First-line Drug For Treatment Research Articles

Modulating NO-GC Pathway in Pulmonary Arterial Hypertension.

The pathogenesis of complex diseases such as pulmonary arterial hypertension (PAH) is entirely rooted in changes in the expression of some vasoactive factors. These play a significant role in the onset and progression of the disease. Indeed, PAH has been associated with pathophysiologic alterations in vascular function. These are often dictated by increased oxidative stress and impaired modulation of the nitric oxide (NO) pathway. NO reduces the uncontrolled proliferation of vascular smooth muscle cells that leads to occlusion of vessels and an increase in pulmonary vascular resistances, which is the mainstay of PAH development. To date, two classes of NO-pathway modulating drugs are approved for the treatment of PAH: the phosphodiesterase-5 inhibitors (PD5i), sildenafil and tadalafil, and the soluble guanylate cyclase activator (sGC), riociguat. Both drugs provide considerable improvement in exercise capacity and pulmonary hemodynamics. PD5i are the recommended drugs for first-line PAH treatment, whereas sGCs are also the only drug approved for the treatment of resistant or inoperable chronic thromboembolic pulmonary hypertension. In this review, we will focus on the current information regarding the nitric oxide pathway and its modulation in PAH.

Multi-drug-resistant tuberculosis and its associated factors among pulmonary tuberculosis patients linked to first-line anti-tuberculosis drugs in north-west Ethiopia

Introduction. Multi-drug-resistant tuberculosis (MDR-TB) is an emerging global challenge. Ethiopia is one of the 20 top countries with the highest estimated numbers of incidents of MDR-TB. Recently, the World Health Organization warned that drug-resistant TB is escalating and called for concerted action to reduce the spread of drug resistance. Hypothesis. The current study investigated MDR-TB in patients receiving first-line anti-TB drug treatment and associated factors. Aim. The study aimed to determine the prevalence of MDR-TB and its associated factors among smear-positive pulmonary TB patients receiving first-line anti-TB drug treatment. Methodology. An institution-based cross-sectional study was employed. All data were collected from laboratory result log books and information via a questionnaire. Samples from 205 smear-positive pulmonary TB patients were selected among first-line drug treatment by a systematic sampling method. Specimens were transported to Felege Hiwot referral hospital laboratory for GeneXpert testing. Factors associated with an outcome variable in binary multi-variable logistic regression analysis at P<0.05 were considered statistically significant variables. An ethical approval letter was taken to the respective health facility and written consent was obtained from each participant. Results. The overall prevalence of MDR-TB was 9.3 % (95 % CI, 5.4 13.7 %). Sign and symptom experience of anti-TB drug side effects [adjusted odds ratio (AOR)=0.18, 95 % CI=0.03–0.99, P=0.049] and co-morbidity (AOR=0.03, 95 % CI=0.01–0.55, P=0.02) were statistically associated with the development of MDR-TB infection Conclusion. The prevalence of MDR-TB was high (9.3 %) and contributed highly to new cases (8.3 %). Factors associated with MDR-TB were previous treatment, co-morbidity and laboratory diagnosis method prior to TB treatment. Therefore, this finding aims to maximize early detection and treatment, strengthening TB infection control, and proper implementation of directly observed therapy short course recommendations to reduce the burden of MDR-TB.

Persistence of biological agents over an eight-year period in rheumatoid arthritis and spondylarthritis patients

ObjectiveTo calculate the persistence, over a period of eight years, the retention rate of first and second-line of treatment with biological agents in patients with rheumatoid arthritis, spondyloarthritis and psoriatic arthritis and to compare retention rates of the various drugs for each pathology. MethodRetrospective observational study that included patients affected by rheumatoid arthritis, spondyloarthritis and psoriatic arthritis, who started treatment with biological agents between January 2009 and December 2012 and followed until December 2016. Results132, 87 and 33 patients were included in rheumatoid arthritis, spondyloarthritis and psoriatic arthritis, respectively. The median retention duration of all biological agents for the first and second-line, was 30.9 months and 14.0 months, respectively for rheumatoid arthritis; 63.06 months and 25.6 months, respectively in spondyloarthritis. Psoriatic arthritis did not reach the median (> 70 months in first-line) (first line p = 0.002). Individual drug survival in first line: the median retention duration of tocilizumab was 58.3 months, followed by etanercept (p = 0.79) in rheumatoid arthritis. For spondyloarthritis, golimumab and etanercept had greater retention than the other drugs (they did not reach the median): adalimumab was 63.0 months and for infliximab was 50.1 months. In psoriatic arthritis, golimumab, infliximab and etanercept not reach the median and they had greater retention than adalimumab (59.4 months). Individual drug survival in second line: tocilizumab was the most persistent drug (median 22.1 months) in rheumatoid arthritis, and golimumab for spondyloarthritis and psoriatic arthritis. ConclusionsTocilizumab and etanercept in rheumatoid arthritis, and golimumab in spondyloarthritis and psoriatic arthritis also, were the most persistent drugs in first-line and second-line treatment.

