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BackgroundIMPAACT 2014 study is a phase I/II, multicenter, open-label, nonrandomized study of doravirine (DOR) co-formulated with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF) as fixed-dose combination (DOR FDC) in adolescents with HIV-1. We report the efficacy, safety, and tolerability of DOR FDC through 96 weeks.MethodsParticipants were adolescents aged 12 to

Pesticides have been pointed out as hormone disruptors and may significantly affect the prognosis of hormone-dependent diseases such as breast cancer (BC). Here, we investigated the impact of occupational pesticide exposure on systemic cortisol levels in female rural workers diagnosed with BC. Occupational exposure was assessed by interviews with a standardized questionnaire. Plasma samples (112 from pesticide-exposed women and 77 from unexposed women) were collected in the afternoon, outside the physiological cortisol peak, and analyzed by a chemiluminescent paramagnetic immunoassay for the quantitative determination of cortisol levels in serum and plasma. The results from both groups were categorized according to patients' clinicopathological and exposure data. BC pesticide-exposed women presented higher levels of cortisol than the unexposed. Higher cortisol levels were also detected in the exposed group with more aggressive disease (triple-negative BC), with tumors over 2 cm, with lymph node metastases, and with high risk of disease recurrence and death. These findings demonstrated that there is an association between pesticide exposure and BC that affected cortisol levels and correlated to poor disease prognosis.

Individuals with Parkinson’s disease (PD) and freezing of gait (FOG) have a loss of presynaptic inhibition (PSI) during anticipatory postural adjustments (APAs) for step initiation. The mesencephalic locomotor region (MLR) has connections to the reticulospinal tract that mediates inhibitory interneurons responsible for modulating PSI and APAs. Here, we hypothesized that MLR activity during step initiation would explain the loss of PSI during APAs for step initiation in FOG (freezers). Freezers (n = 34) were assessed in the ON-medication state. We assessed the beta of blood oxygenation level-dependent signal change of areas known to initiate and pace gait (e.g., MLR) during a functional magnetic resonance imaging protocol of an APA task. In addition, we assessed the PSI of the soleus muscle during APA for step initiation, and clinical (e.g., disease duration) and behavioral (e.g., FOG severity and APA amplitude for step initiation) variables. A linear multiple regression model showed that MLR activity (R2 = 0.32, p = 0.0006) and APA amplitude (R2 = 0.13, p = 0.0097) explained together 45% of the loss of PSI during step initiation in freezers. Decreased MLR activity during a simulated APA task is related to a higher loss of PSI during APA for step initiation. Deficits in central and spinal inhibitions during APA may be related to FOG pathophysiology.

B-cell acute lymphocytic leukemia (B-ALL) is the main neoplasia affecting children worldwide, in which cytotoxic chemotherapy remains the main treatment modality. In this study, we analyzed the profile of inflammatory markers concerning oxidative stress and cytokines in 17 B-ALL patients. Peripheral blood (PB) and bone marrow (BM) samples were collected and evaluated for the pro-oxidative status (nitric oxide products-NOx and hydroperoxides), antioxidants (sulfhydryl groups-SH and total radical-trapping antioxidant parameter-TRAP), and cytokines (TNF-α, IFN-γ), at diagnosis (D0) to and the end of the induction phase (D28). At D28, hydroperoxides were higher in PB, concomitant to TNF-α levels. INF-γ was increased in the BM at D28. Hydroperoxides were higher in patients presenting malignant cells in BM and/or PB after treatment, a condition named minimal residual disease (MRD) when compared to those without MRD at D28. These findings suggest that oxidative stress and cytokines vary across the B-ALL induction phase, and lipid peroxidation is a potential marker associated with MRD status.

Cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesteryl esters for triglyceride (TG) in VLDL/LDL. CETP inhibition, with anacetrapib, increases HDL-cholesterol, reduces LDL-cholesterol, and lowers TG levels. This study describes the mechanisms responsible for TG lowering by examining the kinetics of VLDL-TG, apoC-II, apoC-III, and apoE. Mildly hypercholesterolemic subjects were randomized to either placebo (N = 10) or atorvastatin 20 mg/qd (N = 29) for 4 weeks (period 1) followed by 8 weeks of anacetrapib, 100 mg/qd (period 2). Following each period, subjects underwent stable isotope metabolic studies to determine the fractional catabolic rates (FCRs) and production rates (PRs) of VLDL-TG and plasma apoC-II, apoC-III, and apoE. Anacetrapib reduced the VLDL-TG pool on a statin background due to an increased VLDL-TG FCR (29%; P = 0.002). Despite an increased VLDL-TG FCR following anacetrapib monotherapy (41%; P = 0.11), the VLDL-TG pool was unchanged due to an increase in the VLDL-TG PR (39%; P = 0.014). apoC-II, apoC-III, and apoE pool sizes increased following anacetrapib; however, the mechanisms responsible for these changes differed by treatment group. Anacetrapib increased the VLDL-TG FCR by enhancing the lipolytic potential of VLDL, which lowered the VLDL-TG pool on atorvastatin background. There was no change in the VLDL-TG pool in subjects treated with anacetrapib monotherapy due to an accompanying increase in the VLDL-TG PR.

Law Number 22 Year 2009 concerning Road Traffic and Transportation is intended to realize security and safety and order in traffic. Empirical facts show that the legal compliance of people in traffic on the highway is decreasing. Many road users do not comply with traffic regulations, so that traffic accidents on the road that tend to increase The high number of traffic accidents must be handled by the police professionally by handling accidents based on the established standard operating procedures.

Adma Poliana Cecilio,1 Erika Tomie Takakura,1 Jaqueline Janaina Jumes,1 Jeane Wilhelm dos Santos,1 Ana Cristina Herrera,2 Vanessa Jacob Victorino,3 Carolina Panis11Laboratory of Inflammatory Mediators, State University o West Paraná, UNIOESTE, Campus Francisco Beltrão, Paraná, Brazil; 2Pontifícia Universidade Católica (PUC), Campus Londrina, Paraná, Brazil; 3School of Medicine, Sao Paulo University (FM-USP), Sao Paulo, BrazilAbstract: Notwithstanding the advances in tumor research, diagnosis, and treatment, breast cancer is still a challenge worldwide. This global burden of disease has been associated with population aging and the persistence of cancer-related behaviors. The number of women diagnosed with breast cancer has been estimated as increasing, especially in middle-income countries such as Brazil. Estimates from the Instituto Nacional de Câncer (INCA) point to breast cancer as the major malignant neoplasia in Brazilian women and the main cause of death from cancer in the country. This fact has been associated with increased life expectancy, urbanization, and cancer-related behaviors. Given this scenario, it is clear that there is a need for identifying and discussing which factors have substantially contributed to this growing number of cases in Brazil, including access to treatment, prevention and early diagnosis, weaknesses of the local health policy, and intrinsic genetic peculiarities of the Brazilian population. This review aims to address the role of such factors.Keywords: breast cancer, treatment, prevention, epidemiology, Brazil, cancer screening, mammograms, health policies

