Dual-Activated H2O2-Responsive AIE Probes for Oocyte Quality Assessment.

Nonobstructive azoospermia (NOA) is an important cause of infertility, and intracytoplasmic sperm injection (ICSI) is the mainstay of treatment for these patients. In cases where a sufficient number of sperm (usually 1-2) is not available, the selection of oocytes for ICSI is a difficult problem that must be solved. Here, we constructed a dual-activated oxidative stress-responsive AIE probe, b-PyTPA. The strong donor-acceptor configuration of b-PyTPA leads to twisted intramolecular charge transfer (TICT) effect that quenches the fluorescence of the probe, however, H2O2 would specifically remove the boronatebenzyl unit and release a much weaker acceptor, which inhibits TICT and restores the fluorescence. In addition, the presence of a pyridine salt makes b-PyTPA more hydrophilic, whereas removal of the pyridine salt increases the hydrophobicity of PyTPA, which triggers aggregation and further enhances fluorescence. Thus, the higher the intracellular level of oxidative stress, the stronger the fluorescence. In vitro, this dual-activated fluorescent probe is capable of accurately detecting senescent cells (high oxidative stress). More importantly, b-PyTPA was able to characterize senescent oocytes, as assessed by the level of oxidative stress. It is also possible to identify high quality oocytes from those obtained for subsequent ICSI. In conclusion, this dual-activated oxidative stress-assessment probe enables the quality assessment of oocytes and has potential application in ICSI.

Assessment of Mononuclear/Dinuclear copper acylhydrazone complexes for lung cancer treatment.

Non-platinum metal-based complexes have good potential for cancer treatment. Here, we designed and synthesized five hydrazone copper(II) complexes, [Cu2(HL)2Cl2] 1A, [Cu2(HL)2(NO3)H2O]·NO3 2A, [Cu2(HL)2Br2] 3A, [Cu(L)pyridine] 1B and [Cu(HL)(pyridine)Br] 3B, and evaluated their anti-lung cancer activities. MTT experiments revealed that these copper(II) complexes exhibit higher anticancer activity than cisplatin. Mechanism studies revealed that complex 3A induced G1 phase cell cycle arrest, and induced cell apoptosis via reactive oxygen species (ROS)-mediated mitochondrial dysfunction. Scratch wound healing assay was also performed, revealing that complex 3A have good anti-cell migration activity. Hemolysis assays showed good blood biocompatibility of complex 3A. Furthermore, complex 3A can significantly inhibit the proliferation of A549 3D tumor spheroid. An in vivo anticancer study showed that complex 3A could delays the growth of A549 tumor xenografts with lower systemic toxicity. These results highlight the great possibility of developing highly active copper complexes as anti-lung cancer agents.

Comprehensive characterization and preclinical assessment of an imidazopyridine-based anticancer lead molecule.

Imidazopyridine scaffold holds significant pharmacological importance in the treatment of cancer. An in-house synthesized imidazopyridine-based molecule was found to have promising anticancer activity against breast cancer, lung cancer, and colon cancer. The molecule is an inhibitor of pyruvate kinase M2, the enzyme that elevates tumor growth, metastasis and chemoresistance by directly controlling tumor cell metabolism. Screening of the physicochemical properties of any lead molecules is essential to avoid failure in late-stage drug development. In this research, the physicochemical properties of the molecule including log P, log D, pKa, and plasma protein binding were assessed to check its drug-likeness. Plasma and metabolic stability of the molecule were also evaluated. Moreover, pharmacokinetic profiles of the lead molecule in Sprague-Dawley rats and in vitro metabolite identification studies were also performed. Finally, an in silico software, Pro-Tox-II, was used to predict toxicity of the molecule and its metabolites. Log P, Log D (pH 7.4), pKa, and plasma protein binding of the molecule were found to be 2.03%, 2.42%, 10.4%, and 98%, respectively. The molecule was stable in plasma and metabolic conditions. A total of nine new metabolites were identified and characterized. Cmax and t½ of this molecule were found to be 4016 ± 313.95 ng/mL and 9.57 ± 3.05 h, respectively. Based on the previously reported study and this finding, the molecule can be considered as a promising anticancer lead with potential drug-likeness properties. Further preclinical and clinical drug discovery studies may be initiated in continuation of this study in search of a potential anticancer lead.

