Clinical Drug Trials Research Articles

Regulatory landscape with U.S. patient requirements and Clinical Trial Diversity expectations

The Food and Drug Administration (FDA) has an expectation that products filed for marketing authorization have to include data that are representative of the US patient population. Any foreign clinical data that is submitted has to represent an ethnically diverse population that is generated utilizing qualified Principal Investigators (PIs) and conducted according to Good Clinical Practices (GCP) requirements outlined in 21 CFR 312.120, Foreign clinical studies not conducted under an IND. With the recent passing of the Omnibus Legislation, FDA now also has the authority to require Diversity Plans for all Phase 3 clinical trials of new drugs or “as appropriate, another pivotal study of a new drug.” The FDA has released a guidance document, “Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials” (April 2022), for the industry with expectations to update the document in 2023 now that legislation is passed. This whitepaper discusses the FDA guidance and expectations of sponsors with regards to foreign clinical data and the intersection with enrolling ethnically diverse populations in clinical studies.

An Updated Review For Hyperuricemia and Gout Management; Special Focus on the Available Drug Delivery Systems and Clinical Trials.

Hyperuricemia belongs to metabolic syndromes where increased uric acid levels are identified in the blood serum. Such a syndrome could be responsible for kidney stone formation, gout, hypertension, and chronic kidney diseases. It has been reported that cardiovascular risks have been linked with hyperuricemia. Gout is of the most frequent manifestations due to hyperuricemia; its management involves various pharmacological available options and dietary changes. Throughout the literature, various dosage forms are studied as alternative options to the present drug delivery systems. To update and summarize the current information for gout and hyperuricemia management. Authors have performed a thorough literature research from 2010-2023 using keywords such as hyperuricemia, gout, diagnosis, guidelines, drug delivery and clinical trials. The databases used were PubMed, ScienceDirect. According to our inclusion criteria, all studies which include the previous terms, as well as drugs or other molecules that can be applied for gout and/or hyperuricemia management, were added. In this article, authors have summarized the pathogenesis, diagnosis and updated guidelines for gout and hyperuricemia management. Moreover, the authors have reviewed and discussed current drug delivery systems found in the literature, including drugs targeting the above disorders. Finally, the available clinical trials assessing the efficacy of newer drugs or combinations of the past ones, are being discussed. The available drugs and dosage forms are limited, and therefore, scientific society should focus on the development of more efficient drug delivery systems for hyperuricemia and gout management.

Folate Receptor Alpha—A Secret Weapon in Ovarian Cancer Treatment?

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy worldwide. Due to its nonspecific symptoms and unreliable screening tools, EOC is not diagnosed at an early stage in most cases. Unfortunately, despite achieving initial remission after debulking surgery and platinum-based chemotherapy, most patients experience the recurrence of the disease. The limited therapy approaches have encouraged scientists to search for new detection and therapeutic strategies. In this review, we discuss the role of folate receptor alpha (FRα) in EOC development and its potential application as a biomarker and molecular target in designing new EOC screening and treatment methods. We summarize the mechanisms of the action of various therapeutic strategies based on FRα, including MABs (monoclonal antibodies), ADCs (antibody–drug conjugates), FDCs (folate–drug conjugates), SMDCs (small molecule–drug conjugates), vaccines, and CAR-T (chimeric antigen receptor T) cells, and present the most significant clinical trials of some FRα-based drugs. Furthermore, we discuss the pros and cons of different FR-based therapies, highlighting mirvetuximab soravtansine (MIRV) as the currently most promising EOC-targeting drug.

Recent Advances in Therapeutics for the Treatment of Alzheimer's Disease.