No Brasil, a maior parte dos cultivos de algodão encontra-se em regiões de cerrado dos Estados do Mato Grosso e Bahia, em áreas que naturalmente são constituídas de solos ácidos. Objetivou-se neste trabalho estudar a influência da acidez do solo sobre a persistência dos herbicidas trifloxysulfuron-sodium e pyrithiobac-sodium, utilizando um bioindicador como técnica de detecção. Foram conduzidos simultaneamente quatro experimentos: dois com o herbicida trifloxysulfuron-sodium (7,5 e 15 g ha-1) e dois com o pyrithiobac-sodium (70 e 140 g ha-1). Em todos os tratamentos foi utilizado delineamento experimental inteiramente casualizado, com quatro repetições, em esquema fatorial (3x8+3). Os fatores estudados foram três tipos de solo (com níveis de pH 4,2, 4,9 e 5,5) e oito épocas de semeadura da espécie bioindicadora (0, 30, 60, 90, 120, 150, 180 e 210 DAA), além de três testemunhas sem aplicação do herbicida. A persistência do trifloxysulfuron-sodium na dose de 7,5 g ha-1 não foi influenciada pelos valores de pH. No entanto, na dose de 15 g ha-1 a maior persistência da atividade biológica foi verificada no solo com maior pH. Quando o pyrithiobac-sodium foi aplicado no solo com menor pH, nas doses de 70 e 140 g ha-1, o tempo necessário foi maior para que ocorresse redução da persistência. Contudo, aos 210 DAA não foram observadas diferenças na persistência do pyrithiobac-sodium (70 g ha-1) entre diversos valores de pH. Todavia, na dose de 140 g ha-1 do pyrithiobac-sodium, o solo com maior pH apresentou a maior persistência desse herbicida.In Brazil, most of the areas planted with cotton are located in the cerrado regions of Mato Grosso and Bahia, in naturally acidic soil. The objective of this work was to study the influence of soil acidity on the persistence of trifloxysulfuron-sodium and pyrithiobac-sodium, using a bioindicator as detection technique. Four experiments were conducted simultaneously: two with trifloxysulfuron-sodium (7.5 and 15 g ha-1), and two with pyrithiobac-sodium (70 and 140 g ha-1), using a completely randomized design with four replications in a factorial scheme (3x8+3). Treatments were composed by three types of soil (at pH levels 4.2, 4.9 and 5.5), eight sowing dates for the bio-indicator (0, 30, 60, 90, 120, 150, 180, and 210 DAA), and three control treatments, without herbicide application. The persistence of trifloxysulfuron-sodium at doses of 7.5 g ha-1 was not influenced by the pH values. However, at a dose of 15 g ha-1 the highest increase in the persistence of biological activity was observed in soil with higher pH. When pyrithiobac-sodium was applied to the soil with lower pH, at doses of 70 and 140 g ha-1, a longer time period was needed for persistence to reduce. But at 210 DAS there were no differences in the persistence of pyrithiobac-sodium (70 g ha-1) between the different pH values. However, at the dose of 140 g ha-1 of pyrithiobac-sodium, the soil with the highest pH showed the highest persistence of this herbicide.

The authors describe a 37-year-old female who suffered a mild head injury after a car accident. She was found with an initial Glasgow coma scale score of 15. On further inspection, complete right ophthalmoplegia was observed. Initial computerized tomography (CT) scan of the head was normal, but magnetic resonance imaging showed right oculomotor nerve avulsion. The patient was discharged from the hospital without any improvement in complete ophthalmoplegia. To our knowledge, this is the first radiographically documented case of oculomotor nerve root avulsion with associated irreversible oculomotor nerve palsy after mild head injury. Considering the poor prognosis for recovery of the nerve function, an appropriate counseling should be provided to the patient and family. Neurosurgical techniques for attempting nerve reconstruction have yet to be investigated but could be a new area for clinical and surgical research.

Background: Minimal detectable change (MDC) when assessing balance using the Biodex Balance System (BBS) in patients with Parkinson disease (PD) is currently unknown, limiting the interpretability of the scores.Objective: To determine the MDC on the Anterior/Posterior Stability Index (APSI), Medial/Lateral Stability Index (MLSI), and Overall Stability Index (OSI) from postural stability and fall risk protocols of the BBS in patients with PD.Design: This was a repeated-measures design (at a 1-week interval).Setting: Strength training laboratory of a public university.Patients: 46 patients with PD (men and women) at stages 2 and 3 (67.9 ± 7.4 years old) were assessed in the "on" state (fully medicated).Methods: Patients performed three trials of 20 s for each protocol.Main Outcome Measurements: Absolute and relative MDC (MDC%) calculated for APSI, MLSI, and OSI from the postural stability (stable condition) and fall risk protocols (unstable condition).Results: For the postural stability, the MDC and MDC% were 0.26° and 17% for APSI, 0.41° and 21% for MLSI, and 0.22° and 12% for OSI, respectively. For the fall risk, the MDC and MDC% were 0.51° and 18% for APSI, 0.21° and 15% for MLSI, and 0.41° and 20% for OSI, respectively. These results were considered acceptable, despite indices with high MDC for MLSI (postural stability) and APSI (fall risk).Conclusions: Patients with PD have more mediolateral and anteroposterior changes in the stable and unstable conditions, respectively. These abnormal balance strategies can occur principally due to postural instability of PD. However, our results demonstrated acceptable MDCs in both conditions in all of the assessed axes. Thus, BBS should be incorporated into the clinical evaluation to help therapists to determine if intervention-induced changes in balance are clinically significant or due to measurement error.Level Of Evidence: II. [ABSTRACT FROM AUTHOR]