Republication de : Évaluation de la mise en application des recommandations 2021 de la Société Européenne de Cardiologie pour l'insuffisance cardiaque à fraction d'éjection réduite chez les patients âgés de plus de 75 ans

IntroductionHeart failure is a frequent pathology with a poor prognosis which mainly concerns elderly patients. The recommandations concerning the pharmagical treatment in heart failure with LVEF are reduced on randomized trials carried out on a young population. The aim of this work is to evaluate their application on a population aged ≥ 75. Materials and methodsThis is a retrospective, bicentric cohort, concerning patients hospitalized between September 1, 2021 and March 31, 2023, at the hospital centers of Troyes and Romilly sur Seine. The primary endpoint was a composite endpoint combining rehospitalisation rate or all-cause death rate at 6 months. ResultsA group of 81 patients was included in the study. The average number of treatments is associated with a significant reduction in the rate of hospitalisations ord deaths at 6 months (p = 0,005); as it concerns the level of titration, the analysing comparing the "therapeutic inertia" group and the "current titration/maximum tolerated dose" group did not reveal any significant difference (p = 0,169). ConclusionOur study highlighted the potential positive impact of the application of the latest ESC recommendations concerning first-line drug treatment on the rate of rehospitalisation or death from all causes, in patients with heart failure reduced LVEF aged over 75.

Potentiating sorafenib efficacy against hepatocellular carcinoma via a carrier-free nanomedicine of artesunate prodrug

Sorafenib is a first-line drug for liver cancer treatment, but its clinical efficacy is still limited by drawbacks such as drug tolerance, toxic effects, and low bioavailability. Therefore, it is urgent to find efficient ways to synergize sorafenib with other agents and increase its bioavailability in order to enhance its clinical efficacy. Herein, we report the successful development of a carrier-free nanoplatform of an artesunate prodrug to potentiate the efficacy of sorafenib against hepatocellular carcinoma. The artesunate prodrug was synthesized by conjugating artesunate and linoleic acid through a thioketone (TK) bond. This prodrug can self-assemble in an aqueous solution via a one-step precipitation method. Furthermore, the inclusion of sorafenib during the self-assembly process results in a carrier-free artesunate/sorafenib mixed nanomedicine (SA@NPs) with a uniform and stable particle size. In addition, SA@NPs possess ROS-responsive drug-releasing ability by breaking up thioketone bonds under high H2O2 levels in tumors. The synergistic anticancer effects of SA@NPs have been demonstrated both in vivo and in vitro. SA@NPs can achieve significantly enhanced synergetic ferroptosis of tumor cells and show potentiated sorafenib efficacy against hepatocellular carcinoma. Moreover, SA@NPs have a tumor inhibition rate of 84.2%, which is 1.63-, 4.22-, and 1.29-fold higher than that in the experimental groups treated with free sorafenib, artesunate, and the simplified combined medication of sorafenib/artesunate, respectively. Overall, this work presents a significant advancement in the clinical chemotherapy of liver cancer and may pave the way for promising developments in the compatibility and clinical combination application of traditional Chinese medicine.