Synthesis, molecular modeling Insights, and anticancer assessment of novel polyfunctionalized Pyridine congeners.

The present study describes synthesizing a novel series of polyfunctionalized pyridine congeners 1-18 and assessed for cytotoxic efficacies versus HCT-116, MCF-7, and HepG-2 among one non-cancerous BJ-1 human normal cell. Most compounds were precisely potent anticancer candidate drugs. The molecular impact of the most active compounds 9, 10, 11, 13, 15, and 17 was evaluated after MCF-7 treatment. The gene expression of pro- and ant-apoptosis markers P53, Bax, Caspase-3 and Bcl-2 as well as VEGFR-2 and HER2 were determined. Compounds 13 and 15 induced upregulation of pro-apoptosis of P53, Bax, Caspase-3 and downregulation of anti-apoptosis Bcl-2 gene. However, compound 15 showed higher effect compared to 13 and respective control. Moreover, a slight reduction in HER2 gene expression was detected due to compound 15 treatment, while VEGFR-2 gene was upregulated. In agreement, the immunoblotting analysis showed higher accumulation of P53, Bax, Caspase-3 proteins and of decrease the Bcl-2 protein levels. Furthermore, docking studies united with molecular dynamic simulation exposed compounds 13 and 15 fitting in the middle of the active site at the interface linking the ATP binding site and the allosteric hydrophobic binding pocket. Finally, we performed Petra/Osiris/ Molinspiration (POM) analysis for the newly synthesized compounds. The evaluation of primary in silico parameters revealed significant differences among individual polyfunctionalized pyridine compounds, highlighting the most promising candidates. These preliminary results may help in coordinating and initiating other research projects focused on polyfunctionalized pyridine compounds, especially those with predicted bioactivity, low toxicity, optimal ADME parameters, and promising perspectives.

A potential cost of evolving epibatidine resistance in poison frogs.

BACKGROUND: Some dendrobatid poison frogs sequester the toxin epibatidine as a defense against predators. We previously identified an amino acid substitution (S108C) at a highly conserved site in a nicotinic acetylcholine receptor ß2 subunit of dendrobatid frogs that decreases sensitivity to epibatidine in the brain-expressing α4ß2 receptor. Introduction of S108C to the orthologous high-sensitivity human receptor similarly decreased sensitivity to epibatidine but also decreased sensitivity to acetylcholine, a potential cost if this were to occur in dendrobatids. This decrease in the acetylcholine sensitivity manifested as a biphasic acetylcholine concentration-response curve consistent with the addition of low-sensitivity receptors. Surprisingly, the addition of the ß2 S108C into the α4ß2 receptor of the dendrobatid Epipedobates anthonyi did not change acetylcholine sensitivity, appearing cost-free. We proposed that toxin-bearing dendrobatids may have additional amino acid substitutions protecting their receptors from alterations in acetylcholine sensitivity. To test this, in the current study, we compared the dendrobatid receptor to its homologs from two non-dendrobatid frogs. RESULTS: The introduction of S108C into the α4ß2 receptors of two non-dendrobatid frogs also does not affect acetylcholine sensitivity suggesting no additional dendrobatid-specific substitutions. However, S108C decreased the magnitude of neurotransmitter-induced currents in Epipedobates and the non-dendrobatid frogs. We confirmed that decreased current resulted from fewer receptors in the plasma membrane in Epipedobates using radiolabeled antibodies against the receptors. To test whether S108C alteration of acetylcholine sensitivity in the human receptor was due to (1) adding low-sensitivity binding sites by changing stoichiometry or (2) converting existing high- to low-sensitivity binding sites with no stoichiometric alteration, we made concatenated α4ß2 receptors in stoichiometry with only high-sensitivity sites. S108C substitutions decreased maximal current and number of immunolabeled receptors but no longer altered acetylcholine sensitivity. CONCLUSIONS: The most parsimonious explanation of our current and previous work is that the S108C substitution renders the ß2 subunit less efficient in assembling/trafficking, thereby decreasing the number of receptors in the plasma membrane. Thus, while ß2 S108C protects dendrobatids against sequestered epibatidine, it incurs a potential physiological cost of disrupted α4ß2 receptor function.

