First-line Drug For Treatment Research Articles

Alpha-asarone alleviates cutaneous hyperalgesia by inhibiting hyperexcitability and neurogenic inflammation via TLR4/NF-κB/NLRP3 signaling pathway in a female chronic migraine rat model

Migraine is a highly prevalent neurological disorder. Alpha-asarone (ASA), a major active component found in Acorus tatarinowii, plays a crucial role in analgesia and anti-inflammation for neuropathic pain. This study aimed to assess the efficacy of ASA against migraine and elucidate its potential mechanisms using a well-established inflammatory soup (IS) migraine female rat model. Mechanical pain thresholds were assessed daily before IS infusion, followed by post-infusion administration of ASA. Subsequently, spontaneous locomotor activities, exploratory behavior, short-term spatial memory, and photophobia were blindly evaluated after the final drug administration. The rats were then sacrificed for investigation into the underlying mechanisms of action. Network pharmacology was also employed to predict potential targets and pathways of ASA against migraine. The anti-inflammatory activity of ASA and pathway-related proteins were examined in BV2 cells stimulated with lipopolysaccharides (LPS). The results demonstrated that ASA ameliorated cutaneous hyperalgesia and photophobia while improving spatial memory and increasing exploratory behavior in IS rats. ASA attenuated central sensitization-related indicators and excessive glutamate levels while enhancing GABA synthesis. ASA rescued neuronal loss in the cortex and hippocampus of IS rats. Notably, the ability of ASA to improve spatial memory performance in the Y maze test was not observed with sumatriptan, a first-line treatment drug, suggesting the potential involvement of the TLR4 pathway. Moreover, ASA suppressed microglial activation, reduced pro-inflammatory factors, and downregulated TLR4, MyD88, p–NF–κB/NF-κB, NLRP3, caspase-1, IL-1β, and IL-18. Overall, ASA demonstrated its potential to alleviate hyperalgesia and improve behavioral performance in migraine rats by inhibiting hyperexcitability and microglia-related inflammation.

Andrographolide sensitizes glioma to temozolomide by inhibiting DKK1 expression.

Temozolomide (TMZ) is the first-line chemotherapeutic drug for gliomas treatment. However, the clinical efficacy of TMZ in glioma patients was very limited. Therefore, it is urgently needed to discover a novel approach to increase the sensitivity of glioma cells to TMZ. Western blot, immunohistochemical staining, and qRT-PCR assays were used to explore the mechanisms underlying TMZ promoting DKK1 expression and andrographolide (AND) inhibiting DKK1 expression. HPLC was used to detect the ability of andrographolide (AND) to penetrate the blood-brain barrier. MTT assay, bioluminescence images, magnetic resonance imaging (MRI) and H&E staining were employed to measure the proliferative activity of glioma cells and the growth of intracranial tumors. TMZ can promote DKK1 expression in glioma cells and brain tumors of an orthotopic model of glioma. DKK1 could promote glioma cell proliferation and tumor growth in an orthotopic model of glioma. Mechanistically, TMZ increased EGFR expression and subsequently induced the activation of its downstream MEK-ERK and PI3K-Akt pathways, thereby promoting DKK1 expression in glioma cells. Andrographolide inhibited TMZ-induced DKK1 expression through inactivating MEK-ERK and PI3K-Akt pathways. Andrographolide can cross the blood-brain barrier, the combination of TMZ and andrographolide not only improved the anti-tumor effects of TMZ but also showed a survival benefit in an orthotopic model of glioma. Andrographolide can enhance anti-tumor activity of TMZ against glioma by inhibiting DKK1 expression.

The anthraquinone derivative KA-4s reduces energy metabolism and enhances the sensitivity of ovarian cancer cells to cisplatin.