The purpose of this study was to compare the electromyography of the shoulder muscles during the dumbbell fly on a stable horizontal surface, a stable incline surface, and an unstable surface. Seventeen males participated in three conditions. The first and second training sessions were held for exercise familiarization, to determine maximum voluntary contraction (MVC) normalization procedures, and to determine the load used on the third day in the electromyography exercise protocol. Results of the serratus anterior and the anterior deltoid muscles were higher in the incline condition versus the horizontal position. The activity of the pectoralis major (sternocostal head) was higher during the horizontal position versus the incline position. The unstable surface condition maintained similar muscle activity, but with a less total weight load. This finding suggests that the muscle groups analyzed in these exercises can be used either for rehabilitation or strength gain purposes. [ABSTRACT FROM AUTHOR]

Background: Older adults are at risk of pneumococcal disease and associated morbidity and mortality. This phase 3 study (V114-020) assessed lot-to-lot consistency across safety and immunogenicity outcomes for V114, a 15-valent pneumococcal conjugate vaccine (PCV), in healthy adults aged ≥ 50 years., Methods: Adults were randomized in a 3:3:3:1 ratio to receive a single dose of one of three lots of V114 or 13-valent PCV (PCV13), stratified by age (50-64 years, 65-74 years, and ≥ 75 years). Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) antibodies were evaluated at baseline (Day 1) and 30 days post-vaccination. Non-serious and serious adverse events (AEs) were evaluated post-vaccination through 14 days and Month 6, respectively., Results: Of 2340 participants enrolled, 2282 (97.5%) completed the study. Proportions of participants experiencing ≥ 1 AE were 81.0%, 77.4%, and 78.0% for V114 lots 1, 2, and 3, respectively. Comparison of V114 combined lots with PCV13 showed that proportions of participants experiencing AEs, solicited AEs, and serious AEs were comparable for both vaccines, with the exception of injection-site pain (more frequently reported with V114). OPA geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) at 30 days post-vaccination were comparable across V114 lots, and all lots met predefined equivalence criteria for all 15 vaccine serotypes (lower and upper limits of the 95% confidence intervals of serotype-specific OPA GMT ratios for all possible pairwise comparisons across the three lots were within the equivalence margin of 0.5-2.0). Serotype-specific OPA GMTs and IgG GMCs were comparable in the V114 combined lots and PCV13 groups for the 13 shared serotypes and higher in the V114 group for serotypes unique to V114 (22F and 33F)., Conclusions: V114 is well tolerated with a consistent safety profile and immune response across manufacturing lots., Clinical Trials Registration: NCT03950856 (www.clinicaltrials.gov); 2018-004266-33 (EudraCT)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gretchen Tamms reports a relationship with Merck & Co., Inc., Kenilworth, NJ, USA that includes: employment and equity or stocks. Tulin Shekar reports a relationship with Merck & Co., Inc., Kenilworth, NJ, USA that includes: employment and equity or stocks. Tina Sterling reports a relationship with Merck & Co., Inc., Kenilworth, NJ, USA that includes: employment and equity or stocks. Alison Pedley reports a relationship with Merck & Co., Inc., Kenilworth, NJ, USA that includes: employment and equity or stocks. Patricia Jumes reports a relationship with Merck & Co., Inc., Kenilworth, NJ, USA that includes: employment and equity or stocks. Luwy Musey reports a relationship with Merck & Co., Inc., Kenilworth, NJ, USA that includes: employment and equity or stocks. Jakub K. Simon reports a relationship with Merck & Co., Inc., Kenilworth, NJ, USA that includes: employment and equity or stocks. Ulrike K. Buchwald reports a relationship with Merck & Co., Inc., Kenilworth, NJ, USA that includes: employment and equity or stocks. Ron Dagan reports a relationship with Pfizer that includes: consulting or advisory, funding grants, and speaking and lecture fees. Ron Dagan reports a relationship with Merck Sharp & Dohme that includes: consulting or advisory and funding grants. Ron Dagan reports a relationship with Medimmune that includes: funding grants. Ron Dagan reports a relationship with MeMed that includes: consulting or advisory. Ron Dagan reports a relationship with Biondvax that includes: consulting or advisory., (Copyright © 2022 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA, The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: Two phase 1, open-label studies were conducted to investigate the effect of renal impairment (RI) and organic anion transporter (OAT) inhibition on pharmacokinetics (PK) and safety of relebactam (REL) plus imipenem/cilastatin (IMI)., Methods: Study PN005 evaluated the PK of REL (125 mg) plus IMI (250 mg) in participants with RI vs healthy controls. Study PN019 evaluated the PK of REL (250 mg) and imipenem (500 mg; dosed as IMI) with/without probenecid (1 g; OAT inhibitor) in healthy adults., Results: Geometric mean ratios (RI/healthy matched controls) of area under the concentration-time curve from time 0 to infinity (AUC 0-∞ ; 90% confidence interval) for REL, imipenem and cilastatin increased as RI increased from mild (1.6 [1.1, 2.4], 1.4 [1.1, 1.8] and 1.6 [1.0, 2.5], respectively) to severe (4.9 [3.4, 7.0], 2.5 [1.9, 3.3] and 5.6 [3.6, 8.6], respectively). For all 3 analytes, plasma and renal clearance decreased and corresponding plasma apparent terminal half-life increased with increasing RI. Geometric mean ratios ([probenecid+IMI/REL]/[IMI/REL]) of plasma exposure for REL and imipenem were 1.24 (1.19, 1.28) and 1.16 (1.13, 1.20), respectively. The dose fraction excreted (fe) in the urine decreased progressively from mild to severe RI. Probenecid reduced renal clearance of REL and imipenem by 25 and 31%, respectively. Compared with IMI/REL, coadministration of IMI/REL with probenecid yielded lower fe for REL and imipenem. In both studies, treatment was well tolerated; there were no serious adverse events or discontinuations due to adverse events., Conclusion: RI increased plasma exposure and similarly decreased clearance of REL, imipenem and cilastatin; IMI/REL dose adjustment (fixed-ratio) will be required for patients with RI. Probenecid had no clinically meaningful impact on the PK of REL or imipenem., (© 2019 The British Pharmacological Society.)

