Population Pharmacokinetic of the Diterpenes ent-Polyalthic Acid and Dihydro-ent-Agathic Acid from Copaifera Duckei Oil Resin in Rats.

Copaifera duckei oleoresin is a plant product extensively used by the Brazilian population for multiple purposes, such as medicinal and cosmetic. Despite its ethnopharmacological relevance, there is no pharmacokinetic data on this important medicinal plant. Due to this, we determined the pharmacokinetic profile of the major nonvolatile compounds of C. duckei oleoresin. The diterpenes ent-polyalthic acid and dihydro-ent-agathic acid correspond to approximately 40% of the total oleoresin. Quantification was performed using LC-MS/MS, and the validated analytical method showed to be precise, accurate, robust, reliable, and linear between 0.57 and 114.74 µg/mL plasma and 0.09 to 18.85 µg/mL plasma, respectively, for ent-polyalthic acid and dihydro-ent-agathic acid, making it suitable for application in preclinical pharmacokinetic studies. Wistar rats received a single 200 mg/kg oral dose (gavage) of C. duckei oleoresin, and blood was collected from their caudal vein through 48 h. Population pharmacokinetics analysis of ent-polyalthic and dihydro-ent-agathic acids in rats was evaluated using nonlinear mixed-effects modeling conducted in NONMEN software. The pharmacokinetic parameters of ent-polyalthic acid were absorption constant rate = 0.47 h-1, central and peripheral apparent volume of distribution = 0.04 L and 2.48 L, respectively, apparent clearance = 0.15 L/h, and elimination half-life = 11.60 h. For dihydro-ent-agathic acid, absorption constant rate = 0.28 h-1, central and peripheral apparent volume of distribution = 0.01 L and 0.18 L, respectively, apparent clearance = 0.04 L/h, and elimination half-life = 3.49 h. The apparent clearance, central apparent volume of distribution, and peripheral apparent volume of distribution of ent-polyalthic acid were approximately 3.75, 4.00-, and 13.78-folds higher than those of dihydro-ent-agathic.

Intestinal P-gp activity is reduced in postmenopausal women under breast cancer therapy.

Intestinal P-glycoprotein (P-gp) activity plays a crucial role in modulating the oral bioavailability of its substrates. Fexofenadine has commonly been used as a P-gp probe, although it is important to note the involvement of other drug transporters like, OATP1B1, OATP1B3, and OATP2B1. In vitro studies demonstrated an upregulation of P-gp protein in response to exposure to pregnancy-related hormones. The objective of this study was to investigate how intestinal P-gp activity is impacted by menopausal status. This study sampled fexofenadine plasma concentrations over 0-12 h after probe drug administration from two groups of patients with breast cancer: premenopausal (n = 20) and postmenopausal (n = 20). Fexofenadine plasma concentrations were quantified using liquid-chromatography tandem mass spectrometry. Area under the plasma concentration-time curve from zero to infinity (AUCinf ) was calculated through limited sampling strategies equation. Multiple linear regression was applied on AUCinf , maximum plasma concentration (Cmax ), and time to Cmax . Postmenopausal patients showed a significant increase in Cmax (geometric mean and 95% confidence interval [CI] 143.54, 110.95-176.13 vs. 223.54 ng/mL, 161.02-286.06 and in AUCinf 685.55, 534.98-878.50 vs. 933.54 ng·h/mL 735.45-1184.99) compared to premenopausal patients. The carriers of the ABCB1 3435 allele T displayed higher Cmax values of 166.59 (95% CI: 129.44-214.39) compared to the wild type at 147.47 ng/mL (95% CI: 111.91-194.34, p = 0.02). In postmenopausal individuals, the decrease in P-gp activity of ~40% may lead to an increased plasma exposure of orally administered P-gp substrates.

Effect of Chronic Hepatitis C on the Activity of the Membrane Transporters P-gp and OATP1B1/BCRP on Patients With Different Stages of Hepatic Fibrosis.

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.

Non-invasive follicular thyroid neoplasm with papillary-like nuclear feature: clinical, pathological, and molecular update 5 years after the nomenclature revision.