Ovarian cancer is the leading cause of death from female gynecological cancers. Cisplatin (DDP)is a first-line drug for ovarian cancer treatment. Due to DDP resistance, there is an urgent need for novel therapeutic drugs with improved antitumor activity. AMPK-mediated metabolic regulatory pathways are related to tumor drug resistance. Our study aimed to determine the relationship between reversing DDP resistance with the anthraquinone derivative KA-4s and regulating AMPK energy metabolism in ovarian cancer. The results showed that KA-4s inhibited the proliferation of ovarian cancer cells. The combination of KA-4s with DDP effectively promoted drug-resistant ovarian cancer cell apoptosis and inhibited cell migration and invasion. Moreover, KA-4s decreased the intracellular ATP level and increased the calcium ion level, leading to AMPK phosphorylation. Further studies suggested that the AMPK signaling pathway may be involved in the mechanism through which KA-4s reduce drug resistance. KA-4s inhibited mitochondrial respiration and glycolysis; downregulated the glucose metabolism-related proteins GLUT1 and GLUT4; the lipid metabolism-related proteins SREBP1 and SCD1; and the drug resistance-related proteins P-gp, MRP1, and LRP. The inhibitory effect of KA-4s on GLUT1 was confirmed by the application of the GLUT1 inhibitor BAY-876. KA-4s combined with DDP significantly increased the expression of p-AMPKand reduced the expression of P-gp. In a xenograft model of ovarian cancer, treatment with KA-4s combined with DDP reduced energy metabolism and drug resistance, inducing tumor apoptosis. Consequently, KA-4s might be evaluated as a new agent for enhancing the chemotherapeutic efficacy of treatment for ovarian cancer.

The impact of oxygen content on Staphylococcus epidermidis pathogenesis in ocular infection based on clinical characteristics, transcriptome and metabolome analysis.

This study aims to delineate the etiology and prevalence of isolated pathogens, along with the clinical characteristics of endophthalmitis patients over a 9-year period at hospital in Southwest of China. Additionally, we investigating the metabolic and cellular processes related to environmental factors may offer novel insights into endophthalmitis. We analyzed data pertaining to endophthalmitis patients treated at the Affiliated Hospital of Yunnan University from 2015 to 2023. According to our clinical data, we conducted an experiment based on transcriptomics and metabolomics analysis to verify whether environmental factors affect behavior of S. epidermidis by culturating S. epidermidis under oxic and microoxic condition. In this study, 2,712 fungi or bacteria strains have been analyzed, gram-positive bacteria constituted 65.08%, with S. epidermidis being the most predominant species (25.55%). Ophthalmic trauma was the primary pathogenic factor for S. epidermidis ocular infections. Regarding fluoroquinolones, S. epidermidis exhibited the higher resistance rate to levofloxacin than moxifloxacin. Moreover, our investigation revealed that S. epidermidis in microoxic environment increase in energy metabolism, amino acid metabolism, and membrane transport. Our findings underscore the significance of S. epidermidis as a crucial pathogen responsible for infectious endophthalmitis. It is crucial to exercise vigilance when considering Levofloxacin as the first-line drug for empiric endophthalmitis treatment. The metabolites alteration observed during the commensal-to-pathogen conversion under microoxic condition serve as a pivotal environmental signal contributing to S. epidermidis metabolism remodeling, toward more pathogenic state.

Identification and Validation of Tumor Microenvironment-Associated Signature in Clear-Cell Renal Cell Carcinoma through Integration of DNA Methylation and Gene Expression.