Background: Elbasvir/grazoprevir is a once-daily fixed-dose combination therapy for the treatment of chronic HCV infection, including HCV/HIV coinfection., Objectives: To evaluate the pharmacokinetic interaction of elbasvir and grazoprevir with raltegravir or dolutegravir., Methods: Three open-label trials in healthy adult participants were conducted. In the raltegravir trials, participants received a single dose of raltegravir 400 mg, a single dose of elbasvir 50 mg or grazoprevir 200 mg, and raltegravir with either elbasvir or grazoprevir. In the dolutegravir trial, participants received a single dose of dolutegravir 50 mg alone or co-administered with once-daily elbasvir 50 mg and grazoprevir 200 mg., Results: The raltegravir AUC0-∞ geometric mean ratio (GMR) (90% CI) was 1.02 (0.81-1.27) with elbasvir and 1.43 (0.89-2.30) with grazoprevir. Dolutegravir AUC0-∞ GMR (90% CI) was 1.16 (1.00-1.34) with elbasvir and grazoprevir. The elbasvir AUC0-∞ GMR (90% CI) was 0.81 (0.57-1.17) with raltegravir and 0.98 (0.93-1.04) with dolutegravir. The grazoprevir AUC0-24 GMR (90% CI) was 0.89 (0.72-1.09) with raltegravir and 0.81 (0.67-0.97) with dolutegravir., Conclusions: Elbasvir or grazoprevir co-administered with raltegravir or dolutegravir resulted in no clinically meaningful drug-drug interactions and was generally well tolerated. These results support the assertion that no dose adjustments for elbasvir, grazoprevir, raltegravir or dolutegravir are needed for co-administration in HCV/HIV-coinfected people., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The aims of these phase I trials were to evaluate the pharmacokinetic interaction between elbasvir (EBR) or grazoprevir (GZR) and buprenorphine/naloxone (BUP/NAL). Trial 1 was a single-dose trial in healthy participants. Trial 2 was a multiple-dose trial in participants on BUP/NAL maintenance therapy. Coadministration of EBR or GZR with BUP/NAL had minimal effect on the pharmacokinetics of BUP/NAL, EBR, and GZR. The geometric mean ratios (GMRs (90% CI)) for BUP, norbuprenorphine, and NAL AUC 0-∞ were 0.98 (0.89-1.08), 0.97 (0.86-1.09), and 0.88 (0.78-1.00) in the presence/absence of EBR; 0.98 (0.81-1.19), 1.13 (0.97-1.32), and 1.10 (0.82-1.47) in the presence/absence of GZR. The GMRs (90% CI) for EBR and GZR AUC 0-∞ in the absence/presence of BUP/NAL were 1.22 (0.98-1.52) and 0.86 (0.63-1.18). In conclusion, no dose adjustment for BUP/NAL, EBR, or GZR is required for patients with HCV infection receiving EBR/GZR and BUP/NAL maintenance therapy., (© 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

