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Studies in SIV-infected macaques show that the virus reservoir is particularly refractory to conventional suppressive antiretroviral therapy (ART). We posit that optimized ART regimens designed to have robust penetration in tissue reservoirs and long-lasting antiviral activity may be advantageous for HIV or SIV remission. Here we treat macaques infected with RT-SHIV with oral emtricitabine/tenofovir alafenamide and long-acting cabotegravir/rilpivirine without (n = 4) or with (n = 4) the immune activator vesatolimod after the initial onset of viremia. We document full suppression in all animals during treatment (4-12 months) and no virus rebound after treatment discontinuation (1.5-2 years of follow up) despite CD8 + T cell depletion. We show efficient multidrug penetration in virus reservoirs and persisting rilpivirine in plasma for 2 years after the last dose. Our results document a type of virus remission that is achieved through early treatment initiation and provision of ultra long-lasting antiviral activity that persists after treatment cessation., Competing Interests: Competing interests: J.G.G.-L., M.B.D., W.H., P.W., and W.S. are named in a US Patent Application (No. 18/002,494) entitled “Methods for achieving viral remission using long-acting antiretroviral agents”. The remaining authors declare no competing interests., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: QUANTI-TAF aimed to establish tenofovir-diphosphate (TFV-DP)/emtricitabine-triphosphate (FTC-TP) adherence benchmarks in dried blood spots (DBS) for persons with human immunodeficiency virus (PWH) receiving tenofovir alafenamide/emtricitabine (TAF/FTC)-based antiretroviral therapy (ART)., Methods: For 16 weeks, PWH received TAF/FTC-based ART co-encapsulated with an ingestible sensor to directly measure cumulative (enrollment to final visit) and 10-day adherence. At monthly visits, intraerythrocytic concentrations of TFV-DP and FTC-TP in DBS were quantified and summarized at steady-state (week 12 or 16) as median (interquartile range). Linear mixed-effects models evaluated factors associated with TFV-DP/FTC-TP., Results: Eighty-four participants (11% female, 4% transgender) predominantly receiving bictegravir/TAF/FTC (73%) were enrolled. Ninety-two percent completed week 12 or 16 (94% unboosted ART). TFV-DP for <85% (7/72), 85%-<95% (9/72), and ≥95% (56/72) cumulative adherence was 2696 (2039-4108), 3117 (2332-3339), and 3344 (2605-4293) fmol/punches. Adjusting for cumulative adherence, TFV-DP was higher with boosted ART, lower body mass index, and in non-Black participants. FTC-TP for <85% (14/77), 85%-<95% (6/77), and ≥95% (57/77) 10-day adherence was 3.52 (2.64-4.48), 4.58 (4.39-5.06), and 4.96 (4.21-6.26) pmol/punches. All participants with ≥85% cumulative and 10-day adherence had TFV-DP ≥1800 fmol/punches and FTC-TP ≥2.5 pmol/punches, respectively. Low-level viremia (HIV-1 RNA 20-199 copies/mL) occurred at 18% of visits in 39% of participants with similar TFV-DP (3177 [2494-4149] fmol/punches) compared with suppressed visits (3279 [2580-4407] fmol/punches)., Conclusions: TFV-DP ≥1800 fmol/punches and FTC-TP ≥2.5 pmol/punches represent DBS benchmarks for ≥85% adherence to unboosted TAF/FTC-based ART. Among PWH with high adherence, low-level viremia was common., Clinical Trials Registration: NCT04065347., Competing Interests: Potential conflicts of interest. J. R. C.-M. is an employee of ViiV Healthcare and has received research support from Gilead Sciences, paid to his institution. P. L. A. has received consulting fees from Gilead Sciences, Merck, and ViiV Healthcare and research support from Gilead Sciences, paid to his institution. K. M. B. has received consulting fees from ViiV Healthcare. J. J. K. is an employee of Merck. S. C. M. has received research support from Gilead Sciences, paid to her institution. P. E. A., T. C. C., and D. E. B. are employees of etectRx. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

A novel tedizolid phosphate (TZP) nanoparticle (NP)-loaded buccal film formulation was developed for the treatment of buccal wounds infected with S. aureus. TZP-loaded chitosan NPs were produced and characterized to prepare this composite system. The optimum NP formulation was then loaded into mucoadhesive buccal films. The antibacterial effects of the obtained buccal films were evaluated by in vitro and in vivo studies. The optimum TZP-NP formulation (F8) had a particle size of 177.40 ± 2.97 nm and PDI and ZP values were 0.437 ± 0.002 and 33.9 ± 0.5, respectively. In antibacterial efficacy tests, the optimum NP containing buccal film formulation was used, which released approximately 90 % of TZP within 5 h. TZP-NP-loaded buccal films achieved a 3 log 10 reduction in S. aureus within just 3 h. It was also administered to Wistar albino rats with S. aureus-infected buccal wounds. As a result of in vivo studies, a significant decrease in the number of S. aureus was detected in wound samples treated with TZP-NP-loaded buccal films. In addition, a complete inhibition of growth was observed on the fifth day of the film application. The current work suggested that the TZP-NP-loaded composite films could be promising candidates for effective and long-acting antibacterial treatment of buccal wounds., 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 © 2024 Elsevier B.V. All rights reserved.)

It is critical to understand the impact of significant physiological changes during pregnancy on the extent of maternal and fetal drug exposure. Fostemsavir (FTR) is a prodrug of temsavir (TMR) and is approved in combination with other antiretrovirals for multi-drug-resistant human immunodeficiency virus (HIV) infections. This physiologically based pharmacokinetic model (PBPK) study was used to estimate TMR PK in pregnant populations during each trimester of pregnancy to inform FTR dosing. A PBPK model was developed and validated for TMR using PK data collected following intravenous TMR and oral FTR dosing (immediate-release and extended-release tablets) in healthy volunteers. Predicted TMR concentration-time profiles accurately predicted the reported clinical data and variability in healthy (dense data) and pregnant (sparse data) populations. Predicted versus observed TMR geometric mean (CV%) clearance following intravenous administration was 18.01 (29) versus 17 (21) (L/h). Predicted versus observed TMR AUC 0-inf (ng.h/mL) in healthy volunteers following FTR administration of the extended-release tablet were 9542 (66) versus 7339 (33). The validated TMR PBPK model was then applied to predict TMR PK in a population of pregnant individuals during each trimester. Simulations showed TMR AUC in pregnant individuals receiving FTR 600 mg twice daily was decreased by 25% and 38% in the second and third trimesters, respectively. However, TMR exposure remained within the range observed in nonpregnant adults with no need for dose adjustment. The current PBPK model can also be applied for the prediction of local tissue concentrations and drug-drug interactions in pregnancy., (© 2024 GlaxoSmithKline. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Aims: Many transgender and gender diverse (TGD) individuals have expressed concerns about the potential for oral pre-exposure prophylaxis to affect hormonal concentrations achieved from taking gender-affirming hormone therapy (GAHT). The purpose of this study was to understand the bidirectional effects between hormone and intraerythrocytic tenofovir diphosphate concentrations when switching from tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) to tenofovir alafenamide/emtricitabine (TAF/FTC) in TGD users/nonusers of GAHT., Methods: The study evaluated stored blood samples and dried blood spot cards from TGD adults without HIV who took ≥12 weeks of TDF/FTC and then switched to ≥12 weeks of TAF/FTC for pre-exposure prophylaxis., Results: Thirty-nine individuals met the study inclusion criteria. Regardless of sex assigned at birth and the use of GAHT, there were no significant differences in hormone concentrations when individuals taking GAHT were taking TDF/FTC and then switched to TAF/FTC. Further, there was no significant difference in intraerythrocytic tenofovir diphosphate concentrations between users and nonusers of GAHT., Conclusion: There are no bidirectional effects between hormone and intraerythocytic tenofovir diphosphate concentrations when switching from TDF/FTC to TAF/FTC in TGD users/nonusers of GAHT., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

APV20002 was a multicenter, international, open-label study that began in 2003 investigating the pharmacokinetics, efficacy, and safety of ritonavir-boosted fosamprenavir (FPV/r) oral solution (OS) in combination with nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART) in participants living with HIV-1 aged 4 weeks to <2 years with a primary endpoint at Week 48 (48W). Participants in APV20002 could continue in the study post-48W until FPV OS was locally available in their countries. Children were required to discontinue after reaching >39 kg or if FPV OS had no clinical benefit. Fifty-nine participants were enrolled; 5/59 received a single FPV OS visit for pharmacokinetic determinations. Most (38/54; 70%) were antiretroviral experienced; 39/59 participants had >48 weeks on treatment, 4/39 of whom discontinued after 48 weeks due to an adverse event (AE). At 48W, 88% of participants had HIV-1 RNA <400 copies/mL by Observed analysis; the proportion with HIV-1 RNA <400 copies/mL remained high (84%-100%) through Week 684. The median CD4 + cell count was 1,235 cells/mm 3 [ n = 51] at baseline, 1,690 cells/mm 3 ( n = 41) at Week 48, and 1,280 cells/mm 3 ( n = 21) at Week 180. From baseline to Week 684, 54/59 (92%) participants had ≥1 treatment-emergent AE regardless of causality; 42/59 (71%) had a treatment-emergent grade 2-4 AE, predominantly maximum toxicity: grade 2; 21/59 (36%) and 21/59 (36%) had severe or grade 3/4 AEs. From baseline to Week 684, 14/54 (26%) participants met virologic failure (VF) criteria, 9/14 before 48W. HIV from 1/9 VFs through 48W developed treatment-emergent reduced susceptibility to FPV and 1/9 to lamivudine/emtricitabine. Post-48W, 4/5 participants with VF had phenotype results; all were still susceptible to all study drugs at VF. In conclusion, FPV OS-based ART was efficacious and generally well tolerated in this long-running pediatric study through 684 weeks of treatment, with a safety profile consistent with experience in adults and older children.