The most prevalent chronic neurodegenerative illness in the world is Alzheimer's disease (AD). It results in mental symptoms including behavioral abnormalities and cognitive impairment, which have a substantial financial and psychological impact on the relatives of the patients. The review discusses various pathophysiological mechanisms contributing to AD, including amyloid beta, tau protein, inflammation, and other factors, while emphasizing the need for effective disease-modifying therapeutics that alter disease progression rather than merely alleviating symptoms. This review mainly covers medications that are now being studied in clinical trials or recently approved by the FDA that fall under the disease-modifying treatment (DMT) category, which alters the progression of the disease by targeting underlying biological mechanisms rather than merely alleviating symptoms. DMTs focus on improving patient outcomes by slowing cognitive decline, enhancing neuroprotection, and supporting neurogenesis. Additionally, the review covers amyloid-targeting therapies, tau-targeting therapies, neuroprotective therapies, and others. This evaluation specifically looked at studies on FDA-approved novel DMTs in Phase II or III development that were carried out between 2021 and 2024. A thorough review of the US government database identified clinical trials of biologics and small molecule drugs for 14 agents in Phase I, 34 in Phase II, and 11 in Phase III that might be completed by 2028.

Real-time imaging of cGMP signaling shows pronounced differences between glomerular endothelial cells and podocytes.

Recent clinical trials of drugs enhancing cyclic guanosine monophosphate (cGMP) signaling for cardiovascular diseases have renewed interest in cGMP biology within the kidney. However, the role of cGMP signaling in glomerular endothelial cells (GECs) and podocytes remains largely unexplored. Using acute kidney slices from mice expressing the FRET-based cGMP biosensor cGi500 in endothelial cells or podocytes enabled real-time visualization of cGMP. Stimulation with atrial natriuretic peptide (ANP) or SNAP (NO donor) and various phosphodiesterase (PDE) inhibitors elevated intracellular cGMP in both cell types. GECs showed a transient cGMP response upon particulate or soluble guanylyl cyclase activation, while the cGMP response in podocytes reached a plateau following ANP administration. Co-stimulation (ANP + SNAP) led to an additive response in GECs. The administration of PDE inhibitors revealed a broader basal PDE activity in GECs dominated by PDE2a. In podocytes, basal PDE activity was mainly restricted to PDE3 and PDE5 activity. Our data demonstrate the existence of both guanylyl cyclase pathways in GECs and podocytes with cell-specific differences in cGMP synthesis and degradation, potentially suggesting new therapeutic options for kidney diseases.

Representation of Native Hawaiian and Pacific Islander Individuals in Clinical Trials

Having diverse participants in clinical trials ensures new drug products work well across different demographic groups, making health care safer and more effective for everyone. Information on the extent of Native Hawaiian and Pacific Islander participation in clinical trials is limited. To examine representation of Native Hawaiian and Pacific Islanders in clinical trials leading to the first US Food and Drug Administration (FDA) approvals for the 10 drug products with the top worldwide sales forecasts in 2024. Cross-sectional secondary analysis of existing data from clinical trials that took place from 2006 to 2021 in the US. All clinical trials that were included in the FDA first approval application for the 10 drug products were evaluated in this study. Data were analyzed from February to August 2024. Participation in a clinical drug trial. Comparison of the proportion of Native Hawaiian and Pacific Islander participation in clinical trials for the 10 drug products with top sales forecasts in 2024 to the Native Hawaiian and Pacific Islander population proportion. In this cross-sectional study of 139 062 individuals, Native Hawaiian and Pacific Islander participation in clinical trials for the 10 drug products with top sales forecasts was either unknown or low. For 6 of the 10 drug products (60%), the number of Native Hawaiian and Pacific Islander participants was not documented. All trials that reported Native Hawaiian and Pacific Islander participation had fewer Native Hawaiian and Pacific Islander participants than would be expected based on their US population proportion, with 2 of the differences being statistically significant. Of the trials that disaggregated Native Hawaiian and Pacific Islander participants from other racial groups, the number of Native Hawaiian and Pacific Islander participants was 8 for risankizumab-rzaa (0.38% of participants vs 0.49% of the population; percentage point difference, -0.11%; 95% CI, -0.37% to -0.15%), 7 for bictegravir/emtricitabine/tenofovir alafenamide (0.38% of participants vs 0.49% of the population; percentage point difference, -0.10%; 95% CI, -0.39% to 0.18%), 27 for 4vHPV/9vHPV (0.15% of participants vs 0.46% of the population; percentage point difference, -0.31%; 95% CI, -0.37% to -0.26%), and 90 for BNT162B2 COVID-19 vaccine (0.20% of participants vs 0.52% of the population; percentage point difference, -0.32; 95% CI, -0.36% to -0.27%). In this cross-sectional study, limited documentation and participation of Native Hawaiian and Pacific Islander individuals in clinical trials for drug products with top sales forecasts was found. This is especially concerning because Native Hawaiian and Pacific Islander individuals have a higher risk than other racial groups for type 2 diabetes, cancer, and several other conditions the products examined in this study treat. Given the importance of enrolling Native Hawaiian and Pacific Islander participants in clinical trials, sites should be established in key geographic regions, such as Hawai'i, and postmarket studies should be conducted within Native Hawaiian and Pacific Islander populations.

