo ­simple, sensible y específico­ basado en la aplicación de cromatografía líquida de alta eficiencia acoplada con un detector de arreglo de diodos para la cuantificación de los niveles séricos de voriconazol. Materiales y métodos. Se usó un equipo HPLC-Agilent™, serie-1200, con un detector UVDAD, una columna analítica Eclipse-XDB-C18 y una pre-columna Eclipse-XDB-C18, ambas de la marca Agilent. Como control primario se utilizó voriconazol y como control interno, posaconazol. La validación se hizo cumpliendo todos los criterios de aceptación recomendados por la Food and Drug Administration (FDA). Resultados. Las mejores condiciones cromatográficas se obtuvieron con los siguientes parámetros: temperatura de la columna de 25 °C, detección UV-VWD de 261 nm, volumen de inyección de 50 µl, flujo de 0,8 ml/minuto y un tiempo de corrido de 10 minutos. La fase móvil usada fue acetonitrilo:agua (60:40) y los tiempos finales de retención fueron de 3,13 para voriconazol y de 5,16 minutos para posaconazol. El rango de cuantificación fue desde 0,125 µg/ml hasta 16 µg/ml. Conclusiones. La selectividad y la pureza de la señal cromatográfica, así como los límites de detección y cuantificación estandarizados hacen de esta metodología una excelente herramienta para el seguimiento terapéutico de pacientes tratados con voriconazol o en profilaxis con este fármaco.

Existing and Emerging Technologies for Therapeutic Monitoring of Lithium: A Scoping Review.

BACKGROUND/PURPOSE: Lithium is an effective psychoactive drug. It has a narrow therapeutic margin, with subtherapeutic levels or intoxication commonly occurring. Therapeutic drug monitoring (TDM) of lithium has several barriers. This scoping review aims to describe and analyze existing and emerging technologies for lithium TDM and to describe the lithium quantification parameters (precision, accuracy, detection limit) attributed to each technology. METHOD: PubMed, Scopus, Web of Science, and Google Scholar were searched. Studies that described lithium quantification and complied with PRISMA-ScR guidelines were included. Articles selection was conducted by 2 researchers. Good precision was defined if its relative standard deviation <3%; acceptable, from 3% to 5%; and low, >5%. Accuracy was considered good if the error <5%; acceptable, 5%1 to 0%; and low if it was >10%. RESULTS: Of the 2008 articles found, 22 met the inclusion criteria. Of these, 14 studies concerned laboratory devices, in which precision was found to be low in one third of cases, and half had good precision. Accuracy of one third was good, another third was low, and the remaining third did not report accuracy. The other 8 studies concerned portable devices, in which precision was low in more than 60% of the cases and good in 25% of the studies. Accuracy was low in 50% of the cases, and good in just over a third. Limits of detection included the therapeutic range of lithium in all studies. CONCLUSIONS: Among emerging technologies for lithium TDM, precision and accuracy remain a challenge, particularly for portable devices.

[Validation of the immunological method of kinetic interaction of microparticles in solution (KIMS) for the determination of phenytoin in saliva at the Hospital de Niños de Santísima Trinidad.] / Validación del método inmunológico de interacción cinética de micropartículas en solución (KIMS) para la determinación de fenitoína en saliva en el hospital de Niños de la Santísima Trinidad.

Phenytoin (DFH), is an anticonvulsant widely used for the treatment of different types of seizures.(1) Therapeutic monitoring (TDM) is required for DFH due to its narrow therapeutic range and nonlinear pharmacokinetics, among other characteristics. Monitoring is frequently done on plasma or serum (total drug) through immunological methods. DFH can also be monitored in saliva, which shows a good correlation with plasma. The concentration of DFH in saliva reflects the concentration of free drug and due to the simplicity in its collection, it leads to a less stressful process for the patient. The aim of this study was to validate the immunological method of kinetic interaction of microparticles in solution (KIMS) for the determination of DFH using saliva as biological matrix. Linearity, precision, detection and quantification limit, accuracy and interference were analyzed. Infostat 8.0 student version software was used for statistical analysis. The method was linear in a range between 0.41 and 5ug/ml. The detection and quantification limits were 0.14 and 0.45ug/ml, respectively. The equation of the straight line obtained based on the method comparison between KIMS and HPLC-UV was DFHKIMS= 0,81* DFHHPLC ­ 0,03.  The KIMS method proved to have the necessary analytical characteristics to be applied as a useful and practical tool for the follow-up of those patients with difficult venous access and/or children with chronic DFH treatments.