Objectives: We measured the intracellular concentrations of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in dried blood spots (DBS) for pre-exposure prophylaxis (PrEP) adherence using sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Methods: A total of 191 DBS were obtained from 85 participants who were receiving tenofovir disoproxil fumarate (TDF; 300 mg) and emtricitabine (FTC; 200 mg) as PrEP at the Sexual Health Clinic, National Center for Global Health and Medicine, Tokyo, Japan. DBS punch (3 mm) added to 25 μL of 50% methanol and 400 μL of internal standard solution was used for solid phase extraction. Chromatographic separation was achieved on an Atlantis Premier BEH C18 AX Column (50 mm × 2.1 mm i.d.; particle size 1.7 μm) using gradient elution (flow rate: 0.6 mL/min); injection volume: 7 μL and run time: 5.5 min. Calibration curves for the two drugs were linear in the range 0.05-12.5 ng/punch., Results: We determined the intracellular TFV-DP and FTC-TP concentrations in 191 DBS obtained from 85 patients administered with TDF and FTC as PrEP. The analytical performance data (calibration curve and QC samples) for all the analytical runs met the acceptance criteria. Intracellular concentrations of TFV-DP and FTC-TP in the DBS remained stable for at least 24 h after oral administration., Conclusions: A multiplex LC-MS/MS method was successfully developed for DBS, which can be useful for monitoring the levels of TFV-DP and FTC-TP in individuals receiving PrEP., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Fostemsavir is an approved gp120-directed attachment inhibitor and prodrug for the treatment of human immunodeficiency virus type 1 infection in combination with other antiretrovirals (ARVs) in heavily treatment-experienced adults with multi-drug resistance, intolerance, or safety concerns with their current ARV regimen. Initial in vitro studies indicated that temsavir, the active moiety of fostemsavir, and its metabolites, inhibited organic cation transporter (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs) at tested concentration of 100 uM, although risk assessment based on the current Food and Drug Administration in vitro drug-drug interaction (DDI) guidance using the mechanistic static model did not reveal any clinically relevant inhibition on OCTs and MATEs. However, a DDI risk was flagged with EMA static model predictions. Hence, a physiologically based pharmacokinetic (PBPK) model of fostemsavir/temsavir was developed to further assess the DDI risk potential of OCT and MATEs inhibition by temsavir and predict changes in metformin (a sensitive OCT and MATEs substrate) exposure. No clinically relevant impact on metformin concentrations across a wide range of temsavir concentrations was predicted; therefore, no dose adjustment is recommended for metformin when co-administered with fostemsavir., (© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Onychomycosis, a superficial fungal infection, develops when dermatophytes infect nail plate and beds. Fosravuconazole l-lysine ethanolate (F-RVCZ), a fourth-generation azole antifungal agent with potent antifungal activity and few drug interactions, was highly effective in a clinical trial, with a complete cure rate of 59.4% at 48 weeks after treatment initiation. However, some patients were not completely cured. To achieve a higher complete cure rate, additional therapy needs to be examined. We aimed to examine (i) the criteria for additional F-RVCZ therapy in patients with an inadequate response to initial F-RVCZ treatment for onychomycosis; (ii) the timing of additional therapy; and (iii) the effects of additional treatment. This was a multicenter, open-label, three-arm randomized clinical trial. Patients with onychomycosis were orally administered an approved dose of F-RVCZ for 12 weeks, and its efficacy was assessed at week 24. Patients who demonstrated ≥55% reduction in nail involvement ratio at week 24 were included in Group X and followed up. Patients with <55% reduction were randomly assigned to follow-up (Group A) or additional treatment (Group B) groups. The complete cure rate at week 72 in Group X was 73.3%. In Groups A and B, the complete cure rates were 29.6% and 46.7%, respectively, and were significantly different (P = 0.0414, odds ratio 2.08). During the study, 63 adverse drug reactions were recorded in 59 of the 318 patients (18.6%), for which a causal relationship with F-RVCZ could not be ruled out. In Group B, three of 75 patients (4.0%) experienced three adverse drug reactions, all observed during additional treatment; none were serious. A high complete cure rate is possible without additional F-RVCZ treatment when nail involvement decreases by ≥55% at week 24; however, when the reduction is <55% at week 24, additional F-RVCZ treatment should be considered to improve the cure rate., (© 2024 Japanese Dermatological Association.)

Objective: We assessed the association and concordance between self-reported oral pre-exposure prophylaxis (PrEP) intake in a diary app and intraerythrocytic drug metabolite concentrations., Design: AMPrEP was a prospective demonstration study providing daily and event-driven PrEP to MSM in Amsterdam, the Netherlands (2015-2020)., Methods: Participants could record their PrEP intake in a diary app. Dried blood spots (DBS) were taken at 6, 12, 24, and 48 months and analysed for tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations. We included TFV-DP measurements preceded by diary completion on at least 90% of days in the 6 weeks prior. We examined the association between self-reported PrEP intake (i.e. number of pills) and TFV-DP concentrations using tobit regression with a random intercept per participant. We also calculated concordance between categorized PrEP intake (i.e. <2, 2-3, 4-6 or 7 pills per week) and categorized TFV-DP concentrations (i.e. <350, 350-699,700-1249 or ≥1250 fmol/punch) using weighted Cohen's kappa. Last, we calculated concordance between self-reported recent PrEP intake (yes/no, in past 2 days) and quantifiability of FTC-TP (yes/no) using Cohen's kappa., Results: Seven hundred and fifty-nine DBS measurements from 282 MSM were included. Self-reported PrEP intake was strongly and positively associated with TFV-DP concentration ( β  = 0.77, 95% CI = 0.70-0.84, P  < 0.0001). Concordance between categorized PrEP intake and TFV-DP concentration was moderate ( κ  = 0.44, 95% CI = 0.39-0.50). Concordance between self-reported recent PrEP intake and FTC-TP quantifiability was perfect ( κ  = 0.83, 95% CI 0.76-0.90)., Conclusion: Self-reported PrEP intake in a diary app is strongly correlated with actual use, and therefore reliable for comparing PrEP adherence between groups. Still, suboptimal criterion validity according to clinically relevant categories warrants caution when assessing 6-week reported adherence for individuals., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Triphenyl phosphate (TPhP) is a broad-spectrum organophosphate compound widely used as an additive in several products to prevent ignition. However, its utilization produces a hazardous impact on various organisms. So far, very few studies have investigated the acute toxicity of TPhP at environmentally relevant concentrations in nontarget aquatic species. This study aimed to assess whether the short-term exposure of TPhP (4, 20, and 100 μg L -1 ) affects the oxidative stress, antioxidant activity, biomolecule metabolism, DNA stability, chromosomal integrity, apoptosis, and pathological changes in various organs of Labeo rohita fingerlings. The results illustrated that the reactive oxygen species (ROS) production and lipid peroxidation (LPO) rates were significantly higher in tissues (brain, liver, and kidney) of TPhP-treated groups. Interestingly, superoxide dismutase (SOD) and catalase (CAT) activities were remarkably decreased in tissues following TPhP exposure. The levels of protein, glucose, total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in various tissues were also found to be significantly altered in TPhP-exposed fish fingerlings. These significant alterations in the antioxidant system and biochemical profile induced genotoxic responses such as DNA and chromosomal damage in the fish fingerlings. Furthermore, the incidence of the observed genotoxic responses was also found to be dose-dependent. Likewise, the apoptotic responses were also significantly altered following TPhP acute exposure in L. rohita fingerlings. The subsequent effects on oxidative stress, antioxidant inhibition, dysregulated biomolecule metabolism, and genotoxicity might be the possible reason for the observed pathological changes in various tissues of L. rohita . Taken together, the present findings showed that the toxicity of TPhP is principally associated with exposure concentrations. Therefore, this study illustrates the toxicity risks of TPhP to vertebrate organisms at real-world concentrations.

