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OBJECTIVE: To examine the association between missed CMS Star Ratings quality measures for medication adherence over 3 years for diabetes, hypertension, and hyperlipidemia medications (9 measures) and health care utilization and relative costs. STUDY DESIGN: Retrospective cohort study. METHODS: The study examined eligible patients who qualified for the diabetes, statin, and renin-angiotensin system antagonist medication adherence measures in 2018, 2019, and 2020 and were continuously enrolled in a Medicare Advantage prescription drug plan from 2017 through 2021. Atotal of 103,900 patients were divided into 4 groups based on the number of adherence measures missed (3 medication classes over 3 years): (1) missed 0 measures, (2) missed 1measure, (3) missed 2 or 3 measures, and (4) missed 4 or more measures. To achieve a quality measure, patients had to meet the Pharmacy Quality Alliance 80% threshold of proportion of days covered during the calendar year. RESULTS: The mean age of the cohort was 71.1 years, and 49.9% were female. Compared with patients who missed 0 of 9 adherence measures, those who missed 1 measure, 2 or 3 measures, and 4 or more measures experienced 12% to 26%, 22% to 42%, and 24% to 50% increased risks, respectively, of all-cause and diabetes-related inpatient stays and all-cause and diabetes-related emergency department visits (allPvalues<.01). Additionally, patients who missed 1, 2 or 3, and 4 or more adherence measures experienced 14%, 19%, and 20% higher monthly medical costs, respectively. CONCLUSIONS: Missing Star Ratings quality measures for medication adherence was associated with an increased likelihood of health care resource utilization and increased costs for patients taking medications to treat diabetes, hypertension, and hyperlipidemia. [ABSTRACT FROM AUTHOR]

The pursuit of synthetic receptors with high binding affinities has long been a central focus in supramolecular chemistry, driven by their significant practical relevance in various fields. Despite the numerous synthetic receptors that have been developed, most exhibit binding affinities in the micromolar range or lower. Only a few exceptional receptors achieve binding affinities exceeding 109 M−1, and their substrate scopes remain rather limited. In this context, we introduce SC[5]A, a conjugated corral‐shaped macrocycle functionalized with ten sulfate groups. Owing to its deep one‐dimensional confined hydrophobic cavity and multiple sulfate groups, SC[5]A displays an extraordinarily high binding strength of up to 1011 M−1 towards several size‐matched, rod‐shaped organic dications in water. Besides, its conformation exhibits good adaptability, allowing it to encapsulate a wide range of other guests with diverse molecular sizes, shapes, and functionalities, exhibiting relatively strong affinities (Ka=106–108 M−1). Additionally, we've explored the preliminary application of SC[5]A in alleviating blood coagulation induced by hexadimethrine bromide in vitro and in vivo. Therefore, the combination of ultrahigh binding affinities (towards complementary guests) and adaptive recognition capability (towards a wide range of functional guests) of SC[5]A positions it as exceptionally valuable for numerous practical applications. [ABSTRACT FROM AUTHOR]

Simple Summary: Recent studies have shown a negative association between prior antibiotic use and response rate to immune checkpoint inhibitors (ICIs) in solid tumors, including gynecologic cancers. In this study, use of antibiotics for >14 days prior to ICI treatment was associated with reduced survival. Restricted use and adequate duration and spectrum of antibiotics should be considered when treating patients with recurrent gynecologic cancer. The various response rates to ICI could be attributed to gut dysbiosis. A study of gut microbiota may address the ICI response in the future. Purpose: Antibiotic use preceding immune checkpoint inhibitor (ICI) treatment has been associated with a decreased efficacy of ICI in solid tumors. In this study, we evaluated the effect of antibiotic use before ICI therapy on oncological outcomes. Methods: We examined patients with recurrent gynecologic malignancies at two academic institutions. The clinical data, including antibiotic use within 60 days of ICI initiation, type of antibiotics, reasons for antibiotic use, body mass index, tumor site, chemotherapy-free interval, prior history of radiotherapy, disease control rate (DCR), and overall survival (OS), were assessed. Results: Of 215 patients, 22.9% (n = 47) received antibiotics before ICI treatment. The most common cancer was ovarian (52.1%, n = 112), followed by cervical (24.7%, n = 53) and endometrial (16.7%, n = 36). When we divided the cohort based on antibiotic use before ICIs, there were no significant differences in the DCR and baseline characteristics between the two groups. On multivariate analyses, the variables associated with poor OS were previous use of antibiotics for a cumulative duration of >14 days (HR 2.286, 95% CI 1.210–4.318; p = 0.011); Eastern Cooperative Oncology Group 2 or 3 (HR 4.677, 95% CI 2.497–8.762; p < 0.001); and chemotherapy-free interval of <6 months (HR 2.007, 95% CI 1.055–3.819; p = 0.034). Conclusion: Prior use of antibiotics for a cumulative duration of >14 days was associated with reduced survival in recurrent gynecologic malignancies. [ABSTRACT FROM AUTHOR]

Background and Objective: Polypharmacy is common in older adults, particularly among those living in long-term care facilities. This condition represents a marker of clinical complexity and might directly affect the immunological response. However, there are limited data on the association of polypharmacy with vaccine immunogenicity. This study evaluated the immune response to anti-SARS-CoV-2 vaccines in older residents of long-term care facilities as a function of the number of medications used. Methods: In 478 long-term care facility residents participating in the GeroCovid Vax study, we assessed SARS-CoV-2 trimeric S IgG levels through chemiluminescent assays before the vaccination and after 2, 6, and 12 months. A booster dose was administered between 6- and 12-month assessments. Sociodemographic information and data on chronic diseases and medications were derived from medical records. Based on the number of daily medications, residents were classified into the no polypharmacy (zero to four medications), polypharmacy (five to nine medications), and hyperpolypharmacy (ten or more medications) groups. Results: In the sample (mean age 82.1 years, 69.2% female), 200 (41.8%) residents were taking five or fewer medications/day (no polypharmacy), 229 (47.9%) had polypharmacy, and 49 (10.3%) had hyperpolypharmacy. Using linear mixed models adjusted for potential confounders, we found that hyperpolypharmacy was associated with a steeper antibody decline after 6 months from the first vaccine dose administration (β = − 0.29, 95% confidence interval − 0.54, − 0.03, p = 0.03) than no polypharmacy, while no significant differences were observed at 12 months. Conclusions: The humoral immune response to SARS-CoV-2 vaccination of older residents showed only slight changes as a function of the number of medications taken. Although it seemed less durable among older residents with hyperpolypharmacy, the booster dose administration equalized such a difference. [ABSTRACT FROM AUTHOR]

