Rerouting cardiovascular management following gastric bypass surgery: Dose optimization of carvedilol using population-based analysis.

AIMS: A population-based pharmacokinetic (PK) modeling approach (PopPK) was used to investigate the impact of Roux-en-Y gastric bypass (RYGB) on the PK of (R)- and (S)-carvedilol. We aimed to optimize carvedilol dosing for these patients utilizing a pharmacokinetic/pharmacodynamic (PK/PD) link model. METHODS: PopPK models were developed utilizing data from 52 subjects, including nonobese, obese, and post- RYGB patients who received rac- carvedilol orally. Covariate analysis included anthropometric and laboratory data, history of RYGB surgery, CYP2D6 and CYP3A4 in vivo activity, and relative intestinal abundance of major drug- metabolizing enzymes and transporters. A direct effect inhibitory Emax pharmacodynamic model was linked to the PK model of (S)- carvedilol to simulate the changes in exercise- induced heart rate. RESULTS: A 2-compartmental model with linear elimination and parallel first-order absorptions best described (S)-carvedilol PK. RYGB led to a twofold reduction in relative oral bioavailability compared to nonoperated subjects, along with delayed absorption of both enantiomers. The intestinal ABCC2 mRNA expression increases the time to reach the maximum plasma concentration. The reduced exposure (AUC) of (S)-carvedilol post-RYGB corresponded to a 33% decrease in the predicted area under the effect curve (AUEC) for the 24-hour ß-blocker response. Simulation results suggested that a 50-mg daily dose in post-RYGB patients achieved comparable AUC and AUEC to 25-mg dose in nonoperated subjects. CONCLUSION: Integrated PK/PD modeling indicated that standard dosage regimens for nonoperated subjects do not provide equivalent ß-blocking activity in RYGB patients. This study highlights the importance of personalized dosing strategies to attain desired therapeutic outcomes in this patient cohort.

Mechanistic Framework to Predict Maternal-Placental-Fetal Pharmacokinetics of Nifedipine Employing Physiologically Based Pharmacokinetic Modeling Approach.

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.

Recycled Household Ash in Rice Paddies of Bangladesh for Sustainable Production of Rice Without Altering Grain Arsenic and Cadmium.

In Bangladesh most agronomic biomass (straw, husk, dried dung) is burnt for domestic cooking use. Consequently, the soil is continuously stripped of mineral nutrients and carbon (C) substrate. Here we investigate if recycling of household ash (ash) as fertilizer can sustainably improve soil fertility as well as minimise accumulation of toxic elements (As, Cd) in rice grain. Large scale field trials across two geographic regions (Barind, Madhupur) and two seasons (wet, dry) and with application of 3 fertiliser treatments (NPKS, ash, NPKS + ash) were conducted. At the end of each season, the impact of region*season*treatment on soil microbial comunities, rice yield, and grain quality (As, Cd, nutrient elements) was assessed. When compared to conventional field application rates of NPKS (control), application of ash boosted rice yield by circa. 20% in both regions during wet and dry season, with no effect on rice grain carcinogenic inorganic arsenic (iAs), dimethylarsonic acid (DMA) or cadmium (Cd), but with potential to increase zinc (Zn). For soil microbial communities, a significant region and season effect as well as correlation with elements in rice grain was observed, amongst these Cd, Zn, iAs and DMA. This study illustrates that application of ash can reduce the requirement for expensive chemical fertiliser, whilst at the same time increasing rice yield and maintaining grain quality, making farming in Bangladesh more sustainable and productive. The study also implies that the combined impact of region, season, and soil microbes determines accumulation of elements in rice grain. Supplementary Information: The online version contains supplementary material available at 10.1007/s12403-023-00539-y.

A code for clinical trials centralized monitoring, sharing open-science solutions to high-quality data.

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.

Improving the performance and versatility of microfluidic thread electroanalytical devices by automated injection with electronic pipettes: a new and powerful 3D-printed analytical platform.

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.