Many environmental chemicals are being identified as suspected neurotoxicants based on the findings of both experimental and epidemiological studies. Organophosphate esters (OPEs), which are among the chemicals that have replaced neurotoxic polybrominated diphenyl ethers (PBDEs) after 2004, have also become an important public health topic as evidence regarding their potential for early-life neurotoxicity is growing. In 233 mother child pairs from Cincinnati, OH, we measured concentrations of the OPE metabolites bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), bis-2-chloroethyl phosphate (BCEP), diphenyl phosphate (DPHP), and di-n-butyl phosphate (DNBP) in the urine of pregnant women at 16 and 26 weeks gestation and at delivery. At age 8 years, we assessed children's cognition using the Wechsler Intelligence Scale for Children-IV. In models adjusted for maternal race, income, body mass index, and IQ, maternal urinary BCEP was associated with a modest increase in child full-scale IQ (ß: 0.81 per a ln-unit BCEP increase; 95 % CI: 0.00, 1.61) while other OPEs were not associated with changes in full-scale IQ or any IQ subscales. Maternal serum PBDE concentrations did not confound the relationships between urinary OPE metabolites and child IQ. Using Bayesian kernel machine regression, we did not find that concentrations of a mixture of OPE metabolites during gestation was associated with any child cognition measures. The results of this study are not consistent with other published work, and a larger sample size would be beneficial to explore potential associations more fully. Therefore, additional studies are necessary to continue studying prenatal OPE exposure and child neurodevelopment and behavior., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Recent data show that parasites manipulate the physiology of mosquitoes and human hosts to increase the probability of transmission. Here, we investigate phagostimulant activity of Plasmodium-metabolite, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), in the primary vectors of multiple human diseases, Anopheles coluzzii, An. arabiensis, An. gambiae s.s., Aedes aegypti, and Culex pipiens/Culex torrentium complex species. The addition of 10 µM HMBPP to blood meals significantly increased feeding in all the species investigated. Moreover, HMBPP also exhibited a phagostimulant property in plant-based-artificial-feeding-solution made of beetroot juice adjusted to neutral pH similar to that of blood. The addition of AlbuMAX TM as a lipid/protein source significantly improved the feeding rate of An. gambiae s.l. females providing optimised plant-based-artificial-feeding-solution for delivery toxins to control vector populations. Among natural and synthetic toxins tested, only fipronil sulfone did not reduce feeding. Overall, the toxic-plant-based-artificial-feeding-solution showed potential as an effector in environmentally friendly vector-control strategies., (© 2021. Crown.)

Introduction : For those with heavily treatment experienced (HTE) HIV-1 and virologic failure, therapeutic options are limited. A variety of barriers such as drug resistance, side effects, past intolerance, and administration inability contribute to the need for novel drug classes in this population. Areas Covered : Herein, we review the pharmacology, clinical efficacy, and safety profile of fostemsavir, a first in its class attachment inhibitor recently FDA approved for use. Expert Opinion : Fostemsavir is a well-tolerated oral medication with relatively few drug-drug interactions. Clinical trial data demonstrates virologic and notable immunologic response in conjunction with optimal background therapy in HTE persons living with HIV. Fostemsavir exhibits no cross-resistance with other ARV classes and thus is an important advancement for patients harboring drug-resistant HIV. Further study will be needed to determine outstanding clinical questions such as the role of drug resistance testing and fostemsavir use outside of the HTE population.

Everolimus monotherapy use for metastatic renal cell carcinoma (mRCC) has diminished due to recent approvals of immune checkpoint and VEGF inhibitors. We hypothesized that gene expression associated with everolimus benefit may provide rationale to select appropriate patients. To address this hypothesis, tumors from a phase I/II trial that compared everolimus alone or with BNC105P, a vascular disrupting agent, were profiled using Nanostring as a discovery cohort. A phase III trial (CheckMate 025) was used for validation. Clinical benefit (CB) was defined as response or stable disease for ≥6 months. A propensity score covariate adjustment was used, and model discrimination performance was assessed using the area under the ROC curve (AUC). In a discovery cohort of 82 patients, 35 (43%) were treated with everolimus alone and 47 (57%) received everolimus + BNC105P. Median PFS (mPFS) was 4.9 (95% CI, 2.8-6.2) months. A four-gene signature (ASXL1, DUSP6, ERCC2, and HSPA6) correlated with CB with everolimus ± BNC105P [AUC, 86.9% (95% CI, 79.2-94.7)]. This was validated in 130 patients from CheckMate 025 treated with everolimus [AUC, 60.2% (95% CI, 49.7-70.7)]. Among 43 patients (52.4%) with low expression of an 18-gene signature, everolimus + BNC105P was associated with significantly longer mPFS compared with everolimus alone (10.4 vs. 6.9 months; HR, 0.49; 95% CI, 0.24-1.002; P = 0.047). These signatures warrant further validation to select patients who may benefit from everolimus alone or with a vascular disrupting agent., (©2021 American Association for Cancer Research.)

Nowadays, the incidence of acute bacterial skin and skin structure infection (ABSSSI) is increasing. The increased bioavailability and reduced drug resistance of antibiotics are crucial to obtain a more effective treatment response in these infections. These favorable properties could be achieved by different drug delivery systems such as liposomes. In this study, nanosized, radiolabeled tedizolid phosphate liposomal formulations were prepared and evaluated with their in vitro cellular binding capacity and biocompatible profile for topical treatment of ABSSSI. Liposomes were characterized by evaluation of their visual inspection, particle size (about 190-270 nm), zeta potential value (around 0), and encapsulation efficiency (nearly 10%). The release rate of tedizolid phosphate from liposomes was also studied using dialysis membranes and evaluated kinetically. The stability of formulations was observed at three different temperatures and humidity conditions for 28 days. Afterward, liposomes were labeled with 99m Tc, and the optimal amount of reducing agent (stannous chloride) was determined as 500 μg in this direct labeling procedure. All liposome formulations were successfully radiolabeled with high efficiency and exhibited high radiochemical purity (> 80%) during 6 h in different media. Furthermore, the cellular bindings of liposomal formulations were evaluated in human skin fibroblast cells by measuring the radioactivity. Higher radioactivity values were obtained in CCD-1070Sk cells incubated by liposome formulations compared to sodium pertechnetate. This finding suggested that liposomal formulation increased the cellular binding of radioactivity. By the result of our study, nanosized, tedizolid phosphate encapsulated liposome formulation was found to be a favorable carrier system in the treatment of ABSSSI.