La Fenitoína (DFH), es un anticonvulsivante ampliamente utilizado para el tratamiento de distintos tipos de convulsiones.(1) El monitoreo terapéutico (TDM) es requerido para la DFH debido a su estrecho rango terapéutico y farmacocinética no lineal, entre otras características. Los monitoreos se realizan frecuentemente en plasma o suero (droga total) a través de métodos inmunológicos. También se puede monitorear DFH en saliva, la cual presenta una buena correlación con el plasma. La concentración de DFH en saliva refleja la concentración de droga libre y debido a la simplicidad en su recolección, conlleva a un proceso menos estresante para el paciente. El objetivo del trabajo fue validar el método inmunológico de interacción cinética de micropartículas en solución (KIMS) para la determinación de DFH usando como matriz biológica saliva. Se analizó linealidad, precisión, límite de detección y cuantificación, exactitud e interferencia. Se utilizó el software Infostat 8.0 versión estudiantil para el análisis estadístico. El método fue lineal en un intervalo entre 0,41 y 5ug/ml. Los límites de detección y cuantificación fueron 0,14 y 0,45ug/ml respectivamente. La ecuación de la recta obtenida en base a la comparación de métodos entre KIMS y HPLC-UV fue DFHKIMS= 0,81* DFHHPLC - 0,03.  El método KIMS demostró tener las características analíticas necesarias paran ser aplicada como herramienta útil y práctica para el seguimiento de aquellos pacientes de difícil acceso venoso y/o niños con tratamientos crónicos con DFH.

Dried blood spot sampling for therapeutic drug monitoring: challenges and opportunities.

INTRODUCTION: The use of dried blood spots (DBS) has gained interest in the field of therapeutic drug monitoring (TDM) due to its potential advantages, such as minimally invasive capillary blood collection, potential stabilization of drugs and metabolites at room or high temperatures, and lower biohazard, allowing for inexpensive storage and transportation. However, there are several drawbacks to the clinical use of DBS in TDM, mostly related to hematocrit (Hct) effects, differences between venous and capillary blood concentrations, among others, that must be evaluated during analytical and clinical method validation. AREA COVERED: This review focuses on the most recent publications on the applications of DBS sampling for TDM (2016-2022), with a special focus on the challenges presented by this alternative sampling strategy, as well as the opportunities for clinical applications. Real-life studies presenting clinical applications were reviewed. EXPERT OPINION: With the availability of method development and validation guidelines for DBS-based methods in TDM, higher levels of assay validation standardization have been achieved, expanding the clinical applications of DBS sampling in patient care. New sampling devices that overcome the limitations of classical DBS, such as the Hct effects, will further encourage the use of DBS in routine TDM.

Development and validation of a dried plasma spot LC-MS/MS method for therapeutic monitoring of vancomycin and comparison with enzyme-multiplied immunoassay.

Vancomycin is used as an antimicrobial agent for the treatment of severe gram-positive infections. The importance of therapeutic monitoring of antimicrobials has led to the development of more specific sample preparation techniques capable of identifying with accuracy the concentration of this substance in the organism. An aliquot of 10 µl of plasma was transferred to Whatman 903 paper and dried at room temperature. The extraction method was performed by cutting and transferring the paper to a microtube and adding sodium phosphate buffer and internal standard. The mixture was shaken and centrifuged, and a 5-µl aliquot was injected into the analytical system. The optimization of the main parameters that can influence the extraction efficiency was performed using multivariate approaches to obtain the best conditions. The method developed was validated, providing coefficients of determination higher than 0.994 and a lower limit of quantification of 1 mg/L. Within- and between-run precision ranged from 11.4 to 17.30% and from 6.65 to 13.51%, respectively. This method was successfully applied to 75 samples of patients undergoing vancomycin therapy. The method was rapid, simple, and environmentally friendly with satisfactory analytical performance and was advantageous over the laborious and time-consuming methodologies used in therapeutic drug monitoring routine analyses.