The tumor microenvironment (TME) is crucial in tumor development, metastasis, and response to immunotherapy. DNA methylation can regulate the TME without altering the DNA sequence. However, research on the methylation-driven TME in clear-cell renal cell carcinoma (ccRCC) is still lacking. In this study, integrated DNA methylation and RNA-seq data were used to explore methylation-driven genes (MDGs). Immune scores were calculated using the ESTIMATE, which was employed to identify TME-related genes. A new signature connected with methylation-regulated TME using univariate, multivariate Cox regression and LASSO regression analyses was developed. This signature consists of four TME-MDGs, including AJAP1, HOXB9, MYH14, and SLC6A19, which exhibit high methylation and low expression in tumors. Validation was performed using qRT-PCR which confirmed their downregulation in ccRCC clinical samples. Additionally, the signature demonstrated stable predictive performance in different subtypes of ccRCC. Risk scores are positively correlated with TMN stages, immune cell infiltration, tumor mutation burden, and adverse outcomes of immunotherapy. Interestingly, the expression of four TME-MDGs are highly correlated with the sensitivity of first-line drugs in ccRCC treatment, especially pazopanib. Molecular docking indicates a high affinity binding between the proteins and pazopanib. In summary, our study elucidates the comprehensive role of methylation-driven TME in ccRCC, aiding in identifying patients sensitive to immunotherapy and targeted therapy, and providing new therapeutic targets for ccRCC treatment.

Similarities and differences of bone marrow and peripheral blood samples from acute myeloid leukemia patients in terms of cellular heterogeneity and ex-vivo drug sensitivity.

Bone marrow (BM) evaluation is the de facto standard for diagnosis, molecular analysis, risk stratification, and therapy response assessment in acute myeloid leukemia (AML), but in patients with a high number of circulating blast cells, the peripheral blood (PB) sample could provide similar information as BM. However, there is no large-scale molecular study comparing the two specimens in terms of their gene expression profiles, cellular heterogeneities, and ex-vivo drug sensitivity. We used (i) the BEAT-AML cohort each with detailed molecular data; (ii) cell-type deconvolution to estimate leukemic and immune cell proportions between specimen types; (iii) differential expression (DE) and drug-cell type association analysis; and (iv) logistic regression models to assess the association between induction therapy response, cell-type composition and first-line drug treatment. Results: We identified 207 patients having BM and 116 patients having PB samples. There was a total of 1271 DE genes (false discovery rate<0.05) between BM and PB; the top enriched pathways in terms of DE genes belong to the immune system pathways. Aggregated ex-vivo drug response profiles from the two specimens were largely similar, as were the cellular components, except for the GMP-like cell type (17% in BM vs. 5% in PB, p-value=2×10-7). Among the specimen-specific results, the GMP-like subtype was associated with multiple drug resistance in BM and the ProMono-like subtype in PB. Several cell types were associated with the response to induction therapy, but the impact of specimen type on the interaction of cell type and cytarabine-associated induction therapy was not statistically significant for most cell types. Conclusions: Even though there are molecular and cellular differences between BM and PB samples, they show many similarities in ex-vivo drug response profiles, indicating the clinical utility of the substantially less-invasive PB samples.

Dual-targeted delivery of temozolomide by multi-responsive nanoplatform via tumor microenvironment modulation for overcoming drug resistance to treat glioblastoma.

Glioblastoma (GBM) is the most aggressive primary brain tumor with low survival rate. Currently, temozolomide (TMZ) is the first-line drug for GBM treatment of which efficacy is unfortunately hindered by short circulation time and drug resistance associated to hypoxia and redox tumor microenvironment. Herein, a dual-targeted and multi-responsive nanoplatform is developed by loading TMZ in hollow manganese dioxide nanoparticles functionalized by polydopamine and targeting ligands RAP12 for photothermal and receptor-mediated dual-targeted delivery, respectively. After accumulated in GBM tumor site, the nanoplatform could respond to tumor microenvironment and simultaneously release manganese ion (Mn2+), oxygen (O2) and TMZ. The hypoxia alleviation via O2 production, the redox balance disruption via glutathione consumption and the reactive oxygen species generation, together would down-regulate the expression of O6-methylguanine-DNA methyltransferase under TMZ medication, which is considered as the key to drug resistance. These strategies could synergistically alleviate hypoxia microenvironment and overcome TMZ resistance, further enhancing the anti-tumor effect of chemotherapy/chemodynamic therapy against GBM. Additionally, the released Mn2+ could also be utilized as a magnetic resonance imaging contrast agent for monitoring treatment efficiency. Our study demonstrated that this nanoplatform provides an alternative approach to the challenges including low delivery efficiency and drug resistance of chemotherapeutics, which eventually appears to be a potential avenue in GBM treatment.