Organophosphorus flame retardants (OPFRs) have been extensively used as chemical additives in polymer based consumer products. Among them, Isopropylphenyl phosphate (IPPP) and tripropyl phosphate (TPP) are predominant, which have potential to cause neuro-toxic effects on non-target organisms. As behavior (swimming activity) response is the first adjustment due to neurotoxic stress on the fitness of fish. In this study, the quantified swimming activity of zebrafish (Danio rerio) under IPPP and TPP exposure in an online monitoring system was investigated to assess the neurotoxin effects under long-term exposure periods, no swimming anomalies were observed in the control group. Whereas, in the OPFR exposures ((treatment I: 5 μg/L and treatment II: 25 μg/L), a series of anomalies were identified. Hyperactivity was shown in IPPP treatment I group (5 μg/L), whereas zebrafish swimming activity was declined throughout the study period in IPPP treatment II (25 μg/L), and TPP groups (5 μg/L and 25 μg/L) when compared to the control group. Circadian rhythm was not affected in the present study. The results of the present study indicated that the fitness of test individuals was a valid biomarker for eco-toxicity assessment under unescapable conditions. Hypoactivity of zebrafish signified the neurotoxic effects of IPPP and TPP. A concentration based improvement in swimming activity was observed under recovery conditions, which suggested that recovery capacity along with toxicity responses could be a comprehensive non-invasive technique to assess the eco-toxicity of waterborne chemicals., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Fostemsavir, a prodrug of the first-in-class attachment inhibitor, temsavir, is indicated for heavily treatment-experienced individuals with multidrug-resistant HIV-1. We previously reported superior efficacy of fostemsavir versus placebo in the randomised cohort of the BRIGHTE study after 8-day functional monotherapy (primary endpoint); here we report planned interim analyses through week 96., Methods: BRIGHTE (NCT02362503) is an ongoing multicentre, two-cohort, phase 3 trial, done at 108 centres in 22 countries. We enrolled heavily treatment-experienced adults (≥18 years) failing antiretroviral therapy (HIV-1 RNA ≥400 copies per mL) into two cohorts: the randomised cohort, in which patients with one or two fully active antiretrovirals remaining received oral fostemsavir (600 mg twice a day) or placebo in combination with their failing regimen for 8 days, followed by fostemsavir plus optimised background therapy; or the non-randomised cohort, in which patients with no remaining antiretroviral options received oral fostemsavir (600 mg twice a day) plus optimised background therapy from day 1. Endpoints for the week 96 interim analyses included the proportions of participants with plasma HIV-1 RNA of less than 40 copies per mL, changes from baseline in CD4 cell counts, and the frequency of adverse events, adverse events leading to discontinuation, and deaths. The intention-to-treat exposed population and the safety population both included all participants who received at least one dose of study treatment. The response rates (proportion of participants with HIV-1 RNA <40 copies per mL) in the intention-to-treat exposed population were calculated via snapshot analysis at weeks 24, 48, and 96., Findings: Between Feb 23, 2015, and Aug 11, 2016, 371 participants were enrolled and treated, of which 272 participants were in the randomised cohort and 99 in the non-randomised cohort. 320 (86%) of 371 reported a history of AIDS. In the randomised cohort, rates of virological suppression (HIV-1 RNA <40 copies per mL) increased from 53% (144 of 272) at week 24 to 60% (163 of 272) at week 96. Response rates in the non-randomised cohort were 37% (37 of 99) at week 24 and week 96. Mean increases in CD4 counts from baseline at week 96 were 205 cells per μL (SD 191) in the randomised cohort and 119 cells per μL (202) in the non-randomised cohort. Mean CD4/CD8 ratio increased from 0·20 at baseline to 0·44 at week 96 in the randomised cohort. Few adverse events led to discontinuation (26 [7%] of 371). 12 (4%) of 272 people in the randomised cohort and 17 (17%) of 99 in the non-randomised cohort died; the median baseline CD4 count for participants who died was 11 cells per μL., Interpretation: In heavily treatment-experienced individuals with advanced HIV-1 disease and limited treatment options, fostemsavir-based antiretroviral regimens were generally well tolerated and showed a distinctive trend of increasing virological and immunological response rates through 96 weeks; these findings support fostemsavir as a treatment option for this vulnerable population., Funding: ViiV Healthcare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) affects millions of patients worldwide and is characterized by alpha-synuclein aggregation in dopamine neurons. Molecular tweezers have shown high potential as anti-aggregation agents targeting positively charged residues of proteins undergoing amyloidogenic processes. Here we report that the molecular tweezer CLR01 decreased aggregation and toxicity in induced pluripotent stem cell-derived dopaminergic cultures treated with PD brain protein extracts. In microfluidic devices CLR01 reduced alpha-synuclein aggregation in cell somas when axonal terminals were exposed to alpha-synuclein oligomers. We then tested CLR01 in vivo in a humanized alpha-synuclein overexpressing mouse model; mice treated at 12 months of age when motor defects are mild exhibited an improvement in motor defects and a decreased oligomeric alpha-synuclein burden. Finally, CLR01 reduced alpha-synuclein-associated pathology in mice injected with alpha-synuclein aggregates into the striatum or substantia nigra. Taken together, these results highlight CLR01 as a disease-modifying therapy for PD and support further clinical investigation.

More frequent and widespread nerve agent attacks highlight the need for efficacious pre- and post-exposure organophosphate (OP) counter-measures to protect military and civilian populations. Because of critical targeting of acetylcholinesterase (AChE) in the CNS by OPs, a pre-treatment candidate for preventing/reducing poisoning will be a broadly acting molecule that scavenges OPs in blood before they reach their physiological targets. Prophylactic human butyrylcholinesterase (HuBChE), the leading pretreatment candidate, has been shown to protect against multiple LD 50 's of nerve agents in rodents, macaques, and minipigs. This review describes the development of a HuBChE bioscavenger pretreatment from early proof-of-concept studies to pre-clinical studies with the native injectable enzyme and the development of aerosolized forms of recombinant enzyme, which can be delivered by inhalation nebulizer devices, to effect protection against inhaled OP nerve agents and insecticides. Early animal studies utilized parenteral exposure. However, lungs are the portal of entry for most volatile OP vapors and represent the major means of OP intoxication. In this regard, pretreat-ment with 7.5 mg/kg of HuBChE by IM injection protected minipigs against lethal sarin vapor and prevented AChE inhibition in the blood. This is similar to the five-day protection in macaques by an aerosolized rHuBChE using a nebulizer against aerosolized paraoxon (estimated to be an 8 mg/kg estimated human dose). Importantly, lethal inhaled doses of OP may be smaller relative to the same dose delivered by injection, thus reducing the protective HuBChE dose, while a combination of HuBChE and post-exposure oxime may prolong protection., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Fostemsavir, a prodrug of human immunodeficiency virus attachment inhibitor temsavir (TMR), is in phase III development in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type I (HIV-1) infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive antiviral regimen due to resistance, intolerance, or safety considerations. The proarrhythmic potential of fostemsavir was studied in a thorough QT study and exposure-response modeling was performed at therapeutic and supratherapeutic concentrations of TMR. Fostemsavir 1,200 mg b.i.d. did not result in a clinically meaningful change from placebo in baseline-adjusted Fridericia-corrected QTc (ddQTcF); however, at a supratherapeutic dose of 2,400 mg b.i.d., the upper bound of the two-sided 90% confidence interval (CI) of ddQTcF was 13.2 msec, exceeding the clinically important 10 msec threshold. A linear model of ddQTcF as a function of TMR plasma concentrations described these observations. Based on simulations with this model, TMR concentrations up to 7,500 ng/mL are expected to have an upper 90% CI bound for QTcF ≤ 10 msec. This concentration is 4.2-fold higher than the geometric mean TMR peak plasma concentration (C max ) of 1,770 ng/mL in heavily treatment-experienced HIV-1 infected patients administered fostemsavir 600 mg b.i.d. in the phase III BRIGHTE study (NCT02362503)., (© 2020 ViiV Healthcare/GlaxoSmithKline. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Four commonly used organophosphates (fenitrothion, dichlorvos, chlorpyrifos, and trichlorfon) were orally administered to male Sprague-Dawley rats for five days in order to explore their effects on the activities of liver cytochrome P450 (CYP). In addition, Michaelis-Menten kinetics of the metabolic reactions catalyzed by liver CYPs were analyzed following the addition of these compounds to the assay system to examine their potential inhibitory effects on liver CYPs activities. These reactions included ethoxyresorufin O-deethylation, midazolam 4-hydroxylation, tolbutamide hydroxylation, and bufuralol 1'-hydroxylation for CYP1A, 3A, 2C, and 2D activities, respectively. Total CYP content was also examined after oral administration of each organophosphate. Results revealed that oral giving of fenitrothion inhibited significantly CYP1A and 3A activities while elevated activity of CYP2C. Fenitrothion is a potent inhibitor for CYP1A and 2C with Ki values of 0.42 and 36.1 µM, respectively but had a weak inhibitory effect on CYP2D and 3A with Ki values of 290 and 226 µM, respectively. Chlorpyrifos is a potent inhibitor of CYP1A with Ki 0.24 µM and moderately inhibited CYP2C or 3A with Ki values of 84.8 and 77.7 µM, respectively. On the other hand, dichlorvos and trichlorfon caused extremely low or negligible inhibition of different CYP activities. From these results, it is concluded that both fenitrothion and chlorpyrifos may increase the toxicity of chemicals in environmental living organisms through their potent inhibitory effects on these CYP activities, but dichlorvos and trichlorfon may not.

This is a report on the chemical stability and physical compatibility of intravenous tedizolid phosphate 0.8 mg/mL-sodium rifampicin 2.4 mg/mL and tedizolid phosphate 0.8 mg/mL-meropenem 4 mg/mL combinations in polypropylene 0.9% sodium chloride infusion bags stored at different storage conditions. Triplicate solutions of both admixtures were prepared in 0.9% sodium chloride polypropylene infusion bags and stored under light protection at room temperature (25±2 °C), refrigeration (2-8 °C) or freezing (-15 - -25 °C) conditions. The study was performed using a validated and stability-indicating liquid chromatography (LC) method. For both admixtures and for all storage conditions, at least 90% of the initial drug concentration of tedizolid phosphate remained unchanged throughout the entire study period. Stability of sodium rifampicin at 25±2 °C was determined to be seven hours and six days when it was stored at 2-8 °C. Under the same storage conditions, meropenem was stable for 12 h or 6 days, respectively. Under freezing conditions, sodium rifampicin was stable throughout all 28 days, while stability of meropenem was only 8 days. Solutions of 0.8 mg/mL tedizolid phosphate admixtured with 2.4 mg/mL rifampicin or 4 mg/mL meropenem, in polypropylene 0.9% sodium chloride infusion bags, are stable for at least 7 or 12 hours, respectively, when stored at 25±2 °C. When stored at 2-8 °C, stability was increased to 6 days for both admixtures.

