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This study investigates the influence of pregnancy on the in vivo activity of the intestinal P‐glycoprotein (P‐gp) and hepatic organic anion transporters polypeptide (OATP/BCRP) using, respectively, fexofenadine and rosuvastatin as probe drugs. Eleven healthy participants were investigated during the third trimester of pregnancy (Phase 1, 28 to 38 weeks of gestation) and in the postpartum period (Phase 2, 8 to 12 weeks postpartum). In both phases, after administration of a single oral dose of fexofenadine (60 mg) and rosuvastatin (5 mg), serial blood samples were collected for up to 24 h. Rosuvastatin and fexofenadine in plasma were analyzed by LC‐MS/MS using previously validated methods. The pharmacokinetic parameters of fexofenadine and rosuvastatin (Phoenix WinNonLin software) with normal distribution (Shapiro–Wilk test) are presented as geometric mean and 90% confidence interval. Phases 1 and 2 were compared using the t test (P < .05). Fexofexadine AUC0‐24 values do not differ (P‐value: .0715) between Phase 1 (641.9 ng h/mL [500.6‐823.1]) and Phase 2 (823.8 ng h/mL [641.5‐1057.6]) showing that pregnancy (third trimester) does not alter intestinal P‐gp activity. However, rosuvastatin AUC0‐24 values are higher (P‐value: .00005) in Phase 1 (18.7 ng h/mL [13.3‐26.4]) when compared to Phase 2 (9.5 ng h/mL [6.7‐13.4]), suggesting inhibition of OATP1B1/OATP1B3 transporters. In conclusion, pregnancy assessed during the third trimester does not alter the intestinal P‐gp activity but reduces the activity of hepatic OATP1B1/OATP1B3 transporters. Therefore, adjustments in dosage regimens may be necessary for drugs with low therapeutic index, substrates of the OATP1B1/OATP1B3 transporters, administered during the third trimester of pregnancy. [ABSTRACT FROM AUTHOR]

This study aims to evaluate the impact of liver fibrosis stages of chronic infection with hepatitis C virus (HCV) on the in vivo activity of organic cation transporters (hepatic OCT1 and renal OCT2) using metformin (MET) as a probe drug. Participants allocated in Group 1 (n = 15, mild to moderate liver fibrosis) or 2 (n = 13, advanced liver fibrosis and cirrhosis) received a single MET 50 mg oral dose before direct-acting antiviral (DAA) drug treatment (Phase 1) and 30 days after achieving sustained virologic response (Phase 2). OCT1/2 activity (MET AUC0–24) was found to be reduced by 25% when comparing the two groups in Phase 2 (ratio 0.75 (0.61–0.93), p < 0.05) but not in Phase 1 (ratio 0.81 (0.66–0.98), p > 0.05). When Phases 1 and 2 were compared, no changes were detected in both Groups 1 (ratio 1.10 (0.97–1.24), p > 0.05) and 2 (ratio 1.03 (0.94–1.12), p > 0.05). So, this study shows a reduction of approximately 25% in the in vivo activity of OCT1/2 in participants with advanced liver fibrosis and cirrhosis after achieving sustained virologic response and highlights that OCT1/2 in vivo activity depends on the liver fibrosis stage of chronic HCV infection. [ABSTRACT FROM AUTHOR]

Objectives: Burned bone coloration has been used for decades to help in the bioanthropological analysis of burned human bones. However, there is a variety of factors that can interfere with the coloration manifested by bones exposed to heat, resulting in colors that differ from the usual black to white gradient. In this study, we evaluated possible causes of unusual coloration changes and hues in burned bone. Materials and Methods: For that purpose, defleshed fresh pig (Sus scrofa) ribs as well as fresh and dry human clavicles were burned at four different temperatures (500, 700, 900 and 1100°C) in contact with different materials (CaO, Zn, Fe, Cu, Mn, and polyester cloth). Observable color changes were assessed through naked eye observation and description, Munsell color charts, and reflectance spectrophotometry. Additionally, chemical changes in bone were assessed using Fourier‐transform infrared spectroscopy in attenuated total reflectance (FTIR‐ATR) and x‐ray fluorescence (XRF). Results: Our results showed that some materials did affect usual burned bone coloration (Fe, Mn, Cu, Zn) and correspondent FTIR‐ATR and XRF spectra. As for other materials, although no effect on visual bone coloration was observed, they still affected FTIR‐ATR and XRF spectra (CaO and cloth). Discussion: This study can contribute to the anthropological analysis of burned human remains, providing some answers to what can cause unusual types of heat‐induced colorations. [ABSTRACT FROM AUTHOR]

