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The influence of chronic renal failure on the stereoselective metabolism of rac-metoprolol was investigated in 15 hypertensive patients, 7 of them with chronic renal failure and 8 with normal renal function. They were treated with rac-metoprolol (200 mg) for 7 days. The patients of both groups presented stereoselectivity in metoprolol metabolism, favoring the formation of 1'R-alpha-hydroxymetoprolol (AUC(1(')R/1(')S)(0-24) approximately 2.5) and (R)-metoprolol acidic metabolite (AUC((S)/(R))(0-24) = 0.8), the latter resulting in the plasma accumulation of (S)-metoprolol (AUC((S)/(R))(0-24) = 1.2). Patients with chronic renal failure presented plasma accumulation of the 4 alpha-hydroxymetoprolol isomers and of both metoprolol acidic metabolite enantiomers. A 50% reduction in Cl(R) does not explain the 3- to 4-fold plasma accumulation of metoprolol acidic metabolite in this group, suggesting that other pathways of metoprolol elimination are affected in chronic renal failure in addition to renal excretion. Chronic renal failure does not change the stereoselective kinetic disposition of metoprolol but modifies its stereoselective metabolism, inducing some of the CYP enzymes involved in the formation of the metoprolol acid metabolite. [ABSTRACT FROM AUTHOR]

Renal biopsies of 86 patients with lupus nephritis were assessed according to the WHO classification, and according to activity and chronicity indices. The aim of the present study was to correlate clinical, and histological features (WHO class, activity and chronicity indices, and α-SM actin expression) with the progression of lupus nephritis, and identify the pathological role of α-SM actin in lupus nephritis. The median follow-up time was 75.5±57.3 months. Two patients were grouped as WHO class IIa lupus nephritis, eight patients as class IIb, 16 patients as class III, 25 patients as class IV, 15 patients as class V, and 19 patients as mixed pattern lupus nephritis. Sex, age, race, and the α-SM actin expression in glomeruli and tubulo-interstitial area in WHO class III and IV showed no correlation with clinical follow-up outcome of lupus nephritis. Unfavorable clinical outcome of lupus nephritis was correlated with WHO class IV compared to the other classes, and with the chronicity index in WHO class III patients. [ABSTRACT FROM AUTHOR]

Background: Gabapentin is an effective therapeutic alternative for chronic low back pain, indicated in several guidelines for treating neuropathic pain as first-line medication. This study aimed to describe the pharmacodynamics of gabapentin in the central nervous system of patients with chronic low back pain (CLBP) by using single-photon emission CT (SPECT) with [99mTc]Tc-ECD., Methods: We selected 13 patients with CLBP due to lumbar disc herniation. They underwent SPECT before and after using gabapentin, compared with a SPECT database of healthy volunteers. A second analysis compared regional cerebral blood flow (rCBF) changes between responders and non-responders to gabapentin and the healthy controls., Results: The mean age of patients was 41 years, and the mean pain intensity was 5.92 points, measured by the Numeric Rating Scale. After using gabapentin, SPECT showed an increase of rCBF in the bilateral anterior cingulate gyrus and a decrease of rCBF in periaqueductal gray matter. Non-responder patients with gabapentin showed a post-treatment decrease of rCBF in the paracentral lobule of the brain., Conclusions: A lack of improvement in some patients with gabapentin may be associated with an activated affective circuit of pain, evidenced by the increase of rCBF of the anterior cingulate cortex. A maladaptive brain state in chronic pain can explain the decrease of rCBF in the default mode network structures. Gabapentin acts directly or indirectly on neurons of periaqueductal gray substance by increasing the pain threshold and decreasing the rCBF of this structure., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To enhance the production and availability of influenza vaccines in different regions of the world is paramount to mitigate the global burden of this disease. Instituto Butantan developed and manufactured an embryonated egg-based inactivated split-virion trivalent seasonal influenza vaccine as part of a technology transfer partnership with Sanofi Pasteur., Methods: This is a phase IV, randomized, double-blind, active-controlled, multicenter clinical trial including adults 18-60 and > 60 years recruited during the 2019 southern hemisphere influenza season. Subjects were randomized 1:1 to receive either the Sanofi Pasteur Trivalent Seasonal Influenza Vaccine (SP-TIV) or Instituto Butantan Trivalent Seasonal Influenza Vaccine (IB-TIV). Hemagglutinin inhibition antibody titers were assessed pre-vaccination and 21 days post-vaccination., Results: 624 participants were randomized and vaccinated. In both intention-to-treat and per-protocol analysis, non-inferiority of the SP-TIV versus IB-TIV was demonstrated for the three influenza strains. In the per-protocol analysis, the SP-GMT/IB-GMT ratios for H1N1, H3N2, and B were 0.9 (95%CI, 0.7-1.1), 1.2 (95%CI, 1.0-1.4), and 1.1 (95%CI, 0.9-1.3), respectively. Across vaccination groups, the most common adverse reactions (AR) were limited to the injection-site, including pain and tenderness. The majority of the ARs were graded 1 and/or 2 and lasted less than one day. No serious adverse reaction was observed., Conclusion: This study demonstrated the non-inferiority of the immunogenicity of a single-dose of Instituto Butantan versus a single dose of the Sanofi Pasteur Seasonal Trivalent Influenza Vaccine in adults. Both vaccines were well tolerated and presented similar safety profiles., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Tazio Vanni, Maria da Graça Salomão, Juliana Yukari Kodaira Viscondi, Patrícia Emilia Braga, Anderson da Silva, Roberta de Oliveira Piorelli, Joane do Prado Santos, Vera Lúcia Gattás, Maria Beatriz Bastos Lucchesi, Mayra Martho Moura de Oliveira, Marcelo Eiji Koike are employees of Instituto-Fundação Butantan. Lucia M A Campos, Eduardo B Coelho, Lily Yin Weckx, Amanda Nazareth Lara received research-grant from Fundação Butantan for their roles as principal investigators. Terezinha M Paiva, Maria do Carmo S T Timenetsky are employees of Instituto Adolfo Lutz]., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Recent neuroimaging studies have demonstrated pathological mechanisms related to cerebral neuroplasticity in chronic low back pain (CLBP). Few studies have compared cerebral changes between patients with and without pain in the absence of an experimentally induced stimulus. We investigated the neurobiological substrates associated with chronic low back pain using [ 99m Tc]Tc-ECD brain SPECT and correlated rCBF findings with the numeric rating scale (NRS) of pain and douleur neuropathique en 4 questions (DN4). Ten healthy control volunteers and fourteen patients with neuropathic CLBP due to lumbar disc herniation underwent cerebral SPECT scans. A quantitative comparison of rCBF findings between patients and controls was made using the Statistical Parametric Mapping (SPM), revealing clusters of voxels with a significant increase or decrease in rCBF. The intensity of CLBP was assessed by NRS and by DN4., Results: The results demonstrated an rCBF increase in clusters A (occipital and posterior cingulate cortex) and B (right frontal) and a decrease in cluster C (superior parietal lobe and middle cingulate cortex). NRS scores were inversely and moderately correlated with the intensity of rCBF increase in cluster B, but not to rCBF changes in clusters A and C. DN4 scores did not correlate with rCBF changes in all three clusters., Conclusions: This study will be important for future therapeutic studies that aim to validate the association of rCBF findings with the pharmacokinetic and pharmacodynamic profiles of therapeutic challenges in pain., (© 2022. The Author(s).)