Tris(2-ethylhexyl) phosphate (TEHP, CAS no. 78-42-2) is a plasticizer and a flame retardant, while di(2-ethylhexyl) phosphoric acid (DEHPA, CAS no. 298-07-7) is an oil additive and extraction solvent. Publicly-available information on repeated exposure to these two related organophosphate compounds is fragmentary. Hence, adult male and female Fischer rats were exposed to TEHP (300, 1000 and 3000 mg/kg body weight [BW]/day) or DEHPA (20, 60 and 180 mg/kg BW/day) by gavage for 28 consecutive days, to assess and compare their toxicities. Although significantly impaired BW gains and evidence of TEHP enzymatic hydrolysis to DEHPA were observed only in males, exposures to the highest TEHP and DEHPA doses often resulted in similar alterations of hematology, serum clinical chemistry and liver enzymatic activities in both males and females. The squamous epithelial hyperplasia and hyperkeratosis observed in the non-glandular forestomach of rats exposed to the middle and high DEHPA doses were most likely caused by the slightly corrosive nature of this chemical. Although tubular degeneration and spermatid retention were observed only in the testes of males exposed to the highest TEHP dose, numerous periodic acid-Schiff stained crystalline inclusions were observed in testis interstitial cells at all TEHP dose levels. No-observed-adverse-effect levels for TEHP and DEHPA are proposed, but the lower serum pituitary hormone levels resulting from TEHP and DEHPA exposures and the perturbations of testicular histology observed in TEHP-treated males deserve further investigation. Improved characterization of the toxicity of flame retardants will contribute to better informed substitution choices for legacy flame retardants phased-out over health concerns., (© 2019 Her Majesty the Queen in Right of Canada. Journal of Applied Toxicology published by John Wiley & Sons.)

Lysosomal storage diseases (LSDs) are inherited disorders caused by lysosomal deficiencies and characterized by dysfunction of the autophagy-lysosomal pathway (ALP) often associated with neurodegeneration. No cure is currently available to treat neuropathology in LSDs. By studying a mouse model of mucopolysaccharidosis (MPS) type IIIA, one of the most common and severe forms of LSDs, we found that multiple amyloid proteins including α-synuclein, prion protein (PrP), Tau, and amyloid β progressively aggregate in the brain. The amyloid deposits mostly build up in neuronal cell bodies concomitantly with neurodegeneration. Treating MPS-IIIA mice with CLR01, a "molecular tweezer" that acts as a broad-spectrum inhibitor of amyloid protein self-assembly reduced lysosomal enlargement and re-activates autophagy flux. Restoration of the ALP was associated with reduced neuroinflammation and amelioration of memory deficits. Together, these data provide evidence that brain deposition of amyloid proteins plays a gain of neurotoxic function in a severe LSD by affecting the ALP and identify CLR01 as new potent drug candidate for MPS-IIIA and likely for other LSDs., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: In the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, tenofovir disoproxil fumarate (TDF) use was associated with moderate or severe adverse pregnancy/neonatal outcomes. This study characterized tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations in dried blood spots (DBS) and assessed association between severe adverse pregnancy/neonatal outcomes and TFV-DP concentration., Methods: Retrospective case-control study of PROMISE trial arm-C women randomized to receive TDF, FTC, and ritonavir-boosted lopinavir (LPV/r), who took at least 1 dose of TDF + FTC and had week-4 postrandomization DBS drawn before delivery. Cases, defined as severe adverse pregnancy/neonatal outcomes (very preterm delivery before 34 weeks of gestation, stillbirth ≥20 weeks of gestation, or infant death before 14 days-of-age), were matched to controls (1:2 ratio) by site and gestational age at entry. Week 4 and week 8 DBS samples were assayed for TFV-DP and FTC-TP by liquid chromatography and tandem mass spectrometry. Associations were tested using Wilcoxon rank test and conditional logistic regression., Results: Of 447 PROMISE arm-C women, 33 met case definitions, and overall, 22 cases and 44 controls were analyzed. Median (interquartile range) concentrations of TFV-DP at weeks 4 and 8 were 706 (375-1023) fmol/punch and 806 (414-1265) fmol/punch, respectively. Odds ratio (95% confidence interval) for severe adverse pregnancy/neonatal outcome with natural log of TFV-DP concentrations as the predictor were 1.27 (0.74 to 2.18) and 1.74 (0.66 to 4.60) at weeks 4 and 8, respectively. Median (interquartile range) concentrations of FTC-TP at weeks 4 and 8 were 0.27 (0.05-0.36) pmol/punch and 0.29 (0.05-0.40) pmol/punch, respectively., Conclusions: TFV-DP concentrations in DBS appeared not to be associated with severe adverse pregnancy/neonatal outcomes, although sample size was limited.

Feminizing hormone therapy (FHT) may interact with human immunodeficiency virus preexposure prophylaxis (PrEP). We found that transgender women who took FHT exhibited a 7-fold lower rectal tissue ratio of PrEP's active metabolites vs competing deoxynucleotides compared to cisgender women and men (P = .03) that inversely correlated with estradiol (ρ = -0.79; P < .05). Thus, FHT may negatively impact PrEP efficacy. Clinical Trials Registration . NCT02983110., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Evidence suggests that low concentration perinatal exposure to environmental contaminants, such as organophosphate (OP) is associated with later life insulin resistance and type 2 diabetes. The aim of this work was to investigate whether chronic maternal OP exposure exacerbates metabolic dysfunctions in early-overfed rats. During pregnancy and lactational periods, dams received OP by gavage. To induce neonatal overnutrition at postnatal day 3, pups were standardized to 9 or 3 per nest. At 90-days-old, glucose-insulin homeostasis and insulin release from pancreatic islets were analyzed. While both OP exposure and overfeeding alone did induce diabetogenic phenotypes in adulthood, there was no exacerbation in rats that experienced both. Unexpectedly, the group that experienced both had improved adiposity, metabolic parameters, attenuated insulin release from isolated islets in the presence of glucose and low function of muscarinic acetylcholine receptor M3, as well as an attenuation of beta cell mass hyperplasia. High levels of butyrylcholinesterase and low levels of insulin in milk may contribute to the OP-induced developmental programming. Our study showed that maternal OP exposure may program insulin release as well as endocrine pancreas structure, thus affecting metabolism in adulthood. Our data suggest that while perinatal OP exposure alone increases the risk for later life T2D, it actually reverses many of the programmed metabolic dysfunction that is induced by postnatal overfeeding. These surprising results may suggest that low-dose administration of acetylcholinesterase inhibitors could be of utility in preventing detrimental developmental programming that is caused by early-life overnutrition., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Biomarkers are frequently used in ecotoxicology as they allow to study toxicant effects happening at low concentrations of exposure. However, most sublethal studies only evaluate cellular biomarkers which lack evident ecological relevance. We used a multibiomarker approach to estimate the toxic effects of ethoprophos, an organophosphate insecticide commonly used in banana plantations, on the tropical fish Astyanax aeneus (Characidae). We measured biomarkers at sub-individual (cellular) and individual (metabolism, behavior) levels and examined relationships among these responses. A sublethal exposure to ethoprophos caused a significant (54%) reduction of brain Cholinesterase (ChE) activity, reflecting the pesticide's high neurotoxicity. However, other biomarkers like oxidative stress, biotransformation reactions, and resting metabolic rate were not affected. Exposure to ethoprophos modified antipredator behaviors such as escape response and detection avoidance (light/dark preference): exposed fish escaped slower from a simulated attack and preferred brighter areas in a novel tank. The relationship between ChE activity and reaction time suggests that pesticide-induced ChE inhibition reduces escape ability in fish. Our results provide evidence that impacts of organophosphate pesticides on fish ecological fitness can occur even with short exposures at very low concentrations.

Objectives: Tenofovir alafenamide produces lower plasma tenofovir and higher intracellular tenofovir diphosphate (DP) concentrations than tenofovir disoproxil fumarate but it is likely a victim of interactions with rifampicin. We aimed to investigate the pharmacokinetics of tenofovir alafenamide/emtricitabine with rifampicin., Patients and Methods: Healthy volunteers received tenofovir alafenamide/emtricitabine at 25/200 mg once daily, followed by tenofovir alafenamide/emtricitabine + rifampicin daily followed by tenofovir disoproxil fumarate. Plasma tenofovir alafenamide, tenofovir, emtricitabine and intracellular tenofovir-DP and emtricitabine triphosphate pharmacokinetics and genetic polymorphisms were assessed., Results: Tenofovir alafenamide exposure decreased when tenofovir alafenamide/emtricitabine + rifampicin was used compared with tenofovir alafenamide/emtricitabine [geometric mean ratio (GMR) (90% CI): 0.45 (0.33-0.60)]. Plasma tenofovir and intracellular tenofovir-DP concentrations decreased with rifampicin [GMR (90% CI): 0.46 (0.40-0.52) and 0.64 (0.54-0.75), respectively]. GMR (90% CI) of intracellular tenofovir-DP AUC0-24 for tenofovir alafenamide/emtricitabine + rifampicin versus tenofovir disoproxil fumarate was 4.21 (2.98-5.95). Rifampicin did not affect emtricitabine pharmacokinetics. CYP3A4*22 rs35599367 was associated with higher plasma tenofovir alafenamide AUC0-24 at day 56., Conclusions: Following tenofovir alafenamide/emtricitabine administration with rifampicin, intracellular tenofovir-DP concentrations were still 4.21-fold higher than those achieved by tenofovir disoproxil fumarate, supporting further study during HIV/TB co-infection., (© The Author(s) 2019. 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.)