Drug-drug interactions of immunosuppressants and other drugs in kidney post-transplant recipients

Introduction: Immunosuppressants (ISS) are the most crucial tools used in the therapeutic regimens of transplant recipients. Nevertheless, these drugs are not the only ones adopted by patients; therefore, knowing the possible drug-drug interactions (DDIs) between immunosuppressants and other drugs commonly used in kidney transplant recipients is essential to ensure the effectiveness and safety of treatments. In this way, the objective is analyzing the DDIs between the immunosuppressants and other commonly used medications on kidney transplant adult recipients with active medical records undergoing post-transplant follow-up for 4.4 years (mean). Methods: First, we performed a cross-sectional study based on patients' records, in which the patient's profile and drugs used were examined, and after we analyzed DDIs by the Micromedex Drug Interactions® database. Results: We analyzed 176 patients with a mean age of 47.6(± 12.5); most were male (67.7%), and the majority received a kidney from a deceased donor (81.4%). Patients were exposed to 15.0 (± 5.4) different medicines after the transplantation, and 7.4 (± 4.0) of these medicines were simultaneous. After analyzing the DDIs according to the severity of interaction, documentation quality interaction effect, clinical management and probable interaction mechanism, the most frequent interaction was with tacrolimus, classified as moderate, and the 3 major causes of interaction occurred with azathioprine according to the Micromedex database. The primary medicines involved with immunosuppressant interactions were proton pump inhibitors, ranitidine, domperidone, amlodipine, enalapril, allopurinol, cyclobenzaprine, amitriptyline, fluoxetine, and ciprofloxacin. These DDIs' effects were related to, mainly, increase their immunosuppressant activity. Conclusion: Although the immunosuppressants analyzed lacked many clinical DDIs significance with other medicines, the healthcare team needs to monitor their DDIs' effects to prevent and minimize side effects in transplanted recipients.

Thalidomide measurement in plasma and dried plasma spot by SPE combined with UHPLC-MS/MS for therapeutic drug monitoring.

Aims: To validate an SPE-ultra-HPLC-MS/MS method for thalidomide (THD) measurement in dried plasma spot (DPS). Methods: Extraction included acetonitrile/water clean-up and online SPE. The LOD, LLOQ, linearity, precision, accuracy, recovery, matrix effect, process efficiency, carryover, stability, drug interference and dilution integrity were assessed. Results: The method was linear from 50 to 2000 ng/ml with a LOD of 20 ng/ml and LLOQ of 50 ng/ml. The coefficient of variation for precision was 0.4-7.9% for intra-assay and 1.3-8.9% for interassay, and accuracy was 81.4-97.1%. Adequate matrix effect (100.6-107.0%), recovery (88.7-105.0%) and process efficiency (91.3-109.3%) were registered. DPS was stable for 14 days at room temperature and 45°C ,and for 4 months at -80°C. The method was applied to quantify THD in both wet plasma and DPS from patients with cutaneous lupus receiving THD treatment. The difference between THD wet plasma and DPS concentration was <15%. Conclusion: The method is suitable to quantify THD in DPS.

CoaguChek® XS versus standard laboratory prothrombin time for anticoagulant monitoring in patients with antiphospholipid syndrome.

INTRODUCTION: The standard of care for thrombotic antiphospholipid syndrome (APS) is anticoagulation with vitamin K antagonists (VKAs). Prothrombin time, and its corresponding international normalized ratio (INR), is the laboratory test routinely performed to assess anticoagulation. Self-management of VKA therapy using point-of-care (POC) devices seems to be an attractive option. PURPOSE/OBJECTIVE: To evaluate the accuracy of a POC device (CoaguChek XS) in APS patients by comparing it with venous laboratory INR. Furthermore, we analyzed whether other clinical and laboratory features could interfere with the CoaguChek XS results. PATIENTS AND METHODS: This is a single-center cross-sectional study with 94 APS patients from a tertiary rheumatology clinic performed from August 2014 to March 2015. The comparison between CoaguChek XS and venous laboratory INR results was evaluated using the coefficient of determination (r) followed by the Bland-Altman test. A paired t-test was also applied. A difference of up to ±0.5 INR unit between the two systems was considered clinically acceptable. RESULTS: The mean CoaguChek-INR was 2.94 ± 1.41 and venous laboratory INR was 2.43±0.86, with a correlation coefficient (r) of 0.95. Categorizing INR values in ranges (INR <2, INR 2-3, INR 3-4, and INR >4), we found that the INR >4 group presented a lower correlation (r = 0.64) compared to the other ranges (p < 0.05). Although both methods were highly correlated, CoaguChek XS showed higher values than the venous laboratory INR, with an increased average of 0.42 ± 0.54. Therefore, we proposed a simple linear regression model to predict the venous laboratory INR values, using results obtained from CoaguChek XS. A difference ≤0.5 INR unit between the two systems was observed in 57.4% of patients, and the aPL profile did not influence the results. CONCLUSION: Although CoaguChek XS and venous laboratory INR demonstrated a good linear correlation in the group of INR ≤4, extra caution should be taken in APS patients, since a reasonable proportion of patients can present differences in INR results that are not acceptable. We do not recommend routine POC in APS patients.