Introduction: With the COVID-19 pandemic, hospitals in low-income countries were faced with a triple challenge. First, a large number of patients required hospitalisation because of the infection's more severe symptoms. Second, there was a lack of systematic and broad testing policies for early identification of cases. Third, there were weaknesses in the integration of information systems, which led to the need to search for available information from the hospital information systems. Accordingly, it is also important to state that relevant aspects of COVID-19's natural history had not yet been fully clarified. The aim of this research protocol is to present the strategies of a Brazilian network of hospitals to perform systematised data collection on COVID-19 through the WHO platform., Methods and Analysis: This is a multicentre project among Brazilian hospitals to provide data on COVID-19 through the WHO global platform, which integrates patient care information from different countries. From October 2020 to March 2021, a committee worked on defining a flowchart for this platform, specifying the variables of interest, data extraction standardisation and analysis., Ethics and Dissemination: This protocol was approved by the Research Ethics Committee (CEP) of the Research Coordinating Center of Brazil (CEP of the Hospital Nossa Senhora da Conceicao), on 29 January 2021, under approval No. 4.515.519 and by the National Research Ethics Commission (CONEP), on 5 February 2021, under approval No. 4.526.456. The project results will be explained in WHO reports and published in international peer-reviewed journals, and summaries will be provided to the funders of the study., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

The emergence of potentially pandemic viruses has resulted in preparedness efforts to develop candidate vaccines and adjuvant formulations. We evaluated the dose-sparing effect and safety of two distinct squalene-based oil-in-water adjuvant emulsion formulations (IB160 and SE) with influenza A/H7N9 antigen. This phase I, randomized, double-blind, placebo-controlled, dose-finding trial (NCT03330899), enrolled 432 healthy volunteers aged 18 to 59. Participants were randomly allocated to 8 groups: 1A) IB160 + 15μg H7N9, 1B) IB160 + 7.5μg H7N9, 1C) IB160 + 3.75μg H7N9, 2A) SE + 15μg H7N9, 2B) SE + 7.5μg H7N9, 2C) SE + 3.75μg H7N9, 3) unadjuvanted vaccine 15μg H7N9 and 4) placebo. Immunogenicity was evaluated through haemagglutination inhibition (HI) and microneutralization (MN) tests. Safety was evaluated by monitoring local and systemic, solicited and unsolicited adverse events (AE) and reactions (AR) 7 and 28 days after each study injection, respectively, whereas serious adverse events (SAE) were monitored up to 194 days post-second dose. A greater increase in antibody geometric mean titers (GMT) was observed in groups receiving adjuvanted vaccines. Vaccinees receiving IB160-adjuvanted formulations showed the greatest response in group 1B, which induced an HI GMT increase of 4.7 times, HI titers ≥40 in 45.2% of participants (MN titers ≥40 in 80.8%). Vaccinees receiving SE-adjuvanted vaccines showed the greatest response in group 2A, with an HI GMT increase of 2.5 times, HI titers ≥40 in 22.9% of participants (MN titers ≥40 in 65.7%). Frequencies of AE and AR were similar among groups. Pain at the administration site and headache were the most frequent local and systemic solicited ARs. The vaccine candidates were safe and the adjuvanted formulations have a potential dose-sparing effect on immunogenicity against influenza A/H7N9. The magnitude of this effect could be further explored., Competing Interests: Daniela H Silveira, Juliana Y K Viscondi, Patrícia Emilia Braga, Maria da Graça Salomão, Vera Lúcia Gattás, Maria Beatriz B Lucchesi, Mayra M M de Oliveira, Marcelo E Koike, Milena A Akamatsu and Paulo Lee Ho are employees of Instituto Butantan-Fundação Butantan. Marilda A M Siqueira, Cristiana C Garcia, and Milene D Miranda are employees of Fiocruz. Maria do Carmo S T Timenetsky and Terezinha M Paiva are employees of Instituto Adolfo Lutz. Alexander R Precioso, Tazio Vanni, Beatriz C Thomé, Roberta O Piorelli, Anderson da Silva, Eduardo A Adami, Joane P Santos, and Gabriella Mondini are former employees of Instituto Butantan-Fundação Butantan. Esper G Kallas, Lucia M A Campos, and Eduardo B Coelho received research-grant from Fundação Butantan for their roles as principal investigators. Erin Sparrow, Martin Friede, Christopher B Fox. Anna Marie Beckmann, and Chuong Huynh are scientific and financial sponsors. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Abstract: Determine the most accurate diagnostic criteria of arterial hypertension (AH) for detecting early vascular aging (EVA) defined by pulse wave velocity (PWV) higher than ≥9.2 m/s.Cross-sectional study of a birth cohort started in 1978/79. The following data were collected between April 6, 2016 and August 31, 2017 from 1775 participants: demographic, anthropometric, office blood pressure (BP) measurement, biochemical risk factors, and PWV. A subsample of 454 participants underwent 24-hour ambulatory BP monitoring. The frequencies of AH, and BP phenotypes were calculated according to both guidelines. BP phenotypes (white-coat hypertension, masked hypertension (MHT), sustained hypertension (SH) and normotension) were correlated with risk factors and subclinical target organ damage after adjustment for confounders by multiple linear regression. Receiver operating characteristic curves were constructed to determine the best BP threshold for detecting EVA.A higher frequency of AH (45.1 vs 18.5%), as well as of SH (40.7 vs 14.8%) and MHT (28.9 vs 25.8%) was identified using the 2017 ACC/AHA criteria comparing with 2018 ESC/ESH. EVA was associated with the higher-risk BP phenotypes (SH and MHT, P < .0001) in both criteria. There was a higher accuracy in diagnosing EVA, with the 2017 ACC/AHA criteria. Analysis of the receiver operating characteristic curves showed office BP cutoff value (128/83 mm Hg) for EVA closer to the 2017 ACC/AHA threshold.The 2017 AHA/ACC guideline for the diagnosis of AH, and corresponding ambulatory BP monitoring values, is more accurate for discriminating young adults with EVA. Clinical application of PWV may help identify patients that could benefit from BP levels <130/80 mm Hg., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Sensitization to house dust mites (HDMs) is frequent in patients with atopic dermatitis., Objective: To investigate the efficacy of sublingual immunotherapy (SLIT) with Dermatophagoides pteronyssinus extract in patients with atopic dermatitis sensitized to HDM., Methods: In this randomized, double-blind, placebo-controlled trial, we enrolled 91 patients 3 years or older, with SCORing Atopic Dermatitis (SCORAD) score greater than or equal to 15 and positive skin test result and/or IgE to D pteronyssinus. Patients were stratified according to age (<12 and ≥12 years) to receive HDM SLIT or placebo for 18 months. Primary outcome was a greater than or equal to 15-point decrease in SCORAD score. Secondary outcomes were decreases in SCORAD and objective SCORAD, Eczema Area and Severity Index, visual analog scale for symptoms, and pruritus scale scores; Investigator's Global Assessment 0/1; and decrease greater than or equal to 4 points in Dermatology Life Quality Index. Background therapy was maintained., Results: A total of 66 patients completed the study (35 HDM SLIT, 31 placebo). After 18 months, 74.2% and 58% of patients in the HDM SLIT group and the placebo group, respectively, showed greater than or equal to 15-point decrease in SCORAD score (relative risk, 1.28; 95% CI, 0.89-1.83). Significant SCORAD score decreases from baseline of 55.6% and 34.5% in HDM SLIT and placebo groups (mean difference, 20.4; 95% CI, 3.89-37.3), significant objective SCORAD score decreases of 56.8% and 34.9% in HDM SLIT and placebo groups (mean difference, 21.3; 95% CI, 0.66-41.81), and more patients with Investigator's Global Assessment 0/1 in the HDM SLIT group as compared with the placebo group (14 of 35 vs 5 of 31; relative risk, 2.63; 95% CI, 1.09-6.39) were observed at 18 months., Conclusions: Our results suggest that HDM SLIT may be effective in HDM-sensitized patients as an add-on treatment for atopic dermatitis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: This study reports on the translation, cultural adaptation, and validation of a Portuguese version of the Rotterdam Elderly Pain Observation Scale (REPOS), a Dutch scale to assess pain in patients who cannot communicate, with or without dementia., Methods: This is a multicenter study in pain and neurological units involving Brazil (clinical phase) and the Netherlands (training phase). We performed a retrospective cross-sectional, 2-staged analysis, translating and culturally adapting the REPOS to a Portuguese version (REPOS-P) and evaluating its psychometric properties. Eight health professionals were trained to observe patients with low back pain. REPOS consists of 10 behavioral items scored as present or absent after a 2-min observation. The REPOS score of ≥3 in combination with the Numerical Rating Scale (NRS) of ≥4 indicated pain. The Content Validity Index (CVI) in all items and instructions showed CVI values at their maximum. According to the higher correlation coefficient found between NRS and REPOS-P, it may be suggested that there was an adequate convergent validity., Results: The REPOS-P was administered to 80 patients with a mean age of 60 years (SD 11.5). Cronbach's alpha coefficient showed a moderate internal consistency of REPOS-P (α = 0.62), which is compatible with the original study of REPOS. All health professionals reached high levels of interrater agreement within a median of 10 weeks of training, assuring reproducibility. Cohen's kappa was 0.96 (SD 0.03), and the intraclass correlation coefficient was 0.98 (SD 0.02), showing high reliability of REPOS-P scores between the trainer (researcher) and the trainees (healthcare professionals). The Pearson correlation coefficient was 0.95 (95% confidence interval 0.94-0.97), showing a significant correlation between the total scores of REPOS-P and NRS., Conclusion: The REPOS-P was a valuable scale for assessing elderly patients with low back pain by different healthcare professionals. Short application time, ease of use, clear instructions, and the brief training required for application were essential characteristics of REPOS-P., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 by The Author(s). Published by S. Karger AG, Basel.)