Parasitic nematodes infect billions of people and are mainly controlled by anthelmintic mass drug administration (MDA). While there are growing efforts to better understand mechanisms of anthelmintic resistance in human and animal populations, it is unclear how resistance mechanisms that alter susceptibility to one drug affect the interactions and efficacy of drugs used in combination. Mutations that alter drug permeability across primary nematode barriers have been identified as potential resistance mechanisms using the model nematode Caenorhabditis elegans. We leveraged high-throughput assays in this model system to measure altered anthelmintic susceptibility in response to genetic perturbations of potential cuticular, amphidial, and alimentary routes of drug entry. Mutations in genes associated with these tissue barriers differentially altered susceptibility to the major anthelmintic classes (macrocyclic lactones, benzimidazoles, and nicotinic acetylcholine receptor agonists) as measured by animal development. We investigated two-way anthelmintic interactions across C. elegans genetic backgrounds that confer resistance or hypersensitivity to one or more drugs. We observe that genetic perturbations that alter susceptibility to a single drug can shift the drug interaction landscape and lead to the appearance of novel synergistic and antagonistic interactions. This work establishes a framework for investigating combinatorial therapies in model nematodes that can potentially be translated to amenable parasite species. Author summary: Parasitic nematodes (roundworms) infect billions of people and animals worldwide and are mainly treated with a small number of anthelmintic drugs. The threat of drug resistance and the suboptimal nature of some single-drug treatments have prompted greater exploration of combinatorial drug regimens. However, we know very little about how these drugs may interact in exerting their anthelmintic effects or how these interactions are altered in the backdrop of resistance. We used the model nematode Caenorhabditis elegans to measure drug interactions across a panel of mutant strains that alter potential pathways of drug entry. Mutations in these pathways altered susceptibility to the major anthelmintic classes as measured by animal development. When drugs were administered in pairwise combinations, we observed that some mutations affecting single-drug susceptibility led to shifts in baseline drug antagonism and the appearance of drug synergies. This framework can potentially be translated to investigate drug interactions in amenable parasite species in the future. [ABSTRACT FROM AUTHOR]

Purpose: Dietary fibers and hypoglycemic drugs can be used concomitantly in the treatment of diabetes mellitus. We aimed to perform this review in order to evaluate whether scientific evidence is available regarding the interaction between these components and whether these interactions alter drug absorption. Methods: We conducted a search of the literature for controlled clinical trials that evaluated the occurrence and clinical relevance of interactions between dietary fibers and hypoglycemic drugs. Six databases were searched from inception to April 20, 2020 and trials were eligible for inclusion if they measured changes in drug absorption parameters. Results: In three studies, there were interactions between dietary fibers and hypoglycemic drugs, causing alterations in drug absorption. The other two studies had no significant changes in absorption pharmacokinetic parameters. Conclusions: The physicochemical characteristics of the dietary fiber used, the chemical structure of the drug, and the pharmaceutical form administered are determining factors for the occurrence of alterations in drug absorption. [ABSTRACT FROM AUTHOR]

Introduction. Isobolographic analysis is the preferred method of assessment of pharmacodynamic interactions occurring among drugs administered in mixture in both pre-clinical and clinical studies. Despite its mathematical complexity, rigorous preliminary conditions and various prerequisites to be met, it assesses the pharmacodynamic interactions, classifying them as additive, antagonistic, synergistic or indifferent in nature. These interactions are usually plotted in the Cartesian system of coordinates forming isobolograms. The strength (power) of interactions is calculated and presented as an interaction index. Conclusion. This report provides basic information on the isobolographic analysis used experimentally in preclinical conditions indicating the underestimation of this valuable method in pharmacology and toxicology. [ABSTRACT FROM AUTHOR]

Background Older adults are recommended to receive influenza vaccination annually, and many use statins. Statins have immunomodulatory properties that might modify influenza vaccine effectiveness (VE) and alter influenza infection risk. Methods Using the test-negative design and linked laboratory and health administrative databases in Ontario, Canada, we estimated VE against laboratory-confirmed influenza among community-dwelling statin users and nonusers aged ≥66 years during the 2010–2011 to 2018–2019 influenza seasons. We also estimated the odds ratio for influenza infection comparing statin users and nonusers by vaccination status. Results Among persons tested for influenza across the 9 seasons, 54 243 had continuous statin exposure before testing and 48 469 were deemed unexposed. The VE against laboratory-confirmed influenza was similar between statin users and nonusers (17% [95% confidence interval, 13%–20%] and 17% [13%–21%] respectively; test for interaction, P =.87). In both vaccinated and unvaccinated persons, statin users had higher odds of laboratory-confirmed influenza than nonusers (odds ratios for vaccinated and unvaccinated persons 1.15 [95% confidence interval, 1.10–1.21] and 1.15 [1.10–1.20], respectively). These findings were consistent by mean daily dose and statin type. VE did not differ between users and nonusers of other cardiovascular drugs, except for β-blockers. We did not observe that vaccinated and unvaccinated users of these drugs had increased odds of influenza, except for unvaccinated β-blocker users. Conclusions Influenza VE did not differ between statin users and nonusers. Statin use was associated with increased odds of laboratory-confirmed influenza in vaccinated and unvaccinated persons, but these associations might be affected by residual confounding. [ABSTRACT FROM AUTHOR]

ObjectivesTo evaluate pharmacokinetics and pharmacogenetics of contraceptive implant progestin concentrations in HIV-positive women initiating efavirenz (EFV)-containing or nevirapine (NVP)-containing antiretroviral therapy (ART).DesignWe analyzed stored samples from women self-reporting implant use in the Partners PrEP Study.MethodsPlasma samples collected every 6 months were analyzed for levonorgestrel and etonogestrel concentrations. Progestin concentrations from samples collected after ART initiation were compared with pre-ART concentrations for intraindividual comparisons. We used adjusted linear mixed models to compare hormone concentrations between individuals on EFV and NVP to a no ART group. We then evaluated whether possessing certain alleles with known or possible influences on EFV, NVP, or progestin metabolism were associated with changes in progestin concentrations or modified the association between ART use and progestin concentrations.ResultsOur analysis included 11 women who initiated EFV, 13 who initiated NVP, and 36 who remained ART-naive. In the EFV group, the adjusted geometric mean ratio (aGMR) of levonorgestrel was 0.39 [90% confidence intervals (0.31, 0.49); P

Pancreatic cancer remains one of the most lethal malignancies worldwide. The combination of the first-line standard agent gemcitabine (GEM) with the molecular-targeted drug erlotinib (Er) has emerged as a promising strategy for pancreatic cancer treatment. However, the clinical benefit from this combination is still far from satisfactory due to the unfavorable drug antagonism and the fibrotic tumor microenvironment. Herein, we propose a membrane-camouflaged dual stimuli-responsive delivery system for the co-delivery of GEM and Er into pancreatic cancer cells and tissues to block the antagonism, as well as reshapes profibrotic tumor microenvironment via simultaneous delivery of small interference RNA (siRNA) for synergistic pancreatic cancer treatment. This “all-in-one” delivery system exhibits sensitive GSH and pH-dependent drug release profiles and enhances the inhibitory effects on the proliferation and migration of tumor cells in vitro. Excitingly, the systemic injection of such a biomimetic drug co-delivery system not only resulted in superior inhibitory effects against orthotopic pancreatic tumor and patient-derived tumor (PDX), but also greatly extended the survival rate of tumor-bearing mice. Our findings provide a promising therapeutic strategy against pancreatic cancer through the enhanced synergistic effect of target therapy, chemotherapy and anti-fibrotic therapy, which represents an appealing way for pancreatic cancer treatment.