Green synthesis and biological activities assessment of some new chromeno[2,3-b]pyridine derivatives.

Magnetite nanoparticles (MNPs) composed of γ-Fe2O3 and hydroxyapatite (HAp) were modified by hexamethylen-1,6-diisocyanate (HMDI) followed by thiourea dioxide and used as recyclable catalyst for the synthesis of some newly derivatives of chromeno[2,3-b]pyridine. The products were synthesized in excellent yields via one-pot three-component reactions of 3-cyano-6-hydroxy-4-methyl-pyridin-2(1H)-one with aldehydes and dimedone under solvent-free conditions. The successful synthesis of products were confirmed using Fourier transform infrared (FTIR), proton/carbon nuclear magnetic resonance (1H/13C NMR), and mass spectroscopies as well as physical data (e.g., melting points and elemental composition). The in vitro antioxidant and antifungal activities of the synthesized samples were evaluated using scavenging effects on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and potato dextrose agar (PDA) medium, respectively. Based on results, the chromeno[2,3-b]pyridine derivatives exhibited excellent biological activities that qualified them for biomedical applications.

Statewide Efficacy Assessment of Insect Growth Regulators Against Aedes albopictus (Diptera: Culicidae) in Sabah, Malaysia: An Alternative Control Strategy?

The efficacy of three groups of insect growth regulators, namely juvenile hormone mimics (methoprene and pyriproxyfen), chitin synthesis inhibitors (diflubenzuron and novaluron), and molting disruptor (cyromazine) was evaluated for the first time, against Aedes albopictus Skuse (Diptera: Culicidae) larvae from 14 districts in Sabah, Malaysia. The results showed that all field populations of Ae. albopictus were susceptible towards methoprene, pyriproxyfen, diflubenzuron, novaluron, and cyromazine, with resistance ratio values ranging from 0.50-0.90, 0.60-1.00, 0.67-1.17, 0.71-1.29, and 0.74-1.07, respectively. Overall, the efficacy assessment of insect growth regulators in this study showed promising outcomes and they could be further explored as an alternative to conventional insecticides.

Assessment of the In Vitro and In Vivo Antifungal Activity of NSC319726 against Candida auris.

Candida auris is an emerging yeast pathogen of candidemia with the ability to develop resistance to all current antifungal drug classes. Novel antifungal therapies against C. auris are warranted. NSC319726 is a thiosemicarbazone with an inhibitory effect on fungal ribosome biogenesis that has demonstrated some antifungal activity. In this study, we assessed the in vitro activity and in vivo efficacy of NSC319726 against C. auris. NSC319726 was active in vitro against 22 C. auris isolates from different clades, with MICs ranging from 0.125 to 0.25 mg/liter. Despite complete visual growth inhibition, the effect was described as fungistatic in time-kill curves. Interactions with fluconazole, amphotericin B, and micafungin, as tested by the checkerboard dilution method, were described as indifferent. NSC319726 demonstrated significant effects in rescuing G. mellonella larvae infected with two distinct C. auris isolates, compared to the untreated group. In conclusion, NSC319726 demonstrated in vitro activity against C. auris and in vivo efficacy in an invertebrate model of infection. Its potential role as a novel antifungal therapy in humans should be further investigated. IMPORTANCE Candida auris is emerging as a major public health threat because of its ability to cause nosocomial outbreaks of severe invasive candidiasis. Management of C. auris infection is difficult because of its frequent multidrug-resistant profile for currently licensed antifungals. Here, we show that the thiosemicarbazone NSC319726 was active in vitro against a large collection of C. auris isolates from different clades. Moreover, the drug was well tolerated and effective for the treatment of C. auris infection in an invertebrate model of Galleria mellonella. We conclude that NSC319726 might represent an interesting drug candidate for the treatment of C. auris infection.

