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Nifedipine is used for treating mild to severe hypertension and preventing preterm labor in pregnant women. Nevertheless, concerns about nifedipine fetal exposure and safety are always raised. The aim of this study was to develop and validate a maternal-placental-fetal nifedipine physiologically based pharmacokinetic (PBPK) model and apply the model to predict maternal, placental, and fetal exposure to nifedipine at different pregnancy stages. A nifedipine PBPK model was verified with nonpregnant data and extended to the pregnant population after the inclusion of the fetoplacental multicompartment model that accounts for the placental tissue and different fetal organs within the Simcyp Simulator version 22. Model parametrization involved scaling nifedipine transplacental clearance based on Caco-2 permeability, and fetal hepatic clearance was obtained from in vitro to in vivo extrapolation encompassing cytochrome P450 3A7 and 3A4 activities. Predicted concentration profiles were compared with in vivo observations and the transplacental transfer results were evaluated using 2-fold criteria. The PBPK model predicted a mean cord-to-maternal plasma ratio of 0.98 (range, 0.86-1.06) at term, which agrees with experimental observations of 0.78 (range, 0.59-0.93). Predicted nifedipine exposure was 1.4-, 2.0-, and 3.0-fold lower at 15, 27, and 39 weeks of gestation when compared with nonpregnant exposure, respectively. This innovative PBPK model can be applied to support maternal and fetal safety assessment for nifedipine at various stages of pregnancy.

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Monitoring of clinical trials is critical to the protection of human subjects and the conduct of high-quality research. Even though the adoption of risk-based monitoring (RBM) has been suggested for many years, the RBM approach has been less widespread than expected. Centralized monitoring is one of the RMB pillars, together with remote-site monitoring visits, reduced Source Data Verification (SDV) and Source Document Reviews (SDR). The COVID-19 pandemic promoted disruptions in the conduction of clinical trials, as on-site monitoring visits were adjourned. In this context, the transition to RBM by all actors involved in clinical trials has been encouraged. In order to ensure the highest quality of data within a COVID-19 clinical trial, a centralized monitoring tool alongside Case Report Forms (CRFs) and synchronous automated routines were developed at the clinical research platform, Fiocruz, Brazilian Ministry of Health. This paper describes how these tools were developed, their features, advantages, and limitations. The software codes, and the CRFs are available at the Fiocruz Data Repository for Research-Arca Dados, reaffirming Fiocruz's commitment to Open Science practices.

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Microfluidic cotton thread-based electroanalytical devices (µTEDs) are analytical systems with attractive features such as spontaneous passive flow, low cost, minimal waste production, and good sensitivity. Currently, sample injection in µTEDs is performed by hand using manual micropipettes, which have drawbacks such as inconstant speed and position, dependence of skilled analysts, and need of physical effort of operator during prolonged times, leading to poor reproducibility and risk of strain injury. As an alternative to these inconveniences, we propose, for the first time, the use of electronic micropipettes to carry out automated injections in µTEDs. This new approach avoids all disadvantages of manual injections, while also improving the performance, experience, and versatility of µTEDs. The platform developed here is composed by three 3D-printed electrodes (detector) attached to a 3D-printed platform containing an adjustable holder that keeps the electronic pipette in the same x/y/z position. As a proof-of-concept, both injection modes (manual and electronic) were compared using three model analytes (nitrite, paracetamol, and 5-hydroxytryptophan) on µTED with amperometric detection. As result, improved analytical performance (limits of detection between 2.5- and 5-fold lower) was obtained when using electronic injections, as well as better repeatability/reproducibility and higher analytical frequencies. In addition, the determination of paracetamol in urine samples suggested better precision and accuracy for automated injection. Thus, electronic injection is a great advance and changes the state-of-art of µTEDs, mainly considering the use of more modern and versatile electronic pipettes (wider range of pre-programmed modes), which can lead to the development of even more automated systems.

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The development of miniaturized, sustainable and eco-friendly analytical sensors with low production cost is a current trend worldwide. Within this idea, this work presents  the innovative use of masked stereolithography (MSLA) 3D-printed substrates for the easy fabrication of pencil-drawn electrochemical sensors (MSLA-3D-PDE). The use of a non-toxic material such as pencil (electrodes) together with a biodegradable 3D printing resin (substrate) allowed the production of devices that are quite cheap (ca. US$ 0.11 per sensor) and with low environmental impact. Compared to paper, which is the most used substrate for manufacturing pencil-drawn electrodes, the MSLA-3D-printed substrate has the advantages of not absorbing water (hydrophobicity) or becoming crinkled and weakened when in contact with solutions. These features provide more reproducible, reliable, stable, and long-lasting sensors. The MSLA-3D-PDE, in conjunction with the custom cell developed, showed excellent robustness and electrochemical performance similar to that observed of the glassy carbon electrode, without the need of any activation procedure. The analytical applicability of this platform was explored through the quantification of omeprazole in pharmaceuticals. A limit of detection (LOD) of 0.72 µmol L-1 was achieved, with a linear range of 10 to 200 µmol L-1. Analysis of real samples provided results that were highly concordant with those obtained by UV-Vis spectrophotometry (relative error ≤ 1.50%). In addition, the greenness of this approach was evaluated and confirmed by a quantitative methodology (Eco-Scale index). Thus, the MSLA-3D-PDE appears as a new and sustainable tool with great potential of use in analytical electrochemistry.