Electrochemical sensor based on 3D-printed substrate by masked stereolithography (MSLA): a new, cheap, robust and sustainable approach for simple production of analytical platforms.

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.

Casearia Essential Oil: An Updated Review on the Chemistry and Pharmacological Activities.

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.

Metabolism Characterization and Chemical and Plasma Stability of Casearin B and Caseargrewiin F.

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.

Effect of Roux-En-Y Gastric Bypass in the Pharmacokinetics of (R)-Carvedilol and (S)-Carvedilol.

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.

Pharmacokinetics of Carboplatin in Combination with Low-Dose Cyclophosphamide in Female Dogs with Mammary Carcinoma.

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.

Assessing the contribution of UGT isoforms on raltegravir drug disposition through PBPK modeling.

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.

Exploring the coating of 3D-printed insulating substrates with conductive composites: a simple, cheap and versatile strategy to prepare customized high-performance electrochemical sensors.

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.

Chemometric optimization of salting-out assisted liquid-liquid extraction (SALLE) combined with LC-MS/MS for the analysis of carvedilol enantiomers in human plasma: Application to clinical pharmacokinetics.

Carvedilol is a commonly used antihypertensive whose oral absorption is limited by low solubility and significant first-pass metabolism. This work aimed to apply chemometrics for the optimization of a salting-out assisted liquid-liquid extraction (SALLE) combined with LC-MS/MS to analyze carvedilol enantiomers in plasma samples. Method development and validation were driven for application in pharmacokinetic studies. Parameters that influence the efficiency of SALLE were evaluated using a fractional factorial 24-1 design with 4 factors and a central composite design was used to evaluate the optimal extraction condition. Carvedilol enantiomers and the internal standard lidocaine were separated on an Astec® Chirobiotic® V column and a mixture of methanol:ethanol (90:10, v/v) with 0.02% diethylamine and 0.18% acetic acid as mobile phase. The positive ion mode on electrospray ionization was used to monitor the transitions of m/z 407 > 100 and 235 > 86 for carvedilol enantiomers and lidocaine, respectively. Acetonitrile and ammonium acetate solution were selected for sample preparation by SALLE. Surface graphs and the desirability test were used to define the optimized SALLE conditions which resulted in 93% recovery for both carvedilol enantiomers. The method was linear in the range of 0.5 to 100 ng/mL in plasma, with a lower limit of quantification of 0.5 ng/mL. Within-run and between-run precision (as the relative standard deviation) were all < 9.74% and accuracy (as relative error) did not exceed ± 10.30%. Residual effect and matrix effect were not observed. Carvedilol enantiomers were stable in plasma under the storage, preparation, and analysis conditions. The validated method was successfully applied to analyze carvedilol in plasma samples from patients previously submitted to a Roux-en-Y gastric bypass surgery treated with a single oral dose of 25 mg racemic-carvedilol. Higher plasma concentrations were observed for (R)-(+)-carvedilol when compared to (S)-(-)-carvedilol in two patients post-bariatric surgery.

Simple, fast, and instrumentless fabrication of paper analytical devices by novel contact stamping method based on acrylic varnish and 3D printing.

A new contact stamping method for fabrication of paper-based analytical devices (PADs) is reported. It uses an all-purpose acrylic varnish and 3D-printed stamps to pattern hydrophobic structures on paper substrates. The use of 3D printing allows quickly prototyping the desired stamp shape without resorting to third-party services, which are often expensive and time consuming. To the best of our knowledge, this is the first report regarding the use of this material for creation of hydrophobic barriers in paper substrates, as well as this 3D printing-based stamping method. The acrylic varnish was characterized and the features of the stamping method were studied. The PADs developed here presented better compatibility with organic solvents and surfactants compared with similar protocols. Furthermore, the use of this contact stamping method for fabrication of paper electrochemical devices was also possible, as well as multiplexed microfluidic devices for lateral flow testing. The analytical applicability of the varnish-based PADs was demonstrated through the image-based colorimetric quantification of iron in pharmaceutical samples. A limit of detection of 0.61 mg L-1 was achieved. The results were compared with spectrophotometry for validation and presented great concordance (relative error was < 5% and recoveries were between 104 and 108%). Thus, taking into account the performance of the devices explored here, we believe this novel contact stamping method is a very interesting alternative for production of PADs, exhibiting great potentiality. In addition, this work brings a new application of 3D printing in analytical sciences.