Neurocryptococcosis, a meningoencephalitis caused by Cryptococcus spp, is treated with amphotericin B (AmB) combined with fluconazole. The integrity of the brain-blood barrier and the composition of the cerebrospinal fluid (CSF) may change due to infectious and/or inflammatory diseases such as neurocryptococcosis allowing for the penetration of AmB into the central nervous system. The present study aimed to develop LC-MS/MS methods capable of quantifying AmB in CSF at any given time of the treatment in addition to plasma, plasma ultrafiltrate, with sensitivity compatible with the low concentrations of AmB reported in the CSF. The methods were successfully validated in the four matrices (25 μl, 5-1,000 ng ml -1 for plasma or urine; 100 μl, 0.625-250 ng ml -1 for plasma ultrafiltrate; 100 μl, 0.1-250 ng ml -1 for CSF) using protein precipitation. The methods were applied to investigate the pharmacokinetics of AmB following infusions of 100 mg every 24 h for 16 days administered as a lipid complex throughout the treatment of a neurocryptococcosis male patient. The methods allowed for a detailed description of the pharmacokinetic parameters in the assessed patient in the beginning (4th day) and end of the treatment with AmB (16th day), with total clearances of 7.21 and 4.25 L h -1 , hepatic clearances of 7.15 and 4.22 L h -1 , volumes of distribution of 302.94 and 206.89 L, and unbound fractions in plasma ranging from 2.26 to 3.25%. AmB was quantified in two CSF samples collected throughout the treatment with concentrations of 12.26 and 18.45 ng ml -1 on the 8th and 15th days of the treatment, respectively. The total concentration of AmB in plasma was 31 and 20 times higher than in CSF. The unbound concentration in plasma accounted for 77 and 44% of the respective concentrations in CSF. In conclusion, the present study described the most complete and sensitive method for AmB analysis in plasma, plasma ultrafiltrate, urine, and CSF applied to a clinical pharmacokinetic study following the administration of the drug as a lipid complex in one patient with neurocryptococcosis. The method can be applied to investigate the pharmacokinetics of AmB in CSF at any given time of the treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pippa, Marques, Silva, Vilar, de Haes, Fonseca, Martinez, Coelho, Wichert-Ana and Lanchote.)

We aimed to describe the impact of pertussis on adolescents, adults, and older adults over 2007-2018 in selected Latin American countries by reviewing the literature. We searched the Medline, Embase, Scopus, LILACS, Scielo, Google Scholar, CAPES Journals Web-portal, and Cochrane databases for observational epidemiological studies, clinical trials, and systematic reviews of primary studies. Data were extracted and analyzed for all individuals aged ≥10 years. Of 6,891 studies identified only 25 were eligible. Studies were conducted in Brazil (14), Argentina (4), Colombia (4), Mexico (2) and Chile (1). Epidemiological data among target population were limited. No studies clearly assessed the status of asymptomatic or oligosymptomatic B. pertussis carriers in these age groups. Among all pertussis cases identified, the percentage of patients ≥10 years-old ranged between 2.1% and 66.7% depending on country and sample characteristics. The definition of cases, diagnostic methods, and age groups were not consistent across studies.