Role of heme oxygenase-1 in the antidepressant-like effect of ursolic acid in the tail suspension test.

OBJECTIVES: This study investigated the involvement of heme oxygenase-1 (HO-1) in the antidepressant-like effects of ursolic acid (UA), a plant-derived compound with neuroprotective and antidepressant-like properties. METHODS: Mice received intracerebroventricular injections of zinc protoporphyrin IX (ZnPP) or cobalt protoporphyrin IX (CoPP) to inhibit or induce HO-1, respectively, together with effective (0.1 mg/kg, p.o.) or sub-effective (0.01 mg/kg, p.o.) doses of UA or fluoxetine (10 mg/kg, p.o.). Immobility time was assessed using the tail suspension test (TST) and the ambulatory behaviour with the open field test. HO-1 immunocontent was evaluated in mice hippocampus and prefrontal cortex. KEY FINDINGS: ZnPP prevented the anti-immobility effects of UA and fluoxetine. Combined treatment with a sub-effective dose of CoPP and UA synergistically exerted antidepressant-like effects in the TST. Acute administration of UA or CoPP, but not fluoxetine, increased the HO-1 immunocontent in the hippocampus. None of the treatments altered the HO-1 immunocontent in the prefrontal cortex. CONCLUSIONS: In conclusion, this work shows that increased hippocampal HO-1 content and activity mediate the antidepressant-like effect of UA in the TST.

Comparative analysis of the use and control of thalidomide in Brazil and different countries: is it possible to say there is safety?

INTRODUCTION: One of the biggest drug disasters in history has not prevented thalidomide from being used to treat various clinical conditions. Currently, Brazil has a worrying scenario: high consumption of the drug and, cases of pregnant women using thalidomide, even after adopting restrictive legislation. AREAS COVERED: This review of the literature and legislation sought to comparatively analyze the monitoring of thalidomide use in Brazil and other countries that use this drug. Finally, we discuss the differences between the countries. EXPERT OPINION: This analysis allows us to think beyond the safe use of thalidomide, but the safety provided by any type of monitoring system. It seems that out-patients that use unsafe drugs are exposed to some degree of risk. To improve safety, more extensive improvements are needed than monitoring systems related to the use of thalidomide. Its safe use depends on a drastic reduction in the incidence of leprosy and Erythema Nodosum Leprosum in the world; investment in research and development of safe and effective therapeutic alternatives to thalidomide; improvement of health systems and their health surveillance systems, particularly in primary health care; awareness of health professionals and patients for greater responsibility in the use of medicines, especially thalidomide.

Leukocytes from Patients with Drug-Sensitive and Multidrug-Resistant Tuberculosis Exhibit Distinctive Profiles of Chemokine Receptor Expression and Migration Capacity.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains as a leading infectious cause of death worldwide. The increasing number of multidrug-resistant TB (MDR-TB) cases contributes to the poor control of the TB epidemic. Currently, little is known about the immunological requirements of protective responses against MDR-TB. This is of major relevance to identify immune markers for treatment monitoring and targets for adjuvant immunotherapies. Here, we hypothesized that MDR-TB patients display unique immunophenotypical features and immune cell migration dynamics compared to drug-sensitive TB (DS-TB). Hence, we prospectively conducted an extensive characterization of the immune profile of MDR-TB patients at different time points before and after pharmacological therapy. For this purpose, we focused on the leukocyte expression of chemokine receptors, distribution of different monocyte and lymphocyte subsets, plasma levels of chemotactic factors, and in vitro migration capacity of immune cells. Our comparative cohort consisted of DS-TB patients and healthy volunteer donors (HD). Our results demonstrate some unique features of leukocyte migration dynamics during MDR-TB. These include increased and prolonged circulation of CD3+ monocytes, CCR4+ monocytes, EM CD4+ T cells, EM/CM CD8+ T cells, and CXCR1+CXCR3+ T cells that is sustained even after the administration of anti-TB drugs. We also observed shared characteristics of both MDR-TB and DS-TB that include CCR2+ monocyte depletion in the blood; high plasma levels of MPC-1, CCL-7, and IP-10; and increased responsiveness of leukocytes to chemotactic signals in vitro. Our study contributes to a better understanding of the MDR-TB pathobiology and uncovers immunological readouts of treatment efficacy.

Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial.

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.

Examining therapeutic equivalence between branded and generic warfarin in Brazil: The WARFA crossover randomized controlled trial.

OBJECTIVES: To determine whether the generic and branded warfarins used as anticoagulants in Brazil are therapeutic equivalents based on their international normalized ratio (INR) results. METHODS: This crossover randomized controlled trial had four periods. We used the branded Marevan and two generic versions of warfarin sodium tablets, manufactured by União Química and Teuto laboratories, all purchased from retail drugstores. Eligible participants were outpatients from an anticoagulation clinic at a university hospital in São Paulo, Brazil. They had atrial fibrillation or flutter and had been using warfarin for at least 2 months with an INR therapeutic range of 2.0-3.0. Randomization was by numbered, opaque, sealed envelopes. Healthcare personnel and outcome assessors were blinded to treatments, but patients were not. The primary outcome was the variability in the INR (ΔINR) and secondary outcomes included mean INR. We accepted formulations as equivalent if the 95% confidence interval (CI) of the comparison of ΔINR between branded and generic formulations was within the limit of ±0.49. RESULTS: One hundred patients were recruited and randomized to six sequences of treatment (four sequences with n = 17 and two sequences with n = 16). União Química generic warfarin had equivalent variability in the INR to Marevan (ΔINR +0.09 [95% CI -0.29 to +0.46], n = 84). Comparison between Teuto generic warfarin and Marevan was inconclusive (ΔINR +0.29 [95% CI -0.09 to +0.68], n = 84). CONCLUSIONS: Marevan and União Química warfarin had equivalent therapeutic effectiveness and both could be confidently used for anticoagulation. The comparison between Marevan and TW was inconclusive and does not warrant a statement of equivalence. Our methods are especially important for comparing generic and branded drugs that raise concerns and may be subject of future investigations by regulatory agents. TRIAL REGISTRATION: ClinicalTrials.gov NCT02017197.

Machine Learning-based Prediction Model for Treatment of Acromegaly With First-generation Somatostatin Receptor Ligands.

CONTEXT: Artificial intelligence (AI), in particular machine learning (ML), may be used to deeply analyze biomarkers of response to first-generation somatostatin receptor ligands (fg-SRLs) in the treatment of acromegaly. OBJECTIVE: To develop a prediction model of therapeutic response of acromegaly to fg-SRL. METHODS: Patients with acromegaly not cured by primary surgical treatment and who had adjuvant therapy with fg-SRL for at least 6 months after surgery were included. Patients were considered controlled if they presented growth hormone (GH) <1.0 ng/mL and normal age-adjusted insulin-like growth factor (IGF)-I levels. Six AI models were evaluated: logistic regression, k-nearest neighbor classifier, support vector machine, gradient-boosted classifier, random forest, and multilayer perceptron. The features included in the analysis were age at diagnosis, sex, GH, and IGF-I levels at diagnosis and at pretreatment, somatostatin receptor subtype 2 and 5 (SST2 and SST5) protein expression and cytokeratin granulation pattern (GP). RESULTS: A total of 153 patients were analyzed. Controlled patients were older (P = .002), had lower GH at diagnosis (P = .01), had lower pretreatment GH and IGF-I (P < .001), and more frequently harbored tumors that were densely granulated (P = .014) or highly expressed SST2 (P < .001). The model that performed best was the support vector machine with the features SST2, SST5, GP, sex, age, and pretreatment GH and IGF-I levels. It had an accuracy of 86.3%, positive predictive value of 83.3% and negative predictive value of 87.5%. CONCLUSION: We developed a ML-based prediction model with high accuracy that has the potential to improve medical management of acromegaly, optimize biochemical control, decrease long-term morbidities and mortality, and reduce health services costs.

Meropenem use and therapeutic drug monitoring in clinical practice: a literature review.