Development of novel green and high-throughput microwell spectrophotometric assay for one-step determination of dacomitinib, a recently approved potent drug for first-line treatment of metastatic non-small cell lung cancer

Dacomitinib (DAC) is the most recent drug approved drug for the first-line treatment of patients with metastatic non-small cell lung cancer. This study describes, for the first time, the development of a novel green and high-throughput microwell spectrophotometric assay (MW-SPA) for one-step determination of DAC. The assay was based on formation of a colored charge transfer complex between DAC, as electron donor, with 2,3-dichloro-3,5-dicyano-1,4-benzoquinone, as π-electron acceptor. Ultraviolet–visible spectrophotometry was used to characterize the complex and proposing the reaction mechanism. Under refined optimum reaction conditions, it was employed as a basis for the development of the proposed MW-SPA. The assay was conducted in 96-well assay plates, and the absorbances were measured by an absorbance plate reader. Validation of the assay was performed in accordance with guidelines of the International Council on Harmonization, and all validation parameters were acceptable. The limits of detection and quantitation of the MW-SPA were 1.2 and 3.7 μg/well, respectively. The assay was applied with great distinct success for determining DAC in its bulk form and vizimpro® tablets. The greenness of the assay was ascertained by three distinct metric tools, which conclusively demonstrated the adherence of the assay to principles of green analytical chemistry approach. Moreover, the assay has high throughput capacity as it can simultaneously process large number of micro-volume samples. In conclusion, the proposed MW-SPA is valuable for the rapid and routine determination of DAC for the purposes of quality control.

Near-infrared molecular sensor for visualizing and tracking ONOO- during the process of anti-tuberculosis drug-induced liver damage.

Isoniazid (INH) and pyrazinamide (PZA) are both the first-line anti-tuberculosis drugs in clinical treatment. It is notable that there are serious side effects of the drugs along with upregulation of reactive nitrogen species, mainly including peripheral neuritis, gastrointestinal reactions, and acute drug-induced liver injury (DILI). Among them, DILI is the most common clinical symptom as well as the basic reason of treatment interruption, protocol change, and drug resistance. As vital reactive nitrogen species (RNS), peroxynitrite (ONOO-) has been demonstrated as a biomarker for evaluation and pre-diagnosis of drug-induced liver injury (DILI). In this work, we developed a red-emitting D-π-A type fluorescence probe DIC-NP which was based on 4'-hydroxy-4-biphenylcarbonitrile modified with dicyanoisophorone as a fluorescent reporter and diphenyl phosphinic chloride group as the reaction site for highly selective and sensitive sensing ONOO-. Probe DIC-NP displayed a low detection limit (14.9 nM)and 60-fold fluorescent enhancement at 669 nm in the sensing of ONOO-. Probe DIC-NP was successfully applied to monitor exogenous and endogenous ONOO- in living HeLa cells and zebrafish. Furthermore, we verified the toxicity of isoniazid (INH) and pyrazinamide (PZA) by taking the oxidative stress induced by APAP as a reference, and successfully imaged anti-tuberculosis drug-induced endogenous ONOO- in HepG2 cells. More importantly, we developed a series of mice models of liver injury and investigated the hepatotoxicity caused by the treatment of anti-tuberculosis drugs. At the same time, H&E of mice organs (heart, liver, spleen, lung, kidney) further confirmed thecompetence of probe DIC-NP for estimating the degree of drug-induced liver injury, which laid a solid foundation for medical research.

Impact of Donepezil Supplementation on Alzheimer's Disease-like Pathology and Gut Microbiome in APP/PS1 Mice.

Based on published information, the occurrence and development of Alzheimer's disease (AD) are potentially related to gut microbiota changes. Donepezil hydrochloride (DH), which enhances cholinergic activity by blocking acetylcholinesterase (AChE), is one of the first-line drugs for AD treatment approved by the Food and Drug Administration (FDA) of the USA. However, the potential link between the effects of DH on the pathophysiological processes of AD and the gut microbiota remains unclear. In this study, pathological changes in the brain and colon, the activities of superoxide dismutase (SOD) and AChE, and changes in intestinal flora were observed. The results showed that Aβ deposition in the prefrontal cortex and hippocampus of AD mice was significantly decreased, while colonic inflammation was significantly alleviated by DH treatment. Concomitantly, SOD activity was significantly improved, while AChE was significantly reduced after DH administration. In addition, the gut microbiota community composition of AD mice was significantly altered after DH treatment. The relative abundance of Akkermansia in the AD group was 54.8% higher than that in the N group. The relative abundance of Akkermansia was increased by 18.3% and 53.8% in the AD_G group and the N_G group, respectively. Interestingly, Akkermansia showed a potential predictive value and might be a biomarker for AD. Molecular docking revealed the binding mode and major forces between DH and membrane proteins of Akkermansia. The overall results suggest a novel therapeutic mechanism for treating AD and highlight the critical role of gut microbiota in AD pathology.