Combination therapies have become increasingly researched and used in the treatment and management of complex diseases due to their ability to increase the chances for better efficacy and decreased toxicity. To evaluate drug combinations in drug development, pharmacokinetic and pharmacodynamic interactions between drugs in combination can be quantified using mathematical models; however, it can be difficult to deduce which models to use and how to use them to aid in clinical trial simulations to simulate the effect of a drug combination. This review paper aims to provide an overview of the various methods used to evaluate combination drug interaction for use in clinical trial development and a practical guideline on how combination modeling can be used in the settings of clinical trials. [ABSTRACT FROM AUTHOR]

Anticholinergic burden tools have relevant pharmacological gaps that may explain their limited predictive ability for clinical outcomes. The aim of this study was to provide a universal pharmacological-based list of drugs with their documented affinity for muscarinic receptors. A comprehensive literature review was performed to identify the anticholinergic burden tools. Drugs included in these instruments were searched in four pharmacological databases, and the investigation was supplemented with PubMed. The evidence regarding the potential antagonism of the five muscarinic receptors of each drug was assessed. The proportion of drugs included in the tools with an affinity for muscarinic receptors was evaluated. A universal list of drugs with anticholinergic activity was developed based on their documented affinity for the different subtypes of muscarinic receptors and their ability to cross the blood-brain barrier. A total of 23 tools were identified, including 304 different drugs. Only 48.68%, 47.70%, 48.03%, 43.75%, and 42.76% of the drugs had an affinity to the M1, M2, M3, M4, and M5 receptor, respectively, reported in any pharmacological database. The proportion of drugs with confirmed antagonism varied among the tools (36.8% to 100%). A universal pharmacological-based list of 133 drugs is presented. It should be further validated in different clinical settings. [ABSTRACT FROM AUTHOR]

Selection of an effective drug combination to immobilise African lions (Panthera leo) requires balancing immobilisation effectiveness with potential side effects. We compared the immobilisation effectiveness and changes to physiological variables induced by three drug combinations used for free-ranging African lions. The lions (12 animals per drug combination) were immobilised with tiletamine-zolazepam-medetomidine (TZM), ketamine-medetomidine (KM) or ketamine-butorphanol-medetomidine (KBM). Induction, immobilisation, and recovery were timed, evaluated using a scoring system, and physiological variables were monitored. The drugs used for immobilisation were antagonised with atipamezole and naltrexone. The quality of induction was rated as excellent for all drug combinations and induction times (mean ± SD) did not differ between the groups (10.54 ± 2.67 min for TZM, 10.49 ± 2.63 min for KM, and 11.11 ± 2.91 min for KBM). Immobilisation depth was similar over the immobilisation period in the TZM and KBM groups, and initially light, progressing to deeper in lions administered KM. Heart rate, respiratory rate and peripheral arterial haemoglobin saturation with oxygen were within the expected range for healthy, awake lions in all groups. All lions were severely hypertensive and hyperthermic throughout the immobilisation. Following antagonism of immobilising drugs, lions immobilised with KM and KBM recovered to walking sooner than those immobilised with TZM, at 15.29 ± 10.68 min, 10.88 ± 4.29 min and 29.73 ± 14.46 min, respectively. Only one lion in the KBM group exhibited ataxia during recovery compared to five and four lions in the TZM and KM groups, respectively. All three drug combinations provided smooth inductions and effective immobilisations but resulted in hypertension. KBM had an advantage of allowing for shorter, less ataxic recoveries. [ABSTRACT FROM AUTHOR]

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca's large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.

Due to the lack of safe, effective, and gene-targeted delivery technology. In this study, we have prepared nanobubbles loaded PDLIM5 siRNA (PDLIM5siRNA-NBs) to investigate the transfection efficiency and their antagonism in drug resistance in combination with ultrasound irradiation for non-small-cell lung cancer (NSCLC). Research results show that the PDLIM5 siRNA are effectively bound to the shell of NBs with a mean diameter of 191.6 ± 0.50 nm and a Zeta potential of 11.8 ± 0.68 mV. And the ultrasonic imaging indicated that the PDLIM5 siRNA NBs maintain the same signals as the microbubbles (SonoVue). Under the optimized conditions of 0.5W/m² ultrasound intensity and 1 min irradiation duration, the highest transfection efficiency of PC9GR cells was 90.23 ± 1.45%, which resulted in the inhibition of PDLIM5 mRNA and protein expression. More importantly, the anti-tumor effect of fabricated PDLIM5siRNA-NBs with the help of ultrasound irradiation has been demonstrated to significantly inhibit tumor cell growth and promote apoptosis. Therefore, NBs carrying PDLIM5siRNA may have the potential to act as gene vectors combined with ultrasound irradiation to antagonize drug resistance for NSCLC. [ABSTRACT FROM AUTHOR]

Abstract Background Moderate to severe acute pancreatitis (AP) is associated with a high rate of complications and increased mortality, yet no targeted pharmacologic treatment currently exists. As pain is a dominant symptom in AP, patients are exposed to excess levels of both endo- and exogenous opioids, which may have harmful effects on the course of AP. This trial investigates the effects of the peripherally acting μ-opioid receptor antagonist (PAMORA) methylnaltrexone on disease severity and clinical outcomes in patients with moderate to severe AP. Methods PAMORA-AP is a multicentre, investigator-initiated, double-blind, randomised, placebo-controlled, interventional trial, which will be conducted at four referral centres for acute pancreatitis in Denmark. Ninety patients with early-onset AP (pain onset within 48 h) as well as predicted moderate to severe disease (two or more systemic inflammatory response syndrome criteria upon admission) will be prospectively included. Subsequently, participants will be randomised (1:1) to intravenous treatment with either methylnaltrexone or matching placebo (Ringer’s lactate) during 5 days of admission. The primary endpoint will be the group difference in disease severity as defined and measured by the Pancreatitis Activity Scoring System (PASS) score 48 h after randomisation. Secondary endpoints include daily PASS scores; disease severity according to the Atlanta classification; quantification of need for analgesics, nutritional support, intravenous fluid resuscitation and antibiotics; duration of hospital admissions, readmission rates and mortality. Pain intensity and gut function will be self-reported using validated questionnaires. Exploratory endpoints include circulating levels of pro-and anti-inflammatory markers, polyethylene glycol recovery from the urine, circulating levels of blood markers of intestinal permeability, the prevalence of pancreatic complications on computed tomography (CT) scans, and colon transit time assessed using a CT-based radiopaque marker method. Discussion This trial aims to evaluate the PAMORA methylnaltrexone as a novel targeted pharmacotherapy in patients with moderate to severe AP with the potential benefit of improved patient outcomes. Trial registration ClinicalTrials.gov NCT04743570 . Registered on 28 January 2021. EudraCT 2020-002313-18.

Pharmacological studies have shown that some traditional Chinese medicines (TCMs) have applications in the treatment of Alzheimer's disease (AD). Morinda officinalis How. (MO) is a TCM with a long history and is widely used to tonify kidney Yang. In vitro and in vivo experiments have suggested that MO contains various effective pharmaceutical components and chemicals, including oligosaccharides, anthraquinones, iridoids, flavonoids, amino acids, and trace elements, conferring MO with anti-inflammatory and antioxidant properties. Neuroinflammation and oxidative stress are undoubtedly hallmarks of neurodegeneration, contributing to AD progression. In this mini-review, we summarize the molecular mechanisms, structure-activity relationships, and potential synergistic and antagonistic effects of active components in MO. This discussion highlights the roles of these active components, such as oligosaccharides, anthraquinones, and iridoid glycosides, in the treatment of AD via anti-inflammatory and antioxidant mechanisms, providing a scientific basis for further utilization of MO. [ABSTRACT FROM AUTHOR]