The term non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was proposed in 2016 and incorporated as a new entity in the World Health Organization (WHO) classification of tumours of endocrine organs in 2017. Since then, there has been debate regarding the histological criteria for the diagnosis, the need for molecular studies or the risk of lymph node metastasis or recurrence associated with this entity. Over the years, the concept of NIFTP evolved, now including both small (<1 cm) and large (>4 cm) tumours and oncocytic lesions. On the other hand, recent data on NIFTP in the setting of thyroid follicular nodular disease or frequent coexistence of malignant tumours raised concerns regarding the follow-up of these patients. Today, both pathologists and clinicians still face several challenges in the diagnosis, treatment, and follow-up of patients with NIFTP.

P-Glycoprotein and Organic Anion Transporter Polypeptide 1B/Breast Cancer Resistance Protein Drug Transporter Activity in Pregnant Women Living With HIV.

This study evaluates the influence of pregnancy and HIV infection in conjunction with the use of raltegravir, lamivudine, and tenofovir disoproxil fumarate (combined antiretroviral therapy [cART]) on intestinal P-glycoprotein (P-gp) and hepatic organic anion transporter polypeptide (OATP) 1B1/1B3 and/or breast cancer resistance protein (BCRP) drug transporter activity using rosuvastatin (OATP1B/BCRP) and fexofenadine (P-gp) probes. Single oral doses of 5-mg rosuvastatin and 60-mg fexofenadine were administered to women living with HIV under cART in the third trimester of gestation (n = 15) and postpartum period (n = 10). A control group of 12 healthy nonpregnant women also was investigated. Pharmacokinetic parameters were estimated by using a noncompartmental method and evaluated by t test (P < .05). The rosuvastatin area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC0-last ) value was higher in the third trimester of pregnancy (19.5 [95%CI, 16.8-22.3] ng • h/mL] when compared to postpartum (13.3 [95%CI, 9.3-17.5] ng • h/mL), while the fexofenadine AUC0-last values did not differ between the third trimester of pregnancy (738.0 [95%CI, 611.4-864.6] ng • h/mL) and postpartum period (874.9 [95%CI, 408.2-1342.0] ng• h/mL). The rosuvastatin AUC0-last values did not differ between healthy nonpregnant women (13.8 [95%CI, 10.0-17.6] ng • h/mL) and women living with HIV in the postpartum period (13.3 [95%CI, 9.3-17.5] ng • h/mL), and the fexofenadine AUC0-last values did not differ between the 2 investigated groups (603.6 [95%CI, 467.5-739.7] ng • h/mL vs 874.9 [95%CI, 408.2-1342.0] ng • h/mL). It is suggested that gestation inhibits the hepatic OATP1B1/1B3 and/or BCRP activity but does not alter intestinal P-gp activity. The influence of HIV infection in conjunction with use of cART on OATP1B/BCRP and intestinal P-gp activity was not observed.

Oropharyngeal colostrum administration in neonates with gastroschisis: a randomized clinical trial / Administração orofaríngea de colostro em recém-nascidos com gastrosquise: ensaio clínico randomizado

ABSTRACT Objective: To evaluate the effect of colostrum therapy on days to start a suckling diet in newborns diagnosed with simple gastroschisis. Methods: Randomized clinical trial with newborns diagnosed with simple gastroschisis at a federal hospital in Rio de Janeiro who were randomized to receive oropharyngeal administration of 0.2mL of colostrum or a "sham procedure" during the first 3 days of life. The analysis included clinical outcomes such as days without food, days with parenteral feeding, days until the start of enteral feeding, days to reach complete enteral feeding, sepsis and length of hospital stay. Results: The onset of oral feeding (suction) in patients with simple gastroschisis in both groups occurred at a median of 15 days. Conclusion: The present study showed that there were no significant differences in the use of colostrum therapy and the number of days to the start of enteral feeding and suction diet between groups of newborns with simple gastroschisis.

RESUMO Objetivo: Avaliar o efeito da colostroterapia em dias para iniciar a dieta por sucção em recém-nascidos com diagnóstico de gastrosquise simples. Métodos: Ensaio clínico randomizado com recém-nascidos diagnosticados com gastrosquise simples em um hospital federal no Rio de Janeiro que foram randomizados para receber administração orofaríngea de 0,2mL de colostro ou "procedimento simulado", nos primeiros 3 dias de vida. A análise incluiu desfechos clínicos, como dias sem alimentação, dias com alimentação parenteral, dias para iniciar a alimentação enteral, dias para atingir a alimentação completa, sepse e tempo de internação. Resultados: O início da alimentação por via oral (sucção) na gastrosquise simples, em ambos os grupos, ocorreu com mediana de 15 dias. Conclusão: O presente estudo mostrou que não há diferenças significativas no uso de colostroterapia em dias para início de alimentação enteral e dieta por sucção entre grupos de recém-nascidos com gastrosquise simples.