Principles of pharmacological therapy of comorbid diseases in patients with orthopedic pathology

Comorbidity is one of the leading problems in clinical practice. Interaction of diseases, involutive processes of natural aging and pathomorphosis of drugs significantly change clinical picture and course of the disease, the nature and severity of complications, limit or complicate the treatment and diagnostic process. Objective. To analyze current information on available recommendations for the treatment of comorbid diseases in patients with orthopedic pathology. Materials. An overview of the recommendations of the European Society of Cardiology, European Society of Hypertension, European Society for Vascular Surgery, Ukrainian Gastroenterological Association and American Diabetes Association for the period 2017–2019 is presented. Results. The first stage in the treatment of arterial hypertension is the lifestyle optimization, and the initial therapy of most patients with hypertension should be a combination of two drugs. Management of patients with lower extremity artery disease is associated with an increased risk of any cardiovascular events. Therefore, preventive measures are of particular importance. Gastropathies induced by non-steroidal anti-inflammatory drugs are widespread in orthopedic practice. In the prevention of their occurrence, a well-chosen gastroprotective therapy is important. Once the diagnosis of diabetes is made, lifestyle modification should be started immediately along with the start of pharmacotherapy. Metformin remains the first-line drug for treatment, drugs of other groups can be prescribed when there are contraindications to metformin. In the treatment of neuropathic pain in diabetes or pre-diabetes, only pharmacological treatment strategies are effective. Conclusions. In most cases, a number of comorbidities with timely diagnosis and compliance with the algorithms of medical care can be corrected and treated. Properly selected conservative therapy can reduce the risk of peri- and postoperative complications.

Évaluation de la mise en application des recommandations 2021 de la Société Européenne de Cardiologie pour l'insuffisance cardiaque à fraction d'éjection réduite chez les patients âgés de plus de 75 ans

IntroductionHeart failure is a frequent pathology with a poor prognosis which mainly concerns elderly patients. The recommandations concerning the pharmagical treatment in heart failure with LVEF are reduced on randomized trials carried out on a young population. The aim of this work is to evaluate their application on a population aged ≥ 75. Materials and methodsThis is a retrospective, bicentric cohort, concerning patients hospitalized between September 1, 2021 and March 31, 2023, at the hospital centers of Troyes and Romilly sur Seine. The primary endpoint was a composite endpoint combining rehospitalisation rate or all-cause death rate at 6 months. ResultsA group of 81 patients was included in the study. The average number of treatments is associated with a significant reduction in the rate of hospitalisations ord deaths at 6 months (p = 0,005); as it concerns the level of titration, the analysing comparing the "therapeutic inertia" group and the "current titration/maximum tolerated dose" group did not reveal any significant difference (p = 0,169). ConclusionOur study highlighted the potential positive impact of the application of the latest ESC recommendations concerning first-line drug treatment on the rate of rehospitalisation or death from all causes, in patients with heart failure reduced LVEF aged over 75.

Bivalent Gadolinium Ions Forming Injectable Hydrogels for Simultaneous In Situ Vaccination Therapy and Imaging of Soft Tissue Sarcoma.

Doxorubicin (DOX) is the classic soft tissue sarcomas (STS) first-line treatment drug, while dose-dependent myelosuppression and cardiotoxicity limit its application in clinic. This research intends to apply DOX, which is also an inducer of immunogenic cell death as a part for "in situ vaccination" and conjointly uses PD-1 inhibitors to enhance antitumor efficacy. In order to achieve the sustained vaccination effect and real-time monitoring of distribution in vivo, the in situ forming and injectable hydrogel platform with the function of visualization is established for local delivery. The hydrogel platform is synthesized by hyaluronic acid-dopamine coordinated with gadolinium ions (Gd2+ ). Gd2+ provides the ability of magnetic resonance imaging, meanwhile further cross-linking the hydrogel network. Experiments show excellent ability of sustained release and imaging tracking for the hydrogel platform. In mouse STS models, the "in situ vaccination" hydrogels show the best effect of inhibiting tumor growth. Further analysis of tumor tissues show that "in situ vaccination" group can increase T cell infiltration, promote M1-type macrophage polarization and block elevated PD-1/PD-L1 pathway caused by DOX. These results are expected to prove the potential for synthesized hydrogels to achieve a universal platform for "in situ vaccination" strategies on STS treatments.