Temporal trend of first-line drug choice and treatment continuity for hypertension among citizens 75 years or over - a register-based, cohort study

BackgroundLimited knowledge of antihypertensive treatment of the elderly potentially impedes effective strategies for hypertension management in this growing patient group. We aimed to investigate temporal trends for first-line drug choice for antihypertensive treatment and treatment continuity among patients ≥75 years from 2000 to 2021. MethodsUsing nationwide Danish registers, patients ≥75 years initiated for the first time on antihypertensive drugs: Angiotensin converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARB), beta blockers (BB), calcium channel blockers (CCB), thiazides, or combinations, were identified. Patients with other indications than hypertension were excluded. Treatment continuity was described using claimed prescriptions the first 180 days following study entry. ResultsFrom 2000 to 2021, 170,769 patients (median age 80 years [interquartile range:77–84], 60.3% female) were included. From 2000 to 2003 to 2015–2021 the proportion of first-line drug choice increased for ACEi (8.7% to 14.9%), ARB (4.1% to 23.9%), and CCB (10.7% to 27.6%), decreased for thiazides (60.6% to 15.9%) and remained stable for BB (12.9% to 14.1%) and combinations (2.9% to 3.6%). For 157,457 patients alive after 180 days, discontinuation was highest among patients initiated on thiazides (28.3%) whereas most patients continued the same single drug regimen if they started on ACEi (55.2%), ARB (65.0%), BB (57.2%) or CCB (59.3%). ConclusionsFrom 2000 to 2021 thiazides have been replaced by ACEi, ARB and CCB. Thiazides had the lowest treatment continuity while ARB appeared preferred slightly over ACEi. Differences in adherence in relation to first-line drug choice may warrant scrutiny regarding recommendations for the elderly.

Adjunctive repetitive transcranial magnetic stimulation therapy’s effectiveness in treating a sample of patients with major depressive disorder refractory to first-line drug treatment

BackgroundThe usefulness of repetitious transcranial magnetic stimulation (rTMS) and its protocols in the treatment of major depressive disorder (MDD) remains controversial. This study aimed to evaluate the efficacy of rTMS in treating a sample of patients with MDD who did not respond to conventional treatment.ResultsThe Hamilton Depression Rating Scale (HDRS) scores for the active rTMS group were 19.66 ± 6.70 at baseline, 12.50 ± 6.69 at 2 weeks, and 11.23 ± 6.59 at 4 weeks. The average HDRS scores for the sham rTMS group were 20.03 ± 7.40 at baseline, 19.36 ± 6.86 at 2 weeks, and 18.53 ± 7.10 at 4 weeks (F = 5.98; p < 0.01). The Clinical Global Impression-Severity Scale (CGI-S) scores were significantly lower in the second and fourth weeks than the baseline due to the significant interaction between time effects and the groups (F = 9.95, p = 0.002). This condition was also similar to the CGI-Improvement Scale and Brief Illness Perception Questionnaire (Brief IPQ), and the intervention group showed a significantly lower score than the control group (p < 0.05).ConclusionsThis study showed that rTMS using the employed protocol was promising for patients with MDD resistant to first-line drug therapy. Further studies are required to ensure our observation.Trial registrationTrial registration number: IRCT20190612043877N1Trial registry Record URL: https://irct.behdasht.gov.ir/trial/63919

Nanoparticles Partially Restore Bacterial Susceptibility to Antibiotics.