Incidence and Risk Factors for Concurrent Syndromic Diagnosis in Presumed Idiopathic Developmental Dysplasia of the Hip.

BACKGROUND: Infants referred for developmental dysplasia of the hip (DDH) may have a previously unidentified concomitant diagnosis of syndromic pathology. Our purpose was to examine the incidence of syndromic pathology in infants referred to a tertiary center with presumed idiopathic DDH and identify risk factors and difference in treatment courses between idiopathic and nonidiopathic cohorts. METHODS: A retrospective analysis of a prospective cohort of infants younger than 3 years who were evaluated for DDH between 2008 and 2013 with a minimum 2-year follow-up. The clinical history and treatment were noted to determine the incidence and nature of concomitant syndromic diagnoses, after a confirmed diagnosis of DDH. RESULTS: There were 202 patients: 177 were females (87.6%). Thirteen patients (6.4%) were later diagnosed with a neurologic/syndromic diagnosis. The workup leading to additional diagnosis was initiated by the orthopaedic surgeon in 8 of 13 patients (61.5%). Half of the referrals (4 of 8) made to other specialists were because of an abnormal treatment course (three-failure of typical DDH treatment and one-relapsed clubfeet). 7 of the 8 referrals were made because of developmental delays and decreased tone. 5 of the 13 nonidiopathic patients had other orthopaedic problems. The syndromic diagnoses included three cerebral palsy, two Kabuki syndrome, one Down syndrome, one myopathy, and one neuropathy. The diagnosis was made at an average of 2.3 years (0.04 to 4.7). No notable difference was observed in the incidence of the four known risk factors for DDH in syndromic patients compared with the idiopathic group. The syndromic patients required more open reductions (P = 0.002). DISCUSSION: By the age of 3 years, 6% of the patients treated for DDH were found to have a syndrome or neurologic abnormality, and the referral for workup was made by the treating surgeon greater than 60% of the time.

Suppression of multiple anti-apoptotic BCL2 family proteins recapitulates the effects of JAK2 inhibitors in JAK2V617F driven myeloproliferative neoplasms.

Several lines of research suggest that Bcl-xL-mediated anti-apoptotic effects may contribute to the pathogenesis of myeloproliferative neoplasms driven by JAK2V617F and serve as therapeutic target. Here, we used a knock-in JAK2V617F mouse model and confirmed that Bcl-xL was overexpressed in erythroid progenitors. The myeloproliferative neoplasm (MPN)-induced phenotype in the peripheral blood by conditional knock-in of JAK2V617F was abrogated by conditional knockout of Bcl2l1, which presented anemia and thrombocytopenia independently of JAK2 mutation status. Mx1-Cre Jak2V617W/VF /Bcl2l1f/f mice presented persistent splenomegaly as a result of extramedullary hematopoiesis and pro-apoptotic stimuli in terminally differentiated erythroid progenitors. The pan-BH3 mimetic inhibitor obatoclax showed superior cytotoxicity in JAK2V617F cell models, and reduced clonogenic capacity in ex vivo assay using Vav-Cre Jak2V617F bone marrow cells. Both ruxolitinib and obatoclax significantly reduced spleen weights in a murine Jak2V617F MPN model but did not show additive effect. The tumor burden reduction was observed with either ruxolitinib or obatoclax in terminal differentiation stage neoplastic cells but not in myeloid-erythroid precursors. Therefore, disrupting the BCL2 balance is not sufficient to treat MPN at the stem cell level, but it is certainly an additional option for controlling the critical myeloid expansion of the disease.

Macronutrients of mothers milk of very low birth weight infants: analysis according to gestational age and maternal variables / Macronutrientes do leite materno de recém-nascidos de muito baixo peso: análise segundo idade gestacional e variáveis maternas