Objectives: The CYP2C9 gene have three common alleles, CYP2C9*1 , CYP2C9*2 and CYP2C9*3 , associated with different homozygous ( *1/*1, *2/*2 and *3/*3 ) and heterozygous ( *1/*2 and *1/*3 ) genotypes, which in turn are related to extensive ( g EM), intermediate ( g IM) and poor ( g PM) metabolizers. Likewise, the inter-ethnic variability was intimately associated with different drug metabolism. Therefore, the aim of the present study was predict the metabolizer phenotypes in different Peruvian ethnic groups from lowland (<2,500 m) and highland (>2,500 m)., Methods: TaqMan genotyping assays were performed in a group of 174 healthy unrelated Peruvian individuals., Results: In this study, the allelic comparison between the three eco-regions showed that the CYP2C9*1 was the most common in Andean (96.32%); the *2 was the most frequent in Coast (7.45%, p<0.05). Regarding the *3 was the most common in Amazonian (6.25%, p<0.05). In a corroborative manner, the g EM was the most common in Andean (94.74%), the g IM in Coast (17.02%) and g PM in Amazonian (6.25%) populations., Conclusions: Our study provides a valuable source of information about to metabolizer phenotype drugs in different Peruvian ethnic groups. In this way, it could be established suitable genetic-dosage medicaments for various common diseases in these heterogenetic populations., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Venlafaxine (VEN) is a P-glycoprotein (P-gp) substrate, and nifedipine has been described by in vitro and experimental studies as a P-gp inhibitor. The present study aimed to investigate whether nifedipine alters the kinetic disposition of VEN enantiomers and their metabolites in healthy subjects. A crossover study was conducted in 10 healthy subjects phenotyped as extensive metabolizers for cytochrome P450 (CYP) 2D6, CYP2C19, and CYP3A. In phase 1, the subjects received a single oral dose of 150 mg racemic VEN, and in phase 2, a single oral dose of 40 mg nifedipine was administered with the VEN treatment. Plasma concentrations of VEN enantiomers and their metabolites O-desmethylvenlafaxine and N, O- didesmethylvenlafaxine (ODV and DDV, respectively) were evaluated by liquid chromatography with tandem mass spectrometry up to 72 hours after drug administration. Phase 2 was compared with phase 1 using the 90% confidence interval (CI) of the ratio of geometric means for C max and area under the curve (AUC). AUC enantiomeric ratios S-(+)/R-(-) were evaluated within each and between phases using the Wilcoxon test (P ≤ .05). The kinetic disposition of VEN was enantioselective (phase 1) with VEN S-(+)/R-(-) AUC ratio median of 2.83 (AUC 0-∞ , 526 vs 195 ng·h/mL). However, AUC median did not differ between enantiomers for the metabolites ODV (1971 vs 2226 ng·h/mL) and DDV (199 vs 151 ng·h/mL). The 90%CI of the ratio of geometric means showed that the phases are bioequivalent. A single oral dose of 40 mg nifedipine did not alter VEN enantiomer pharmacokinetics in healthy subjects., (© 2020, The American College of Clinical Pharmacology.)

Objective: To qualify a 3C approach model of dual-energy X-ray absorptiometry (DXA) to estimate multicomponent resting energy expenditure (REE) referenced by indirect calorimetry (IC)., Methods: A sample of 155 college students, of both sexes (18-30 years old) was evaluated. Anthropometric measures, REE by IC, and whole-body DXA-scans were performed. The REE for each body component was determined after transforming the components from the molecular (DXA) to the organ tissue level. Bland-Altman and proportional bias analyses were used to verify agreement between REE measured (REE IC ) and estimated (REE DXA )., Results: Statistically significant differences were found for all sex comparisons (P < .001), except for age (P = .950). Differences from the final sex-specific models' were not found between REE IC and REE DXA (P > .05). Men also presented greater expenditure (P < .001) in each component, except for adipose tissue. The plots confirmed the validity of the model for both sexes, with low difference values between the measured and estimated REE. The mean of the differences of REE IC and REE DXA showed heteroscedasticity of the data for men (P = .004). The same error tendency was not evident for women (P = .333)., Conclusions: This 3C model, estimating REE from a multicomponent approach, allows a new application of DXA as tool for understanding intraindividual differences in terms of the mass of metabolically active tissue. Sex and populational differences should be taken in account. Consequently, we present qualified sex-specific DXA models that can be applied in different contexts such as health and sports, besides considering interpersonal differences in terms of energy expenditure., (© 2020 Wiley Periodicals LLC.)

Background: Propolis is rich in polyphenols, especially flavonoids and phenolic acids, and has significant antioxidant activity, shown mainly in " in vitro " studies., Objective: The aim of this study was to evaluate the antioxidant efficacy and safety of a standardized propolis extract in healthy volunteers., Design: A two-phase sequential, open-label, nonrandomized, before and after clinical trial., Methods: Healthy participants received two EPP-AF® doses (375 and 750 mg/d, P.O, tid) during 7 ± 2 days, starting with the lower doses. Immediately before starting EPP-AF® administration and at the end of each 7-day dosing schedule, blood and urine samples were collected for quantification of 8-OHDG (8-hydroxydeoxyguanosine) and 8-ISO (8-isoprostanes) in urine and GSH (reduced glutathione), GSSG (oxidized glutathione), SOD (superoxide dismutase), FRAP (Ferric Reducing Antioxidant Power), vitamin E, and MDA (malondialdehyde) in plasma., Results: In our study, we had 34 healthy participants (67.7% women, 30 ± 8 years old, 97% white). The 8-ISO, a biomarker of lipid peroxidation, decreased with both doses of EPP-AF® compared to baseline (8-ISO, 1.1 (0.9-1.3) versus 0.85 (0.75-0.95) and 0.89 (0.74-1.0), ng/mg creatinine, P < 0.05, for 375 and 750 mg/d EPP-AF® doses versus baseline, mean and CI 95%, respectively). 8-OHDG, a biomarker of DNA oxidation, was also reduced compared to baseline with 750 mg/d doses (8-OHDG, 15.7 (13.2-18.1) versus 11.6 (10.2-13.0), baseline versus 750 mg/d, respectively, ng/mg creatinine, P < 0.05). Reduction of biomarkers of oxidative stress damage was accompanied by increased plasma SOD activity (68.8 (66.1-73.3) versus 78.2 (72.2-80.5) and 77.7 (74.1-82.6), %inhibition, P < 0.0001, 375 and 750 mg/d versus baseline, median and interquartile range 25-75%, respectively) and by increased GSH for 375 mg/d EPP-AF® doses (1.23 (1.06-1.34) versus 1.33 (1.06-1.47), μ mol/L, P < 0.05)., Conclusion: EPP-AF® reduced biomarkers of oxidative stress cell damage in healthy humans, with increased antioxidant enzymatic capacity, especially of SOD. This trial is registered with the Brazilian Registry of Clinical Trials (ReBEC, RBR-9zmfs9)., Competing Interests: AAB reported personal fees from Apis Flora Ind. Coml. Ltda. outside the submitted work. All other authors have nothing to disclose., (Copyright © 2020 Débora P. Diniz et al.)

