Pharmacological Research Articles

Review of the monograph by Kolbin A. S., Zyryanov S. K., Belousov D. Yu. "Pharmacovigilance" 2025

The 2nd revised and supplemented edition of “Pharmacovigilance” has been published. This book discusses the drug safety and pharmacovigilance systems from the viewpoint of clinical pharmacology. The history of drug safety studies is given in details. The main definitions and classifications of adverse events are presented below. A separate chapter will examine the pharmacovigilance system in the EAEU member states. The textbook is intended for students, residents, postgraduates, clinical pharmacologists, physicians of other specialties, holders of registration certificates, and researchers.

Assessment of quality of presentation of clinical trial results in Russia in accordance with CONSORT standards

The gold standard for presenting evidence of the effectiveness and safety of medical procedures is randomized controlled trials (RCTs). For the research results to be available to other specialists and have potential weight in the scientific community, they must be described and published in accordance with generally accepted international standards, CONSORT, or Consolidated standards of reporting trials.Objective: to analyze the quality of presenting the results of clinical trials in the Russian Federation in accordance with CONSORT standards.Materials and methods. The following Russian journals were selected for the study: "Scientific and Practical Rheumatology", "Good Clinical Practice", "Social and Clinical Psychiatry", "S. S. Korsakov Journal of Neurology and Psychiatry". The selection of target journals was based on two main indicators of the journal rating in the Russian Science Citation Index; according to the SCIENCE INDEX rating and the rating of psychiatric journals by the impact factor RSCI 2016. Journals in the fields of biomedicine (Scientific and Practical Rheumatology), clinical pharmacology (Good Clinical Practice), and journals in the fields of psychology and psychiatry (Social and Clinical Psychiatry, S. S. Korsakov Journal of Neurology and Psychiatry) were selected. Each article was assessed according to the CONSORT checklist items, and the presence or absence of data on the presented items was noted. When studying the articles, the presence or absence of a flowchart in the article was also analyzed, which significantly improves the quality of the written article and compliance with international standards for the design of articles for medical journals.Results. The articles analyzed with the results of RCTs in journals met most of the necessary criteria. The authors paid the least attention to such details of the methodology when publishing a description of the sample calculation (2 out of 5 publications), the type of randomization (2 out of 5 publications), the mechanism of blinding participants (3 out of 5 publications), and implementation and masking (1 out of 5 publications). The inaccessibility of this information may have distorted the reader’s perception and trust in the results.Conclusion. The results show that the reviewed Russian medical journals declare requirements and recommendations for the publication of articles in accordance with the CONSORT standards. To increase readers' confidence in the practical and scientific significance of RCTs, it is necessary to consider the CONSORT requirements and strive to follow them.

Novel Approaches to Monitor Pharmacokinetics and Metabolism of Gemcitabine-Ibandronate Conjugate in Mice and Dogs

Background. The use of the bone-seeking properties of bisphosphonates (BPs) to target the delivery of therapeutic drugs is a promising approach for the treatment of bone metastases. Currently, the most advanced example of this approach is a gemcitabine-ibandronate conjugate (GEM-IB), where the bone-targeting BP ibandronate (IB) is covalently linked to the antineoplastic agent gemcitabine (GEM) via a spacer phosphate group. In the present study, we describe the development of a new analytical platform to evaluate the metabolism and pharmacokinetics of GEM-IB in mice and dogs and the results of proof-of-concept studies assessing the pharmacokinetics of GEM-IB in dogs and mice. Methods. We validated analytical platforms to analyze GEM-IB and five of its major metabolites IB, gemcitabine-5′-phosphate (GEMMP), gemcitabine (GEM), 2′,2′-difluoro-2′-deoxyuridine-5′-phosphate (dFdUMP), and 2′,2′-difluoro-2′-deoxyuridine (dFdU) and performed proof-of-concept pharmacokinetic studies in mice (5 mg/kg i.p.) and dogs (5 mg/kg i.v.). Results. Intra- and inter-run accuracy and imprecision (3 days) of the assays met the (FDA) acceptance criteria. The proof-of-concept plasma pharmacokinetic studies in mice showed AUCs of 1278, 10,652, 405, 38, 1063, 3389, and 38 h·ng/mL for GEM-IB, IB, GEMMP, dFdU-MP, GEM, and dFdU, respectively. In dog plasma, AUCs of 295, 5725, 83, 11, 1625, and 6569 h·ng/mL were observed for GEM-IB, IB, GEMMP, dFdUMP, GEM, and dFdU. Conclusions. Pharmacokinetic studies in dogs and mice showed that GEM-IB is rapidly converted to IB and GEM; dFdU is formed (from GEM) with a delay. The rapid disappearance of GEM-IB from circulation could be explained by a combination of metabolism and rapid distribution to tissue/bone.