Pancreatic cancer remains one of the most lethal malignancies worldwide. The combination of the first-line standard agent gemcitabine (GEM) with the molecular-targeted drug erlotinib (Er) has emerged as a promising strategy for pancreatic cancer treatment. However, the clinical benefit from this combination is still far from satisfactory due to the unfavorable drug antagonism and the fibrotic tumor microenvironment. Herein, we propose a membrane-camouflaged dual stimuli-responsive delivery system for the co-delivery of GEM and Er into pancreatic cancer cells and tissues to block the antagonism, as well as reshapes profibrotic tumor microenvironment via simultaneous delivery of small interference RNA (siRNA) for synergistic pancreatic cancer treatment. This "all-in-one" delivery system exhibits sensitive GSH and pH-dependent drug release profiles and enhances the inhibitory effects on the proliferation and migration of tumor cells in vitro. Excitingly, the systemic injection of such a biomimetic drug co-delivery system not only resulted in superior inhibitory effects against orthotopic pancreatic tumor and patient-derived tumor (PDX), but also greatly extended the survival rate of tumor-bearing mice. Our findings provide a promising therapeutic strategy against pancreatic cancer through the enhanced synergistic effect of target therapy, chemotherapy and anti-fibrotic therapy, which represents an appealing way for pancreatic cancer treatment. A membrane-camouflaged dual stimuli-responsive delivery system was proposed for the co-delivery of gemcitabine, erlotinib and small interference RNA (siIRAK4) for synergistic pancreatic cancer treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Most aggressive lymphomas are treated with combination chemotherapy, commonly as multiple cycles of concurrent drug administration. Concurrent administration is in theory optimal when combination therapies have synergistic (more than additive) drug interactions. We investigated pharmacodynamic interactions in the standard 4-drug "CHOP" regimen in peripheral T-cell lymphoma (PTCL) cell lines and found that CHOP consistently exhibits antagonism and not synergy. We tested whether staggered treatment schedules could improve tumor cell kill by avoiding antagonism, using in vitro models of concurrent or staggered treatments. Surprisingly, we observed that tumor cell kill is maximized by concurrent drug administration despite antagonistic drug-drug interactions. We propose that an ultrasensitive dose response, as described in radiology by the linear-quadratic (LQ) model, can reconcile these seemingly contradictory experimental observations. The LQ model describes the relationship between cell survival and dose, and in radiology has identified scenarios favoring hypofractionated radiotherapy-the administration of fewer large doses rather than multiple smaller doses. Specifically, hypofractionated treatment can be favored when cells require an accumulation of DNA damage, rather than a "single hit," to die. By adapting the LQ model to combination chemotherapy and accounting for tumor heterogeneity, we find that tumor cell kill is maximized by concurrent administration of multiple drugs, even when chemotherapies have antagonistic interactions. Thus, our study identifies a new mechanism by which combination chemotherapy can be clinically beneficial that is not contingent on positive drug-drug interactions., (©2024 American Association for Cancer Research.)

We conducted a study in Japan using terror management theory (N = 115) to examine these predictions: first, personal morality salience (MS) would increase antagonism against worldview-threatening others; second, priming to reinforce collective identity would be more effective to strengthen participants' sense of security and thus lower antagonism toward an in-group critic under personal MS than collective MS. The results revealed a significant interaction between MS types and identity priming. Participants were most tolerant toward worldview-threatening others upon awareness of a crisis threatening the group providing them collective identity. These findings provide insight into understanding individual behaviors during social unrest. [ABSTRACT FROM AUTHOR]

• Successful combination therapies are determined by drug-drug interactions (DDIs). • We propose a graph theory to characterize how drugs work together in a network. • It combines interdisciplinary elements to disentangle and interrogate DDIs. • We develop a generic tool to infer personalized and context-specific DDI networks. The simultaneous use of multiple medications causes drug–drug interactions (DDI) that impact therapeutic efficacy. Here, we argue that graph theory, in conjunction with game theory and ecosystem theory, can address this issue. We treat the coexistence of multiple drugs as a system in which DDI is modeled by game theory. We develop an ordinary differential equation model to characterize how the concentration of a drug changes as a result of its independent capacity and the dependent influence of other drugs through the metabolic response of the host. We coalesce all drugs into personalized and context-specific networks, which can reveal key DDI determinants of therapeutical efficacy. Our model can quantify drug synergy and antagonism and test the translational success of combination therapies to the clinic. [ABSTRACT FROM AUTHOR]

Synergistic drug combinations could achieve increase of therapeutic efficacy and reduce risk of drug resistance and toxicity via targeting multiple genes, signaling pathways or mutations simultaneously. Comparatively antagonistic drug combinations decrease the therapeutic efficacy of co-prescribed drugs and even occasionally cause severe adverse effects. The existing computational methods generally treat drug synergy as binary classification with drug antagonism neglected, and the training data are so small as to riskily lead to model overfitting. In this study, we propose a self-contained machine learning framework to predict drug synergy, antagonism and additivity simultaneously. This framework trains a three-class l2-regularized logistic regression model on large-scale drug-drug interactions with therapeutic efficacy from DrugBank. Moreover, the proposed framework represents drug pairs via simple profiles of drug-targeted genes and cellular processes so as to well explain the molecular mechanism behind drug-drug interactions and reduce data complexity. Cross validation and independent test show that the proposed framework achieves encouraging performance and outperforms the existing computational methods. We further employ the proposed framework to predict the synergy and antagonism of known cancer-associated drug combinations and analyse the molecular mechanisms via GO and pathways enrichment analyses. The predictions and unravelled mechanisms potentially provide insights into for drug combinatorial therapies of cancers. [ABSTRACT FROM AUTHOR]

Cynanchum otophyllum C.K.Schneid.PI.Wilson, commonly referred as "Qingyangshen" (QYS), is a traditional folk medicine from Yunnan, renowned for its efficacy in neurological and psychiatric disorders. Glycosides isolated from QYS have shown promise in alleviating epilepsy, however, mechanisms of action and specific molecular targets remain to be elucidated. The study aimed to evaluate the anticonvulsant effects of Qingyangshen glycosides M1 (M1), a C 21 steroidal glycoside from QYS, on pentylenetetrazol (PTZ)-induced convulsions in zebrafish (Danio rerio), and its neuroprotective effect on Glutamate (Glu)-induced damage to PC12 cells, and importantly to identify its potential molecular targets. To evaluate anticonvulsant activity of M1, 7 days-post-fertilization (7-dpf) animals were pretreated (by immersion) and then exposed to PTZ (10 mM) solution. Furthermore, Glu-induced PC12 cell damage was employed to investigate the neuroprotective and anti-apoptotic capacity. Cells were pretreated with various concentrations of M1 (0–10 μM) for 12 h and then co-treated with Glu (15 mM) for an additional 24 h. The cell viability, apoptosis rate and apoptosis-related proteins (p-PI3K, PI3K, Akt, p-Akt, CREB, p-CREB, BDNF, Bax and Bcl-2) were measured using CCK-8, annexin V/PI and Western blot assays. To model the expected interaction between M1 and candidate cannabinoid receptor type 1 (CB 1 R), ERK phosphorylation, molecular docking, and drug affinity responsive target stability (DARTS) techniques were employed. Finally, CB 1 R antagonist Rimonabant (Rim) was validated by co-administration in both zebrafish and cells to confirm the requirement of CB 1 R for M1 efficacy. At a concentration of 400 μM, M1 dramatically reversed PTZ-induced convulsive-like behaviors in zebrafish, as evidenced by a significant reduction in locomotor activity. In the context of Glu-induced cytotoxicity, M1 (10 μM) demonstrated a notable increase in cell viability and suppressed apoptosis through modulation of the Bax/Bcl-2 ratio and activation of the PI3K/Akt/CREB/BDNF signaling axis. These effects were facilitated through CB 1 R activation. In contrast, Rim dampened the beneficial activities of M1 as a cannabinoid agonist. These results demonstrated that M1 as a potential CB 1 R activator, exhibiting anticonvulsive effects in a PTZ-induced zebrafish model and neuroprotective properties via the PI3K/Akt/CREB/BDNF signaling axis in a Glu-induced PC12 cell injury model. Notably, the observed seizure relief attenuated by CB 1 R chemical antagonism. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Essential oils (EOs), derived from aromatic plants, exhibit properties beneficial to health, such as anti-inflammatory, anti-oxidative, antidiabetic, and antiaging effects. However, the effect of EOs and their interaction in binary combinations against tyrosinase is not yet known. Objective: To evaluate the underlying mechanisms of EOs and their interaction in binary combinations against tyrosinas. Design: We explored to investigate the inhibitory effect of 65 EOs and the interaction among cinnamon, bay, and magnolia officinalis in their binary combinations against tyrosinase. In addition, the main constituents of cinnamon, bay, and magnolia officinalis were analyzed by gas chromatography--mass spectrometry (GC--MS). Results: The results showed that the most potent EOs against tyrosinase were cinnamon, bay, and magnolia officinalis with IC50 values of 25.7, 30.8, and 61.9 µg/mL, respectively. Moreover, the inhibitory mechanism and kinetics studies revealed that cinnamon and bay were reversible and competitive-type inhibitors, and magnolia officinalis was a reversible and mixed-type inhibitor. In addition, these results, assessed in mixtures of three binary combinations, indicated that the combination of cinnamon with bay at different dose and at dose ratio had a strong antagonistic effect against tyrosinase. Magnolia officinalis combined with cinnamon or bay experienced both antagonistic and synergistic effect in anti-tyrosinase activity. Conclusion: It is revealed that natural EOs would be promising to be effective anti-tyrosinase agents, and binary combinations of cinnamon, bay, and magnolia officinalis might not have synergistic effects on tyrosinase under certain condition. [ABSTRACT FROM AUTHOR]