Protective Effect of Andropraphis Paniculata Aqueous Extract (EAAp) Against Isoniazid and Rifampicin-Induced Rat Liver Damage

Isoniazid (INH) and rifampicin (RIF) are first-line antituberculosis drugs (OAT) in tuberculosis treatment that are used for at least 6 months. The use of OAT has been associated with toxic reactions in the liver and causes hepatitis. This study aimed to determine the effect of an aqueous extract of Andrographis paniculata (EAAp) on liver damage induced by INH and RIF. Method: Male Sprague-Dawley rats weighing 250–300g were divided into 5 groups, each consisting of 6 mice. Animals were given isoniazid and rifampicin at 100 mg/kg, respectively, to induce liver damage, silymarin (25 mg/kg) for the positive control group, and Ap extract at doses of 200mg and 300 mg/kg for the test group. All treatments were given orally once daily for 28 days. Measurement of serum aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), bilirubin, and liver histopathology levels was carried out to determine the effect of EAAp on liver damage by INH and RIF. Results: Rats treated with INH+RIF were hepatotoxic, as evidenced by increased serum ALT, AST, and ALP activity, total bilirubin levels, and histopathological changes in the liver. Administration of Ap extract doses of 200 mg/kg and 300 mg/kg significantly decreased liver biochemical and histological changes caused by OAT. Conclusions: EAAp has a protective effect against hepatotoxic-induced INH and RIF in animal models.

Immunoglobulin genes expressed in lymphoblastoid cell lines discern and predict lithium response in bipolar disorder patients.

Bipolar disorder (BD) is a neuropsychiatric mood disorder manifested by recurrent episodes of mania and depression. More than half of BD patients are non-responsive to lithium, the first-line treatment drug, complicating BD clinical management. Given its unknown etiology, it is pertinent to understand the genetic signatures that lead to variability in lithium response. We discovered a set of differentially expressed genes (DEGs) from the lymphoblastoid cell lines (LCLs) of 10 controls and 19 BD patients belonging mainly to the immunoglobulin gene family that can be used as potential biomarkers to diagnose and treat BD. Importantly, we trained machine learning algorithms on our datasets that predicted the lithium response of BD subtypes with minimal errors, even when used on a different cohort of 24 BD patients acquired by a different laboratory.This proves the scalability of our methodology for predicting lithium response in BD and for a prompt and suitable decision on therapeutic interventions.

Molecular analysis of rpoB gene mutation in MTB detected isolates in a tertiary care centre (AGMC) of North-East, India

BackgroundRifampicin (RIF), one of the first line drug in treatment of tuberculosis. It acts on rpoB gene which encodes RNA polymerase β subunit. In 95% of RIF resistant cases, mutations are present in rpoB gene. Most of them are within 81bp RIF-resistance determining region (RRDR).Xpert MTB/RIF assay has been tremendously revolutionalised the diagnosis of tuberculosis (TB).Also sequencially detect bacteria and resistance to rifampicin (rif).Approximately 96% of rif-resistant Mycobacterium tuberculosis (MTB) strains worldwide, showed mutations in a region at the 507-533rd amino acid residuals (81 bp) in the MTB rpoB gene. Here evaluation is made about frequent regions of amplification and mutation in various codons of 81bp of rpoB gene in rif sensitive and rif resistant cases. MethodsA total of 4116 samples were received at Mycobacteriology laboratory, AGMC and processed in CBNAAT.Data of MTB detected samples were collected & statistically analysed to detect frequency of amplification & no amplification in various regions of 81bp of rpoB genes. ResultsOut of 4116 samples, MTB was detected in 1323 samples. Among them 1291 (97.58%) cases were Rif sensitive (RS) and 32 (2.41%) cases were rif resistance (RR).Most of the MTBC detected samples showed amplification in probe A then in probe C.78.12% rif resistant cases showed mutation in either of the probe, commonest is probe E. Study also showed low bacillary loads in most of the RR cases. ConclusionStudy highlighted variations in amplification of different regions of 81bp of rpoB gene in MTBC detected cases. North-east India, like other part of world, also showed highest frequency of mutation in probe E in rif resistant cases.