High pressure assisted synthetic approach for novel 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine and 5,6-dihydrobenzo[h]quinoline derivatives and their assessment as anticancer agents.

A novel, expedient and effective methodology for the synthesis of distinctly substituted 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine and 5,6-dihydrobenzo[h]quinoline systems has been developed with a new synthetic platform. This process includes ammonium acetate-mediated cyclocondensation reactions of 3-oxo-2-arylhydrazonopropanals with benzosuberone and tetralone precursors, respectively, using the high-pressure Q-tube reactor, which has been found to be superior to both conventional heating and microwave irradiation. The novel protocol benefits from its high atom efficiency, economy, ease of workup, broad substrate scope and is also applicable to gram-scale synthesis. To identify and confirm the newly synthesized targeted compounds, the X-ray single-crystal as well as all possible spectroscopic methods were utilized. The cytotoxicity of the newly synthesized 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine 4a-j and 5,6-dihydrobenzo-[h]quinolines derivatives 6a-e were preliminary examined toward three cell lines of human cancer; lung cancer (A549), breast cancer (MCF-7) and colon cancer (HCT-116), by applying the MTT colorimetric assay. The achieved results reflected the promising profile of the prepared compounds in this study against cancer cells and have shown that members from the synthesized 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine 4a-j exhibited promising cytotoxicity's against MCF-7, and A549 cancer cells respectively, while the HCT-116 (colon) cancer cells were inhibited by certain examples of 5,6-dihydrobenzo[h]quinoline derivatives 6c,d. These promising results could serve as a good primary base for further research into the design of anticancer drugs.

Cost-effectiveness of antithrombotic agents for atrial fibrillation in older adults at risk for falls: a mathematical modelling study.

BACKGROUND: Antithrombotic drugs decrease stroke risk in patients with atrial fibrillation, but they increase bleeding risk, particularly in older adults at high risk for falls. We aimed to determine the most cost-effective antithrombotic therapy in older adults with atrial fibrillation who are at high risk for falls. METHODS: We conducted a mathematical modelling study from July 2019 to March 2020 based on the Ontario, Canada, health care system. We derived the base-case age, sex and fall risk distribution from a published cohort of older adults at risk for falls, and the bleeding and stroke risk parameters from an atrial fibrillation trial population. Using a probabilistic microsimulation Markov decision model, we calculated quality-adjusted life years (QALYs), total cost and incremental cost-effectiveness ratios (ICERs) for each of acetylsalicylic acid (ASA), warfarin, apixaban, dabigatran, rivaroxaban and edoxaban. Cost data were adjusted for inflation to 2018 values. The analysis used the Ontario public payer perspective with a lifetime horizon. RESULTS: In our model, the most cost-effective antithrombotic therapy for atrial fibrillation in older patients at risk for falls was apixaban, with an ICER of $8517 per QALY gained (5.86 QALYs at $92 056) over ASA. It was a dominant strategy over warfarin and the other antithrombotic agents. There was moderate uncertainty in cost-effectiveness ranking, with apixaban as the preferred choice in 66% of model iterations (given willingness to pay of $50 000 per QALY gained); edoxaban, 30 mg, was preferred in 31% of iterations. Sensitivity analysis across ranges of age, bleeding risk and fall risk still favoured apixaban over the other medications. INTERPRETATION: From a public payer perspective, apixaban is the most cost-effective antithrombotic agent in older adults at high risk for falls. Health care funders should implement strategies to encourage use of the most cost-effective medication in this population.