Interactions among drugs play a critical role in the killing efficacy of multi-drug treatments. Recent advances in theory and experiment for three-drug interactions enable the search for emergent interactions-ones not predictable from pairwise interactions. Previous work has shown it is easier to detect synergies and antagonisms among pairwise interactions when a rescaling method is applied to the interaction metric. However, no study has carefully examined whether new types of normalization might be needed for emergence. Here, we propose several rescaling methods for enhancing the classification of the higher order drug interactions based on our conceptual framework. To choose the rescaling that best separates synergism, antagonism and additivity, we conducted bacterial growth experiments in the presence of single, pairwise and triple-drug combinations among 14 antibiotics. We found one of our rescaling methods is far better at distinguishing synergistic and antagonistic emergent interactions than any of the other methods. Using our new method, we find around 50% of emergent interactions are additive, much less than previous reports of greater than 90% additivity. We conclude that higher order emergent interactions are much more common than previously believed, and we argue these findings for drugs suggest that appropriate rescaling is crucial to infer higher order interactions.

Background: Moderate to severe acute pancreatitis (AP) is associated with a high rate of complications and increased mortality, yet no targeted pharmacologic treatment currently exists. As pain is a dominant symptom in AP, patients are exposed to excess levels of both endo- and exogenous opioids, which may have harmful effects on the course of AP. This trial investigates the effects of the peripherally acting μ-opioid receptor antagonist (PAMORA) methylnaltrexone on disease severity and clinical outcomes in patients with moderate to severe AP.Methods: PAMORA-AP is a multicentre, investigator-initiated, double-blind, randomised, placebo-controlled, interventional trial, which will be conducted at four referral centres for acute pancreatitis in Denmark. Ninety patients with early-onset AP (pain onset within 48 h) as well as predicted moderate to severe disease (two or more systemic inflammatory response syndrome criteria upon admission) will be prospectively included. Subsequently, participants will be randomised (1:1) to intravenous treatment with either methylnaltrexone or matching placebo (Ringer's lactate) during 5 days of admission. The primary endpoint will be the group difference in disease severity as defined and measured by the Pancreatitis Activity Scoring System (PASS) score 48 h after randomisation. Secondary endpoints include daily PASS scores; disease severity according to the Atlanta classification; quantification of need for analgesics, nutritional support, intravenous fluid resuscitation and antibiotics; duration of hospital admissions, readmission rates and mortality. Pain intensity and gut function will be self-reported using validated questionnaires. Exploratory endpoints include circulating levels of pro-and anti-inflammatory markers, polyethylene glycol recovery from the urine, circulating levels of blood markers of intestinal permeability, the prevalence of pancreatic complications on computed tomography (CT) scans, and colon transit time assessed using a CT-based radiopaque marker method.Discussion: This trial aims to evaluate the PAMORA methylnaltrexone as a novel targeted pharmacotherapy in patients with moderate to severe AP with the potential benefit of improved patient outcomes.Trial Registration: ClinicalTrials.gov NCT04743570 . Registered on 28 January 2021. EudraCT 2020-002313-18. [ABSTRACT FROM AUTHOR]

Candida auris is an emerging and drug‐resistant pathogen. Drug combination is a promising approach against such pathogens. This study was conducted to provide an overview of all the studied drug combinations against C. auris. Relevant articles reporting results of any drug/non‐drug combinations against C. auris were found by a systematic search in PubMed, Scopus and Web of Science (ISI), and in Google Scholar up to 1 October 2020. From 187 articles retrieved in the primary search, 23 met the inclusion criteria. In total, 124 different combinations including antifungal with antifungal (45), antifungal with other antimicrobials (11), antifungal with non‐antimicrobials (32), antifungal with natural compounds (25) and between natural compounds (11) have been reported. Complete or partial synergistic effects have been reported for 3 out of 45 (6.67%) combinations of two antifungal agents, 8 out of 11 (72.73%) combinations involving antifungal agents and antimicrobials, 15 out of 32 (46.88%) of combinations between antifungal agents with non‐antimicrobials, 16 out of 25 (64%) of combinations involving antifungal agents and natural compounds, and 3 out of 11 (22.27%) of combinations involving multiple natural compounds. Antagonistic interactions have been reported for 1 out of 32 (3.13%) and 8 out of 25 (32%) of combinations between antifungal drugs with non‐antimicrobials and with natural compounds, respectively. Different drugs/compounds could potentiate the activity of antifungal drugs using this approach. However, despite the availability of this promising initial data, many more studies will be required to elucidate whether favourable interactions observed in vitro might translate into tangible clinical benefits. [ABSTRACT FROM AUTHOR]

Objectives: To determine the antimicrobial effect of Thujaorientalis (TO) and ciprofloxacin alone against Escherichia Coli (E.Coli). To compare the combined antimicrobial effect of TO and ciprofloxacin against E. Coli. Study Design: Laboratory experimental study. Place and Duration of Study: This in vitro study was performed at Khyber Girls Medical College, Peshawar, from Jan to Jul 2018. Methodology: Antibacterial activity of TO extracts alone and in combination with ciprofloxacin against E.Coli was evaluated by using disc-diffusion and minimum inhibitory concentration method. E. coli clinical strains were collected from Rehman Medical Institute and Northwest General Hospital Peshawar, and American Type Culture Collection [ATCC] strains (number 23922) of these bacteria were collected from Agriculture University Peshawar. The organisms were tested six times with crude extract and fractionation with different solvents such as n-hexane, chloroform, ethyl acetate and butanol at concentrations of 1, 4, 8, 12, 16, 20, 24, 30 and 36 mg/ml. The mean minimum inhibitory concentration and fractional inhibitory concentration index were obtained to report the synergism. The data was analysed using SPSS version 21. Results: Antibacterial activity of different fractions of plant was interpreted as synergy, indifference and antagonism against E.Coli. Fractional inhibitory concentration index for E.Coli ranged from 3 to 1.05, which showed antagonism and indifferent effect of combination of plant extract with ciprofloxacin. Conclusion: Synergism between TO and ciprofloxacin was shown against E.Coli by disc diffusion method while no synergistic effects were found through minimum inhibitory concentration.