Mutated IL-32θ (A94V) inhibits COX2, GM-CSF and CYP1A1 through AhR/ARNT and MAPKs/NF-κB/AP-1 in keratinocytes exposed to PM10

Exposure to particulate matter (PM) in the air harms human health. Most studies on particulate matter’s (PM) effects have primarily focused on respiratory and cardiovascular diseases. Recently, IL-32θ, one of the IL-32 isoforms, has been demonstrated to modulate cancer development and inflammatory responses. This study revealed that one-point mutated IL-32θ (A94V) plays an important role in attenuating skin inflammation. IL-32θ (A94V) inhibited PM-induced COX-2, a pro-inflammatory cytokine GM-CSF and CYP1A1 in PM-exposed human keratinocytes HaCaT cells. IL-32θ (A94V) modulating effects were mediated via down-regulating ERK/p38/NF-κB/ AP-1 and AhR/ARNT signaling pathways. Our study indicates that PM triggers skin inflammation by upregulating COX-2, GM-CSF and CYP1A1 expression. IL-32θ (A94V) suppresses the expressions of COX-2, GM-CSF, and CYP1A1 by blocking the nuclear translocation of NF-κB and AP-1, as well as inhibiting the activation of the AhR/ARNT signaling pathway. Our findings offer valuable insights into developing therapeutic strategies and potential drugs to mitigate PM-induced skin inflammation by inhibiting the ERK/p38/NF-κB/AP-1 and AhR/ARNT signaling pathways.

A review of the Bovis Calculus’s intervention mechanism and clinical application in ischemic stroke

BackgroundBovis Calculus (BC), also named Niuhuang in Chinese, is utilized as a resuscitation drug in Traditional Chinese Medicine (TCM) for the treatment of neurological disorders. Ischemic stroke (IS) is a significant global public health issue that currently lacks safe and effective therapeutic drugs. Ongoing efforts are focused on identifying effective treatment strategies from Traditional, Complementary, and Integrative Medicine. Noticeably, BC has been used in TCM for thousands of years to prevent or treat IS-related diseases.MethodsThe historical origins of BC in the treatment of IS were investigated through the examination of ancient Chinese medical texts. Furthermore, the chemical components of BC were analyzed, and its mechanisms of action against IS were summarized using literature sourced from databases such as Web of Science, PubMed, and China National Knowledge Infrastructure. Information on Chinese medicine preparations and clinical reports was also integrated to provide an overview of modern applications and safety considerations.ResultsBC mainly includes chemical components such as bile pigments, bile acids, cholesterol, proteins amino acids, and trace elements. Additionally, the efficacy of BC in treating cerebral ischemia/reperfusion injury (CI/RI) is certain, particularly due to the components of bile pigments, bile acids, and amino acids that can interfere with the enzymatic cascade reaction of CI/RI through multiple components, targets, and pathways. The active components of BC exert neuroprotective effects by reducing microcirculation disturbance, excitatory amino acid toxicity, and oxidative stress injury in the acute stage; inhibiting inflammatory injury, apoptosis, and blood-brain barrier (BBB) disruption in the subacute stage; and promoting angiogenesis and neurogenesis in the restoration stage. Furthermore, as a crude drug, BC appears in many Chinese patent medicine (CPM) preparations for the treatment of IS, and clinical and preclinical studies have proved its safety.ConclusionThe use of BC in the treatment of IS has a long history, proven efficacy, and widespread application. Future efforts should focus on elucidating its mechanisms of action and exploring its applications.