ABSTRACT Objective: To analyze the composition of macronutrients present in the milk of mothers of preterm newborn infants (PTNB) - protein, fat, carbohydrate, and calories - by gestational age (GA), chronological age (CA) and maternal variables. Methods: Longitudinal study that analyzed 215 milk samples from the 51 mothers of PTNB admitted in three Neonatal Intensive Care Units of Rio de Janeiro from May/2013-January/2014. Milk collection was performed by pickup pump, on a fixed day of each week until discharge. The spectrophotometric technique with Infrared Analysis (MilkoScan Minor 104) was used for the quantitative analysis. A sample of 7 mL of human milk was taken from the total volume of milk extracted by the mother. The data was grouped by GA (25-27, 28-31, 32-36, 37-40 weeks) and by CA (zero to 4, 5-8, 9-12, 13-16 weeks). Results: Protein, carbohydrate, fat and calories did not show any pattern of change, with no difference among groups of GA. When the macronutrients were analyzed by groups of CA, protein decreased, with significant difference between the first two groups of CA. Carbohydrates, fat and calories presented increasing values in all groups, without significant differences. Weight gain during pregnancy, maternal hypertension and maternal age were associated with changes in fat and calories in the first moment of the analysis of milk. Conclusions: There was a significant decrease in the levels of protein during the first eight weeks after birth. CA may be an important factor in the composition of human milk.

RESUMO Objetivo: Analisar a composição dos macronutrientes presentes no leite de mães de recém-nascidos pré-termo (RNPT) - gorduras, carboidratos e calorias - por idade gestacional (IG), idade cronológica (IC) e variáveis maternos. Métodos: Estudo longitudinal para analisar 215 amostras de leite de 51 mães de RNPT admitidos em três unidades neonatais do Rio de Janeiro de maio/2013 a janeiro/2014. A coleta de leite foi realizada por bomba coletora, em dia fixo a cada semana até a alta. Utilizou-se a técnica espectrofotométrica com análise de infravermelho (MilkoScan Minor 104) para a análise quantitativa. Uma amostra de 7 mL de leite humano foi retirada do volume total de leite extraído pela mãe. Os dados foram agrupados por IG (25-27, 28-31, 32-36 e 37-40 semanas) e por IC (0-4, 5-8, 9-12 e 13-16 semanas). Resultados: Proteínas, carboidratos, gorduras e calorias não apresentaram nenhum padrão de mudança, não havendo diferença entre os grupos de IG. Quando os macronutrientes foram analisados por grupos de IC, a proteína diminuiu, com diferença significante entre os dois primeiros grupos de IC. Carboidratos, gorduras e calorias apresentaram valores crescentes em todos os grupos, sem diferença estatística. O ganho de peso durante a gestação, a presença de hipertensão arterial e a idade materna foram associados a alterações de gordura e calorias no primeiro momento da análise do leite. Conclusões: Observou-se redução estatisticamente significante nos níveis de proteína durante as primeiras oito semanas após o nascimento. A IC pode ser um fator importante na composição do leite humano.

Analysis of daunorubicin and its metabolite daunorubicinol in plasma and urine with application in the evaluation of total, renal and metabolic formation clearances in patients with acute myeloid leukemia.

This report presents improved analysis methods of daunorubicin (DAUN) and its metabolite daunorubicinol (DAUNOL) in small volumes of plasma, as total and unbound concentrations, as well as in urine. This study also presents the pharmacokinetics of DAUN and DAUNOL in patients (n = 12) diagnosed with acute myeloid leukemia treated with intravenous DAUN (60 mg/m2/day, for three days). Serial blood and urine samples were collected up to 144 h after the beginning of the first infusion. The analytical methods presented no significant matrix effect. The linear ranges were 0.1-1000 ng/mL in plasma, 0.05-40 ng/mL in ultrafiltrate and 0.5-3000 ng/ml in urine. The precision and accuracy presented coefficients of variation and standard errors lower than 15 % in the three matrices. The methods allowed for the quantification of samples up to 144 h after the beginning of the first infusion. Unbound fractions for DAUN and DAUNOL were 23.91 % (17.33-32.99) and 29.23 % (25.84-33.07), respectively. The fraction recovered in urine was 4.40 % (3.87-5.03) for DAUN and 7.91 % (6.86-9.19) for DAUNOL. Total 292.96 L/h (261.74-327.90), renal 13.01 L/h (11.44-14.88), and hepatic 280.26 L/h (248.40-317.91) clearances of DAUN, as well as the DAUNOL formation clearance 23.41 L/h (19.09-28.97), were evaluated.

Preoperative mental health status is a significant predictor of postoperative outcomes in adolescents treated with hip preservation surgery.