The growing resistance of bacteria to antibiotics is one of the main public health problems nowadays. The influence of silver nanoparticle (AgNP) pretreatment of 220 cows with mastitis on the susceptibility of Staphylococcus epidermidis bacteria to 31 antibiotics was studied. The obtained results were compared with the previous results for Escherichia coli, Streptococcus dysgalactiae, and Staphylococcus aureus. For all four bacteria, an increase in susceptibility (9.5-21.2%) to 31 antibiotics after cow treatment with AgNPs was revealed, while after first-line antibiotic drug treatment as expected, the susceptibility decreased (11.3-27.3%). These effects were explained by (1) the increase in the contribution of isolates with efflux effect after antibiotic treatments and its decrease after AgNP treatment and (2) the changes in bacteria adhesion and anti-lysozyme activity after these treatments. The effect of the increasing antibacterial activity of antibiotics after AgNP treatment was the most pronounced in the case of E. coli and was minimal in the case of S. epidermidis. With AgNP treatment, the time of recovery decreased by 26.8-48.4% compared to the time of recovery after treatment with the first-line antibiotic drugs. The AgNP treatment allows for achieving the partial restoration of the activity of antibiotics.

Exposure to resistant fungi across working environments and time

Antifungal resistance has emerged as a significant health concern with increasing reports of resistant variants in previously susceptible species. At present, little is known about occupational exposure to antifungal-resistant fungi. This study aimed to investigate Danish workers' occupational exposure to airborne fungi resistant to first-line treatment drugs. A retrospective study was performed on a unique collection of personal exposure samples gathered over a twenty-year period from Danish working environments, in sectors including agriculture, animal handling, waste management, and healthcare. A total of 669 samples were cultivated at 37 °C and fungal colonies were identified using MALDI-TOF MS. Subsequently, identification was confirmed by amplicon sequencing the genes of calmodulin and beta-tubulin to unveil potential cryptic species.Infectious fungi (495 isolates from 23 species) were tested for resistance against Itraconazole, Voriconazole, Posaconazole, and Amphotericin B. Working environments were highly variable in the overall fungal exposure, and showed vastly different species compositions. Resistance was found in 30 isolates of the species Aspergillus fumigatus (4 of 251 isolates), A. nidulans (2 of 13), A. niger complex (19 of 131), A. versicolor (3 of 18), and A. lentulus (2 of 2). Sequence analysis revealed several cryptic species within the A. niger complex including A. tubingensis, A. luchuensis, and A. phoenicis. Among the resistant A. fumigatus isolates, two contained the well-described TR34/L98H mutation in the cyp51A gene and promoter region, while the remainder harbored silent mutations.The results indicate that the working environment significantly contributes to exposure to resistant fungi, with particularly biofuel plant workers experiencing high exposure. Differences in the prevalence of resistance across working environments may be linked to the underlying species composition.

Evaluation of the Modulatory Effects of Capsicum Chinensis Methanol Extract in Streptozotocin-Induced Diabetic Neuropathic Pain in Mice

Diabetes is one of the common causes of neuropathic pain. The first-line treatment drugs used in alleviating neuropathic pain can cause adverse effects. Therefore, the aim of this study is to evaluate the analgesic property of Capsicum chinensis, since the plant was reported to be used against chronic pain in traditional medicine. Streptozotocin-induced diabetes was adopted to model neuropathy in mice and the antihyperalgesic effect of the extract was evaluated using a hot plate test, cold allodynia test, and Randall- Selitto paw pressure test. The plasma level of pain-associated inflammatory biomarkers like interleukin-6 (IL-6) and tissue necrotic factor-α (TNF-α) was also measured. Treatment with varying doses of extract (1, 2.5, and 5 mg/kg) significantly (p &lt; 0.05) increased the mean reaction time to thermal pain during hot and cold plate tests. During the Paw pressure test, reaction time was significantly prolonged in the treatment groups and the plasma level of TNF-α and IL-6 were reduced (p &lt; 0.05). The extract showed a better antihyperalgesic effect than the positive control drug (gabapentin). The result obtained showed that Capsicum chinensis extract can alleviate diabetes neuropathic pain in mice models with a better analgesic effect thanthe control drug (gabapentin).