This study shows the development and validation of two enantioselective LC-MS/MS methods for the determination of fexofenadine in biological matrices including the elution order determination. Plasma (200 µL) or urine (50 µL) aliquots were added to the internal standard solution [(S)-(-)-metoprolol] and extracted in the acid medium with chloroform. Resolution of the (R)-(+)- and (S)-(-)-fexofenadine enantiomers was performed in a Chirobiotic V column. The methods showed linearity at the range of 0.025-100 ng/mL plasma and 0.02-10 µg/mL urine for each fexofenadine enantiomer. These methods were applied to the maternal-fetal pharmacokinetics of fexofenadine enantiomers in plasma and urine of parturient women (n = 8) treated with a single oral 60 mg dose of racemic fexofenadine. Enantiomeric ratio in plasma (AUC 0-∞( R )-(+)/( S )-( - ) ) was close to 1.5, nevertheless in urine was closed to unity. The transplacental transfer was approximately 18% for both fexofenadine enantiomers. The enantioselective methods can also be useful in future clinical studies of chiral discrimination of drug transporters., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Plasma concentration data points (n = 2,640) from 16 healthy adults were used to develop and validate limited sampling strategies (LSS) for estimation of phenotypic metrics for CYP enzymes and the ABCB1 transporter, using a cocktail of subtherapeutic doses of the selective probes caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A), losartan (CYP2C9), omeprazole (CYP2C19), and fexofenadine (ABCB1). All-subsets linear regression modelling was applied to estimate the AUC 0-12h for caffeine, fexofenadine, and midazolam, and the AUC 0-12h ratio of metoprolol: α-OH metoprolol and omeprazole:5-OH omeprazole. LSS-derived metrics were compared with the parameters' 'best estimates' obtained by non-compartmental analysis using all plasma concentration data points. The correlation coefficient ( R 2 ) was used to identify the LSS equations that provided the best fit for n timed plasma samples, and the jack-knife statistics was used as an additional validation procedure for the LSS models. Single time-point LSS models provided R 2 values greater than 0.95 ( R 2 > 0.95) for the AUC 0-12h ratio of metoprolol:α-OH metoprolol and omeprazole:5-OH omeprazole, whereas 2 time-point models were required for R 2 > 0.95 for the AUC 0-12h of caffeine, fexofenadine, and midazolam. Increasing the number of sampling points to three led to minor increases in R 2 and/or the bias or prediction of the estimates. In conclusion, the LSS models provided accurate prediction of phenotypic indices for CYP1A2, CYP2C19, CYP2D6, CYP3A, and ABCB1, when using subtherapeutic doses of selective probes for these enzymes and transporter., (Copyright © 2020 Coelho, Cusinato, Ximenez, Lanchote, Struchiner and Suarez-Kurtz.)

Objective: We described pertussis epidemiological trends in Brazil between 2010 and 2015. We also assessed tetanus, diphtheria and acellular pertussis (Tdap) vaccine coverage among pregnant women from 2014, the year of the introduction of Tdap maternal immunization recommendation in Brazil, to 2016. Methods: Epidemiological data for incidence, prevalence, hospitalization, mortality, and maternal vaccination coverage were calculated based on the Brazilian public surveillance databases. Results: The epidemiological data analysis results showed that the pertussis average incidence rate (IR) was 2.19/100,000 inhabitants for all ages, with a peak in 2014 (4.03/100,000 inhabitants) and highest incidence in <1-year-old children (IR = 175.20/100,000). 97.6% of pertussis deaths (405/415) were in <1-year-old children. Maternal immunization coverage was 9.2% in 2014, 40.4% in 2015, and 33.8% in 2016. Conclusions: Pertussis incidence and pertussis-related deaths increased in Brazil from 2010 to 2014 and decreased in 2015. In the two years, 2015 and 2016 that followed the NIP recommendation, Tdap vaccination coverage of pregnant women was low and varying from region to region. More efforts and national plans would help increase awareness and maternal immunization coverage.

Background: Tamoxifen is considered a prodrug of its active metabolite endoxifen, which is dependent on the CYP2D6 and CYP3A enzymes. Tamoxifen pharmacokinetic variability influences endoxifen exposure and, consequently, its clinical outcome. This study investigated the impact of hormonal status on the pharmacokinetics of tamoxifen and its metabolites in TAM-treated breast cancer patients., Methods: TAM-treated breast cancer patients (n = 40) previously believed to have CYP3A activity within the normal range based on oral midazolam and phenotyped as CYP2D6 normal metabolizers using oral metoprolol were divided into two groups according to premenopausal (n = 20; aged 35-50 years) or postmenopausal (n = 20; aged 60-79 years) status. All patients were treated with 20 mg/day tamoxifen for at least three months. Serial plasma samples were collected within the 24 h dose interval for analysis of unchanged tamoxifen, endoxifen, 4-hydroxytamoxifen and N-desmethyltamoxifen quantified by LC-MS/MS. CYP activities were assessed using midazolam apparent clearance (CYP3A) and the metoprolol/alfa-hydroxymetoprolol plasma metabolic ratio (CYP2D6). CYP3A4, CYP3A5 and CYP2D6 SNPs and copy number variation were investigated using TaqMan assays., Results: Postmenopausal status increased steady-state plasma concentrations (Css) of tamoxifen (116.95 vs 201.23 ng/mL), endoxifen (8.01 vs 18.87 ng/mL), N-desmethyltamoxifen (485.16 vs 843.88 ng/mL) and 4-hydroxytamoxifen (2.67 vs 4.11 ng/mL). The final regression models included hormonal status as the only predictor for Css of tamoxifen [β-coef ± SE, p-value (75.03 ± 17.71, p = 0.0001)] and 4-hydroxytamoxifen (1.7822 ± 0.4385, p = 0.0002), while endoxifen Css included hormonal status (8.578 ± 3.402, p = 0.02) and race (11.945 ± 2.836, p = 0.007). For N-desmethyltamoxifen Css, the final model was correlated with hormonal status (286.259 ± 76.766, p = 0.0007) and weight (- 8.585 ± 3.060, p = 0.008)., Conclusion: The premenopausal status was associated with decreased endoxifen plasma concentrations by 135% compared to postmenopausal status. Thus, the endoxifen plasma concentrations should be monitored mainly in the premenopausal period to maintain plasma levels above the efficacy threshold value., Trial Registration: RBR-7tqc7k.