Impulse control and correlation to dopamine agonist serum concentrations in people with Parkinson's disease

BackgroundImpaired impulse control is often seen in Parkinson’s disease (PD) patients using dopamine agonists.MethodsWe performed a therapeutic drug monitoring study of 100 PD patients using ropinirole or pramipexole extended release. Three blood samples were collected on the same day. Serum concentrations were measured, and 24 h area under the curve (AUC) calculated. The validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) was used for assessing impulse control.ResultsTotal ropinirole drug exposure showed weak, but significant correlation to the QUIP-RS score. No correlation between pramipexole serum concentrations and QUIP-RS was found. In ropinirole patients, both agonist dose and total dopaminergic treatment were correlated with QUIP-RS. Duration of ropinirole treatment correlated with impaired impulse control, and duration of dopaminergic treatment of any type correlated with QUIP-RS scores in both ropinirole and pramipexole patients.ConclusionsOur main finding is that impaired impulse control is correlated to both total drug exposure (AUC) and dopamine agonist dose for ropinirole, but not for pramipexole. These observations indicate that different strategies may be useful for treating PD patients with impaired impulse control: ropinirole dose reduction could be beneficial, whereas pramipexole treatment may have to be stopped.

Trends in ready-to-use portable electrochemical sensing devices for healthcare diagnosis.

Compared withprevious decades, healthcare has emerged as a key global concern in light of the recurrent outbreak of pandemics. The initial stage in the provision of healthcare involves the process of diagnosis. Countries worldwide advocate for healthcare research due to its efficacy and capacity to assist diverse populations. Enhanced levels of healthcare management can be attained by the implementation of rapid diagnostic procedures and cognitive data analysis. Therefore, there is a constant need for smart therapeutics, analytical tools, and diagnostic systems to improve health and well-being. The past decade witnessed enormous growth in the sensing detection systems integrated into smartphones with printed electrodes and wearable patches for the screening of various healthcare diagnostics biomarkers and therapeutic drugs. This review focuses on the expansion of point-of-care technologies and their incorporation into a broader array of portable devices, a critical aspect in the context of decentralized societies and their healthcare systems. Discussions are broadly focused on the different sensing platforms such as solid electrodes, screen-printed electrodes, and paper-based sensing strategies for the detection of various biomarkers and therapeutic drugs. We also discuss the next-generation healthcare wearable sensing device importance and future research possibilities. Finally, theportable electrochemical sensing devices and their future perspective developments towards healthcare diagnosisare critically summarized.

Investigator-Initiated Clinical Pharmacokinetic Studies in Resource-Limited Settings: Minimal Requirements and Practical Guidance.

Clinical pharmacology studies are critical for determining the efficacy and safety of drugs. Due to the resource-intensive nature of these studies, most have been conducted in high-income countries, leading to a significant gap in clinical pharmacology data for patients in low- and middle-income countries. This paper provides an overview of the minimal requirements for performing a clinical pharmacology investigator-initiated trial (IIT), including pharmacokinetic sampling. We identify common challenges in resource-limited settings and propose strategies to overcome them. This guideline covers regulatory approval, participant recruitment, drug storage, sample collection and handling, transport, bioanalytical analysis, and data management tailored to the constraints of resource-limited settings. Strategies are proposed to minimize resource demands, including simplified study designs, the use of technologies like whole blood microsampling, and opportunities for collaboration. The goal is to provide practical guidance for those seeking to perform a clinical pharmacology IIT in resource-limited settings to improve safe and effective drug treatment for patients worldwide. Beyond the scope of this guideline is a detailed step-by-step guide on how to perform clinical pharmacology studies.