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Casearia species are found in the America, Africa, Asia, and Australia and present pharmacological activities, besides their traditional uses. Here, we reviewed the chemical composition, content, pharmacological activities, and toxicity of the essential oils (EOs) from Casearia species. The EO physical parameters and leaf botanical characteristics were also described. The bioactivities of the EOs from the leaves and their components include cytotoxicity, anti-inflammatory, antiulcer, antimicrobial, antidiabetic, antioxidant, antifungal, and antiviral activities. The main components associated with these activities are the α-zingiberene, (E)-caryophyllene, germacrene D, bicyclogermacrene, spathulenol, α-humulene, ß-acoradiene, and δ-cadinene. Data on the toxicity of these EOs are scarce in the literature. Casearia sylvestris Sw. is the most studied species, presenting more significant pharmacological potential. The chemical variability of EOs components was also investigated for this species. Caseria EOs have relevant pharmacological potential and must be further investigated and exploited.

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Oral preparations of Casearia sylvestris (guacatonga) are used as antacid, analgesic, anti-inflammatory, and antiulcerogenic medicines. The clerodane diterpenes casearin B and caseargrewiin F are major active compounds in vitro and in vivo. The oral bioavailability and metabolism of casearin B and caseargrewiin F were not previously investigated. We aimed to assess the stability of casearin B and caseargrewiin F in physiological conditions and their metabolism in human liver microsomes. The compounds were identified by UHPLC-QTOF-MS/MS and quantified by validated LC-MS methods. The stability of casearin B and caseargrewiin F in physiological conditions was assessed in vitro. Both diterpenes showed a fast degradation (p < 0.05) in simulated gastric fluid. Their metabolism was not mediated by cytochrome P-450 enzymes, but the depletion was inhibited by the esterase inhibitor NaF. Both diterpenes and their dialdehydes showed a octanol/water partition coefficient in the range of 3.6 to 4.0, suggesting high permeability. Metabolism kinetic data were fitted to the Michaelis-Menten profile with KM values of 61.4 and 66.4 µM and Vmax values of 327 and 648 nmol/min/mg of protein for casearin B and caseargrewiin F, respectively. Metabolism parameters in human liver microsomes were extrapolated to predict human hepatic clearance, and suggest that caseargrewiin F and casearin B have a high hepatic extraction ratio. In conclusion, our data suggest that caseargrewiin F and casearin B present low oral bioavailability due to extensive gastric degradation and high hepatic extraction.

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Roux-en-Y gastric bypass is one of the most common surgical treatments for obesity due to the effective long-term weight loss and remission of associated comorbidities. Carvedilol, a third-generation ß-blocker, is prescribed to treat cardiovascular diseases. This drug is a weak base with low and pH-dependent solubility and dissolution and high permeability. As the changes in the gastrointestinal tract anatomy and physiology after roux-en-Y gastric bypass can potentially affect drug pharmacokinetics, this study aimed to assess the effect of roux-en-Y gastric bypass on the pharmacokinetics of carvedilol enantiomers. Nonobese (n = 15, body mass index < 25 kg/m2 ), obese (n = 19, body mass index ≥ 30), and post-roux-en-Y gastric bypass subjects submitted to surgery for at least 6 months (n = 19) were investigated. All subjects were administered a single oral dose of 25-mg racemic carvedilol, and blood was sampled for up to 24 hours. Plasma concentrations of (R)- and (S)-carvedilol were determined by liquid chromatography-tandem mass spectrometry. The maximum plasma concentration (Cmax ) and the area under the plasma concentration-time curve (AUC) of (R)-carvedilol were 2- to 3-fold higher than (S)-carvedilol in all groups. Obese subjects have shown reduced Cmax of (R)- and (S)-carvedilol without changing the AUC. Post-roux-en-Y gastric bypass subjects presented a 3.5-fold reduction in the Cmax of the active (S)-carvedilol and a 1.9 reduction in the AUC from time 0 to infinity compared to nonobese subjects. The time to reach Cmax of (S)-carvedilol increased 2.5-fold in post-roux-en-Y gastric bypass subjects compared to obese or nonobese. Although the ß-blockade response was not assessed, the reduced exposure to carvedilol in subjects post-roux-en-Y gastric bypass may be clinically relevant and require dose adjustment.