Initiation response, maximized therapeutic efficacy, and post-treatment effects of biological targeted therapies in myasthenia gravis: a systematic review and network meta-analysis.

As targeted drug development in myasthenia gravis (MG) continues to advance, it is important to compare the efficacy of these drugs for better clinical decision-making. However, due to the varied regimens and dosages used in clinical trials for different drugs, a standardized comparison between them is necessary. This study enrolled participants in phase II and III trials of innovative targeted drugs for MG. The primary outcome was the change in Quantitative Myasthenia Gravis score (MG-QMG) from baseline. The efficacy of all drugs at four time points was separately analyzed at four time points: initiation 1 week, initiation 4 weeks, maximized response, and post last dose 4 weeks. A network meta-analysis was conducted to compare the results of the different drugs. A total of 9 drugs, including Efgartigimod, Rozanolixizumab, Batoclimab, Eculizumab, Belimumab, Zilucoplan, Ravulizumab, Nipocalimab, Rituximab, derived from 12 studies were analyzed. At the initiation 1-week time point, three drugs exhibited significant improvement compared to the placebo effect: Efgartigimod, Zilucoplan, Rozanolixizumab. At the initiation 4-week time point, four drugs showed significant improvement compared to the placebo effect: Efgartigimod, Rozanolixizumab, Batoclimab, Zilucoplan. At the maximized response time point, six drugs achieved significant improvement compared to the placebo effect: Efgartigimod, Rozanolixizumab, Batoclimab, Eculizumab, Zilucoplan, Ravulizumab. At the post last dose 4-week point, all drugs statistically showed no significant difference from the placebo. Although the MG subtypes were not consistent across trials, within the regimen design of each trial, neonatal Fc receptor inhibitors-represented by Efgartigimod, Rozanolixizumab, and Batoclimab-exhibited the most effective response rates when compared to complement and B-cell inhibitor drugs.

International comparison and assessment of the quality of drug clinical trial implementation in China based on scientific regulatory system

Objective: To analyze the international status and level of clinical trial quality in China, and explore the advantages and value of scientific regulation of clinical research quality in China. Methods: The data is sourced from the relevant reports publicly released by the National Medical Products Administration (NMPA), the inspection reports and announcements published by the Center for Food and Drug Inspection of the NMPA, the inspection data displayed on the official website of the U.S. Food and Drug Administration (FDA), as well as clinical diagnosis and treatment guidelines issued by the National Comprehensive Cancer Network (NCCN) of United States and the Chinese Society of Clinical Oncology (CSCO) (data as of July 21, 2023). This data provides an analysis of the regulatory status of the implementation of clinical drug trials in China, inspection data, and the approval and market entry of new oncology drugs and feedback from their practical application. Results: The clinical trial quality inspection systems of China and the United States are generally aligned, with similar inspection subjects, focus areas, and public disclosure pathways. However, each has its characteristics in terms of inspection targets and types. The quality of clinical trial data in China has been continuously improving. Between 2009-2015 and 2016-July 2023, China underwent 25 and 20 FDA Bioresearch Monitoring (BIMO) inspections, respectively. The inspection results showing "No Action Indicated" (NAI) improved from 48.0% to 85.0%, while "Voluntary Action Indicated" (VAI) decreased from 44.0% to 15.0%. Official Action Indicated (OAI) measures were required in 2009 and 2012. Compared to the 2009-2015 period, there has been a clear upward trend in the quality of clinical trial data since 2016. From 2016 to July 2023, the number of new oncology drugs developed by Chinese pharmaceutical companies and included in professional guidelines has steadily increased. Specifically, 37 drugs (58.7%) were included in the 2022 edition of the CSCO guidelines, and 15 drugs (23.8%) were included in the 2023 edition of the NCCN guidelines, with 10 of these drugs featured in both guidelines. Conclusions: The implementation quality of clinical trials in China has gained a certain level of international recognition and competitiveness. This progress is attributed to national macro-level guidance, a unique institutional model, and clinical practices aligned with international standards. In the future, it will be necessary to further strengthen the scientific regulatory system and enhance clinical research capabilities to continue advancing the high-quality development of clinical trials.