Objectives: Glucocorticoids have anti-inflammatory, transrepression-mediated effects, although adverse events (AEs; transactivation-mediated effects) limit long-term use in patients with rheumatoid arthritis (RA). We evaluated the efficacy and safety of fosdagrocorat (PF-04171327), a dissociated agonist of the glucocorticoid receptor, versus prednisone or placebo., Methods: In this 12-week, phase II, randomised controlled trial, 323 patients with moderate to severe RA were randomised 1:1:1:1:1:1:1 to fosdagrocorat (1 mg, 5 mg, 10 mg or 15 mg), prednisone (5 mg or 10 mg) or placebo, once daily. The primary endpoints (week 8) were American College of Rheumatology 20% improvement criteria (ACR20) responses, and percentage changes from baseline in biomarkers of bone formation (procollagen type 1 N-terminal peptide [P1NP]) and resorption (urinary N-telopeptide to urinary creatinine ratio [uNTx:uCr]). Safety was assessed., Results: ACR20 responses with fosdagrocorat 10 mg and 15 mg were superior to placebo, and fosdagrocorat 15 mg was non-inferior to prednisone 10 mg (week 8 model-predicted ACR20 responses: 47%, 61%, 69% and 73% vs 51%, 71% and 37% with fosdagrocorat 1 mg, 5 mg, 10 mg and 15 mg vs prednisone 5 mg, 10 mg and placebo, respectively). Percentage changes from baseline in P1NP with fosdagrocorat 1 mg, 5 mg and 10 mg met non-inferiority criteria to prednisone 5 mg. Corresponding changes in uNTx:uCr varied considerably. All fosdagrocorat doses reduced glycosylated haemoglobin levels. AEs were similar between groups; 63 (19.5%) patients reported treatment-related AEs; 9 (2.8%) patients reported serious AEs. No patients had adrenal insufficiency, treatment-related significant infections or laboratory abnormalities. No deaths were reported., Conclusion: In patients with RA, fosdagrocorat 10 mg and 15 mg demonstrated efficacy similar to prednisone 10 mg and safety similar to prednisone 5 mg., Trial Registration Number: NCT01393639., Competing Interests: Competing interests: FB has received consultancy fees, honoraria and travel expenses from Pfizer Inc. VS is a consultant for Pfizer Inc. EBL has acted as a consultant for Pfizer Inc. BT, RR, AG and JH-H are employees of Pfizer Inc. DM was an employee of Pfizer Inc at the time the trial was conducted.

Purpose: The primary objective of this study was to determine the recommended dose of the vascular disrupting agent, BNC105P, in combination with gemcitabine and carboplatin in patients with ovarian cancer in first or second relapse with a minimum 4 month progression-free interval after last platinum., Methods: Patients received carboplatin AUC4 on day 1 in combination with escalating doses of 800 or 1000 mg/m 2 gemcitabine on days 1 and 8 and escalating doses of 12 or 16 mg/m 2 BNC105P on days 2 and 9 every 21 days for a maximum for six cycles. Maintenance treatment with 16 mg/m 2 BNC105P treatment continued for a maximum of six additional cycles. Patients were followed for safety and anti-tumor activity., Results: Fifteen patients were enrolled in the study. Adverse events were most commonly of hematological origin. Dose-limiting toxicities (thrombocytopenia and neutropenia) occurred in two patients at the dose level of 800 mg/m 2 gemcitabine, carboplatin AUC4 and 16 mg/m 2 BNC105P. No dose-limiting toxicities were observed at a dose level of gemcitabine 1000 mg/m 2 , carboplatin AUC4 and BNC105P 12 mg/m 2 . BNC105P as a single agent was well tolerated at a dose of 16 mg/m 2 in maintenance treatment. Ten patients (67%) achieved a complete or partial response according to CA125 and/or RECIST response criteria, four of 13 (31%) responded by RECIST alone. The median progression-free survival was 5.9 months., Conclusions: We have established that BNC105P 12 mg/m 2 with gemcitabine 1000 mg/m 2 and carboplatin AUC4 is the recommended dose level and has an acceptable toxicity profile. Further exploration of BNC105P in the ovarian cancer setting is planned.

A rare case of 70-year-old woman with adult T-cell leukemia/lymphoma who developed multifocal choroiditis from a dissemination of Cryptococcus neoformans is reported. Ophthalmologic examination revealed multiple yellowish choroidal lesions in the posterior pole of both eyes. Sequential optical coherence tomographic images disclosed the involvement of the choroid and the consecutive changes in its architecture during the course of treatment. The recognition of these ocular manifestations may be important for the rapid diagnosis of C. nerformans-disseminated diseases. Rapid diagnosis and prompt therapy with intravitreal injection as well as systemic fosfluconazole and liposomal amphotericin B led to clinical improvement of intraocular cryptococcosis., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Purpose: Organophosphates, commonly used in agricultural pesticides, pose high risks and incidences of poisoning. In the present study, we investigated the relative risk and clinical severity, including laboratory results, of non-oral route poisoning (NORP) patients, compared to oral route poisoning (ORP) patients., Materials and Methods: A single institutional toxicology database registry was utilized to gain information on clinical laboratory results on organophosphate poisoning patients who visited the emergency department (ED) between January 2000 and October 2016. Clinical outcomes, such as mortality and complication rates, were compared using 1:2 propensity score matching in the total cohort., Results: Among a total of 273 patients in our study, 34 experienced NORP. After 1:2 propensity score matching, rates of respiratory complications and mortality were higher in the ORP group than in the NORP group. However, there was no difference in hospitalization time and time spent in the intensive care unit between the two groups. Compared with ORP patients after matching, the relative risk of mortality in NORP patients was 0.34, and the risk of respiratory distress was 0.47. The mean level of pseudocholinesterase was significantly higher in the NORP group than in the ORP group, while recovery rates were similar between the two groups., Conclusion: Although the majority of NORP patients were admitted to the ED with unintentional poisoning and the relative risk of NORP was lower than that for ORP, we concluded that NORP is as critical as ORP. Considerable medical observation and intensive therapeutic approaches are also needed for NORP patients., Competing Interests: The authors have no financial conflicts of interest., (© Copyright: Yonsei University College of Medicine 2018.)

Pre-exposure prophylaxis (PrEP) with antiretroviral (ARV) drugs are effective at preventing human immunodeficiency virus (HIV) transmission. However, implementation of PrEP presents significant challenges due to poor user adherence, low accessibility to ARVs and multiple routes of HIV exposure. To address these challenges, we developed the nanochannel delivery implant (NDI), a subcutaneously implantable device for sustained and constant delivery of tenofovir alafenamide (TAF) and emtricitabine (FTC) for HIV PrEP. Unlike existing drug delivery platforms with finite depots, the NDI incorporates ports allowing for transcutaneous refilling upon drug exhaustion. NDI-mediated drug delivery in rhesus macaques resulted in sustained release of both TAF and FTC for 83 days, as indicated by concentrations of TAF, FTC and their respectively metabolites in plasma, PBMCs, rectal mononuclear cells and tissues associated with HIV transmission. Notably, clinically relevant preventative levels of tenofovir diphosphate were achieved as early as 3 days after NDI implantation. We also demonstrated the feasibility of transcutaneous drug refilling to extend the duration of PrEP drug delivery in NHPs. Overall, the NDI represents an innovative strategy for long-term HIV PrEP administration in both developed and developing countries., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infections in adults. We evaluated the pharmacokinetics of tedizolid in elderly subjects to guide dosing recommendations. In an open-label phase 1 study (ClinicalTrials.gov identifier NCT01496677), 14 elderly (≥65 years) and 14 younger control (18-45 years) subjects each received a single oral dose of tedizolid phosphate 200 mg. Blood samples were collected before dose and more than 72 hours after dose. The pharmacokinetic parameters of tedizolid after a single dose were similar in both age groups. Geometric mean ratios (elderly/younger controls) and corresponding 90% confidence intervals were maximum observed plasma concentration (C max ), 1.091 (0.917-1.297); AUC from time 0 extrapolated to infinity (AUC 0-∞ ), 1.132 (0.954-1.343). Tedizolid plasma exposure was similar in elderly and younger control subjects. The findings indicated that after intravenous or oral administration of tedizolid phosphate 200 mg once daily, no dose adjustment was warranted in elderly subjects to achieve therapeutic levels., (© 2018, The American College of Clinical Pharmacology.)