Identification of novel antimicrobial compounds targeting Mycobacterium tuberculosis shikimate kinase using in silico hierarchical structure-based drug screening

The development of new anti-TB drugs to prevent the spread of multidrug-resistant Mycobacterium tuberculosis (Mtb) strains is imperative. Mtb shikimate kinase (MtSK) was selected as the target protein to screen for new anti-TB drugs. We performed hierarchical in silico screening using a library of 154,118 compounds to search for novel compounds that could bind to the active site of MtSK. The growth-inhibitory effects of the candidate compounds on Mycobacterium smegmatis were evaluated in vitro. Nine of the 11 candidate compounds exhibited inhibitory effects against mycobacteria in vitro. The inhibitory activity of Compound 2 (IC50 = 1.39 μM) was higher than that of isoniazid, the first-line drug for TB treatment. Moreover, Compound 2 did not exhibit toxicity against mammalian cells and Escherichia coli. Molecular dynamics simulations using the MtSK-Compound 2 complex structure in a timeframe of 100 ns suggested that Compound 2 could stably bind to MtSK. The binding free energy of Compound 2 was estimated to be −37.96 kcal/mol using the MM/PBSA method, demonstrating that Compound 2 can stably bind to MtSK. These in silico and in vitro results indicated that Compound 2 is a promising hit compound for the development of novel anti-TB drugs.

Design, Implementation, and Coordination of Malaria Therapeutic Efficacy Studies in Nigeria in 2018.

Prior to 2018, malaria therapeutic efficacy studies (TESs) in Nigeria were implemented separately at different sites, as assigned by the National Malaria Elimination Program (NMEP). In 2018, however, the NMEP engaged the Nigerian Institute of Medical Research to coordinate the 2018 TESs in 3 of 14 sentinel sites with the objective of standardizing their conduct across all three sites: Enugu, Kano, and Plateau states in three of six geopolitical zones. Artemether-lumefantrine and artesunate-amodiaquine, the two first-line drugs for treatment of acute uncomplicated malaria in Nigeria, were tested in both Kano and Plateau states. In Enugu State, however, artemether-lumefantrine and dihydroartemisinin-piperaquine were the test drugs, with dihydroartemisinin-piperaquine being tested for potential inclusion in Nigerian treatment policy. The TES was conducted in 6-month to 8-year-old children and was funded by the Global Fund with additional support from the WHO. A multipartite core team comprised of the NMEP, the WHO, the U.S. Presidential Malaria Initiative, academia, and the Nigerian Institute of Medical Research was set up to oversee the execution of the 2018 TES. This communication reports best practices adopted to guide its coordination, and lessons learned during in the process, including applying developed standard operating procedures, powering the sample size adequately for each site to report independently, training the investigating team for fieldwork, facilitating stratification of decisions, determining efficiencies derived from monitoring and quality assessment, and optimizing logistics. The planning and coordination of the 2018 TES activities is a model of a consultative process for the sustainability of antimalarial resistance surveillance in Nigeria.

Colon-Targeting Angelica sinensis Polysaccharide Nanoparticles with Dual Responsiveness for Alleviation of Ulcerative Colitis.