Revolutionizing Patient Safety: Machine Learning and AI for the Early Detection of Adverse Drug Reactions and Drug-Induced Toxicity

Adverse drug reactions and drug-induced toxicity provide significant issues in drug research, jeopardizing patient safety and driving up healthcare costs. Toxicity has a greater potential impact than infectious diseases since it is less visible. Early diagnosis of these difficulties is critical to determining a drug's safety and viability profile. The combination of machine learning and artificial intelligence has marked a watershed moment in the identification of early adverse drug reactions and toxicity. These computational approaches enable rapid, extensive, and precise prediction of likely adverse drug reactions and toxicity even before practical drug manufacture, preclinical testing, and clinical trials. This paradigm change strives to create more efficient and safe drugs, lowering the likelihood of drug withdrawal. This comprehensive review investigates the critical role of machine learning and artificial intelligence in quickly detecting adverse drug reactions and toxicity, including approaches from data mining to deep learning. It lists essential databases, modelling techniques, and software that may be used to model and predict a wide range of toxicities and adverse drug reactions. This review provides a comprehensive overview, outlining recent developments and projecting future opportunities in machine learning and artificial intelligence-driven rapid identification of adverse drug reactions and drug-induced toxicity. It highlights the capabilities of these technologies and their enormous potential to improve patient safety and revolutionize medication discovery.

Exploring the efficacy of cholinergic agents for the treatment of psychostimulant use disorder: a systematic review.

No drugs are currently validated to treat psychostimulant use disorder (PUD). Pathophysiological studies consistently highlight the contribution of cholinergic mechanisms in psychostimulant use, including the vulnerability to PUD, paving the way for potential therapeutic strategies. The aim of this systematic review is to describe and discuss the efficacy of cholinergic agents in drug trials for patients with PUD. A systematic review was conducted on April 4, 2024 in MedLine, Embase and Cochrane Library databases on controlled clinical drug trial of cholinergic agents in humans with PUD, psychostimulant abuse or dependence and psychostimulant use in recent year. Twenty-eight articles were included, twenty-one on cocaine and seven on amphetamines. Cholinergic agents used in these studies were biperiden (a muscarinic antagonist), mecamylamine (a nicotinic antagonist), nicotinic agonists, acetylcholinesterase inhibitors (AChEI), or citicoline. Two types of trials were identified. There were seventeen randomized controlled clinical trials evaluating cholinergic agents on psychostimulant use reduction in outpatients seeking treatment. Additionally, we retrieved eleven short-term «proof-of-concept» laboratory trials mainly with supervised psychostimulant administration and/or triggered craving challenges. Outpatient trials were heterogeneous and for most, inconclusive. Only two studies on galantamine (AChEI) and citicoline, reported a significant reduction of cocaine consumption. «Proof-of-concept» laboratory trials showed no evidence of efficacy on the selected outcomes, notably on craving. This review does not support the current prescription of cholinergic agents to treat PUD. Replication clinical trials notably on galantamine or other AChEI, and proof-of-concept trials on comedown symptoms will be necessary to identify a potential therapeutic indication for cholinergic agents in PUD.

Glial-modulating agents for the treatment of pain: a systematic review.