PURPOSE: This study was designed to evaluate predictive factors that influence pain, mental health symptoms and postoperative outcomes at six-months post-hip preservation surgery (HPS) in adolescent surgical candidates. METHODS: In total, 58 HPS candidates (39 female, 19 male; mean age 15.53 years (10 to 19)) were evaluated. Diagnoses included: acetabular dysplasia (34); idiopathic femoroacetabular impingement (15); Perthes disease (six); avascular necrosis (six); and slipped capital femoral epiphysis (six). All patients underwent periacetabular osteotomy (36), surgical hip dislocation (17) or arthroscopy (five). Patients completed the following: Numerical Pain Rating Scale (NPRS); Child Health Questionnaire-87 (CHQ-87); Pediatric Symptom Checklist-Youth (PSC-Y), preoperatively and six months postoperatively. A single psychologist assessed patients in clinics and one to two additional appointments. RESULTS: In all, 78% of patients reported one to three years of pain prior to HPS (modified Harris hip score). All pain scores (NPRS) significantly decreased at six months postoperatively. Preoperative mental health scores (CHQ-87) significantly predicted postoperative pain scores (F(1, 57) = 4.07; p < 0.048; R2 = 0.068). Mental health symptoms (PSC-Y) decreased significantly (p < 0.001). Patients who were seen by a psychologist two or more times reported better six-month postoperative outcomes than those seen once: usual pain (NPRS; p = 0.012); patient-reported physical function (CHQ-87; p = 0.029); and mental health (PSC-Y; p = 0.019). HPS patients seen ≥ 60 days prior to surgery showed marked improvements at six months compared with patients seen < 60 days prior to surgery. CONCLUSION: HPS candidates evaluated preoperatively by psychology, as part of an integrated treatment approach, demonstrated statistically significant improvements in pain, health-related quality of life and mental health symptoms. Two+ visits, more than 60 days prior to surgery appears to be impactful. Preoperative pain and mental health symptoms were predictive of postoperative pain.Level of Evidence: II.

Rectus-sparing approach to the periacetabular osteotomy in adolescents preserves hip flexion strength.

PURPOSE: The classic periacetabular osteotomy (PAO) approach can result in hip flexor weakness in adolescents. The rectus-sparing approach (PAO-RS) preserves the origin of the rectus femoris tendon which may prevent hip flexor weakness and improve functional outcome. METHODS: This is a prospective analysis of adolescents treated with a PAO or PAO-RS. The PAO group included 24 hips/21 patients (18 female, meanage 16 years (sd 4)); the PAO-RS group included ten hips (eight female, mean age 16 years (sd 1)). Preoperatively, the PAO group had decreased hip flexion strength compared with the PAO-RS group (83 Nm/kg versus 102 Nm/kg). A subset of PAO patients (n = 13 hips/12 patients, nine female, mean age 15 years (sd 3)) were matched for preoperative flexion strength to the PAO-RS group. Radiographic parameters, modified Harris hip score (mHHS), isokinetic hip strength and instrumented motion analysis preoperatively, six months and one-year postoperatively were compared. RESULTS: There were no differences in preoperative deformity, postoperative correction or degree of correction between groups. Hip flexor strength decreased significantly at six months in the PAO group compared with the PAO-RS group (-35 Nm/kg versus -7 Nm/kg; p = 0.012), as did hip flexion pull-off power (1.33 W/kg PAO versus 1.76 W/kg PAO-RS; p = 0.010). Hip flexion strength improved from six months to one year in the PAO group, with no significant differences in strength at one year between groups (80 Nm/kg versus 90 Nm/kg). There were no differences between groups in mHHS any time point; both groups improved significantly postoperatively. CONCLUSION: Preserving the rectus femoris may lead to improved short-term hip flexor strength and pull-off power. Further assessment at long-term follow-up is needed to determine if this strength leads to improved functional outcomes. LEVEL OF EVIDENCE: II.

"Horário do Soninho": uma estratégia para reduzir os níveis de pressão sonora em uma unidade de terapia intensiva neonatal / Quiet time: a strategy to reduce sound pressure levels in a neonatal intensive care unit