Intestinal immune dysfunction and gut microbiota dysbiosis are critically causative factors in the pathogenesis of ulcerative colitis (UC); however, the current first-line drugs for UC treatment in clinics often remain great challenges due to their nontargeting therapeutic efficacy and severe side effects. In the current study, colon-targeting nanoparticles based on Angelica sinensis polysaccharide with pH- and redox-responsiveness were fabricated to specifically release the naturally active compound ginsenoside Rh2 in the colonic inflammatory site, which greatly alleviated the UC symptoms and improved the gut microbial homeostasis. These dual responsive Rh2-loaded nanoparticles (Rh2/LA-UASP NPs) with a particle size of 117.00 ± 4.80 nm were prepared using the polymer LA-UASP obtained by grafting A. sinensis polysaccharide with urocanic acid and α-lipoic acid (α-LA). As expected, these Rh2/LA-UASP NPs achieved dual pH- and redox-responsive drug release at pH 5.5 and 10 mM GSH. The stability, biocompatibility, and in vivo safety experiments exhibited these prepared nanoparticles had excellent colon-targeting ability and significant accumulation of Rh2 in the inflammatory colon. Meanwhile, these Rh2/LA-UASP NPs could escape from lysosomes and be efficiently internalized into intestinal mucosal cells, thereby effectively inhibiting the release of proinflammatory cytokines. The animal experiments indicated that Rh2/LA-UASP NPs significantly improved the integrity of intestinal mucosa and increased the colon length compared with UC mice. Additionally, the weight loss, histological damage, and inflammation level were greatly ameliorated. The homeostasis of intestinal flora and the level of short-chain fatty acids (SCFAs) were significantly improved after being treated with Rh2/LA-UASP NPs in UC mice. Our study proved that these Rh2/LA-UASP NPs with dual pH-and redox-responsiveness are promising candidates for UC treatment.

Sulfonylated Indeno[1,2-c]quinoline Derivatives as Potent EGFR Tyrosine Kinase Inhibitors.

The epidermal growth factor receptor (EGFR) has been considered a potential target for lung cancer therapy due to its essential role in regulating the survival and proliferation of cancer cells. Although erlotinib, a potent EGFR tyrosine kinase (EGFR-TK) inhibitor, has been used as the first-line drug for lung cancer treatment, acquired drug resistance caused by the T790M secondary mutation of EGFR-TK inevitably develops after a median response duration of 9-13 months. Thus, the search for promising compounds to effectively target EGFR-TK has become an imperative necessity. In this study, the kinase inhibitory activities of a series of sulfonylated indeno[1,2-c]quinolines (SIQs) against EGFR-TK were experimentally and theoretically investigated. Among the 23 SIQ derivatives studied, eight compounds showed enhanced EGFR-TK inhibitory activity (IC50 values of ca. 0.6-10.2 nM) compared to the known drug erlotinib (IC50 of ∼20 nM). In a cell-based assay in human cancer cell lines with EGFR overexpression (A549 and A431 cells), the eight selected SIQs all showed more significant cytotoxicity against A431 than A549 cells, consistent with the higher EGFR expression in A431 cells. Molecular docking and FMO-RIMP2/PCM calculations revealed that SIQ17 occupies the ATP-binding site of EGFR-TK, where its sulfonyl group is mainly stabilized by C797, L718, and E762 residues. Triplicate 500 ns molecular dynamics (MD) simulations also confirmed the binding strength of SIQ17 in complex with EGFR. Overall, the potent SIQ compounds obtained in this work could be further optimized for developing novel anticancer drug candidates targeting EGFR-TK.

E060 Testing a new prototype osteoporosis shared decision-making intervention in UK Fracture Liaison Services: patient and clinician perspectives of ‘iFraP’