Assessment of the susceptibility status of Aedes aegypti (Diptera: Culicidae) populations to pyriproxyfen and malathion in a nation-wide monitoring of insecticide resistance performed in Brazil from 2017 to 2018.

BACKGROUND: Chemical mosquito control using malathion has been applied in Brazil since 1985. To obtain chemical control effectiveness, vector susceptibility insecticide monitoring is required. This study aimed to describe bioassay standardizations and determine the susceptibility profile of Ae. aegypti populations to malathion and pyriproxyfen, used on a national scale in Brazil between 2017 and 2018, and discuss the observed impacts in arbovirus control. METHODS: The diagnostic-doses (DD) of pyriproxyfen and malathion were determined as the double of adult emergence inhibition (EI) and lethal doses for 99% of the Rockefeller reference strain, respectively. To monitor natural populations, sampling was performed in 132 Brazilian cities, using egg traps. Colonies were raised in the laboratory for one or two generations (F1 or F2) and submitted to susceptibility tests, where larvae were exposed to the pyriproxyfen DD (0.03 µg/l) and adults, to the malathion DD determined in the present study (20 µg), in addition to the one established by the World Health Organization (WHO) DD (50 µg) in a bottle assay. Dose-response (DR) bioassays with pyriproxyfen were performed on populations that did not achieve 98% EI in the DD assays. RESULTS: Susceptibility alterations to pyriproxyfen were recorded in six (4.5%) Ae. aegypti populations from the states of Bahia and Ceará, with Resistance Ratios (RR95) ranging from 1.51 to 3.58. Concerning malathion, 73 (55.3%) populations distributed throughout the country were resistant when exposed to the local DD 20 µg/bottle. On the other hand, no population was resistant, and only 10 (7.6%) populations in eight states were considered as exhibiting decreased susceptibility (mortality ratios between 90 and 98%) when exposed to the WHO DD (50 µg/bottle). CONCLUSIONS: The feasibility of conducting an insecticide resistance monitoring action on a nation-wide scale was confirmed herein, employing standardized and strongly coordinated sampling methods and laboratory bioassays. Brazilian Ae. aegypti populations exhibiting decreased susceptibility to pyriproxyfen were identified. The local DD for malathion was more sensitive than the WHO DD for early decreased susceptibility detection.

Edoxaban and the Issue of Drug-Drug Interactions: From Pharmacology to Clinical Practice.

Edoxaban, a direct factor Xa inhibitor, is the latest of the non-vitamin K antagonist oral anticoagulants (NOACs). Despite being marketed later than other NOACs, its use is now spreading in current clinical practice, being indicated for both thromboprophylaxis in patients with non-valvular atrial fibrillation (NVAF) and for the treatment and prevention of venous thromboembolism (VTE). In patients with multiple conditions, the contemporary administration of several drugs can cause relevant drug-drug interactions (DDIs), which can affect drugs' pharmacokinetics and pharmacodynamics. Usually, all the NOACs are considered to have significantly fewer DDIs than vitamin K antagonists; notwithstanding, this is actually not true, all of them are affected by DDIs with drugs that can influence the activity (induction or inhibition) of P-glycoprotein (P-gp) and cytochrome P450 3A4, both responsible for the disposition and metabolism of NOACs to a different extent. In this review/expert opinion, we focused on an extensive report of edoxaban DDIs. All the relevant drugs categories have been examined to report on significant DDIs, discussing the impact on edoxaban pharmacokinetics and pharmacodynamics, and the evidence for dose adjustment. Our analysis found that, despite a restrained number of interactions, some strong inhibitors/inducers of P-gp and drug-metabolising enzymes can affect edoxaban concentration, just as it happens with other NOACs, implying the need for a dose adjustment. However, our analysis of edoxaban DDIs suggests that given the small propensity for interactions of this agent, its use represents an acceptable clinical decision. Still, DDIs can be significant in certain clinical situations and a careful evaluation is always needed when prescribing NOACs.

Validation and clinical application of dried blood spot assay for quantitative assessment of edoxaban in healthy adults.