Purpose. Statins are a class of drugs widely used in clinical practice for their lipid-lowering and pleiotropic effects. In recent years, a correlation between statins and platelet function has been unveiled in the literature that might introduce new therapeutic indications for this class of drugs. This review is aimed at summarizing the mechanisms underlying statin-platelet interaction in the cardiologic scenario and building the basis for future in-depth studies. Methods. We conducted a literature search through PubMed, Embase, EBSCO, Cochrane Database of Systematic Reviews, and Web of Science from their inception to June 2020. Results. Many pathways could explain the interaction between statins and platelets, but the specific effect depends on the specific compound. Some could be mediated by enzymes that allow the entry of drugs into the cell (OATP2B1) and others by enzymes that mediate their activation (PLA2, MAPK, TAX2, PPARs, AKT, and COX-1), recruitment and adhesion (LOX-1, CD36, and CD40L), or apoptosis (BCL2). Statins also appear to have a synergistic effect with aspirin and low molecular weight heparins. Surprisingly, they seem to have an antagonistic effect with clopidogrel. Conclusion. There are many pathways potentially responsible for the interactions between statins and platelets. Their effect appears to be closely related, and each single effect can be barely measured. Also, the same compound might have complex downstream signaling with potentially opposite effects, i.e., beneficial or deleterious. The multiple clinical implications that can be derived as a result of this interaction, however, represent an excellent reason to develop future in-depth studies. [ABSTRACT FROM AUTHOR]

Corticotropin releasing factor receptor 1 (CRF1) is the key receptor that mediates stress-related body responses. However to date there are no CRF1 antagonists that have shown clinical efficacy in stress-related diseases. We investigated the inhibitory effects of a new generation, topology 2 selective CRF1 antagonists, NGD 98-2 and NGD 9002 on exogenous and endogenous CRF-induced stimulation of colonic function and visceral hypersensitivity to colorectal distension (CRD) in conscious rats. CRF1 antagonists or vehicle were administered orogastrically (og) or subcutaneously (sc) before either intracerebroventricular (icv) or intraperitoneal (ip) injection of CRF (10 µg/kg), exposure to water avoidance stress (WAS, 60 min) or repeated CRD (60 mmHg twice, 10 min on/off at a 30 min interval). Fecal pellet output (FPO), diarrhea and visceromotor responses were monitored. In vehicle (og)-pretreated rats, icv CRF stimulated FPO and induced diarrhea in >50% of rats. NGD 98-2 or NGD 9002 (3, 10 and 30 mg/kg, og) reduced the CRF-induced FPO response with an inhibitory IC50 of 15.7 and 4.3 mg/kg respectively. At the highest dose, og NGD 98-2 or NGD 9002 blocked icv CRF-induced FPO by 67-87% and decreased WAS-induced-FPO by 23-53%. When administered sc, NGD 98-2 or NGD 9002 (30 mg/kg) inhibited icv and ip CRF-induced-FPO. The antagonists also prevented the development of nociceptive hyper-responsivity to repeated CRD. These data demonstrate that topology 2 CRF1 antagonists, NGD 98-2 and NGD 9002, administered orally, prevented icv CRF-induced colonic secretomotor stimulation, reduced acute WAS-induced defecation and blocked the induction of visceral sensitization to repeated CRD.

Psychopathy and narcissism are multidimensional constructs with substantial overlap. Low agreeableness (i.e., antagonism) features prominently in clinical and theoretical descriptions of both disorders. The authors examined whether antagonism components of their assessments accounted for the overlap between narcissism and psychopathy. Next, they tested whether the antagonism components were responsible for the relations that narcissism and psychopathy bore to aggression outcomes. Using multiple regression, the authors found that the low agreeableness component accounted for the majority of overlap between psychopathy and narcissism, nearly all of the variance in narcissism's relations with aggression outcomes, and the majority of variance in psychopathy's relations with aggression outcomes. Disinhibitory traits, which serve to distinguish psychopathy from narcissism, accounted for incremental variance in aggression outcomes for psychopathy. Results are discussed in the context of the overlap between narcissism and psychopathy. The authors argue that low agreeableness is largely responsible for the maladaptive outcomes associated with grandiose narcissism and psychopathy. [ABSTRACT FROM AUTHOR]

Individuals with an inherited BRCA1 or BRCA2 mutation have an elevated risk of developing breast cancer. The resulting tumors typically lack homologous recombination repair as do a subset of sporadic tumors with acquired BRCA deficiency. Clinical responses to monotherapy with platinum drugs or poly PARP inhibitors (PARPi) have been shown for BRCA-associated cancers. However, there are limited data on combination therapy with PARPi and platinum drugs, the mechanism of action of this combination, and the role of BRCA1 or BRCA2 in chemosensitivity. We compared the efficacy of ABT-888 (a PARPi) with that of cisplatin or carboplatin (platinum drugs) alone or in combinations by examining the survival of treated Brca-proficient and -deficient mouse embryonic stem cells. In addition, drug-induced growth inhibition of a BRCA1 and a BRCA2 null cell line were compared with their isogenic BRCA-complemented lines. Although each monotherapy killed or inhibited proliferation of Brca/BRCA-deficient cells, an enhanced effect was observed after treatment with ABT-888 in combination with carboplatin. Moreover, the ABT-888/carboplatin combination delayed tumor growth in Brca2 xenografts. The drugs caused DNA damage and apoptosis. Along with greater PARP activity in Brca/BRCA-deficient cells, these effects correlated with increased chemosensitivity. Our data suggest that ABT-888 and carboplatin combination treatment will be more successful than monotherapy in addressing many BRCA-associated cancers. A randomized phase II trial has recently been initiated to test this hypothesis to assist in the discovery of more effective therapies for patients with BRCA.

Background: Recent cryo-electron microscopic imaging studies have shown that in addition to binding to the classical extracellular benzodiazepine binding site of the α1β3γ2L γ-aminobutyric acid type A (GABAA) receptor, diazepam also binds to etomidate binding sites located in the transmembrane receptor domain. Because such binding is characterized by low modulatory efficacy, the authors hypothesized that diazepam would act in vitro and in vivo as a competitive etomidate antagonist.Methods: The concentration-dependent actions of diazepam on 20 µM etomidate-activated and 6 µM GABA-activated currents were defined (in the absence and presence of flumazenil) in oocyte-expressed α1β3γ2L GABAA receptors using voltage clamp electrophysiology. The ability of diazepam to inhibit receptor labeling of purified α1β3γ2L GABAA receptors by [H]azietomidate was assessed in photoaffinity labeling protection studies. The impact of diazepam (in the absence and presence of flumazenil) on the anesthetic potencies of etomidate and ketamine was compared in a zebrafish model.Results: At nanomolar concentrations, diazepam comparably potentiated etomidate-activated and GABA-activated GABAA receptor peak current amplitudes in a flumazenil-reversible manner. The half-maximal potentiating concentrations were 39 nM (95% CI, 27 to 55 nM) and 26 nM (95% CI, 16 to 41 nM), respectively. However, at micromolar concentrations, diazepam reduced etomidate-activated, but not GABA-activated, GABAA receptor peak current amplitudes in a concentration-dependent manner with a half-maximal inhibitory concentration of 9.6 µM (95% CI, 7.6 to 12 µM). Diazepam (12.5 to 50 µM) also right-shifted the etomidate-concentration response curve for direct activation without reducing the maximal response and inhibited receptor photoaffinity labeling by [H]azietomidate. When administered with flumazenil, 50 µM diazepam shifted the etomidate (but not the ketamine) concentration-response curve for anesthesia rightward, increasing the etomidate EC50 by 18-fold.Conclusions: At micromolar concentrations and in the presence of flumazenil to inhibit allosteric modulation via the classical benzodiazepine binding site of the GABAA receptor, diazepam acts as an in vitro and in vivo competitive etomidate antagonist. [ABSTRACT FROM AUTHOR]