Introdução: Estudos mostram que o ambiente muito estimulante, com altos níveis sonoros, interfere negativamente no desenvolvimento e crescimento de recém-nascidos. Objetivo: verificar se o "horário do soninho" é capaz de reduzir os níveis de pressão sonora em uma unidade de cuidados neonatais. Método: Trata-se de uma pesquisa transversal. A medida do nível de pressão sonora foi realizada durante 15 dias não consecutivos, com tempo de avaliação de 30 minutos antes, 1 hora durante e 30 minutos após o "horário do soninho" Resultado: Observamos uma redução dos níveis de pressão sonora durante o "horário do soninho" (p = 0,00). Essa redução permaneceu no período dos 30 minutos subsequentes, com diferença estatisticamente significante quando comparada ao período antes do "horário do soninho" (p = 0,00). Conclusão: O "horário do soninho" é uma ferramenta capaz de reduzir o nível de pressão sonora em uma unidade de terapia intensiva neonatal. (AU)

Objective: Verify if the "quiet time" is able to reduce the sound pressure levels in a neonatal care unit. Method: It is a cross-sectional research. The measurement of the sound pressure level was performed during 15 non-consecutive days with an evaluation time of 30 minutes before, 1 hour during and 30 minutes after the "quiet time" Result: We observed a reduction of the sound pressure levels during the hours of quiet time (p = 0.00). This reduction remained in the period of the subsequent 30 minutes, with a statistically significant difference when compared to the period before sleep time (p = 0.00). Conclusion: The "quiet time is a tool capable of reducing sound pressure level in a neonatal intensive care unit. (AU)

Objectivo: Verificar si el "tiempo de silencio" puede reducir los niveles de presión acústica en una unidad de cuidados neonatales. Método: Investigación transversal. La medición del nivel de presión sonora se realizó durante 15 días no consecutivos con un tiempo de evaluación de 30 minutos antes, 1 hora durante y 30 minutos después del "tiempo de silencio". Resultado: Observamos una reducción de los niveles de presión sonora durante las horas de tiempo de silencio (p = 0.00). Esta reducción se mantuvo en el período de los siguientes 30 minutos, con una diferencia estadísticamente significativa en comparación con el período anterior al tiempo de sueño (p = 0,00). Conclusión: el "tiempo de silencio es una herramienta capaz de reducir el nivel de presión acústica en una unidad de cuidados intensivos neonatales. (AU)

Systemic Lupus Erythematosus Activity Affects the Sinusoidal Uptake Transporter OATP1B1 Evaluated by the Pharmacokinetics of Atorvastatin.

The present study assessed the effect of systemic lupus erythematosus (SLE) activity, a chronic and inflammatory autoimmune disease, on the sinusoidal uptake transporter OATP1B1 using atorvastatin (ATV) as a probe drug. Fifteen healthy subjects, 13 patients with controlled SLE (SLEDAI 0-4), and 12 patients with uncontrolled SLE (SLEDAI from 6 to 15), all women, were investigated. Apparent total clearance of midazolam (MDZ), a marker of CYP3A4 activity, did not vary among the three investigated groups. The controlled and uncontrolled SLE groups showed higher plasma concentrations of MCP-1 and TNF-α, while the uncontrolled SLE group also showed higher plasma concentrations of IL-10. The uncontrolled SLE group showed higher area under the curve (AUC) for ATV (60.47 (43.76-83.56) vs. 30.56 (22.69-41.15) ng⋅hour/mL) and its inactive metabolite ATV-lactone (98.74 (74.31-131.20) vs. 49.21 (34.89-69.42) ng⋅hour/mL), and lower apparent total clearance (330.7 (239.30-457.00) vs. 654.5 (486.00-881.4) L/hour) and apparent volume of distribution (2,609 (1,607-4,234) vs. 7,159 (4,904-10,450) L), when compared to the healthy subjects group (geometric mean and 95% confidence interval). The pharmacokinetics of ATV and its metabolites did not differ between the healthy subject group and the patients with controlled SLE group. In conclusion, uncontrolled SLE increased the systemic exposure to both ATV and ATV-lactone, inferring inhibition of OATP1B1 activity, once in vivo CYP3A4 activity assessed by oral clearance of MDZ was unaltered. The inflammatory state, not the disease itself, was responsible for the changes described in the uncontrolled SLE group as a consequence of inhibition of OATP1B1, because systemic exposure to ATV and its metabolites were not altered in patients with controlled SLE.

Detection of allopurinol and oxypurinol in canine urine by HPLC/MS-MS: Focus on veterinary clinical pharmacokinetics.