Development of highly sensitive electrochemical sensor using new graphite/acrylonitrile butadiene styrene conductive composite and 3D printing-based alternative fabrication protocol.

Here, a novel electrically conductive thermoplastic material composed of graphite/acrylonitrile butadiene styrene (G/ABS) is reported for the first time. This material was explored on the production of 3D printing-based electrochemical sensors with enhanced sensitivity using a novel fabrication approach. The developed G/ABS electrodes showed lower charge transfer resistance (157 vs. 3279 Ω), higher electroactive area (0.61 vs. 0.19 cm2) and peak currents ca. 69% higher when compared with electrodes fabricated using carbon black/polylactic acid (CB/PLA) commercial filament, which has been widely explored in recent literature. Moreover, the G/ABS sensor provided satisfactory repeatability, reproducibility and stability (relative standard deviations (RSDs) were 1.14%, 6.81% and 10.62%, respectively). This improved performance can be attributed to the fabrication protocol developed here, which allows the incorporation of greater amounts of conductive material in the polymeric matrix. The G/ABS electrode also required a simpler and quicker protocol for activation when compared to CB/PLA. As proof of concept, the G/ABS sensor was employed for electroanalytical quantification of paracetamol (PAR) in pharmaceutical products. The linear concentration range was observed from 0.20 to 30 µmol L-1 and the limit of detection achieved was 54 nmol L-1, much lower than several recent studies dealing with the same analyte. The sensitivity of the G/ABS electrode regarding PAR was also far better when compared to CB/PLA sensor (0.50 µA/µmol L-1 vs. 0.12 µA/µmol L-1). Analyses in commercial pill samples showed good accuracy (recoveries ca. 108%) and precision (RSDs < 5%), suggesting great potential for use of this novel conductive thermoplastic in electroanalytical applications based on 3D printing.

Population pharmacokinetics of gabapentin in patients with neuropathic pain: Lack of effect of diabetes or glycaemic control.

AIMS: Gabapentin (GBP) is widely used to treat neuropathic pain, including diabetic neuropathic pain. Our objective was to evaluate the role of diabetes and glycaemic control on GBP population pharmacokinetics. METHODS: A clinical trial was conducted in patients with neuropathic pain (n = 29) due to type 2 diabetes (n = 19) or lumbar/cervical disc herniation (n = 10). All participants were treated with a single oral dose GBP. Blood was sampled up to 24 hours after GBP administration. Data were analysed with a population approach using the stochastic approximation expectation maximization algorithm. Weight, body mass index, sex, biomarkers of renal function and diabetes, and genotypes for the main genetic polymorphisms of SLC22A2 (rs316019) and SLC22A4 (rs1050152), the genes encoding the transporters for organic cations OCT2 and OCTN1, were tested as potential covariates. RESULTS: GBP drug disposition was described by a 1-compartment model with lag-time, first-order absorption and linear elimination. The total clearance was dependent on estimated glomerular filtration rate. Population estimates (between-subject variability in percentage) for lag time, first-order absorption rate, apparent volume of distribution and total clearance were 0.316 h (10.6%), 1.12 h-1 (10.7%), 140 L (7.7%) and 14.7 L/h (6.97%), respectively. No significant association was observed with hyperglycaemia, glycated haemoglobin, diabetes diagnosis, age, sex, weight, body mass index, SLC22A2 or SLC22A4 genotypes. CONCLUSION: This population pharmacokinetics model accurately estimated GBP concentrations in patients with neuropathic pain, using estimated glomerular filtrationrate as a covariate for total clearance. The distribution and excretion processes of GBP were not affected by hyperglycaemia or diabetes.

Cetirizine Reduces Gabapentin Plasma Concentrations and Effect: Role of Renal Drug Transporters for Organic Cations.