Usefulness of a TDM-Guided Approach for Optimizing Teicoplanin Exposure in the Treatment of Secondary Bloodstream Infections Caused by Glycopeptide-Susceptible Enterococcus faecium

To assess the clinical usefulness of teicoplanin optimized by means of a therapeutic drug monitoring (TDM)-guided approach for treating secondary bloodstream infections (BSIs) caused by Enterococcus faecium. Hospitalized patients having in the period 1 March 2021–31 October 2024 a documented BSI caused by glycopeptide-susceptible Enterococcus faecium being treated with teicoplanin as definitive targeted therapy optimized by means of a real-time TDM-guided expert clinical pharmacological advice (ECPA) program were retrospectively included. Teicoplanin trough concentrations (Cmin) ranging from 20 to 30 mg/L were defined as the desired target of efficacy based on international guidelines. Univariate analysis was performed for assessing variables potentially associated with microbiological failure (defined as persistence at the infection site of the index Enterococcus faecium strain after more than 7 days from starting treatment as documented by follow-up blood cultures). Overall, 67 patients (median age 70 years; male 55.2%) were included. Catheter-related BSIs (50.7%) and intrabdominal/biliary tract (29.9%) infections were the main sources of Enterococcus faecium BSI. The desired target of teicoplanin Cmin was attained in 62.7% of patients at the first TDM assessment and significantly increased to 85.1% (p = 0.003) at subsequent TDM-guided ECPA instances during the overall treatment course. Microbiological eradication was obtained in 95% of cases (63/67). In the univariate analysis, failing effective source control was the only variable associated with an increased risk of microbiological failure (75.0% vs. 12.7%; p = 0.01). Targeted TDM-guided teicoplanin therapy, coupled with effective source control of the primary infection site by granting microbiological eradication in the vast majority of cases, may be considered a reasonable strategy for managing glycopeptide-susceptible Enterococcus faecium secondary BSIs.

NLRP3 Inflammasome-Mediated Osteoarthritis: The Role of Epigenetics

The prevalence of osteoarthritis (OA) notably surges with age and weight gain. The most common clinical therapeutic drugs are painkillers, yet they cannot impede the deteriorating course of OA. Thus, understanding OA’s pathogenesis and devising effective therapies is crucial. It is generally recognized that inflammation, pyroptosis, and OA progression are tightly linked. The activation of NLRP3 inflammasome can lead to the discharge of the pro-inflammatory cytokines Interleukin-1β and IL-18, intensifying subsequent inflammatory reactions and promoting OA development. Conversely, the imbalance caused by deacetylase-regulated NLRP3 inflammasome underlies the chronic mild inflammation related to degenerative diseases. Therefore, this article expounds on the mechanism of OA pathogenesis and the role of histone deacetylases (HDACs) in NLRP3 inflammasome-triggered OA, and illustrates the application of HDAC inhibitors in OA, striving to provide more insights into novel OA treatment approaches.

Pegylated NIR Fluorophore-Conjugated OBHSA Prodrug for ERα-Targeted Theranostics with Enhanced Imaging and Long-Term Retention

In recent years, the near-infrared (NIR) fluorescence theranostic system has garnered increasing attention for its advantages in the simultaneous diagnosis- and imaging-guided delivery of therapeutic drugs. However, challenges such as strong background fluorescence signals and rapid metabolism have hindered the achievement of sufficient contrast between tumors and surrounding tissues, limiting the system’s applicability. This study aims to integrate the pegylation strategy with a tumor microenvironment-responsive approach. A novel esterase-activated EPR strategy prodrug, OBHSA-PEG-DCM, was designed. This prodrug links OBHSA, a protein degrader capable of efficient ERα protein degradation, to the PEG-modified fluorescent group (dicyanomethylene-4H-pyran, DCM) via an ester bond. This integration facilitates targeted drug delivery and enhances the retention of the fluorescent group within the tumor, allowing distinct in vivo tumor imaging periods. Experimental results show that, benefiting from overexpressed esterase in cancer cells, OBHSA-PEG-DCM can be efficiently hydrolyzed, releasing OBHSA and pegylated DCM. OBHSA demonstrated potent inhibition against MCF-7 cells (IC50 = 1.09 μM). Simultaneously, pegylated DCM exhibited remarkable in vivo imaging capabilities, lasting up to 12 days in mice, due to the enhanced permeability and retention (EPR) effect. OBHSA-PEG-DCM holds promise as a theranostic agent for ERα-positive breast cancer, offering both therapeutic and diagnostic capabilities. Importantly, this study highlights the utility of pegylated NIR fluorophores for long-circulating drug delivery systems, addressing current challenges in achieving high-contrast tumor imaging and effective targeted drug release.