Allopurinol is the most commonly used drug for the treatment of hyperuricemia in people, and in view of the risks of fatal hypersensitivity in patients with renal dysfunction, doses based on the glomerular filtration rate are proposed. In veterinary medicine, allopurinol is used in the treatment of canine leishmaniasis (CanL) caused by Leishmania infantum owing to the drug action of inhibiting the parasite's RNA synthesis. However, renal dysfunction frequently ensues from disease progression in dogs. The purpose of the present study was to standardize and validate a sensitive high-performance liquid chromatography-mass spectrometric (HPLC-MS/MS) method to determine the concentration of allopurinol and its active metabolite oxypurinol in canine urine for clinical pharmacokinetic investigation. Urine samples of eleven (11) dogs with naturally occurring CanL and in the maintenance phase of the treatment with alopurinol were used. For the chromatographic analysis of urine, the mobile phase consisted of a solution of 0.1 % formic acid (88 %) in 10 mM ammonium acetate. Separation of allopurinol and oxypurinol occurred in a flow of 0.8 mL/min on a C8 reverse phase column 5 µm, and acyclovir was the internal standard. The HPLC-MS/MS method was validated by reaching the limits of detection and quantification, reproducibility and linearity. The lower limit of quantification achieved by the method was 10 µg/mL for both allopurinol and oxypurinol. Calibration curves were prepared in blank urine added with allopurinol at concentrations of 10-1000 µg/mL, and oxypurinol at 10-200 µg/mL. Coefficients of variation of less than 15 % between intracurrent and intercurrent accuracy values were observed for both allopurinol and oxypurinol. Urine test samples remained stable after being subjected to freeze-thaw cycles and remaining at room temperature for 4 h. The method proved to be adequate to quantify allopurinol and oxypurinol in urine samples from dogs under treatment.

Total, renal and hepatic clearances of doxorubicin and formation clearance of doxorubicinol in patients with breast cancer: Estimation of doxorubicin hepatic extraction ratio.

Doxorubicin (DOX) is a cytotoxic drug which has remained as an essential component of chemotherapy regiment for breast cancer. The cardiotoxicity of DOX is related to the accumulation of its main metabolite doxorubicinol (DOXOL) in the cardiac tissue. Although the pharmacokinetics of DOX shows high interindividual variability, there are no significant covariates to improve dose adjustment. The present study reports the pharmacokinetics of both DOX and DOXOL in a homogeneous population of young female patients with breast cancer (n = 12) making use of a standardized drug association, evaluated in the very first chemotherapy cycle, using plasma and urine data that allowed the calculation of the renal clearance of DOX, the formation clearance of DOXOL and the hepatic clearance of DOX. The extensive data availability also made it possible to estimate the hepatic extraction ratio of DOX for the investigated population, as well as to determine DOXOL unbound fraction in plasma for the first time in humans. DOX and DOXOL simultaneous analysis in plasma, plasma ultrafiltrate, and urine were performed by liquid chromatography coupled to mass spectrometry (LC-MS/MS). The pharmacokinetics profile of both DOX and DOXOL showed high variability (geometric coefficient of variation of area under the plasma concentration versus time curve extrapolated to infinity was approximately 215 %). The geometrics means were 0.26 for DOXOL/DOX AUC ratio, 15 % and 17 % for unbound fractions of DOX and DOXOL, respectively, 30.70 L⋅h-1 for total clearance, 0.66 L⋅h-1 for renal clearance, 29.97 L⋅h-1 for hepatic clearance and 0.39 L⋅h-1 for the formation clearance of the metabolite DOXOL. The 95 % confidence interval of the estimated hepatic extraction ratio of DOX ranged from 0.14 to 0.79, which characterizes DOX as a drug of low, intermediate or high hepatic extraction ratio.

Freshwater mollusks from three reservoirs of Piauí, northeastern Brazil / Moluscos límnicos de três reservatórios do Piauí, nordeste do Brasil

Abstract: The pronounced dry season determines the characteristics of the semiarid region of Brazil. Numerous small reservoirs are built to overcome this condition, accumulating multiple uses and causing important changes in the landscape and the local biota. Considering the limited amount of information about the malacofauna of reservoirs, mainly in the Northeast region of the country, this inventory provides a list of mollusks from three important reservoirs located in the city of São Julião, state of Piauí. The collections were carried out monthly between May/2017 and April/2018, sampling a total of 11,149 mollusks, corresponding to the species Melanoides tuberculata (Müller, 1774) (n = 9,724), Biomphalaria straminea (Dunker, 1848) (n = 1,361) and Pomacea lineata (Spix, 1827) (n = 64). The richness of mollusks from the three reservoirs was low, similar to those described in studies conducted in other regions of Northeast Brazil. There was a significant difference in the abundance of M. tuberculata and B. straminea among the studied reservoirs. These environments are not connected and are installed in urban and rural areas, presenting different ecological conditions. The relationship between the human population and the reservoirs, associated with the lack of sanitation, increases the risks of spreading waterborne diseases besides the development of environmental imbalance by the introduction of exotic species.