• XRF can detect Fe traces from blades in fresh human bone. • XRF can detect Fe traces from blades in human bone burned fresh. • XRF is not useful to detect blade traces in bone that has been previously inhumed. Heat-induced fractures can be hard to distinguish from sharp force traumas. This challenge can negatively impact medico-legal analysis. The present study aimed to experimentally assess if X-ray fluorescence (XRF) can be used to detect chemical traces transferred from the blade of a sharp instrument onto both fresh and dry human bones. This was performed by inducing sharp force traumas with five different instruments on 20 fresh and 20 dry human clavicles. All bone samples were probed before and after experimental burning (at 500 °C, 700 °C, 900 °C and 1100 °C). Our results show that XRF is potentially useful for detecting iron traces in fresh human bone, both unburned and burned. However, we were not able to clearly detect iron traces from the blades in bones that have been previously inhumed, since exogenous iron acquired during diagenesis masks the iron traces originating from the blade. [ABSTRACT FROM AUTHOR]

This work aimed to evaluate the total, unbound, renal, and hepatic clearances of raltegravir (RAL) and the formation and elimination clearances of raltegravir glucuronide (RAL GLU) in pregnant women living with HIV. The participants received RAL 400 mg twice daily during the third trimester (n = 15) of gestation, delivery (n = 15), and the postpartum period (n = 8). Pharmacokinetic parameter values were calculated on the basis of plasma and urine data using noncompartmental methods. RAL clearances for the third trimester of gestation were as follows: total clearance: geometric mean, 63.63 L/h (95% CI, 47.5–85.25); renal clearance: geometric mean, 2.56 L/h (95% CI, 1.96–3.34); hepatic clearance: geometric mean, 60.52 L/h (95% CI, 44.65–82.04); and unbound clearance: geometric mean, 281.14 L/h (95% CI, 203.68–388.05). RAL GLU formation and elimination clearances for the third trimester of gestation were 7.57 L/h (95% CI, 4.94–11.6) and 8.71 L/h (95% CI, 6.71‐11.32), respectively. No differences were observed in RAL GLU pharmacokinetic parameters between the third trimester of gestation and the postpartum period, except for higher formation (7.57 vs 4.03 L/h) and elimination (8.71 vs 4.92 L/h) clearances during the third trimester. The findings based on plasma and urine data are consistent with an increase in the hepatic uridine 5′ diphospho‐glucuronosyltransferase isoenzymes activities involved in RAL metabolism during pregnancy, and the formation of RAL GLU is a minor route of RAL elimination. Compared to the postpartum period, in the third trimester of gestation, the similar RAL plasma exposure in pregnant women reinforces the maintenance of an RAL regimen including a 400‐mg oral dose twice daily during pregnancy. [ABSTRACT FROM AUTHOR]

The activity of the membrane transporters organic anion‐transporting polypeptide 1B1 (OATP1B1) & breast cancer resistance protein (BCRP) (rosuvastatin) and P‐glycoprotein (P‐gp) (fexofenadine) was evaluated in patients with chronic hepatitis C virus (HCV) infection (n = 28), genotypes 1 and 3, investigated before the treatment with direct‐acting antiviral agents (Phase 1) and up to 30 days after the assessment of the virologic response (Phase 2). Participants allocated in Groups 1 (n = 15; F0/F1 and F2, mild to moderate liver fibrosis) and 2 (n = 13; F3 and F4, advanced course of liver fibrosis/cirrhosis) received in both phases fexofenadine (10 mg) and rosuvastatin (2 mg). OATP1B1 & BCRP activity (rosuvastatin area under the plasma concentration‐time curve of rosuvastatin from time zero to infinity (AUC0–∞)) was reduced in Groups 1 and 2, respectively, by 25% (ratio 0.75 (0.53–0.82), P < 0.01) and 31% (ratio 0.69 (0.46–0.85), P < 0.05) in Phase 1 compared with Phase 2. OATP1B1 & BCRP activity was reduced in Phases 1 and 2, respectively, by 49% (median ratio 1.51 (1.17–2.20), P < 0.05) and 61% (ratio 1.39 (1.16–2.02), P < 0.01) in Group 2 compared with Group 1. P‐gp activity (fexofenadine AUC0–∞) was also reduced in Phase 1 compared with Phase 2 (ratio Phase2/Phase1 0.79 (0.66–0.96) in Group 1 and 0.81 (0.69–0.96) in Group 2) as well as in Group 2 compared with Group 1 in both Phases (ratio Group2/Group1 1.47 (1.08–2.01) in Phase 1 and 1.51 (1.10–2.07) in Phase 2). Thus, clinicians administering OATP1B1 & BCRP and P‐gp substrates with low therapeutic indexes should consider the evolution of the treatment and the stage of HCV infection. [ABSTRACT FROM AUTHOR]