Aim: Dried blood spot (DBS) is a sampling approach that offers several advantages over plasma and whole blood (WB) sampling, but several factors, such as hematocrit and temperature, can adversely affect quantitation. Methodology & results: In an open-label, three-way crossover study in healthy subjects, we explored the correlation between DBS, WB and plasma samples, and between DBS samples from finger-prick and venipuncture blood for measuring edoxaban and its metabolite M-4 using LC-MS/MS. The methods were validated comprehensively. The incurred sample reanalysis experiments demonstrated quantitation reproducibility in all three matrices. Overall, there was a good correlation (near perfect concordance for edoxaban) among plasma, WB and DBS measurements. M-4 concentrations in DBS and WB were lower than in plasma. Conclusion: These results indicate using DBS may be used as an alternative methodology to measure edoxaban pharmacokinetics.

Preclinical Safety Assessment of a Highly Selective and Potent Dual Small-Molecule Inhibitor of CBP/P300 in Rats and Dogs.

Cyclic adenosine monophosphate-response element (CREB)-binding protein (CBP) and EP300E1A-binding protein (p300) are members of the bromodomain and extraterminal motif (BET) family. These highly homologous proteins have a key role in modulating transcription, including altering the status of chromatin or through interactions with or posttranslational modifications of transcription factors. As CBP and p300 have known roles for stimulating c-Myc oncogenic activity, a small-molecule inhibitor, GNE-781, was developed to selectively and potently inhibit the CBP/p300 bromodomains (BRDs). Genetic models have been challenging to develop due to embryonic lethality arising from germline homozygous mutations in either CBP or P300. Hence, the purpose of this study was to characterize the role of dual inhibition of these proteins in adult rats and dogs. Repeat dose toxicity studies were conducted, and toxicologic and pathologic end points were assessed. GNE-781 was generally tolerated; however, marked effects on thrombopoiesis occurred in both species. Evidence of inhibition of erythroid, granulocytic, and lymphoid cell differentiation was also present, as well as deleterious changes in gastrointestinal and reproductive tissues. These findings are consistent with many preclinical (and clinical) effects reported with BET inhibitors targeting BRD proteins; thus, the current study findings indicate a likely important role for CBP/p300 in stem cell differentiation.

The cognitive cost of reducing relapse to cocaine-seeking with mGlu5 allosteric modulators.

RATIONALE: Cocaine use disorder (CUD) remains difficult to treat with no FDA-approved medications to reduce relapse. Antagonism of metabotropic glutamate receptor 5 (mGlu5) has been demonstrated to decrease cocaine-seeking but may also further compromise cognitive function in long-term cocaine users. OBJECTIVES: Here we assessed the effect of repeated administration of negative or positive allosteric modulators (NAM or PAM) of mGlu5 on both cognitive performance and (context+cue)-primed cocaine-seeking after prolonged abstinence (≥ 45 days). METHODS: Adult male Sprague-Dawley rats underwent 6 days of short-access (1 h/day) and 12 days of long-access (6 h/day) cocaine self-administration. Rats were then trained and tested in a delayed match-to-sample (DMS) task to establish baseline working memory performance over a 5-day block of testing. Next, rats received daily systemic administration of the mGlu5 NAM 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride (MTEP; 3 mg/kg), the mGlu5 PAM 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB; 30 mg/kg) or vehicle prior to DMS testing during a block of 5 days, followed by a 5-day washout DMS testing block. RESULTS: MTEP and CDPPB decreased drug-seeking in response to cocaine-associated cues after prolonged abstinence. However, repeated treatment with MTEP impaired working memory, while CDPPB had no effects on performance. CONCLUSIONS: These results emphasize the relevance of evaluating cognitive function within the context of investigating pharmacotherapies to treat CUD. Further research is needed to determine how two mechanistically different pharmacological compounds can exert the same behavioral effects to reduce cocaine-seeking.