Abstract Background/Aims Shared decision-making (SDM) is a joint process in which a person and healthcare professional work together to reach decisions about care. The Improving uptake of Fracture Prevention drug treatments (iFraP) study developed a prototype theoretically-informed intervention consisting of a computerised decision aid (DA) and Fracture Liaison Service (FLS) clinician training package to improve SDM about osteoporosis medicines. This abstract focuses on the early prototype iFraP in-practice testing phase that explored perceived acceptability of iFraP by those using it, barriers to, and facilitators of, implementation of the prototype iFraP in practice, and necessary changes required ahead of a full-scale randomised controlled trial (RCT). Methods In-practice testing was conducted at one FLS site. Participating FLS clinicians completed the prototype iFraP clinician training package, covering enhanced communication skills (e.g SDM, risk communication and health literacy techniques). Consenting patients with a recent fragility fracture referred for an FLS consultation were eligible to participate. Three cycles of iFraP in-practice testing were completed. Each cycle included observed iFraP consultations and post-consultation patient think-aloud interviews. After each complete cycle, the FLS clinician(s) was interviewed. Data were analysed using a framework approach. The Theoretical Framework of Acceptability and Theoretical Domains Framework facilitated understanding of iFraP acceptability and barriers to, and facilitators of, implementation. Results Four FLS clinicians (3 nurses, 1 allied health professional) completed the iFraP clinician training and delivered 10 iFraP consultations (8 face-to-face, 2 telephone) using the iFraP DA with participating patients (n = 3 cycle 1; n = 3 cycle 2; n = 4 cycle 3). In total, the four FLS clinicians completed 7 interviews, with all 10 patients completing a post-consultation interview. Findings demonstrate that patients and clinicians perceived the prototype iFraP DA as acceptable. Clinicians suggested that the iFraP DA supported them to elicit and address patient perceptions, increase patient involvement, and provide patients with sufficient and accessible information. Patients and clinicians expressed wanting to use iFraP in future FLS appointments, with some clinicians continuing to use the DA outside of iFraP in-practice testing. Identified barriers included: some clinicians questioned both the use of iFraP DA with patients not recommended first-line drug treatment; and, expressed concern that iFraP DA could extend the consultation length. Our findings demonstrated necessary updates to meet user needs and overcome identified barriers to iFraP intervention use, including presentation and structural changes to support integration of the iFraP DA into the consultation flow. Clinicians also provided feedback to improve the training package, including the need to demonstrate the DA in use, and increased allocated time to practice using the DA. Conclusion The iFraP intervention was perceived as acceptable, with the potential to support SDM about osteoporosis medicines. The iFraP RCT will now test our improved iFraP intervention across 3 FLS sites in England. Disclosure L. Bullock: None. N. Tyler: None. M. Thompson: None. S. Ryan: Grants/research support; the General Nursing Council for England and Wales Trust. J. Lefroy: None. S. Leyland: None. J. Fleming: None. E.M. Clark: None. S. Thomas: Other; owns Prescribing Decision Support Ltd that developed the iFraP decision aid. C. Gidlow: None. C.P. Iglesias-Urrutia: None. T.W. O'Neill: Grants/research support; supported by the NIHR Manchester Biomedical Research Centre. C.D. Mallen: Grants/research support; funded by the NIHR Applied Research Collaboration West Midlands, funded by the NIHR School for Primary Care Research. C. Jinks: Grants/research support; part funded by NIHR Applied Research Collaboration (ARC) West Midlands. Z. Paskins: Grants/research support; funded by the National Institute for Health Research (NIHR) [Clinician Scientist Award (CS-2018-18-ST2-010)/NIHR Academy].

Abstract 6636: Metformin suppresses tumor immune evasion through downregulation of PD-L1 expression in cancer cells and PD-1 expression in NK cells and T cells

Abstract Up-regulation of programmed cell death 1 (PD-1) receptor on T cells and its ligand (PD-L1) on cancer cells is reported in various tumor microenvironment, and the interaction between PD-L1 and PD-1 inhibits the cytotoxic activity of NK cells and T cells, allowing cancer cells to evade immune destruction. Extensive studies suggested that metformin, the most widely used first-line drug for treatment of type 2 diabetes, had a potential efficacy of enhancing anti-tumor immune response. However, the detail mechanisms underlying the efficacy are unknown. Here, we showed that metformin decreases AKT-mediated β-catenin S552 phosphorylation and β-catenin transactivation in an AMPK activation-dependent manner, resulting in reduced CD274 transcription in cancer cells. In the cocultures of cancer cells with NK cells or T cells, cancer cells induced PD-1 protein stability and expression in the NK cells and T cells, these PD-1 upregulation was also observed in infiltrated NK cells and T cells in vivo mouse tumors. Metformin reduced the half-life and expression of PD-1 in an AMPK activation-dependent manner in vitro and in vivo. These inhibitory roles of metformin in PD-L1 expression in cancer cells and in cancer cell-induced PD-1 expression in NK cells and T cells led to ameliorated the cancer cell-reduced cytotoxic activity of NK cells and T cells and inhibited tumor growth in vivo models. These findings suggest that metformin may act as both PD-L1 and PD-1 blockades within tumor microenvironment, providing a mechanistic insight for the efficacy of metformin to improve immunotherapy in human cancer. Citation Format: Su Hwan Park, Jong-Ho Lee. Metformin suppresses tumor immune evasion through downregulation of PD-L1 expression in cancer cells and PD-1 expression in NK cells and T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6636.