Objectives: Pregnancy is a time of increased HIV acquisition risk and pregnancy reduces concentrations of antiretrovirals used for treatment. We assessed whether pregnancy lowers concentrations of tenofovir (TFV) and tenofovir-diphosphate (TFV-DP) among HIV-uninfected women using oral preexposure prophylaxis (PrEP)., Methods: We analyzed data from an open-label PrEP study, comparing concentrations of TFV in plasma and TFV-DP in dried blood spots (DBS) among 37 pregnant women and 97 nonpregnant women. Analyses controlled for adherence from daily electronic monitoring., Results: The average plasma concentration of TFV among pregnant women was 34.7 ng/ml with 22.2 average recorded doses over the prior month versus 86.5 ng/ml with 23.1 doses among nonpregnant women. After controlling for adherence, TFV concentrations were 58% lower among pregnant women, a statistically significant difference of -50.4 ng/ml (95% CI -68.3 to -32.5). The average TFV-DP concentration was 450.3 fmol/punch among pregnant women and 636.7 fmol/punch among nonpregnant women. This difference was not statistically significant after adjusting for adherence; however, among those with quantifiable TFV-DP, concentrations were 27% lower during pregnancy [-202 fmol/punch (95% CI -384 to -19)]. Among participants with samples before and during pregnancy, there were significant decreases during pregnancy, controlling for adherence: -28.1 ng/ml TFV (95% CI -52.3 to -4.0) and -289.2 fmol/punch TFV-DP (95% CI -439.0 to -139.3)., Conclusion: Consistent with studies among HIV-infected women on ART, we found TFV and TFV-DP concentrations were lower during pregnancy. There is no established TFV concentration threshold to achieve HIV prevention. Additional pharmacokinetic studies and studies of PrEP efficacy in pregnancy are needed.

Purpose of Review: Even in the era of modern HAART, antiretroviral (ARV) failure and emergence of drug resistance is still a problem worldwide. New classes with different mechanisms of action are needed to overcome this challenge. After the integrase inhibitors were launched, more than a decade ago, no new classes were added to the ARV armamentarium., Recent Findings: Fostemsavir (FTR) is an attachment inhibitor, active regardless of viral tropism, without cross-resistance to any of the existing ARV compounds. A phase 3 study showed a reduction in plasma viral RNA of 1.21-1.73 log10 copies/ml from baseline after 8 days of functional monotherapy; at 48 weeks, up to 82% of patients treated with FTR and an optimized background ARV regimen achieved virological suppression below 50 copies/ml., Summary: FTR is an investigational HIV drug with a novel mechanism of action that demonstrates virologic activity in HIV-infected treatment-experienced individuals.

We comprehensively studied the complexity of the mode of action of adjuvants by uncoupling the parameters contributing to the spray process during foliar application of agrochemicals. The ethoxylated sorbitan esters Tween 20 and Tween 80 improved the efficiency of pinoxaden (PXD) in controlling grass-weed species in greenhouse experiments by aiding retention, having humectant properties, maintaining the bioavailability, and increasing the cuticular penetration of PXD. The nonethoxylated sorbitan esters Span 20 and Span 80 showed minimal effects on retention, droplet hydration, or cuticular penetration, resulting in reduced PXD effects in the greenhouse. Tris(2-ethylhexyl)phosphate (TEHP) does not contribute much to retention and spreading but strongly enhances the diffusion of PXD across isolated P. laurocerasus cuticular membranes. As TEHP was most efficient in controlling the growth of grass-weed species, we propose that the direct effect of penetration aids on cuticular permeation plays a key role in the efficiency of foliar-applied agrochemicals.

The objective of this open-label, randomised (i.e. 2:1 ratio), Phase 3 study was to compare the efficacy and safety of tedizolid phosphate 200 mg, once-daily treatment with that of linezolid 600 mg, twice-daily treatment for 7-14 days in Japanese adult patients (N = 125) with skin and soft tissue infections (SSTIs) and/or for 7-21 days for those with SSTI-related bacteraemia, caused by confirmed or highly suspected methicillin-resistant Staphylococcus aureus (MRSA). Primary outcome was clinical cure rate at test-of-cure (TOC, in SSTI: 7-14 days, in bacteraemia: 4-6 weeks after end-of-therapy [EOT]) time point in the microbiologically evaluable MRSA (ME-MRSA) population (N = 39). Secondary endpoints were clinical and microbiological response rates at EOT. Safety parameters were evaluated in the safety analysis population up to follow up. Data analysis was descriptive in nature. Baseline characteristics of patients were similar between treatment groups. At TOC in the ME-MRSA population, clinical cure rate was similar in tedizolid phosphate (92.6%) and linezolid (88.9%) groups. At EOT, clinical cure (tedizolid phosphate: 93.1%, linezolid: 90.0%) and microbiological success (tedizolid phosphate: 93.1%, linezolid: 100.0%) rates were similar in the ME-MRSA population. Both treatments were well tolerated; overall treatment-emergent adverse events (TEAEs) in tedizolid phosphate (79.5%) and linezolid (75.6%) treatment groups were similar. Drug-related TEAEs were numerically lower with tedizolid phosphate versus linezolid (30.1%; 39.0%, respectively), as well as gastrointestinal (21.7%; 26.8%) and myelosuppression-related (2.4%; 22.0%) TEAEs. One death occurred in the linezolid group. Tedizolid phosphate may be an appropriate antibiotic for the treatment of SSTIs in Japanese adult patients. International clinical trial registration number: NCT01967225. Japanese clinical trial registration number: JapicCTI-132308., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Adherence is critical for efficacy of tenofovir disoproxil fumarate/emtricitabine (FTC) as preexposure prophylaxis (PrEP)., Methods: Between February 2013 and February 2016, 398 men who have sex with men and transgender women were randomized 1:1 to receive individualized texting for adherence building (iTAB) or standard care (SoC) for 48 weeks. The primary endpoint was dried blood spot (DBS) tenofovir diphosphate (TFV-DP) concentrations at both week 12 and the last on-drug visit of >719 fmol/punch (ie, adequate adherence). Secondary outcomes included DBS TFV-DP concentrations of >1246 fmol/punch (ie, near-perfect adherence) and plasma FTC >350 ng/mL (consistent with dosing within the past 24 hours)., Results: Concentrations >719 fmol/punch of TFV-DP were found in 88.6% of participants at week 12 and 82.5% at week 48. For the primary endpoint, the study arms did not differ (72.0% in iTAB and 69.2% in SoC; P > .05). For the secondary composite endpoint of >1246 fmol/punch the iTAB arm was superior to SoC (33.5% vs 24.8%; P = .06), reaching statistical significance when adjusting for age (odds ratio, 1.56 [95% confidence interval, 1.00-2.42]; P < .05). At week 48, iTAB was superior to SoC for near-perfect adherence (51.0% vs 37.4%; P = .02). At week 12, iTAB was superior to SoC for dosing in past 24 hours by plasma FTC (47.5% vs 33.3%; P = .007), but not at weeks 24, 36, and 48 (all P > .05)., Conclusions: Automated text messaging is a low-burden tool that improves durability of near-perfect PrEP adherence., Clinical Trials Registration: NCT01761643.

Objective: We describe and compare the local and systemic pharmacokinetics (PK) of tenofovir (TFV) and TFV-diphosphate (TFV-DP) in healthy premenopausal (PRE) and postmenopausal (POST) women using TFV 1% gel and correlate local PK with other mucosal end points., Methods: PRE (n = 20) and POST (n = 17) women used 2 doses of TFV 1% vaginal gel, separated by 2 hours. Blood and cervicovaginal samples were obtained 3 and 23 hours after the second dose. PRE women used gel in the follicular and luteal phases of the menstrual cycle. POST women used gel at baseline and again after approximately 2 months of treatment with 0.01% vaginal estradiol (E2) cream., Results: Median TFV concentrations in cervicovaginal aspirate (ng/mL) and vaginal tissue (ng/mg) were significantly higher in PRE (4.3E10, 49.8) versus POST women (2.6E10, 2.2). POST women had significantly higher median molecular ratios of TFV-DP to TFV (3.7%) compared with PRE (0.19%). After vaginal E2 treatment, the local and systemic PK end points in POST women were generally similar to PRE women (all P values > 0.05). Importantly, median vaginal tissue TFV-DP concentrations (fmol/mg) among PRE, POST, and POST women after E2 therapy were similar (292.5, 463.3, and 184.6, respectively). Vaginal tissue TFV concentrations were significantly positively correlated with vaginal epithelial thickness, whereas vaginal tissue TFV-DP concentrations were positively correlated with density of vaginal CD4 and CD8 immune cells., Conclusions: The state of the cervicovaginal mucosa has a significant impact on local and systemic PK of a topically applied microbicide.