Cost-effectiveness of a fixed combination of netupitant and palonosetron (NEPA) relative to aprepitant plus granisetron (APR + GRAN) for prophylaxis of chemotherapy-induced nausea and vomiting (CINV): a trial-based analysis.

PURPOSE: To assess, from a United States (US) perspective, the cost-effectiveness of chemotherapy-induced nausea and vomiting (CINV) prophylaxis using a single dose of netupitant and palonosetron in a fixed combination (NEPA) versus aprepitant plus granisetron (APR + GRAN), each in combination with dexamethasone, in chemotherapy-naïve patients receiving highly emetogenic chemotherapy (HEC). METHODS: We analyzed patient-level outcomes over a 5-day post-HEC period from a randomized, double-blind, phase 3 clinical trial of NEPA (n = 412) versus APR + GRAN (n = 416). Costs and CINV-related utilities were assigned to each subject using published sources. Parameter uncertainty was addressed via multivariate probabilistic sensitivity analyses (PSA). RESULTS: Compared to APR + GRAN, NEPA resulted in a gain of 0.09 quality-adjusted life-days (QALDs) (4.04 vs 3.95; 95% CI -0.06 to 0.25) and a significant total per-patient cost reduction of $309 ($943 vs $1252; 95% CI $4-$626), due principally to $258 in lower medical costs of CINV-related events ($409 vs $668; 95% CI -$46 to $572) and $45 in lower study drug costs ($531 vs $577). In the PSA, NEPA resulted in lower costs and higher QALD in 86.5% of cases and cost ≤ $25,000 per quality-adjusted life-year gained in 97.8% of cases. CONCLUSIONS: This first-ever economic analysis using patient-level data from a phase 3 trial comparing neurokinin-1 receptor antagonist (NK1 RA) antiemetic regimens suggests that NEPA is highly cost-effective (and in fact cost-saving) versus an aprepitant-based regimen in post-HEC CINV prevention. Actual savings may be higher, as we focused only on the first chemotherapy cycle and omitted the impact of CINV-related chemotherapy discontinuation.

Chronic hepatitis delta: A state-of-the-art review and new therapies.

Chronic delta hepatitis is the most severe form of viral hepatitis affecting nearly 65 million people worldwide. Individuals with this devastating illness are at higher risk for developing cirrhosis and hepatocellular carcinoma. Delta virus is a defective RNA virus that requires hepatitis B surface antigen for propagation in humans. Infection can occur in the form of a co-infection with hepatitis B, which can be self-limiting, vs superinfection in a patient with established hepatitis B infection, which often leads to chronicity in majority of cases. Current noninvasive tools to assess for advanced liver disease have limited utility in delta hepatitis. Guidelines recommend treatment with pegylated interferon, but this is limited to patients with compensated disease and is efficacious in about 30% of those treated. Due to limited treatment options, novel agents are being investigated and include entry, assembly and export inhibitors of viral particles in addition to stimulators of the host immune response. Future clinical trials should take into consideration the interaction of hepatitis B and hepatitis D as suppression of one virus can lead to the activation of the other. Also, surrogate markers of treatment efficacy have been proposed.

Fitness costs of sulfoxaflor resistance in the cotton aphid, Aphis gossypii Glover.

Aphis gossypii Glover is an economically important pest of numerous crops throughout the world. Some field populations of A.gossypii in China have developed moderate level of resistance to sulfoxaflor, a newly released sulfoximine insecticide for management of sap-feeding pests. To evaluate the effect of sulfoxaflor resistance on the fitness cost of A. gossypii, the life history traits of sulfoxaflor-resistant strain (SulR) and an isogenic susceptible strain (SS) were compared using the age-stage, two-sex life table approach. The results showed that the resistant strain had a reduction in fitness (relative fitness = 0.917), along with significantly decreases in longevity, fecundity, net reproductive (R0), mean generation time (T) and gross reproductive rate (GRR). Compared to the susceptible strain, SulR strain showing a shorter developmental duration of each nymph instar stage. Moreover, the adult pre-oviposition period (APOP) and total preoviposition period (TPOP) of SulR strain were also significantly shorter than that of the susceptible strain. Investigation of six development and reproduction related genes indicated that EcR, USP and JHBP were overexpressed in the SulR strain, while the mRNA transcript level of Vg was decreased significantly compared to the susceptible strain. These results suggest that there is a fitness cost associated with sulfoxaflor resistance in A. gossypii and the different expression of EcR, USP, JHBP, and Vg may play very important role in this trade-off.