Gabapentin (GBP) is an organic cation mainly eliminated unchanged in urine, and active drug secretion has been suggested to contribute to its renal excretion. Our objective was to evaluate the potential drug-drug interaction between GBP and cetirizine (CTZ), an inhibitor of transporters for organic cations. An open-label, 2-period, crossover, nonrandomized clinical trial was conducted in patients with neuropathic pain to evaluate the effect of CTZ on GBP pharmacokinetics. Twelve participants were treated with a single dose of 300 mg GBP (treatment A) or with 20 mg/d of CTZ for 5 days and 300 mg GBP on the last day of CTZ treatment (treatment B). Blood sampling and pain intensity evaluation were performed up to 36 hours after GBP administration. The interaction of GBP and CTZ with transporters for organic cations was studied in human embryonic kidney (HEK) cells expressing the organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), and OCTN1. CTZ treatment resulted in reduced area under the concentration-time curve and peak concentration compared with treatment A. In treatment B, the lower plasma concentrations of GBP resulted in reduced pain attenuation. GBP renal clearance was similar between treatments. GBP has low apparent affinity for OCT2 (concentration of an inhibitor where the response [or binding] is reduced by half [IC50 ] 237 µmol/L) and a high apparent affinity for hMATE1 (IC50 1.1 nmol/L), hMATE2-K (IC50 39 nmol/L), and hOCTN1 (IC50 2.1 nmol/L) in HEK cells. At therapeutic concentrations, CTZ interacts with hMATE1 and OCTN1. In summary, CTZ reduced the systemic exposure to GBP and its effect on neuropathic pain attenuation. However, CTZ × GBP interaction is not mediated by the renal transporters.

Design of novel, simple, and inexpensive 3D printing-based miniaturized electrochemical platform containing embedded disposable detector for analytical applications.

This paper describes the development of a novel, simple, and inexpensive electrochemical device containing an integrated and disposable three-electrode system for detection. The base of this platform consists on a PDMS structure containing microchannels which were prototyped using 3D-printed molds. Pencil graphite leads were inserted into these microchannels and utilized as working, counter and reference electrodes in a novel design. Morphological analysis and electrochemical experiments with benchmark redox probes were carried out in order to evaluate the performance and characterize the miniaturized device proposed. Even using inexpensive materials and a simple fabrication protocol, the electrochemical platform developed provided good repeatability and reproducibility over a low cost (ca. $2 per device), acceptable lifetime (ca. 250 voltammetric runs) and extremely reduced consumption of samples and reagents (order of µL). As proof of concept, the analytical feasibility of the platform was investigated through the simultaneous determination of dopamine (DOPA) and acetaminophen (AC). The two analytes showed linear dependence on the concentration range from 1 to 15 µM and the LODs achieved were 0.21 µM for DOPA and 0.29 µM for AC. Moreover, the platform was successfully applied on the determination of DOPA and AC in spiked blood serum and urine samples. The results obtained with the device described here were better than some reports in literature that use more costly electrodic materials and complex modification steps for the detection of the same analytes.

Pharmacogenomics in chronic pain therapy: from disease to treatment and challenges for clinical practice.

Pharmacogenomics (PGx) has emerged as an encouraging tool in chronic pain therapy. Genetic variations associated with drug effectiveness or adverse reactions (amitriptyline/nortriptyline/codeine/oxycodone/tramadol-CYP2D6, amitriptyline-CYP2C19, carbamazepine-HLA-A, carbamazepine/oxcarbazepine-HLA-B) can be used to guide chronic pain management. Despite this evidence, many obstacles still need to be overcome for the effective clinical implementation of PGx. To translate the pharmacogenetic testing into actionable clinical decisions, the Clinical Pharmacogenetics Implementation Consortium has been developing guidelines for several drug-gene pairs. This review will show the applicability of PGx in chronic pain from disease to treatment; report the drug-gene pairs with strongest evidences in the clinic; and the challenges for the clinical implementation of PGx.