We conducted two phase I trials to evaluate the pharmacokinetic interactions between elbasvir (EBR), grazoprevir (GZR), and methadone (MK-8742-P010 and MK-5172-P030) in non-hepatitis C virus (HCV)-infected participants on methadone maintenance therapy. Coadministration of EBR or GZR with methadone had no clinically meaningful effect on EBR, GZR, or methadone pharmacokinetics. The geometric mean ratios (GMRs) for R- and S-methadone AUC 0-24 were 1.03 (90% confidence interval (CI), 0.92-1.15) and 1.09 (90% CI, 0.94-1.26) in the presence/absence of EBR; and 1.09 (90% CI, 1.02-1.17) and 1.23 (90% CI, 1.12-1.35) in the presence/absence of GZR. The GMRs for EBR and GZR AUC 0-24 in participants receiving methadone relative to a healthy historical cohort not receiving methadone were 1.20 (90% CI, 0.94-1.53) and 1.03 (90% CI, 0.76-1.41), respectively. These results indicate that no dose adjustment is required for individuals with HCV infection receiving stable methadone therapy and the EBR/GZR fixed-dose regimen., (© 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Elbasvir (MK-8742) and grazoprevir (MK-5172; Merck & Co, Inc, Kenilworth, New Jersey) are hepatitis C virus (HCV)-specific inhibitors of the nonstructural protein 5A phosphoprotein and the nonstructural protein 3/4A protease, respectively. The aims of these studies were to evaluate the antiviral activity and safety of different doses of elbasvir or grazoprevir each administered as monotherapy to participants infected with either HCV genotype (GT) 1 or GT3., Methods: These 2 double-blind, randomized, placebo-controlled, sequential-panel, multiple ascending dose studies were conducted to assess the safety and pharmacodynamics of 5 days of once-daily elbasvir or 7 days of once-daily grazoprevir in adult male participants chronically infected with either HCV GT1 or GT3., Findings: Oral administration of elbasvir or grazoprevir once daily exhibited potent antiviral activity in participants with chronic GT1 or GT3 HCV infections. HCV RNA levels declined rapidly (within 1 day for elbasvir and 2 days for grazoprevir). At 50 mg of elbasvir once daily, the mean maximum reductions in HCV RNA from baseline were 5.21, 4.17, and 3.12 log 10 IU/mL for GT1b-, GT1a-, and GT3-infected participants, respectively. At 100 mg of grazoprevir once daily, the mean maximum reductions in HCV RNA from baseline were 4.74 and 2.64 log 10 IU/mL for GT1- and GT3-infected participants., Implications: The results in the elbasvir monotherapy study showed that 10 to 50 mg of elbasvir was associated with a rapid decline in HCV viral load; the results in the grazoprevir monotherapy study suggest that doses of 50 mg of grazoprevir and higher are on the maximum response plateau of the dose-response curve for GT1-infected participants. The results of these proof-of-concept studies provided preliminary data for the selection of the dosages of elbasvir and grazoprevir to test in Phase II and III clinical studies. ClinicalTrials.gov identifiers: NCT00998985 (Protocol 5172-004) and NCT01532973 (Protocol 8742-002)., (Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.)