In vitro assessment of edoxaban anticoagulant effect in pediatric plasma.

INTRODUCTION: Anticoagulant therapy in pediatric patients remains an issue and safer therapies, such as direct oral anticoagulants could overcome the limitations of conventional anticoagulant treatments in this population. Edoxaban, a factor Xa inhibitor, is used for the prevention and treatment of venous thromboembolism. Due to its pharmacokinetic characteristics, edoxaban is a promising candidate molecule for children. This study compared edoxaban in vitro effect in children and adults. MATERIALS AND METHODS: Blood samples were prospectively collected from 87 adults and 97 children (n = 12: <2 year-old; n = 8: 2-4 year-old; n = 9: 5-7 year-old; n = 14: 8-9 year-old; n = 10: 10-13 year-old; n = 15: 14-15 year-old; and n = 29: 16-18 year-old). Plasma samples were supplemented in vitro with edoxaban to a final concentration of 50, 150 or 300 ng/mL, and then edoxaban effect on prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen (Clauss assay), specific anti-factor Xa activity and thrombin generation assay (TGA) (with 5pM tissue factor and 4 nM phospholipids) was evaluated. RESULTS: PT, aPTT, and specific anti-Xa activity exhibited similar dose-dependent responses to edoxaban in the different age groups. The reduction of thrombin peak, the most edoxaban-sensitive TGA parameter, was similar in adults and children, but for the youngest group (<2 year-old) where the peak value reduction (median [Q1-Q3]) was higher than in adults (51% [44-59] versus 40% [32-46], p < 0.01; 74% [63-80] versus 65% [58-70], p < 0.05; and 84% [73-88] versus 76% [70-80], p < 0.05 for 50, 150 and 300 ng/mL edoxaban, respectively). CONCLUSIONS: Edoxaban in vitro effect are comparable in children and adults except in the <2-year-old group.

Quantitative assessment of oligomeric amyloid ß peptide binding to α7 nicotinic receptor.

BACKGROUND AND PURPOSE: Progressive dysfunction of cholinergic transmission is a well-known characteristic of Alzheimer's disease (AD). Amyloid ß (Aß) peptide oligomers are known to play a central role in AD and are suggested to impair the function of the cholinergic nicotinic ACh receptor α7 (α7nAChR). However, the mechanism underlying the effect of Aß on α7nAChR function is not fully understood, limiting the therapeutic exploration of this observation in AD. Here, we aimed to detect and characterize Aß binding to α7nAChR, including the possibility of interfering with this interaction for therapeutic purposes. EXPERIMENTAL APPROACH: We developed a specific and quantitative time-resolved FRET (TR-FRET)-based binding assay for Aß to α7nAChR and pharmacologically characterized this interaction. KEY RESULTS: We demonstrated specific and high-affinity (low nanomolar) binding of Aß to the orthosteric binding site of α7nAChR. Aß binding was prevented and reversed by the well-characterized orthosteric ligands of α7nAChR (epibatidine, α-bungarotoxin, methylylcaconitine, PNU-282987, S24795, and EVP6124) and by the type II positive allosteric modulator (PAM) PNU-120596 but not by the type I PAM NS1738. CONCLUSIONS AND IMPLICATIONS: Our TR-FRET Aß binding assay demonstrates for the first time the specific binding of Aß to α7nAChR, which will be a crucial tool for the development, testing, and selection of a novel generation of AD drug candidates targeting Aß/α7nAChR complexes with high specificity and fewer side effects compared to currently approved α7nAChR drugs. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.