Objectives: To determine the antimicrobial effect of Thujaorientalis (TO) and ciprofloxacin alone against Escherichia Coli (E.Coli). To compare the combined antimicrobial effect of TO and ciprofloxacin against E. Coli. Study Design: Laboratory experimental study. Place and Duration of Study: This in vitro study was performed at Khyber Girls Medical College, Peshawar, from Jan to Jul 2018. Methodology: Antibacterial activity of TO extracts alone and in combination with ciprofloxacin against E.Coli was evaluated by using disc-diffusion and minimum inhibitory concentration method. E. coli clinical strains were collected from Rehman Medical Institute and Northwest General Hospital Peshawar, and American Type Culture Collection [ATCC] strains (number 23922) of these bacteria were collected from Agriculture University Peshawar. The organisms were tested six times with crude extract and fractionation with different solvents such as n-hexane, chloroform, ethyl acetate and butanol at concentrations of 1, 4, 8, 12, 16, 20, 24, 30 and 36 mg/ml. The mean minimum inhibitory concentration and fractional inhibitory concentration index were obtained to report the synergism. The data was analysed using SPSS version 21. Results: Antibacterial activity of different fractions of plant was interpreted as synergy, indifference and antagonism against E.Coli. Fractional inhibitory concentration index for E.Coli ranged from 3 to 1.05, which showed antagonism and indifferent effect of combination of plant extract with ciprofloxacin. Conclusion: Synergism between TO and ciprofloxacin was shown against E.Coli by disc diffusion method while no synergistic effects were found through minimum inhibitory concentration. [ABSTRACT FROM AUTHOR]

English language and its warlike knowing apparatuses dominate global academic practice, including the repertoire of critique in social sciences. But what might be done about this? The paradox is that if we fight this, we simply rehearse the same logic of antagonism. This article tries to avoid this bind, experimenting instead with an alternative apparatus – an approach that values the art of balancing. In presenting this approach, shi-as-reasoning (shì, 勢), I take inspiration from Dr Hsu, a Chinese medical (CM) doctor in Taiwan, who avoids fighting viruses while treating patients with SARS in biomedically dominated clinics, and who publishes his work in English-language biomedical research journals. In doing so, he balances among the complexities of shi in the body of diseased patients, possible herbal interventions (decoctions), the contexts of CM practices in Taiwan, and English-language dominated biomedical research. Since this article describes Dr Hsu's practices in English, it makes use of elements taken from the material semiotics of social science, Dr Hsu's accounts of CM, and the logic of the non-antagonistic interplay between yin and yang. Following the lead of Dr Hsu, it thus suggests that a shi -inflected-reasoning might help to rebalance a situation that is imbalanced as a result of the domination of English in academia. [ABSTRACT FROM AUTHOR]

Excitotoxicity mediated by the N-methyl-D-aspartate receptor (NMDAR) is believed to be a primary mechanism of neuronal injury following stroke. Thus, many drugs and therapeutic peptides were developed to inhibit either the NMDAR at the cell surface or its downstream intracellular death-signaling cascades. Nevertheless, the majority of focal ischemia studies concerning NMDAR antagonism were performed using the intraluminal suture-induced middle cerebral arterial occlusion (MCAO) model, which produces a large cortical and subcortical infarct leading to hypothalamic damage and fever in experimental animals. Here, we investigated whether NMDAR antagonism by drugs and therapeutic peptides was neuroprotective in a mouse model of distal MCAO (dMCAO), which produces a small cortical infarct sparing the hypothalamus and other subcortical structures. For establishment of this model, mice were subjected to dMCAO under normothermic conditions or body-temperature manipulations, and in the former case, their brains were collected at 3–72 h post-ischemia to follow the infarct development. These mice developed cortical infarction 6 h post-ischemia, which matured by 24–48 h post-ischemia. Consistent with the hypothesis that the delayed infarction in this model can be alleviated by neuroprotective interventions, hypothermia strongly protected the mouse brain against cerebral infarction in this model. To evaluate the therapeutic efficacy of NMDAR antagonism in this model, we treated the mice with MK801, Tat-NR2B9c, and L-JNKI-1 at doses that were neuroprotective in the MCAO model, and 30 min later, they were subjected to 120 min of dMCAO either in the awake state or under anesthesia with normothermic controls. Nevertheless, NMDAR antagonism, despite exerting pharmacological effects on mouse behavior, repeatedly failed to show neuroprotection against cerebral infarction in this model. The lack of efficacy of these treatments is reminiscent of the recurrent failure of NMDAR antagonism in clinical trials. While our data do not exclude the possibility that these treatments could be effective at a different dose or treatment regimen, they emphasize the need to test drug efficacy in different stroke models before optimal doses and treatment regimens can be selected for clinical trials. [ABSTRACT FROM AUTHOR]

Anarchist thought often adopts an anti-political stance. Generally opposed to any form of rule or domination, anarchists have recently embarked on sustained critiques of common understandings of democracy. Despite such critiques, experiences with participatory decision-making in spokescouncils and occupations suggest that anarchism retains some democratic commitments. Indeed, any number of anarchist thinkers have highlighted those commitments from time to time -- for example, Murray Bookchin's libertarian municipalism (with its apparent "polis envy") or David Graeber's more recent claim that anarchism is "democracy without the government." As anarchists elaborate a utopian vision and sketch the outlines of a new society, it is vital to develop an anarchistic conception of democracy. This essay identifies criteria to be met by a democratic anarchism and highlights the models of democracy that might guide anarchist thinking. On such a basis, anarchists can outline a compatible understanding of democracy, one that lies somewhere between antagonism and consensus. [ABSTRACT FROM AUTHOR]

Introduction: Anti-Microbial Resistance (AMR) is a pandemic which threatens modern medicine. There is a lack of effective drug treatment due to the slow pace, high cost and low achievable sales prices of new antibiotic monotherapies. New hope comes in the shape of antibiotic combination therapy, which although used by mother nature, is under-explored and could provide the solution to AMR.Areas covered: We performed a search of Pubmed and Medline using the keywords 'combination therapy', 'antimicrobial resistance' for articles between 1930 and 2019, as supplemented with other relevant references to our knowledge. We have reviewed the theoretical considerations for combination development and examine the existing and future clinical indications of combination therapies. We have discussed the potential of antibiotic combinations to provide therapeutic synergy, rejuvenating the effectiveness of old antibiotics to which the bacteria had developed resistance previously. We have examined the current thinking and evidence on resistance reduction using combination therapies, with a review on toxicity and drug-drug antagonism.Expert opinion: Antibiotic combination therapy, exploiting synergies, old-drug rejuvenation and resistance reduction could provide the solution to AMR. The number of pharmaceutical companies in this area is likely to expand, bringing promising combinations to the bedside, to save millions of lives worldwide. [ABSTRACT FROM AUTHOR]