A green bioanalytical spectrofluorimetric approach for estimation of Avapritinib anti-tumor drug; application to quality control and clinical studies.

Gastrointestinal stromal tumors (GISTs) account for about 80% of the mesenchymal tumors of the GI tract. About 5000-6000 patients are diagnosed in the United States (US) alone, and up to 14.5 cases per million discovered in Europe annually. Avapritinib (AVP) is a potent selective targeted medication that has been recently approved, by the US Food and Drug Administration, in 2020 for treatment of GISTs. AVP is currently considered the first-line treatment for mutant GIST, which is resistant to other medications. This in turn stimulates the need for fast, green, and efficient methods for routine AVP estimation in quality control and clinical studies. The proposed approach designs a spectrofluorimetric tool to estimate AVP in different matrices, based on a nucleophilic substitution reaction. A highly fluorescent product was measured at 535 nm following excitation at 470 nm. The research procedure was bioanalytically validated within AVP range between 80 and 900 ng mL-1, where the limit of quantitation (LOQ) was 15.78 ng mL-1. The developed approach was successfully applied to investigate AVP in content uniformity testing of tablet dosage forms, and biological plasma in AVP pharmacokinetic study. The proposed approach could be recommended for AVP therapeutic drug monitoring.

Identifying MTHFD1 and LGALS4 as Potential Therapeutic Targets in Prostate Cancer Through Multi-Omics Mendelian Randomization Analysis

Background: Prostate cancer remains one of the leading causes of cancer-related mortality in men worldwide. The treatment of it is currently based on surgical removal, radiotherapy, and hormone therapy. It is crucial to improve therapeutic prospects for the diagnosis and treatment of prostate cancer via drug target screening. Methods: We integrated eQTL data from the eQTLGen Consortium and pQTL data from UK Biobank Proteome Plasma Proteins (UKB-PPP) and deCODE health datasets. MR analyses (SMR, heterogeneity in dependent instruments (HEIDI), IVW, Wald ratio, weighted median, and MR-Egger) were used to screen candidate genes associated with prostate adenocarcinoma (PRAD) risk. Candidate genes were further verified through TCGA-based gene expression profile, survival analysis, and immune microenvironment evaluations. TIDE analysis was utilized to investigate gene immunotherapy response. Single-cell RNA sequencing data from the GSE176031 dataset were used to investigate the gene expression patterns. The Drug Bank, Therapeutic Target Database and Drug Signatures Database were utilized to predict targeted drugs for candidate genes. Results: MTHFD1 and LGALS4 were identified as promising therapeutic targets for PRAD, with evidence provided at multi-omics levels. LGALS4 was predominantly expressed in malignant cells and was correlated with enhanced immune checkpoint pathways, increased TIDE scores, and immunotherapy resistance. In contrast, MTHFD1was expressed in both tumor and microenvironmental cells and was associated with poor survival. Drug target prediction suggested that there are no currently approved drugs specifically targeting MTHFD1 and LGALS4. Conclusions: Our study identified MTHFD1 and LGALS4 as potential preventive targets for PRAD. However, future experiments are warranted to assess the utility and effectiveness of these candidate proteins.

Bioinformatic Analysis for Exploring Target Genes and Molecular Mechanisms of Cadmium-Induced Nonalcoholic Fatty Liver Disease and Targeted Drug Prediction.