WHAT IS KNOWN AND OBJECTIVE: Meropenem, a carbapenem antibiotic, is widely prescribed for the treatment of life-threatening infections. The main parameter associated with its therapeutic success is the percentage of time that the levels remain above the minimum inhibitory concentration. Inadequate levels of meropenem can lead to therapeutic failure and increase the possibility of microbial resistance. The employment of strategies involving dose regimens and drug pharmacodynamics has become increasingly important to optimize therapies. In the present study, we conducted a review with the purpose of assembling information about the clinical use of meropenem and therapeutic drug monitoring. METHODS: A literature review emphasizing the application of therapeutic drug monitoring (TDM) of meropenem in clinical practice has been done. To identify articles related to the topic, we performed a standardized search from January 21, 2020 to December 21, 2020, using specific descriptors in PubMed, Lilacs and Embase. RESULTS AND DISCUSSION: In total, 35 studies were included in the review. The daily dose of meropenem commonly ranged from 3 to 6 g/day. Critically ill patients and those with impaired renal function appear to be the most suitable patients for the application of meropenem TDM, in order to guide therapy. We observed that most of the studies recommend TDM and that, in nine locations, the TDM of meropenem and of other beta-lactams is a routine practice. TDM data can help to maximize the clinical outcomes of the treatment with meropenem. It can also improve the patient care by providing suitable levels of meropenem, guiding the most appropriate dose regimens, which is the main parameter associated with therapeutic success. WHAT IS NEW AND CONCLUSION: The findings from this review suggest that the therapeutic monitoring of meropenem can be beneficial, since it adjusts the treatment and aids clinical outcomes. It does so by indicating the appropriate dosage and preventing failure, toxicity and possible antimicrobial resistance. The multidisciplinary effort, basic knowledge and communication among the medical team are also essential.

Neural and subjective effects of inhaled N,N-dimethyltryptamine in natural settings.

BACKGROUND: N,N-dimethyltryptamine is a short-acting psychedelic tryptamine found naturally in many plants and animals. Few studies to date have addressed the neural and psychological effects of N,N-dimethyltryptamine alone, either administered intravenously or inhaled in freebase form, and none have been conducted in natural settings. AIMS: Our primary aim was to study the acute effects of inhaled N,N-dimethyltryptamine in natural settings, focusing on questions tuned to the advantages of conducting field research, including the effects of contextual factors (i.e. "set" and "setting"), the possibility of studying a comparatively large number of subjects, and the relaxed mental state of participants consuming N,N-dimethyltryptamine in familiar and comfortable settings. METHODS: We combined state-of-the-art wireless electroencephalography with psychometric questionnaires to study the neural and subjective effects of naturalistic N,N-dimethyltryptamine use in 35 healthy and experienced participants. RESULTS: We observed that N,N-dimethyltryptamine significantly decreased the power of alpha (8-12 Hz) oscillations throughout all scalp locations, while simultaneously increasing power of delta (1-4 Hz) and gamma (30-40 Hz) oscillations. Gamma power increases correlated with subjective reports indicative of some features of mystical-type experiences. N,N-dimethyltryptamine also increased global synchrony and metastability in the gamma band while decreasing those measures in the alpha band. CONCLUSIONS: Our results are consistent with previous studies of psychedelic action in the human brain, while at the same time the results suggest potential electroencephalography markers of mystical-type experiences in natural settings, thus highlighting the importance of investigating these compounds in the contexts where they are naturally consumed.

Simultaneous quantification of cyclosporin, tacrolimus, sirolimus and everolimus in whole blood by UHPLC-MS/MS for therapeutic drug monitoring.

The aim of this study was to develop and validate a UHPLC-MS/MS assay to quantify cyclosporin (CYC), tacrolimus (TAC), sirolimus (SIR) and everolimus (EVE) in human whole blood for therapeutic drug monitoring. Analytes were extracted from 50 µL human whole blood by protein precipitation. The separation of the drugs was performed on an Acquity UPLC BEH C18 column. Analytes were eluted with a mobile phase consisting of 2 mM ammonium acetate with 0.1% formic acid (v/v) in deionised water and 2 mM ammonium acetate with 0.1% formic acid (v/v) in methanol at a flow rate of 300 µL/min in gradient elution. The method performance was evaluated by analysing patient blood samples and/or external quality control samples [proficiency testing (PT) scheme]. The method was linear from 23.75 to 1094.0, 1.3 to 42.4, 1.3 to 47.0 and 1.2-41.6 µg/mL for CYC, TAC, SIR and EVE, respectively. The within- and between-assay reproducibility results were ˂ 11%. Results from PT and patient sample quantification were comparable to those obtained previously by an in-house validated method using protein precipitation and liquid-liquid extraction. This method showed good analytical performance for quantifying CYC, TAC, SIR and EVE in whole blood over their respective calibration ranges.