Ethnopharmacological Relevance: Propolis has been employed extensively in many cultures since ancient times as antiseptic, wound healing, anti-pyretic and others due to its biological and pharmacological properties, such as immunomodulatory, antitumor, anti-inflammatory, antioxidant, antibacterial, antiviral, antifungal, antiparasite activities. But despite its broad and traditional use, there is little knowledge about its potential interaction with prescription drugs., Aim of the Study: The main objective of this work was to study the potential herbal-drug interactions (HDIs) of EPP-AF® using an in vivo assay with a cocktail approach., Materials and Methods: Subtherapeutic doses of caffeine, losartan, omeprazole, metoprolol, midazolam and fexofenadine were used. Sixteen healthy adult volunteers were investigated before and after exposure to orally administered 125 mg/8 h (375 mg/day) EPP-AF® for 15 days. Pharmacokinetic parameters were calculated based on plasma concentration versus time (AUC) curves., Results: After exposure to EPP-AF®, it was observed decrease in the AUC 0-∞ of fexofenadine, caffeine and losartan of approximately 18% (62.20 × 51.00 h.ng/mL), 8% (1085 × 999 h.ng/mL) and 13% (9.01 × 7.86 h.ng/mL), respectively, with all 90% CIs within the equivalence range of 0.80-1.25. On the other hand, omeprazole and midazolam exhibited an increase in AUC 0-∞ of, respectively, approximately 18% (18.90 × 22.30 h.ng/mL) and 14% (1.25 × 1.43 h.ng/mL), with the upper bounds of 90% CIs slightly above 1.25. Changes in pharmacokinetics of metoprolol or its metabolite α-hydroxymetoprolol were not statistically significant and their 90% CIs were within the equivalence range of 0.80-1.25., Conclusions: In conclusion, our study shows that EPP-AF® does not clinically change CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A activities, once, despite statistical significant, the magnitude of the changes in AUC values after EPP-AF® were all below 20% and therefore may be considered safe regarding potential interactions involving these enzymes. Besides, to the best of our knowledge this is the first study to assess potential HDIs with propolis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background The MDR1 gene presents several genetic polymorphisms with pharmacological implications. Therefore, the aim of the present study is to establish the genotype and allele frequencies of 3435C>T polymorphism of MDR1 gene into Peruvian populations (Coastal, Andean and Amazonian ecoregions), even considering the altitude (lowland <2500 m and highland >2500 m). Methods The polymorphism was analyzed by TaqMan genotyping assays in a group of 181 healthy unrelated Peruvian individuals. The comparison of genotype and allele frequencies of 3435C>T polymorphism was made with the Pearson test (X2), and, to calculate the genotype distributions, the Hardy-Weinberg equilibrium (HWE) was used. Results In all populations evaluated in this study, the genotype frequency distributions met HWE assumptions. The comparison between genotype and allele frequencies showed significant differences (p < 0.05), when the Andean, Coastal and Amazonian populations were compared. Also, significant differences (p < 0.05) were obtained when these populations were compared considering their altitudes. Likewise, in comparison with countries like USA, Finland, Nigeria and Kenya, the results showed significant differences (p < 0.05). Conclusions This investigation allowed us to establish the genotype and allele frequencies of 3435C>T polymorphism in different Peruvian populations, considering the geographic localization and even the altitude.

Drug transporters and CYP enzymes are important sources of pharmacokinetics (PK) variability in drug responses and can cause various pharmacological and toxicological consequences, leading to either toxicity or an insufficient pharmacological effect. In recent years, the cocktail approach was developed to determine in vivo CYP and transporters activities, but these approaches are somewhat limited. We described the development and validation of three sensitive and specific LC-MS/MS assays for the determination of P-gp and major human CYP isoenzyme activities following oral administration of a drug cocktail of subtherapeutic doses (lower than 10 times) of caffeine (CAF), omeprazole (OME), losartan (LOS), midazolam (MDZ), metoprolol (METO) and fexofenadine (FEX) in healthy volunteers. The three validated methods were selective for all tested analytes. No interference or matrix effect was observed for the mass transition and retention times for all compounds monitored. Additionally, assays were linear over a wide range, and limits of quantification varied between 0.01-5 ng/mL plasma. The coefficients of variation obtained in the precision studies and the inter- and intra-assay accuracies were less than 15%, guaranteeing the reproducibility and repeatability of the results. All substrates and metabolites were stable in plasma during freeze-thaw cycles. Three healthy volunteers were selected based on genotyping for CYP2C9, CYP2C19 and CYP2D6. One volunteer was genotyped as an extensive metabolizer (EM) for all tested CYP isoforms, one volunteer was genotyped as a poor metabolizer (PM) for the CYP2C9 isoform (CYP2C9*3/*3), and one volunteer was genotyped as a PM for the CYP2D6 isoform (CYP2D6*4/*4). The methods allowed the quantification of all analytes over the entire sampling period (12 h) in all studied genotypes. Thus, the analytical methods described here were sufficiently sensitive for use in low-dose pharmacokinetic studies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The plant metabolite 3,4,5-tri-O-galloylquinic acid methyl ester (TGAME, compound 6) was synthesized, and its potential effect on calcium oxalate monohydrate (COM) crystal binding to the surface of Madin-Darby canine kidney cells type I (MDCKI) and crystal growth in a Drosophila melanogaster Malpighian tubule (MT) model were investigated. Membrane, cytosolic, and total annexin A1 (AxA1), α-enolase, and heat shock protein 90 (HSP90) amounts were examined by Western blot analysis after subcellular fractionation, then confirmed by immunofluorescence staining of cultured cells. Pretreatment of MDCKI cells with TGAME for up to 6 h significantly diminished COM crystal binding in a concentration-dependent manner. TGAME significantly inhibited AxA1 surface expression by immunofluorescence microscopy, whereas intracellular AxA1 increased. Western blot analysis confirmed AxA1 expression changes in the membrane and cytosolic fractions of compound-treated cells, whereas whole cell AxA1 remained unchanged. TGAME also significantly decreased the size, number, and growth of calcium oxalate (CaOx) crystals induced in a Drosophila melanogaster MT model and possessed a potent antioxidant activity in a DPPH assay.