NQO1 Mediates Lenvatinib Resistance by Regulating ROS-induced Apoptosis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated death worldwide. As a first-line drug for advanced HCC treatment, lenvatinib faces a significant hurdle due to the development of both intrinsic and acquired resistance among patients, and the underlying mechanism remains largely unknown. The present study aims to identify the pivotal gene responsible for lenvatinib resistance in HCC, explore the potential molecular mechanism, and propose combinatorial therapeutic targets for HCC management. Cell viability and colony formation assays were conducted to evaluate the sensitivity of cells to lenvatinib and dicoumarol. RNA-Seq was used to determine the differences in transcriptome between parental cells and lenvatinib-resistant (LR) cells. The upregulated genes were analyzed by GO and KEGG analyses. Then, qPCR and Western blotting were employed to determine the relative gene expression levels. Afterwards, the intracellular reactive oxygen species (ROS) and apoptosis were detected by flow cytometry. PLC-LR and Hep3B-LR were established. There was a total of 116 significantly upregulated genes common to both LR cell lines. The GO and KEGG analyses indicated that these genes were involved in oxidoreductase and dehydrogenase activities, and reactive oxygen species pathways. Notably, NAD(P)H:quinone oxidoreductase 1 (NQO1) was highly expressed in LR cells, and was involved in the lenvatinib resistance. The high expression of NQO1 decreased the production of ROS induced by lenvatinib, and subsequently suppressed the apoptosis. The combination of lenvatinib and NQO1 inhibitor, dicoumarol, reversed the resistance of LR cells. The high NQO1 expression in HCC cells impedes the lenvatinib-induced apoptosis by regulating the ROS levels, thereby promoting lenvatinib resistance in HCC cells.

In vitro activity of ceftazidime/avibactam, cefiderocol, meropenem/vaborbactam and imipenem/relebactam against clinical strains of the Stenotrophomonas maltophilia complex.

Infections caused by Stenotrophomonas maltophilia and related species are increasing worldwide. Unfortunately, treatment options are limited, whereas the antimicrobial resistance is increasing. We included clinical isolates identified as S. maltophilia by VITEK 2 Compact. Ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam, cefiderocol, quinolones, and tetracycline family members were evaluated by broth microdilution method and compared with first-line treatment drugs. Minimum inhibitory concentrations (MICs) were reported for all antibiotics. We sequenced the Whole Genome of cefiderocol resistant strains (CRSs) and annotated their genes associated with cefiderocol resistance (GACR). Presumptive phylogenetic identification employing the 16S marker was performed. One hundred and one clinical strains were evaluated, sulfamethoxazole and trimethoprim, levofloxacin and minocycline showed susceptibilities of 99.01%, 95.04% and 100% respectively. Ceftazidime was the antibiotic with the highest percentage of resistance in all samples (77.22%). Five strains were resistant to cefiderocol exhibiting MIC values ≥ 2 μg/mL (4.95%). The β-lactamase inhibitors meropenem/vaborbactam and imipenem/relebactam, failed to inhibit S. maltophilia, preserving both MIC50 and MIC90 ≥64 μg/mL. Ceftazidime/avibactam restored the activity of ceftazidime decreasing the MIC range. Tigecycline had the lowest MIC range, MIC50 and MIC90. Phylogeny based on 16S rRNA allowed to identify to cefiderocol resistant strains as putative species clustered into Stenotrophomonas maltophilia complex (Smc). In these strains, we detected GARCs such as Mutiple Drug Resistance (MDR) efflux pumps, L1-type β-lactamases, iron transporters and type-1 fimbriae. Antimicrobial resistance to first-line treatment is low. The in vitro activity of new β-lactamase inhibitors against S. maltophilia is poor, but avibactam may be a potential option. Cefiderocol could be considered as a potential new option for multidrug resistant infections. Tetracyclines had the best in vitro activity of all antibiotics evaluated.

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&lt;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.