Cadmium (Cd) is a widely available metal that has been found to have a role in causing nonalcoholic fatty liver disease (NAFLD). However, the detailed toxicological targets and mechanisms by which Cd causes NAFLD are unknown. Therefore, the present work aims to reveal the main targets of action, cellular processes, and molecular pathways by which cadmium causes NAFLD. As shown in the bioinformatics analysis, there were 74 main targets of action for cadmium-induced NAFLD, hemopoietic cell kinase (HCK), EPH receptor A2 (EPHA2), MYC proto-oncogene (MYC), lysyl oxidase (LOX), dipeptidyl peptidase 7 (DPP7), nuclear factor erythroid 2-related factor 2 (NFE2L2), dual specificity phosphatase 6 (DUSP6), CD2 cytoplasmic tail binding protein 2 (CD2BP2), notch receptor 3 (NOTCH3), and phospholipase A2 group IVA (PLA2G4A) were screened as core genes. Testing these core genes in other databases, three differentially expressed genes, HCK, MYC, and DUSP6 were verified and used as targets for drug prediction in DsigDB; decitabine and retinoic acid were screened as potential therapeutic drugs for NAFLD based on the p-value and the combined score. The results of molecular docking showed that the predicted drugs can bind well to the core targets. In conclusion, cadmium is associated with NAFLD; the identified cadmium-toxicity targets, HCK, MYC, and DUSP6, may serve as biomarkers for the diagnosis of NAFLD and predicted drugs, decitabine and retinoic acid may have a potential role in the treatment of NAFLD.

Involvement of HLADQA1*05 in Patients with Inflammatory Bowel Disease Treated with Anti-TNF Drugs

Background: Over the past decade, TNF inhibitors such as Infliximab and Adalimumab have become central to Inflammatory Bowel Diseases treatment, greatly enhancing patient outcomes. However, immunogenicity—where anti-drug antibodies diminish effectiveness—remains an issue, often requiring dose changes or combination therapies. Pharmacogenomics is increasingly applied in IBD to personalise treatment, especially since genetic factors like the HLA-DQA1*05 variant heighten the immunogenicity risk with IFX. This study aims to examine the relationship between the HLA-DQA1*05 variant and response loss or antibody development in patients regularly monitored on IFX or ADA. Methods: Sixty-five paediatric IBD patients were enrolled, with therapeutic drug monitoring (TDM) of IFX and ADA, conducted using immunoenzymatic assays. The presence of the HLA-DQA1*05 T>C allele variant was also tested using a Biomole HLA-DQA1 Real-time PCR kit. Results: The HLA-DQA1*05 rs2097432 T>C allele was present in 54% of patients on IFX and 69% of those on ADA. No statistically significant differences were found between HLA carriers and non-carriers across any of the three analysed groups: IFX, ADA and the overall anti-TNFα. Conclusions: Our study suggests that the HLA-DQA1*05 allele does not increase the risk of secondary loss of response to anti-TNF therapy, likely because most patients were on a combination of anti-TNF agents and immunomodulators, which can lower anti-drug antibody production. Testing for HLA-DQA105 can aid in personalising treatment and optimising therapy to minimise immunogenicity risks.

Potential drug targets for asthma identified through mendelian randomization analysis