This study describes the development and validation of a method for the analysis of unbound plasma concentrations of oxcarbazepine (OXC) and of the enantiomers of its active metabolite 10-hydroxycarbazepine (MHD) [S-(+)- and R-(-)-MHD] using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Additionally, the free fraction of the drug is described in healthy volunteers (n=12) after the oral administration of 300mg OXC/12h for 5days. Plasma aliquots of 200μL were submitted to ultrafiltration procedure and 50μL of the ultrafiltrate were extracted with a mixture of tert-butyl methyl ether:dichloromethane (2:1, v/v). OXC and the MHD enantiomers were separated on a OD-H chiral phase column. The method was linear in the range of 4.0-2.0μg/mL for OXC and of 20.0-6.0μg/mL plasma for the MHD enantiomers. The limit of quantification was 4ng for OXC and 20ng for each MHD enantiomer/mL plasma. The intra- and inter-day precision and inaccuracy were less than 15%. The free fraction at the time of peak plasma concentration of OXC was 0.27 for OXC, 0.37 for S-(+)-MHD and 0.42 for R-(-)-MHD. Enantioselectivity in the free fraction of MHD was observed, with a higher proportion of R-(-)-MHD compared to S-(+)-MHD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Nebivolol is a drug available as a racemate of d-nebivolol (SRRR) and lnebivolol (RSSS). In human liver microsomes, CYP2D6 mainly catalyses the metabolism of lnebivolol, while CYP2C19 catalyses the metabolism of d-nebivolol. Nebivolol stereoselective pharmacokinetics has been described only for extensive metabolizers (EM)., Objective: To describe the stereoseletive nebivolol pharmacokinetics in CYP2D6 poor metabolizers (PM) and to assess whether the phenotype has an impact on nebivolol pharmacokinetics., Methods: Three healthy volunteers PM phenotyped (ratios of 20.1, 220 and 244 for the 8 h urinary excretion of metoprolol/alfa-hydroxymetoprolol) received a single oral dose of racemic nebivolol and sequential blood samples were collected between zero (predose) and 48 h., Results: The obtained data were compared to 22 EM subjects with normal kidney function enrolled in our previous study. For both isomers, Cmax, Tmax and AUC0-48 were significantly greater in the PM group compared to the EMs (p = 0.006 - 0.001). For d-nebivolol, Cmax, Tmax and AUC0-48 were, on average, 5.9, 2.7 and 15.0 larger in PMs. The corresponding values for l-nebivolol were 4.4, 2.7 and 17.5., Conclusion: The decline in plasma concentration of both nebivolol isomers in PM phenotypes, especially those with MR of 220 and 244, which indicate minimal or absent CYP2D6 activity, points to alternative mechanisms for nebivolol elimination. Collectively, our results are the first to show the significant impact of CYP2D6 PM phenotype on the metabolic disposition and in vivo exposure to both nebivolol isomers., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Oxcarbazepine is indicated for the treatment of partial or generalised tonic-clonic seizures. Most of the absorbed oxcarbazepine is converted into its active metabolite, 10-hydroxycarbazepine (MHD), which can exist as R-(-)- and S-(+)-MHD enantiomers. Here we describe the influence of the P-glycoprotein (P-gp) inhibitor verapamil, on the disposition of oxcarbazepine and MHD enantiomers, both of which are P-gp substrates. Healthy subjects (n=12) were randomised to oxcarbazepine or oxcarbazepine combined with verapamil at doses of 300mg b.i.d. and 80mg t.i.d., respectively. Blood samples (n=185) were collected over a period of 12h post oxcarbazepine dose. An integrated PK model was developed using nonlinear mixed effects modelling using a meta-analytical approach. The pharmacokinetics of oxcarbazepine was described by a two-compartment model with absorption transit compartments and first-order elimination. The concentration-time profiles of both MHD enantiomers were characterised by a one-compartment distribution model. Clearance estimates (95% CI) were 84.9L/h (69.5-100.3) for oxcarbazepine and 2.0L/h (1.9-2.1) for both MHD enantiomers. The volume of distribution was much larger for oxcarbazepine (131L (97-165)) as compared to R-(-)- and S-(+)-MHD (23.6L (14.4-32.8) vs. 31.7L (22.5-40.9), respectively). Co-administration of verapamil resulted in a modest increase of the apparent bioavailability of oxcarbazepine by 12% (10-28), but did not affect parent or metabolite clearances. Despite the evidence of comparable systemic levels of OXC and MHD following administration of verapamil, differences in brain exposure to both moieties cannot be excluded after P-glycoprotein inhibition., (Copyright © 2017. Published by Elsevier B.V.)

Carvedilol, a drug available as a racemic mixture, is metabolised into hydroxyphenylcarvedilol (OHC) by CYP2D6 and O-desmethylcarvedilol (DMC) by CYP2C9 followed by conjugation to glucuronides. In contrast to other β-adrenergic receptor antagonists, carvedilol does not induce insulin resistance or worsen glycaemic control in diabetic hypertensive patients. This study aims to investigate the implications of type 2 diabetes (T2DM) on the pharmacokinetics of carvedilol enantiomers using an integrated population pharmacokinetic modelling approach. In total, 14 T2DM patients with good glycaemic control receiving standard doses of metformin and glibenclamide were evaluated along with a control group of 13 healthy subjects. Serial blood samples were collected up to 24h after administration of a single 25mg dose of racemic carvedilol. A multicompartmental population pharmacokinetic model describing the enantioselective disposition of the parent compound, OHC and DMC was developed in NONMEM v7.2. Even though data are limited, it appears that despite inhibition of CYP2C9 due to long-term glibenclamide administration to T2DM patients, overall no differences are observed in the total clearance of carvedilol when compared to healthy subjects (43.1 vs. 45.9L/h for (S)-(-)-carvedilol and 29.0 vs. 33.1L/h for (R)-(+)-carvedilol). These results provide evidence of a compensatory mechanism for the inhibition of CYP2C9, with higher contribution of CYP2D6 activity to the elimination of carvedilol. Consequently, no dose adjustment is recommended for carvedilol in T2DM patients receiving glibenclamide and metformin., (Copyright © 2017. Published by Elsevier B.V.)

This review aims to identify in the literature the prevalence and factors associated with Sexual Violence (SV) against adolescents and adult women. It were reviewed the population-based study, published between 2011 and 2016, in English, Portuguese and Spanish, in Pubmed / Medline, Lilacs and SciELO databases. The studies were analyzed and described, detailing their characteristics and information on prevalence and factors associated with SV. Of the 3,002 articles found, according to the eligibility criteria, 15 studies were objects of this review. Most studies focus on Asia and Africa, which also have the highest prevalence of SV. The predominantly investigated age group was 15-49 years. There was a great variation in the prevalence of SV among the countries, when SV was analyzed by intimate partner, it varied from 1 % in Germany in the current relationship to 92 % Zimbabwe. In relation to the associated factors, low educational level, young age, mental health conditions and sexual and reproductive health, as well as the use of alcohol and other drugs are highlighted. The review highlights the need to deepen studies on sexual violence to contribute to public policies, to combat violence against women and to gender equity.

Purpose: Rocuronium (ROC) is a neuromuscular blocker mainly eliminated by biliary excretion dependent on organic anion transporting polypeptide 1A2 (OATP1A2) hepatocellular uptake. However, the influence of SLCO1A2 (gene encoding OATP1A2) genetic polymorphism on ROC pharmacokinetics was never described before. The objective of this work was to evaluate the influence of genetic polymorphisms of SLCO1A2 on the pharmacokinetics of rocuronium (ROC)., Methods: Patients undergoing elective surgeries under general anesthesia using rocuronium as a neuromuscular blocker were genotyped for SLCO1A2 polymorphisms in the coding region (41A>G, 382A>T, 404A>T, 502C>T, 516A>C, 559G>A, 830C>A, and 833delA) and in the promoter region (-1105G>A, -1032G>A, -715T>C, -361G>A, and -189&#95;-188insA). Rocuronium pharmacokinetic parameters were estimated by non-compartmental analysis., Results: None of the patients had heterozygous or homozygous variant of 404A>T, 382A>T, 502C>T, 833delA, 830C>A, 41A>G, and -715T>C. A linkage disequilibrium was found between -1105G>A and -1032G>A genotypes. Patients genotyped as -A or AA (n = 17) for SLCO1A2 -189&#95;-188InsA showed reduced total clearance of ROC compared to patients genotyped as -/- (n = 13) (151.6 vs 207.1 mL/min, p ≤ 0.05). The pharmacokinetics parameters of ROC were not significantly different between other SLCO1A2 genotypes., Conclusion: SLCO1A2 -189&#95;-188InsA polymorphism is related to the reduced clearance of rocuronium in patients submitted to elective surgeries under general anesthesia., Trial Registration: NCT 02399397 ( ClinicalTrials.gov ).