Resumo: O período de seca pronunciado marca a região semiárida brasileira. Para superação dessa condição inúmeros reservatórios de pequeno porte são construídos, acumulando múltiplos usos e causando alterações importantes na paisagem e na biota local. Considerando as poucas informações sobre a malacofauna de reservatórios, principalmente na região nordeste do país, este trabalho apresenta o inventário das espécies de moluscos provenientes de três importantes reservatórios localizados no município de São Julião, estado do Piauí. As coletas foram realizadas mensalmente entre os meses de maio/2017 e abril/2018. Foi amostrado um total de 11.149 moluscos, correspondentes as espécies Melanoides tuberculata (Müller, 1774) (n=9,724), Biomphalaria straminea (Dunker, 1848) (n=1,361) e Pomacea lineata (Spix, 1827) (n=64). A riqueza de moluscos amostrados nos três reservatórios foi baixa, não diferindo daquelas descritas em estudos realizados em outras regiões do Nordeste do Brasil. Houve diferença significativa na abundância de M. tuberculata e B. straminea entre os reservatórios estudados os quais não são conectados e encontram-se instalados em áreas urbana e rurais, com condições ambientais distintas. A relação entre a população humana da região e os reservatórios, juntamente com a falta de saneamento representam riscos à propagação de doenças transmitidas pela água e desequilíbrio ambiental pela introdução de espécies exóticas.

Utilização de indicadores de desempenho em um Comitê de Ética em Pesquisa no Rio de Janeiro - Brasil / Utilización de indicadores de desempeño en un Comité de Ética en Investigación en Rio de Janeiro, Brasil / Use of Performance Indicators in a Research Ethics Committee in Rio de Janeiro, Brazil

Resumo: O presente estudo tem como principais objetivos utilizar os indicadores desenvolvidos como ferramenta para avaliar o desempenho do Comitê de Ética em Pesquisa de uma instituição Federal no Rio de Janeiro, quanto à eficiência e eficácia de sua operação, e determinar os motivos que fazem com que a duração do processo de aprovação dos projetos analisados exceda a meta de 60 dias. Com base em uma revisão da literatura foram desenvolvidos indicadores para avaliar os processos do CEP usando um modelo de estrutura-processo-resultado. Para observar tendências nos indicadores avaliados, foram extraídos e analisados os dados relacionados a todos os protocolos submetidos ao CEP entre janeiro de 2009 e dezembro de 2014. O comitê de ética do presente estudo utilizou indicadores para identificar os pontos críticos dos seus processos e assim melhorar seu desempenho.

Resumen: El presente estudio tiene como principales objetivos utilizar los indicadores desarrollados como herramienta para evaluar el desempeño del Comité de Ética en Investigación de una institución Federal en Rio de Janeiro, en cuanto a la eficiencia y eficacia de su operación, y determinar los motivos que hacen que la duración del proceso de aprobación de los proyectos analizados exceda la meta de 60 días. Con base en una revisión de la literatura fueron desarrollados indicadores para evaluar los procesos del CEI usando un modelo de estructura-proceso-resultado. Para observar tendencias en los indicadores evaluados, fueron extraídos y analizados los datos relacionados a todos los protocolos sometidos al CEI entre enero de 2009 y diciembre de 2014. El comité de ética del presente estudio utilizó indicadores para identificar los puntos críticos de sus procesos y, así, mejorar su desempeño.

Abstract: The main objective of this study is to use the indicators developed as a tool to evaluate the performance of the Research Ethics Committee of a Federal institution in Rio de Janeiro, regarding the efficiency and effectiveness of its operation, and determine the reasons that make that the length of the approval process of the analyzed projects exceeds the 60-day goal. Based on a review of the literature, indicators were developed to evaluate the processes of the RES using a structure-process-result model. To observe trends in the indicators evaluated, the data related to all the protocols submitted to the RES between January 2009 and December 2014 were extracted and analyzed. The ethics committee of the present study used indicators to identify the critical points of its processes in order to improve its performance.