Background: Four-factor prothrombin complex concentrate (4F-PCC) is US Food and Drug Administration approved for the urgent reversal of coagulation factor deficiency induced by a vitamin K antagonist complicated by acute major bleeding or in situations in which invasive procedures are urgently needed. Although recent evidence suggests the superiority of 4F-PCC over plasma for on-label indications, the off-label use of 4F-PCC has not been rigorously studied.Study Design and Methods: Eighty-nine patients receiving 4F-PCC at a single institution from July 2016 to December 2017 were retrospectively analyzed. Two cohorts, "On-Label" and "Off-Label" uses of 4F-PCC, were evaluated, comparing patient characteristics, blood utilization, and clinical outcomes including in-hospital mortality.Results: Patients receiving 4F-PCC for off-label reasons (n = 46) were younger and sicker compared to those receiving 4F-PCC for on-label reasons (n = 43). Notably, the mortality rate for off-label use was approximately twofold greater than the mortality rate for on-label use (26 of 46 [56.5%] vs. 12 of 43 [27.9%]; p = 0.006). Patients receiving 4F-PCC for off-label reasons received more units per patient of each blood component than their on-label counterparts. The average cost estimate per patient for 4F-PCC was similar (approx. $4300) in each cohort.Conclusion: 4F-PCC is an effective but expensive treatment option for those requiring urgent reversal of vitamin K antagonist-induced coagulopathy. However, providers should be conscious of the high costs and questionable efficacy when using 4F-PCC off-label. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether mineralocorticoid (MC) antagonism enhances brown adipose tissue (BAT) function in humans. Materials and Methods: In a randomized double‐blind, cross‐over designed trial, 10 healthy adults (two men, eight women) underwent 2 weeks of spironolactone (100 mg/d) treatment and placebo, with an intervening 2‐week wash‐out period. BAT function was assessed in response to cooling and to a mixed meal. Metabolic activity was measured by fluoro‐deoxyglucose (FDG) uptake (maximal standardized uptake value, SUVmax) using PET‐CT. Thermogenic activity was measured by skin temperatures overlying supraclavicular (SCL) BAT depots using infrared thermography. Postprandial metabolism was measured by energy production rate (EPR) and lipid synthesis using indirect calorimetry. Results: During cooling, BAT metabolic activity (SUV 6.30 ± 2.16 vs 3.98 ± 1.34; P < 0.05) and volume (54.9 ± 22.8 vs 21.6 ± 11.8 cm3; P < 0.05) were significantly higher, and mean SCL temperature decreased by a smaller degree (−0.3°C°± 0.2°C vs −0.9°C ± 0.2°C; P = 0.05) with spironolactone treatment. A mixed meal increased SCL temperature and EPR. The postprandial rise in SCL temperature (+0.4°C ± 0.1°C vs +0.1°C ± 0.1°C; P < 0.05) but not in EPR was greater during spironolactone treatment. Postprandial lipid synthesis occurred in three participants with placebo but in none with spironolactone treatment (P = 0.06). Conclusion: MC antagonism enhanced human BAT function in response to cooling and to a meal during which lipid synthesis was suppressed. As postprandial EPR comprises energy dissipated as heat and energy required to store nutrients, the reduction in lipid synthesis during MC antagonism is a probable consequence of concurrent stimulation of BAT thermogenesis. The shift in energy usage from storage to heat dissipation indicates that MC antagonists may have therapeutic benefit for obesity. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Compability of P. ginseng and S. raphani was investigated through HPA axis regulation effect and saponin content. • S. raphani could reduced saponin content in compatibility uses with P. ginseng. • S. raphani could also weaken the HPA axis regulation effect of P. ginseng in vivo. • This study strengthened the usage in TCM that P. ginseng should not taken together with S. raphani. Abstract Semen raphani (S. raphani) and Panax ginseng (P. ginseng) is one of eighteen counters in Traditional Chinese Medicine (TCM). This study was aimed to investigate the antagonistic effect of S. raphani on P. ginseng. Three extractions were obtained with single P.ginseng extraction (GW), mixture of P.ginseng and S. raphani extraction (GWSW) and co-extraction of P.ginseng and S. raphani (GSW). Saponin were detected and fingerprinted after LC-Q-TOF-MS identification. The effect of three extractions on HPA regulation was evaluated through the indicators of plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) in mouse. Results showed that saponin contents in three extractions were 1.236 ± 0.048 mg/mL, 1.220 ± 0.034 mg/mL and 0.966 ± 0.05 mg/mL for GW, GWSW, GSW separately. Twenty-seven saponin monomers were identified in both GW and GWSW while only twenty-four saponin monomers were identified in GSW with saponin monomers decreased on different levels. GW could change levels of CORT and ACTH in quiet and stressed mice (P < 0.05) compared to saline group while GSW and GWSW could not. These results suggested that S. raphani could inhibit saponin dissolution of P.ginseng which could directly result in the reduced saponin content. More importantly, it was found in this study that S. raphani could weaken the effect of P.ginseng in vivo no matter they were extracted together or not. This study explained the antagonistic effect of S. raphani on P.ginseng and strengthened the usage in TCM that P.ginseng should not taken together with S. raphani. [ABSTRACT FROM AUTHOR]

Folate is vital for cell development and growth. It is involved in one-carbon transfer reactions essential for the synthesis of purines and pyrimidines. It also acts in conjunction with cobalamin (vitamin B12) as a fundamental cofactor in the remethylation cycle that converts homocysteine to methionine. A deficiency in folate or vitamin B12 can lead to elevated homocysteine level, which has been identified as an independent risk factor in several health-related conditions. Adequate folate levels are essential in women of childbearing age and in pregnant women, and folate deficiency is associated with several congenital malformations. Low folate levels can be caused by dietary deficiencies, a genetic predisposition or treatment with medicines that affect folate concentration. Women who are pregnant or of child-bearing age commonly use medicines, so it is important to identify the basic biochemical mechanisms by which medicines interfere with the folate-homocysteine-methionine pathway. This review focuses on prescription medicines associated with folate disruption. It also summarizes their undesirable/toxic effects. Recommendations regarding folate supplementation during medical therapy are also reviewed. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Evaluated the protective effects on the nervous system when EGCG was administered simultaneously with formaldehyde. • 3 mg/m3 formaldehyde caused learning and memory disorders in mice. • EGCG activated the Nrf2 signaling pathway to relieve formaldehyde-induced neurotoxicity. • The antagonistic effect of EGCG on formaldehyde gradually became evident in the range of 20–500 mg/kg. Abstract The toxicity of formaldehyde (FA) has always been of great concern, particularly since its use is unavoidable. On the other hand, epigallocatechin-3-gallate (EGCG), an active substance in tea polyphenols, has been shown to demonstrate physiological protective functions by in both epidemiological and zoological studies, particularly in the nervous system. The study described here, aims to explore whether EGCG can alleviate the neurotoxic effects induced by formaldehyde. After 14 days of exposure to 3 mg/m3 formaldehyde, mice exhibited significant cognitive impairment. In the FA group, a significant increase in iNOS level compared with the control group was observed. The reduced GSH level was significantly decreased. The levels of IL-1β, TNF-α and Caspase-3 were obviously raised, while H&E and Nissl staining illustrated significant neuronal damage. After administering EGCG as a protective agent, all the above observed changes were reversed, and the protective effect of EGCG became gradually evident in the 20–500 mg/kg range. Immunohistochemistry results showed that EGCG could activate the Nrf2 signaling pathway, thus alleviating the oxidative damage caused by formaldehyde. [ABSTRACT FROM AUTHOR]