Background:: The diterpene Sclareol has antimicrobial action, cytotoxic and cytostatic effects and anti-tumor activities. However, researches on the cardiovascular system are scarce., Objective:: This study was designed to investigate the mechanisms involved in the Sclareol cardiovascular effect in normotensive and hypertensive rats., Methods:: The arterial hypertension was promoted using 2-kidneys 1-clip model in rats. The effect of sclareol on blood pressure was performed by using three dose (10, 20 and 40 mg/kg). Cumulative dose-response curves for Sclareol were determined for endothelium-intact and endothelium-denuded aortic rings in presence or absence of L-NAME and ODQ. The NOx levels were measure in the plasma sample., Results:: The Sclareol administration in vivo caused a significant reduction in blood pressure in both groups. In vitro the sclareol promoted relaxation in aorta, with endothelium, pre-contracted to Phe. The inhibitors of the nitric oxide synthase and soluble guanylate cyclase were as efficient as the removal of endothelium, in inhibiting the Sclareol-induced relaxation. Otherwise, it was no change of NOx. Also, for unknown reasons, the Sclareol is not selective for hypertensive animals., Conclusion:: The diterpene Sclareol showed in vivo hypotensive and in-vitro vasodilator effects; The chemiluminescence plasmatic NO analysis showed no significant difference between groups and The Sclareol exhibit better effect on normotensive than hypertensive animals to reduce blood pressure. It is concluded that the diterpenes metabolites would be a promising source prototype for the development of new agents in the cardiovascular therapy., Fundamento:: O diterpeno Esclareol tem ação antimicrobiana, efeitos citotóxicos e citostáticos e atividades antitumorais. No entanto, pesquisas sobre o sistema cardiovascular são escassas., Objetivo:: Este estudo foi desenvolvido para investigar os mecanismos envolvidos no efeito cardiovascular de Esclareol em ratos normotensos e hipertensos., Métodos:: A hipertensão arterial foi promovida utilizando modelo de 2 clones de 1-clipe em ratos. O efeito do esclareol sobre a pressão arterial foi realizado utilizando três doses (10, 20 e 40 mg/kg). As curvas dose-resposta cumulativas para Esclareol foram determinadas para anéis aórticos endotélio-intactos e desprovidos de endotélio na presença ou ausência de L-NAME e ODQ. Os níveis de NOx foram medidos na amostra de plasma., Resultados:: A administração de Esclareol in vivo causou uma redução significativa na pressão sanguínea em ambos os grupos. In vitro o esclareol promoveu relaxamento na aorta, com endotélio, pré-contraído a Phe. Os inibidores da óxido nítrico sintase e da guanilato ciclase solúvel foram tão eficientes quanto a remoção do endotélio, na inibição do relaxamento induzido por Esclareol. Por outra parte, não houve mudança de NOx. Além disso, por razões desconhecidas, o Sclareol não é seletivo para animais hipertensos., Conclusão:: O diterpeno Esclareol apresentou efeitos hipotensores in vivo e vasodilatadores in vitro; A análise de NO plasmático por quimioluminescência não mostrou diferença significativa entre os grupos e O Esclareol exibe melhor efeito sobre os animais normotensos do que hipertensos para reduzir a pressão arterial. Conclui-se que os metabólitos de diterpenos seriam um protótipo de fonte promissora para o desenvolvimento de novos agentes na terapia cardiovascular.

The aim of this study was to evaluate the enantioselective pharmacokinetics of cyclophosphamide and its metabolites 4-hydroxycyclophosphamide and carboxyethylphosphoramide mustard in patients with systemic or multiple sclerosis. Patients with systemic sclerosis (n = 10) or multiple sclerosis (n = 10), genotyped for the allelic variants of CYP2C9*2 and CYP2C9*3 and of the CYP2B6 G516T polymorphism, were treated with 50 mg cyclophosphamide/kg daily for 4 days. Serial blood samples were collected up to 24 hours after administration of the last cyclophosphamide dose. Cyclophosphamide, 4-hydroxycyclophosphamide, and carboxyethylphosphoramide enantiomers were analyzed in plasma samples using liquid chromatography-tandem mass spectrometry coupled to chiral column Chiralcel OD-R or Chiralpak AD-RH. Cytokines IL-2, IL-4, IL-6, IL-8, IL-10, IL- 12p70, IL-17, TNF-α, and INT-δ in the plasma samples collected before cyclophosphamide infusion were analyzed by Milliplex MAP human cytokine/chemokine. Pharmacokinetic parameters showed higher plasma concentrations of (S)-(-)-cyclophosphamide (AUC 215.0 vs 186.2 μg·h/mL for multiple sclerosis patients and 219.1 vs 179.2 μg·h/mL for systemic sclerosis patients) and (R)-4-hydroxycyclophosphamide (AUC 5.6 vs 3.7 μg·h/mL for multiple sclerosis patients and 6.3 vs 5.6 μg·h/mL for systemic sclerosis patients) when compared to their enantiomers in both groups of patients, whereas the pharmacokinetics of the carboxyethylphosphoramide metabolite was not enantioselective. Cytokines' plasma concentrations were similar between multiple and systemic sclerosis groups. The pharmacokinetics of cyclophosphamide is enantioselective in patients with systemic sclerosis and multiple sclerosis, with higher plasma concentrations of the (S)-(-)-cyclophosphamide enantiomer due to the preferential formation of the (R)-4-hydroxycyclophosphamide metabolite., (© 2017, The American College of Clinical Pharmacology.)

Carvedilol is available in clinical practice as a racemate in which (S)-(-)-carvedilol is a β- and α 1 -adrenergic antagonist and (R)-(+)-carvedilol is only an α 1 -adrenergic antagonist. Carvedilol is mainly metabolized by glucuronidation, by CYP2D6 to hydroxyphenylcarvedilol (OHC), and by CYP2C9 to O-desmethylcarvedilol (DMC). This study evaluated the pharmacokinetics of carvedilol enantiomers and their metabolites OHC and DMC in healthy volunteers (n = 13) and in type 2 diabetes mellitus patients with good glycemic control (n = 13). The healthy subjects were enrolled to receive either a 25-mg oral single dose of carvedilol alone (no DDI) or carvedilol simultaneously with 5 mg glibenclamide and 500 mg metformin (DDI), whereas type 2 diabetes mellitus patients who were on long-term treatment with glibenclamide (5 mg/8 h) and metformin (500 mg/8 h) were enrolled to receive only a single oral dose of 25 mg carvedilol. The plasma concentrations of the (R)-(+)-carvedilol, (R)-(+)-DMC, and (R)-(+)-OHC were higher than those of (S)-(-)-carvedilol, (S)-(-)-DMC, and (S)-(-)-OHC in all investigated groups. The pharmacokinetics of the carvedilol enantiomers did not differ between the groups. However, the AUC values of the DMC enantiomers were lower in the type 2 diabetes mellitus patients than in the healthy volunteers (DDI and no DDI) [(R)-(+), 6.9, 10.4, 11.9 ng·h/mL; and (S)-(-), 2.4, 4.3, 4.0 ng·h/mL, respectively]. In contrast, the AUC values of the OHC enantiomers were higher in the type 2 diabetes mellitus patients [(R)-(+), 13.9, 6.6, 4.9 ng·h/mL; and (S)-(-), 7.2, 1.5, 1.5 ng·h/mL], which explains the fact that the carvedilol pharmacokinetics was unchanged., (© 2017, The American College of Clinical Pharmacology.)