Glomerulopathy and body weight gain were noted after chronic oral administration of a novel nonsteroidal dissociated agonist of the glucocorticoid receptor compound, fosdagrocorat, to beagle dogs fed an ad libitum diet. To further investigate the role of diet and treatment with either fosdagrocorat or the glucocorticoid comparator, prednisone, on renal safety, a 13-week investigative study was conducted in beagle dogs. Renal histopathology, clinical chemistry, urinalysis, glomerular filtration rate (GFR), body weight, heart rate, blood pressure (BP), and hematology were investigated in restricted- and ad libitum-fed dogs administered prednisone (2.2 mg/kg/d), fosdagrocorat (5 mg/kg/d), or vehicle for 13 weeks. Glomerulopathy was primarily observed in fosdagrocorat- and prednisone-treated ad libitum but not in feed-restricted or ad libitum vehicle-treated dogs. Kidneys in dogs from the prednisone-treated ad libitum had the greatest incidence and severity of tubular degenerative changes. Increased urine volume and decreased urine-specific gravity were present in prednisone- and fosdagrocorat-treated dogs, regardless of diet. These changes were not associated with consistent changes in GFR. Fosdagrocorat or prednisone treatment ad libitum dogs had the greatest increase in body weight gain. Sporadic changes in systolic and diastolic BP were noted in fosdagrocorat- and prednisone-treated groups. Significant reductions in serum cortisol and absolute eosinophils were noted in both ad libitum- and restriction-fed prednisone- and fosdagrocorat-treated dogs. In conclusion, prednisone-treated dogs fed ad libitum had greater glucocorticoid-induced renal effects than those dosed with fosdagrocorat.

Objective: Auditory brainstem response (ABR) testing is the gold-standard procedure for hearing evaluation in pediatric patients who cannot complete a behavioral hearing test. The amount of audiological information obtained depends on the quality of the patient's sleep during the test. In this retrospective database review, we aimed to assess the amount and the characteristics of the audiological information obtained in ABR testing in pediatric patients with age-appropriate sedation., Methods: A retrospective chart review was conducted on 501 consecutive ABR sedation sessions performed between January 2014 and June 2016 at the Tel Aviv Medical Center. Oral triclofos was used for the sedation of younger patients (3-24 months) and intravenous propofol for older patients (>24 months). The dataset included 370 triclofos sessions (in 337 patients) and 131 propofol sessions (in 126 patients)., Results: None of the children developed complications, and all were discharged on the same day of the evaluation. Among the hearing-impaired children, a mean of 10 (1.8 SD) ABR threshold measurements was obtained from propofol-sedated patients and 9.4 (2.8 SD) measurements from those sedated with triclofos (P = 0.039). The major characteristics of the hearing loss, including its degree, type, and configuration, were obtained from all propofol-sedated patients and from 95% of those sedated with triclofos., Conclusions: A comprehensive evaluation of hearing status can be obtained in ABR testing with age-appropriate sedation. An average number of ∼10 threshold measurements were obtained during ABR testing with age-appropriate sedation, thus allowing for the evaluation of the degree, type and configuration of the hearing loss., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Antiretroviral drug concentrations at sites of HIV exposure are important drivers that influence the development of HIV pre-exposure chemoprophylaxis strategies and regimens. We assessed the effect of collection method-in the presence or absence of tissue culture medium-on tenofovir (TFV) and tenofovir diphosphate (TFV-DP) concentrations in colonic biopsies. We find significant baseline interbiopsy variation in TFV (38% CV) and TFV-DP (33% CV) concentrations. Incubation in medium leads to a fluid absorption-driven twofold increase in tissue weight with a concomitant 75% decrease in weight-adjusted tissue TFV concentrations 120 min post-incubation. In contrast, adjusted TFV-DP concentrations decrease by only 25% during the same period, with this difference not achieving statistical significance. Although colonic biopsies should be collected in the absence of medium for accurate TFV concentrations, the presence of medium does not significantly impact TFV-DP-dependent pharmacokinetic or pharmacodynamic assays. Appropriate assessment of tissue drug concentrations should account for biopsy collection method and drug mechanism of action.

Background: We evaluated safety and tolerability of tedizolid phosphate at the 200-mg once-daily dose approved for 6-day treatment of skin and skin-structure infections., Research Design and Methods: Clinical adverse event (AE) and laboratory data were pooled across completed clinical studies (13 phase 1, two phase 2, and two phase 3), for all participants who received ≥1 dose of tedizolid 200 mg, linezolid 600 mg (phase 3 only), or placebo (phase 1 only)., Results: 1280 participants received tedizolid (phase 1: n = 355; phase 2/3: n = 925). In total, 13% received >6 doses of tedizolid (range: 7-21); in phase 2/3, 94% of participants received ≥5 doses (range: 5-10). Drug-related AEs occurred in 27% of participants (most commonly gastrointestinal reactions in 13% of participants and headache in 4%). Most AEs were mild-moderate in severity; <1% of participants discontinued treatment due to AEs. Tedizolid and linezolid had similar frequency, severity, and types of drug-related AEs. Tolerability in clinically important subpopulations (obese, n = 346; elderly, n = 99; renal impairment, n = 40; hepatic disease/impairment, n = 294) appeared comparable to the overall population., Conclusions: Tedizolid, given orally or intravenously at 200 mg, has a favorable safety profile. Clinical trial and postmarketing experience with treatment ≥7 days is limited.

Background: Fostemsavir is a prodrug of temsavir, an attachment inhibitor that binds to HIV-1 gp120, blocking viral attachment to host CD4 T-cells. The phase 2b trial AI438011 investigated the safety, efficacy, and dose-response of fostemsavir vs ritonavir-boosted atazanavir (ATV/r) in treatment-experienced, HIV-1-infected subjects., Methods: Two hundred fifty-one treatment-experienced subjects with baseline (BL) susceptibility to study drugs [temsavir half-maximal inhibitory concentration (IC50) <100 nM, PhenoSense Entry assay] received fostemsavir or ATV/r, each with tenofovir disoproxil fumarate + raltegravir. Subjects meeting resistance-testing criteria were assessed for emergent viral drug resistance. Changes in temsavir IC50 from BL was given a conservative technical cutoff (>3-fold increase)., Results: 66/200 fostemsavir and 14/51 ATV/r subjects had resistance testing performed; 44/66 and 9/14 were successfully tested using the PhenoSense GT assay. No subjects had emergent tenofovir disoproxil fumarate or ATV resistance. Six fostemsavir-treated subjects developed emergent raltegravir resistance. 29/66 fostemsavir-treated subjects had an evaluable phenotype using PhenoSense Entry (which tests for viral susceptibility to temsavir) and 13/29 exhibited >3-fold increase in temsavir IC50 from BL. gp120 population sequencing was successful in 11/13 subjects and 7 had emergent substitutions in gp120 associated with reduced temsavir susceptibility (S375, M426, or M434). However, 5/13 fostemsavir-treated subjects achieved subsequent suppression to <50 copies/mL before the week 48 database lock, regardless of key gp120 substitutions., Conclusions: Response rates remained similar across study arms regardless of BL nucleoside reverse transcriptase inhibitor, nonnucleoside reverse transcriptase inhibitor, and protease inhibitor resistance-associated mutations. Emergent changes in viral susceptibility occurred more frequently with fostemsavir compared with ATV/r. However, the full impact of temsavir IC50 changes and emergent HIV-1 gp120 substitutions, and thus appropriate clinical cutoffs, requires further study. Fostemsavir is being evaluated in a phase 3 trial in heavily treatment-experienced subjects.

Human immunodeficiency virus-1 (HIV-1) infection currently requires lifelong therapy with drugs that are used in combination to control viremia. The indole-3-glyoxamide 6 was discovered as an inhibitor of HIV-1 infectivity using a phenotypic screen and derivatives of this compound were found to interfere with the HIV-1 entry process by stabilizing a conformation of the virus gp120 protein not recognized by the host cell CD4 receptor. An extensive optimization program led to the identification of temsavir (31), which exhibited an improved antiviral and pharmacokinetic profile compared to 6 and was explored in phase 3 clinical trials as the phosphonooxymethyl derivative fostemsavir (35), a prodrug designed to address dissolution- and solubility-limited absorption issues. In this drug annotation, we summarize the structure-activity and structure-liability studies leading to the discovery of 31 and the clinical studies conducted with 35 that entailed the development of an extended release formulation suitable for phase 3 clinical trials.

Dissociated agonists of the glucocorticoid receptor (DAGRs) show similar antiinflammatory effects but improved tolerability compared with standard glucocorticoid receptor (GR) agonists. The prodrug fosdagrocorat (PF-04171327), with active DAGR metabolite PF-00251802 (Metabolite-1), is postulated to show superior efficacy over placebo and prednisone in patients with moderate to severe rheumatoid arthritis (RA). We investigated the population pharmacokinetics of active Metabolite-1 and its active metabolite PF-04015475 (Metabolite-2) in patients with moderate to severe RA enrolled in a 12-week, phase II, randomized, double-blind study (NCT01393639). A simultaneous fit of a two-compartment model for Metabolite-1 and a one-compartment model for Metabolite-2 provided an adequate fit to the data. Significant covariates included weight, with an additional female effect on clearance of Metabolite-1 (∼26%) and Metabolite-2 (∼33%) compared with males. Age influenced clearance of Metabolite-1. In combination, age, weight, and sex predicted >twofold differences in area under the concentration-time curve of Metabolite-1 at the extremes., (© 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)