BackgroundThe emergence of new molecular targeted drugs marks a breakthrough in asthma treatment, particularly for severe cases. Yet, options for moderate-to-severe asthma treatment remain limited, highlighting the urgent need for novel therapeutic drug targets. In this study, we aimed to identify new treatment targets for asthma using the Mendelian randomization method and large-scale genome-wide association data (GWAS).MethodsWe utilized GWAS data from the UK Biobank (comprising 56,167 patients and 352,255 control subjects) and the FinnGen cohort (including 23,834 patients and 228,085 control subjects). Genetic instruments for 734 plasma proteins and 154 cerebrospinal fluid proteins were derived from recently published GWAS. Bidirectional Mendelian randomization analysis, Steiger filtering, colocalization, and phenotype scanning were employed for reverse causal inference detection, further substantiating the Mendelian randomization results. A protein-protein interaction network was also constructed to reveal potential associations between proteins and asthma medications.ResultsUnder Bonferroni significance conditions, Mendelian randomization analysis revealed causal relationships between seven proteins and asthma. In plasma, we observed that an increase of one standard deviation in IL1R1[1.30 (95% CI 1.20–1.42)], IL7R[1.07 (95% CI 1.04–1.11)], ECM1[1.03 (95% CI 1.02–1.05)], and CD200R1[1.18 (95% CI 1.09–1.27)] were associated with an increased risk of asthma, while an increase in ADAM19 [0.87 (95% CI 0.82–0.92)] was found to be protective. In the brain, each 10-fold increase in IL-6 sRa [1.29 (95% CI 1.15–1.45)] was associated with an increased risk of asthma, while an increase in Layilin [0.61 (95% CI 0.51–0.73)] was found to be protective. None of the seven proteins exhibited a reverse causal relationship. Colocalization analysis indicated that ECM1 (coloc.abf-PPH4 = 0.953), IL-6 sRa (coloc.abf-PPH4 = 0.966), and layilin (coloc.abf-PPH4 = 0.975) shared the same genetic variation as in asthma.ConclusionA causal relationship exists between genetically determined protein levels of IL1R1, IL7R, ECM1, CD200R1, ADAM19, IL-6 sRa, and Layilin (LAYN) and asthma. Moreover, the identified proteins may serve as attractive drug targets for asthma, especially ECM1 and Layilin (LAYN). However, further research is required to comprehensively understand the roles of these proteins in the occurrence and progression of asthma.

A Review of Research and Development on Lung Cancer Drugs

With an incidence of 1.2 million new cases reported annually worldwide, 80% of which are non-small cell lung cancer, the majority of which are advanced at the time of diagnosis and have a poor prognosis, lung cancer continues to be the leading cause of cancer-related mortality in many countries. The effectiveness of chemotherapy for advanced lung cancer is still lacking, despite notable advancements in this area. The most prevalent histologic form of lung cancer is non-small cell lung cancer (NSCLC). Platinum-based chemotherapy is the conventional treatment for individuals with advanced non-small cell lung cancer (NSCLC), although it has a high rate of side effects and is not very effective. In recent years, molecular targeted therapy has become an important therapeutic tool for patients with advanced NSCLC with the continuous development of lung cancer targets and molecular targeted drugs. At present, these drugs have been successfully applied in the clinic and achieved remarkable efficacy, creating a new era of molecularly targeted therapy for NSCLC. The paper summarizes the progress of molecularly targeted therapy for advanced NSCLC. Targeted therapeutic drugs are now widely used in clinical practice and play an important role in tumor treatment, but most of them are resistant after a period of time. In addition, the high price limits their uses in general patients. Therefore, new drugs with lower efficacy, smaller side effects, a longer effective time, and a reasonable price are expected to come out as soon as possible

The effect of an additional pre-extubational loading dose of caffeine citrate on mechanically ventilated preterm infants (NEOKOFF trial): Study protocol for a multicenter randomized clinical trial.