This study evaluates the influence of streptozotocin-induced diabetes on the kinetic disposition and metabolism of mexiletine (MEX) enantiomers in rats. Animals in the control (n = 6 for each blood collection time), diabetic (single intravenous dosage of 45 mg x [(kg body mass).sup.-1] of streptozotocin), and insulin-treated groups (diabetic rats treated daily with 2 IU insulin) received by gavage a single dose of 10 mg x [(kg body mass).sup.-1] racemic MEX. MEX enantiomers and the metabolites hydroxymethylmexiletine (HMM) and p-hydroxymexiletine PHM) were analyzed by LC-MS/MS. Statistical analysis was based on a serial sacrifice design, and parameter estimation was performed using a Bayesian modeling procedure. Area under the curve (AUC) for the (-)-(R) enantiomers of MEX, HMM, and PHM did not differ between the control and diabetic groups. However, AUC for (+)-(S)-MEX and (+)-(S)-HMM were lower in the diabetic than in the control group. Insulin treatment recovered glucose levels to normal and the (+)-(S)-MEX AUC and (+)-(S)-HMM AUC became similar to the AUCs observed in the nondiabetic animals. Key words: mexiletine, enantiomers, metabolites, pharmacokinetics, diabetes, insulin, rats. Cette etude evalue l'influence du diabete induit par la streptozotocine sur la disposition cinetique et le metabolisme des enantiomeres de la mexiletine (MEX) chez le rat. Les animaux des groupes controle (n = 6a chaque prelevement sanguin), diabetique (une seule dose i.v. de 45 mg x [(kg de masse corporelle).sup.-1] de streptozotocine) et traite a l'insuline (diabetique traite quotidiennement avec 2 UI d'insuline) ont recu par gavage une seule dose de 10 mg x [(kg de masse corporelle).sup.-1] d'un melange racemique de MEX. Les enantiomeres de MEX et leurs metabolites, la hydroxymethylmexiletine (HMM) et la p-hydroxymexiletine (PHM), ont ete analyses par LC-MS/MS. L'analyse statistique a ete basee sur des donnees issues d'un protocole de sacrifice seriel et l'estimation parametrique a ete realisee par une modelisation Bayesienne. Les aires sous la courbe (ASC) des enantiomeres (-)-(R) de MEX, de HMM et de PHM ne differaient pas significativement entre les groupes controle et diabetique. Toutefois les ASC de (+)-(S)-MEX et (+)-(S)-HMM etaient plus faibles chez le groupe diabetique comparativement au groupe controle. Le traitement a l'insuline permettait de retablir les niveaux normaux de glucose et les ASC de (+)-(S)-MEX et de (+)-(S)-HMM similaires a ceux des animaux non diabetiques. [Traduit par la Redaction] Mots-cles: mexiletine, enantiomeres, metabolites, pharmacocinetique, diabete, insuline, rats., Introduction Mexiletine (MEX; 1-(2,6-dimethylfenoxi)-2-aminopropane), a drug available as a racemic mixture of (-)-R and (+)-(S) enantiomers, is used clinically for alleviating neuropathic pain in diabetes (Andriaensen et al. 2005). The [...]

Bone heat‐induced changes complicate osteometric stature estimation of human remains from forensic settings. The validity of current methods has not been tested to a great extent. Our aim was to determine how precise are stature estimations obtained from three different approaches, namely by using (i) Rösing's method (Rösing 1977), (ii) a 10% shrinkage correction factor (Strzałko et al. 1972) and (iii) chemosteometry (Gonçalves et al. 2020). For this purpose, pre‐ and post‐burned head measurements from the humerus, radius and femur were used. The sample comprised 46 human skeletons of known sex and age‐at‐death. These were experimentally burnt to maximum temperatures ranging from 700 to 1100°C (attained after 90–188 min) for other research purposes. Stature estimations were performed through measurements in both pre‐burned and burned bones using the three approaches and based on the method of Olivier and Tissier (1975). Mean absolute differences and the relative technical errors of measurements (TEM%) between the pre‐burned and the estimations were calculated. Absolute mean differences indicated that the chemosteometric approach allowed for potentially more precise stature estimations than the other two procedures. However, the TEM% was very low for all approaches (smaller or close to 1%), and stature estimations were thus well within the error margin reported by Olivier and Tissier (1975). Results suggest that the chemosteometric approach enables more accurate predictions of the actual heat‐induced shrinkage of each bone thus rendering more precise stature estimations. Nonetheless, the other procedures also provided quite reliable estimations although they require confirmation that the bone is calcined. [ABSTRACT FROM AUTHOR]