Preclinical research supports a critical role for nervous system glia in pain pathophysiology. This systematic review of human trials of potential glia-modulating drugs for the prevention or treatment of pain followed a predefined search strategy and protocol registration. We searched for English language, randomized, double-blind trials comparing putative glia-modulating drugs to placebo or other comparators. The primary outcomes included validated participant-reported measures of pain intensity or relief and, in studies of opioid administration, measures of opioid consumption and/or opioid-related adverse effects. Twenty-six trials (2132 participants) of glial modulators (12 minocycline, 11 pentoxifylline, and 3 ibudilast) were included. Because of clinical heterogeneity related to study drug, participant population, outcome measures, and trial design, no meta-analysis was possible. Only 6 trials reported a positive effect of the treatment (pentoxifylline-4 trials; minocycline-2 trials), whereas 11 trials reported mixed results and 9 trials reported no effect. This review does not provide convincing evidence of efficacy of current pharmacological targets of nervous system glial function for pain treatment or prevention. However, in light of ample preclinical evidence of the importance of neuroimmune signalling and glial functions in pain pathophysiology, continued strategic human research is anticipated to identify (1) drugs with maximal activity as selectively targeted glial modulators, (2) the necessary timing and duration of pharmacological glial modulation needed for pain prevention or treatment for specific injuries or pain conditions, and (3) the best design of future clinical trials of glial-targeted drugs for pain treatment and/or prevention.

Clinical trials of drugs: Current state of the regulatory problem and proposals for reform

Not available.

Panorama dos principais estudos clínicos sobre medicamentos contra tuberculose no Brasil e no mundo

Introduction: This article provides a comprehensive overview of tuberculosis (TB) drug clinical trials conducted in Brazil and globally. TB is highlighted as one of the leading lethal infectious diseases, facing the growing challenge of drug resistance. Objective: The study aims to map recent advances and identify gaps and challenges in the search for effective treatments for TB, emphasizing Brazil’s contribution, which is known for its research in tropical diseases. Method: An analysis of clinical trials related to TB was conducted, focusing on the geographical diversity of the studies and the intersectoral collaboration between governments, academic institutions, and non-governmental organizations. The survey covered research at both national and international levels. Results: The results indicate a significant increase in the number of clinical trials, reflecting a growing interest and investment in research and development (R&D) aimed at combating TB. Regions with high disease incidence have received special attention. Collaboration between different sectors has been crucial in promoting progress. Conclusions: Despite the advances, the study underscores important challenges, such as the need for more R&D investments and the urgency of public policies to facilitate access to new drugs. The article highlights the importance of continuous and collaborative efforts in developing safe and accessible treatments, as well as the effective integration of innovations into the healthcare system, with special attention to vulnerable populations.

IMPACT OF REAL-LIFE ENVIRONMENTAL EXPOSURES ON REPRODUCTION: A contemporary review of machine learning to predict adverse pregnancy outcomes from pharmaceuticals, including DDIs.

Clinical drug trials often do not include pregnant people due to health risks; therefore, many medications have an unknown effect on the developing fetus. Machine learning QSAR models have been used successfully to predict the fetal risk of pharmaceutical use during pregnancy. Those undergoing pregnancy are often excluded from clinical drug trials due to the risk that participation would pose to their health and the health of the developing fetus. However, they often require pharmaceuticals to manage health conditions that, if left untreated, could harm themselves or the fetus. This can mean that such individuals take one or more pharmaceuticals during pregnancy, many of which have unknown reproductive effects. Machine learning models have been used to successfully predict a number of reproductive toxicological outcomes for pharmaceuticals, including transplacental transfer, US Food and Drug Administration safety rating, and drug interactions. Models use quantitative chemical and structural features of active compounds as inputs to make predictions concerning the outcome of interest using computational algorithms. Models are validated and evaluated rigorously with metrics such as accuracy, area under the receiver operator curve, sensitivity, and precision. Results from these models can be a potential source of valuable information for pregnant people and their medical providers when making decisions regarding therapeutic drug use. This review summarizes current machine learning applications to make predictions about the risk and toxicity of medication use during pregnancy. Our review of the recent literature revealed that machine learning quantitative structure-activity relationship models can be used successfully to predict the transplacental transfer and the US Food and Drug Administration pregnancy safety category of pharmaceuticals; such models have also been employed to predict drug interactions, though not specifically during pregnancy. This latter topic is a potential area for future research. In this review, no single algorithm or descriptor-calculation software emerged as the most widely used, and their performances depend on a variety of factors, including the outcome of interest and combination of such algorithms and software.