People with hepatitis C virus (HCV) infection who have failed treatment with an all-oral regimen represent a challenging treatment population. The present studies evaluated the safety and efficacy of grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, in participants who had failed an NS5A inhibitor-containing regimen. C-SURGE (PN-3682-021) and C-CREST Part C (PN-3682-011 and -012) were open-label, multicenter studies. Participants who had previously relapsed following an NS5A inhibitor-containing all-oral regimen were retreated with grazoprevir 100 mg, ruzasvir 60 mg, and uprifosbuvir 450 mg alone for 24 weeks or with ribavirin for 16 weeks. The primary efficacy endpoint was sustained virologic response (HCV RNA below the limit of quantitation [<15 IU/mL]) 12 weeks after treatment completion (SVR12). In C-SURGE, SVR12 was achieved by 49/49 (100%) and 43/44 (98%) genotype (GT)1 participants in the 24-week no ribavirin arm and the 16-week plus ribavirin arm (lost to follow-up, n = 1), respectively. In C-CREST Part C, SVR12 was achieved by 23/24 (96%) participants treated for 16 weeks with ribavirin (GT1, 2/2 [100%]; GT2, 13/14 [93%]; GT3, 8/8 [100%]). One participant with GT2 infection discontinued study medication after a single dose of grazoprevir, ruzasvir, and uprifosbuvir plus ribavirin due to serious adverse events of vomiting and tachycardia. The presence of baseline resistance-associated substitutions had no impact on SVR12. No participant who completed treatment in either study experienced virologic failure., Conclusion: Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, for 16 or 24 weeks was safe and highly effective in participants with HCV infection who had previously failed NS5A inhibitor-containing therapy. (Hepatology 2017;66:1794-1804)., (© 2017 by the American Association for the Study of Liver Diseases.)

Background: Individuals treated with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibit a reduction in both LDL cholesterol and apolipoprotein B (ApoB) in response to monotherapy or combination therapy with a statin. It is not clear how anacetrapib exerts these effects; therefore, the goal of this study was to determine the kinetic mechanism responsible for the reduction in LDL and ApoB in response to anacetrapib., Methods: We performed a trial of the effects of anacetrapib on ApoB kinetics. Mildly hypercholesterolemic subjects were randomized to background treatment of either placebo (n = 10) or 20 mg atorvastatin (ATV) (n = 29) for 4 weeks. All subjects then added 100 mg anacetrapib to background treatment for 8 weeks. Following each study period, subjects underwent a metabolic study to determine the LDL-ApoB-100 and proprotein convertase subtilisin/kexin type 9 (PCSK9) production rate (PR) and fractional catabolic rate (FCR)., Results: Anacetrapib markedly reduced the LDL-ApoB-100 pool size (PS) in both the placebo and ATV groups. These changes in PS resulted from substantial increases in LDL-ApoB-100 FCRs in both groups. Anacetrapib had no effect on LDL-ApoB-100 PRs in either treatment group. Moreover, there were no changes in the PCSK9 PS, FCR, or PR in either group. Anacetrapib treatment was associated with considerable increases in the LDL triglyceride/cholesterol ratio and LDL size by NMR., Conclusion: These data indicate that anacetrapib, given alone or in combination with a statin, reduces LDL-ApoB-100 levels by increasing the rate of ApoB-100 fractional clearance., Trial Registration: ClinicalTrials.gov NCT00990808., Funding: Merck & Co. Inc., Kenilworth, New Jersey, USA. Additional support for instrumentation was obtained from the National Center for Advancing Translational Sciences (UL1TR000003 and UL1TR000040).