Minimizing the duration of mechanical ventilation is one of the most important therapeutic goals during the care of preterm infants at neonatal intensive care units (NICUs). The rate of extubation failure among preterm infants is between 16% and 40% worldwide. Numerous studies have been conducted on the assessment of extubation suitability, the optimal choice of respiratory support around extubation, and the effectiveness of medical interventions. Since the Caffeine Therapy for Apnea of Prematurity (CAP) trial, caffeine has become one of the essential drugs at NICUs. However, the optimal dosage and timing for adequate effectiveness still need to be more conclusive. Previous studies suggest that higher doses of caffeine treatment increase the success rate of extubation. Therefore, we aim to determine whether using a single additional loading dose of caffeine citrate one hour prior to extubation impacts the success rate of extubation. The study is an open-label, multicenter randomized clinical trial testing the effectiveness and safety of pre-extubational loading dose of caffeine citrate. Inclusion criteria will be infants born before the 32nd gestational week, before the first extubation attempt after at least 48 hours of mechanical ventilation, and a signed parental informed consent. A total of 226 patients will be randomly allocated to either the experimental or control group. The randomization will be stratified by gestational age and antenatal steroid prophylaxis. Preterm infants in the experimental group will receive an additional intravenous (IV) loading dose (20 mg/kg) of caffeine citrate one hour before the first planned extubation, in addition to the standard dosing regimen (20 mg/kg caffeine citrate IV on the first day of life and 5 to 10 mg/kg IV or orally caffeine citrate each consecutive day). Preterm infants in the control group will receive the standard dosing regimen. The primary outcome will be reintubation within 48 hours. A pre-extubational loading dose of caffeine citrate can reduce extubation failure. Obtaining evidence on this feature has the potential to contribute to finding the optimal dosing regimen. The study protocol was approved by the Hungarian Ethics Committee for Clinical Pharmacology of the Medical Research Council and National Institute of Pharmacy and Nutrition (OGYÉI/6838-11/2023). ClinicalTrials.gov identifier NCT06401083 Registered 06. May 2024.; EudraCT number: 2022-003202-77.

1,2,4-triazole-3-carboxamides induces G2/M cell cycle arrest in ovarian cancer cell lines

Introduction. Ovarian cancer is one of the most common gynecological cancers worldwide, which is difficult to diagnose and treat. the high mortality rate from ovarian cancer makes the development of new therapeutic drugs relevant. Ribavirin (RBV), commonly used antiviral agent, revealed the anticancer potential, however, it led to the development of severe side effects as well. RBV derivatives were previously synthesized and tested as putative anticancer drugs in the models of hematological malignancies. The aim of this study was to estimate the anticancer effects of and RBV derivatives (MGs) in ovarian cancer cells in vitro. Material and Methods. Cytotoxic and cytostatic effects of the MGs on ovarian cancer cells (OVCAR3 and OVCAR4) were assessed using the MTT assay and cell counting with trypan blue staining. distribution of cell cycle phases and induction of apoptosis was evaluated using flow cytometry with propidium iodide and annexin V-FITC staining. Results. 1,2,4-triazole-3-carboxamides inhibited the proliferation and induced cell cycle arrest of ovarian cancer cells in vitro. Conclusion. these results provide the rationale for further studies of 1,2,4-triazole-3-carboxamides as anticancer drugs.

Biosimilars in Focus: Evaluating Their Role Compared to Adalimumab in Clinical Practice

Introduction and Purpose: Adalimumab, a TNF-α inhibitor, is a cornerstone treatment for autoimmune and inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Despite its efficacy, the high cost of adalimumab (Humira®) limits accessibility. The emergence of biosimilars offers cost-effective alternatives with comparable efficacy, safety, and immunogenicity. This article reviews the role of adalimumab biosimilars, their clinical equivalence, and potential to address healthcare challenges. Materials and Methods: A comprehensive literature review was conducted to evaluate the structural, functional, and clinical parity of adalimumab biosimilars with the reference product. Key studies on pharmacokinetics, efficacy, safety, therapeutic drug monitoring (TDM), and real-world outcomes were analyzed. Results:Adalimumab biosimilars demonstrate equivalent pharmacokinetic profiles and clinical efficacy across conditions, with comparable remission rates and safety profiles. Innovations, such as citrate-free formulations and advanced delivery devices, enhance patient adherence. Biosimilars significantly reduce treatment costs, increasing accessibility, especially in resource-constrained settings. Challenges remain in patient acceptance and managing therapy transitions. Conclusion:Biosimilars are transformative in addressing the cost barrier of biologic therapies, maintaining therapeutic equivalence to adalimumab while expanding access globally. Enhanced TDM and patient-centered strategies are essential for optimizing outcomes and maximizing their adoption in clinical practice.