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This prospective study aimed to evaluate the effect of metronomic cyclophosphamide on carboplatin's tolerability, efficacy, and pharmacokinetics in dogs with mammary carcinoma. Sixteen female dogs with mammary carcinoma were divided into groups: 300 mg/m2 intravenous (i.v.) carboplatin therapy (G1 = 8) or 300 mg/m2 i.v. carboplatin which was associated with 12.5 mg/m2 oral cyclophosphamide in a metronomic regimen (G2 = 8). The investigated animals underwent a clinical evaluation, a mastectomy, a carboplatin chemotherapy, and serial blood sampling for the pharmacokinetic analysis. The adverse events and survival rates were monitored. A non-compartmental analysis was applied to calculate the pharmacokinetic parameters of carboplatin in the 2nd and 4th chemotherapy cycles. Carboplatin PK showed high interindividual variability with a 10-fold variation in the area under the plasma concentration−time curve (AUC) in G1. The systemic plasma exposure to carboplatin was equivalent in both of the treatments considering the AUC and maximum plasma concentration (Cmax) values. Although the red blood cells (p < 0.0001), platelets (p = 0.0005), total leukocytes (p = 0.0002), and segmented neutrophils (p = 0.0007) were reduced in G2, the survival rate increased (p = 0.0044) when it was compared to G1. In conclusion, adding low daily doses of cyclophosphamide to a carboplatin therapy showed promising outcomes in female dogs with mammary tumors.

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This work aimed to develop a physiologically based pharmacokinetic (PBPK) model for raltegravir accounting for UDP-glucuronosyltransferase (UGT) metabolism to assess the effect of UGT gene polymorphisms. Raltegravir elimination was evaluated using Km and Vmax values from human recombinant systems and UGT tissue scalar considering liver, kidney, and intestine. The predicted/observed ratios for raltegravir PK parameters were within a 2-fold error range in UGT1A1 poor and normal metabolizers, except in Asian UGT1A1 poor metabolizers. This PBPK modeling approach suggests that UGT1A3 is the main contributor to raltegravir's metabolism. UGT1A3 and UGT1A1 gene polymorphisms might have an additive effect on raltegravir's drug disposition and response. The final model accounting for hepatic, renal, and intestinal UGT metabolism, biliary clearance, and renal excretion improved model predictions compared with the previously published models. This PBPK model with the quantitative characterization of raltegravir elimination pathways can support dose adjustments in different clinical scenarios.

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The development of 3D-printed electrochemical sensors by fused deposition modeling (FDM) has been increasing exponentially in the last five years. In this context, commercial conductive filaments composed of a blend of carbon particles (e.g., graphene or carbon black (CB)) and insulating thermoplastic polymers (e.g., polylactic acid (PLA) or acrylonitrile butadiene styrene (ABS)) have been widely used for electrode fabrication. However, such materials may be expensive and the electrodes when used "as-printed" exhibit poor electrochemical performance as a function of the low content of conductive particles in the composition (∼10 to 20 wt%), which requires one or more post-treatment steps (e.g. polishing, chemical, electrochemical, and photochemical) to reach good electrochemical performance. In this technical note a less used approach to produce "ready-to-use" electrochemical platforms based on 3D printing is explored, which consists of the coating of 3D-printed insulating substrates with homemade conductive composites. To demonstrate the potentiality of this alternative protocol, 3D-printed ABS insulating substrates at two geometries were coated in a highly loaded graphite (55 wt%) homemade composite (G-ABS) and evaluated for the detection of the ferri/ferrocyanide redox probe and model analytes in stationary and hydrodynamic 3D-printed systems (nitrite in micro-flow injection analysis/µFIA and paracetamol in batch injection analysis/BIA, respectively). The analytical parameters acquired with the coated electrodes were comparable to those obtained using conventional electrodes (glassy carbon, boron-doped diamond and carbon screen-printed) and 3D-printed sensors fabricated with commercial filaments. Moreover, the inclusion of carbon black in the fluid conductive composite was demonstrated as a perspective to obtain modified coated 3D-printed surfaces easily for the first time. This alternative "do it yourself" strategy is promising for the large-scale production of very cheap (US$ 0.08) and high-performance electrodes based on FDM 3D printing. Moreover, this approach dispenses the acquisition of commercial conductive filaments and the laborious development of homemade filaments.

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