Rationale: Apolipoprotein(a) [apo(a)] is the defining protein component of lipoprotein(a) [Lp(a)], an independent risk factor for cardiovascular disease. The regulation of Lp(a) levels in blood is poorly understood in part due to technical challenges in measuring Lp(a) kinetics. Improvements in the ability to readily and reliably measure the kinetics of apo(a) using a stable isotope labeled tracer is expected to facilitate studies of the role of Lp(a) in cardiovascular disease. Since investigators typically determine the isotopic labeling of protein-bound amino acids following acid-catalyzed hydrolysis of a protein of interest [e.g., apo(a)], studies of protein synthesis require extensive protein purification which limits throughput and often requires large sample volumes. We aimed to develop a rapid and efficient method for studying apo(a) kinetics that is suitable for use in studies involving human subjects., Methods: Microfluidic device and tandem mass spectrometry were used to quantify the incorporation of [(2)H3]-leucine tracer into protein-derived peptides., Results: We demonstrated that it is feasible to quantify the incorporation of [(2)H3]-leucine tracer into a proteolytic peptide from the non-kringle repeat region of apo(a) in human subjects. Specific attention was directed toward optimizing the multiple reaction monitoring (MRM) transitions, mass spectrometer settings, and chromatography (i.e., critical parameters that affect the sensitivity and reproducibility of isotopic enrichment measurements). The results demonstrated significant advantages with the use of a microfluidic device technology for studying apo(a) kinetics, including enhanced sensitivity relative to conventional micro-flow chromatography, a virtually drift-free elution profile, and a stable and robust electrospray., Conclusions: The technological advances described herein enabled the implementation of a novel method for studying the kinetics of apo(a) in human subjects infused with [(2)H3]-leucine., (Copyright © 2013 John Wiley & Sons, Ltd.)

Laropiprant (LRPT) has been shown to reduce flushing symptoms induced by niacin and has been combined with niacin for treatment of dyslipidemia. LRPT, a potent PGD(2) receptor (DP1) antagonist that also has modest activity at the thromboxane receptor (TP), may have the potential to alter platelet function either by enhancing platelet reactivity through DP1 antagonism or by inhibiting platelet aggregation through TP antagonism. Studies of platelet aggregation ex vivo and bleeding time have shown that LRPT, at therapeutic doses, does not produce clinically meaningful alterations in platelet function. The present study was conducted to assess platelet reactivity to LRPT using methods that increase the sensitivity to detect changes in platelet responsiveness to collagen and ADP. The responsiveness of platelets was quantified by determining the EC(50) of collagen to induce platelet aggregation ex vivo. At 24 hours post-dose on Day 7, the responsiveness of platelets to collagen-induced aggregation was similar following daily treatment with extended-release niacin (ERN) 2 g/LRPT 40 mg or ERN 2 g. At 2 hours post-dose on Day 7, the EC(50) for collagen-induced platelet aggregation was approximately two-fold higher in the presence of LRPT, consistent with a small, transient inhibition of platelet responsiveness to collagen. There was no clinical difference between treatments for bleeding time, suggesting that this small effect on collagen EC(50) does not result in a clinically meaningful alteration of platelet function in vivo. The results of this highly sensitive method demonstrate that LRPT does not enhance platelet reactivity when given alone or with ERN.

This study assessed the potential pharmacokinetic interaction and safety/tolerability of taranabant and phentermine coadministration. This was a randomized, double-blind, 3-panel, fixed-sequence study in healthy participants. Panels A, B, and C evaluated the safety/tolerability of phentermine 15 mg coadministered with taranabant 0.5, 1, and 2 mg for 7 days (panel A) and 28 days (panels B and C). In panels A and C, phentermine 15 mg was administered both with (7 days, panel A; 28 days, panel C) and without (7 days) taranabant 0.5 mg or 2 mg to evaluate pharmacokinetics. The primary endpoint was phentermine AUC(0-24 h) in panels A and C. Secondary endpoints were changes from baseline in blood pressure and heart rate for all panels. The geometric mean ratios and 90% confidence intervals for phentermine AUC(0-24 h) in the presence/absence of taranabant 0.5 mg and 2 mg were 1.08 (0.99, 1.17) and 1.04 (0.98, 1.10), respectively. No significant differences in blood pressure and heart rate were observed with any treatment versus placebo. Coadministration of taranabant 0.5 mg, 1 mg, and 2 mg with phentermine was well tolerated with no pharmacokinetic interaction and did not result in meaningful changes in blood pressure or heart rate versus placebo.