Increases in amyloid-β42 slow cognitive and clinical decline in Alzheimer's disease trials.

Positive effects of new anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer's disease (AD) have been attributed to brain amyloid reduction. However, most anti-Aβ antibodies also increase the CSF levels of the 42-amino acid isoform (Aβ42). We evaluated the associations of changes in CSF Aβ42 and brain Aβ-PET with cognitive and clinical end points in randomized trials of anti-Aβ drugs that lowered (β- and γ-secretase inhibitors) or increased CSF Aβ42 levels (anti-Aβ monoclonal antibodies) to test the hypothesis that post-treatment increases in CSF Aβ42 levels are independently associated with cognitive and clinical outcomes. From long-term (≥12 months) randomized placebo-controlled clinical trials of anti-Aβ drugs published until November 2023, we calculated the post-treatment versus baseline difference in ADAS-Cog (cognitive subscale of the Alzheimer's Disease Assessment Scale) and CDR-SB (Clinical Dementia Rate-Sum of Boxes) and z-standardized changes in CSF Aβ42 and Aβ-PET Centiloids (CL). We estimated the effect size [regression coefficients (RCs) and confidence intervals (CIs)] and the heterogeneity (I2) of the associations between AD biomarkers and cognitive and clinical end points using random-effects meta-regression models. We included 25 966 subjects with AD from 24 trials. In random-effects analysis, increases in CSF Aβ42 were associated with slower decline in ADAS-Cog (RC: -0.55; 95% CI: -0.89, -0.21, P = 0.003, I2 = 61.4%) and CDR-SB (RC: -0.16; 95% CI: -0.26, -0.06, P = 0.002, I2 = 34.5%). Similarly, decreases in Aβ-PET were associated with slower decline in ADAS-Cog (RC: 0.69; 95% CI: 0.48, 0.89, P < 0.001, I2 = 0%) and CDR-SB (RC: 0.26; 95% CI: 0.18, 0.33, P < 0.001, I2 = 0%). Sensitivity analyses yielded similar results. Higher CSF Aβ42 levels after exposure to anti-Aβ drugs are independently associated with slowing cognitive impairment and clinical decline. Increases in Aβ42 may represent a mechanism of potential benefit of anti-Aβ monoclonal antibodies in AD.

Inclusion of phase III clinical trial costs in health economic evaluations

IntroductionProtocol-driven trial activities contribute to the utility gain demonstrated in the phase III clinical trial of a new drug. If this utility gain cannot be distinguished from the effects of the new drug itself, protocol-driven trial costs cannot be easily dismissed for consistency reasons. This study aims to estimate the impact of including per-patient costs of phase III clinical trials on the incremental cost-effectiveness ratio (ICER).MethodsThe analysis utilized a modeling approach with secondary data from an ad-hoc literature review, considering both societal and payer perspectives. While the costs of phase III clinical trials may cancel out during the period of “normal” life-years due to the incremental cost calculation, they do not cancel out when differential early treatment termination occurs (e.g., due to differential mortality). Assuming the presence of differential mortality, per-patient phase III trial costs were calculated for the period of added life-years. These costs were then included in the ICER of a new drug, under the assumption that direct patient-related costs constitute 30–70% of the total trial costs. Capital costs were also incorporated from a societal perspective.ResultsBased on assumptions of $40,000 out-of-pocket expenses per patient enrolled in a phase III trial and a life expectancy gain of three months, incremental costs increased by $27,000 from a societal perspective. From a payer perspective, the estimate was $12,000.ConclusionsThe costs of phase III trials are a relevant component of the ICER, and excluding it is generally not appropriate for consistency reasons. Properly considering these trial costs is essential for a comprehensive evaluation of a new drug’s cost-effectiveness.

No Impact of Concomitant Medications on Efficacy and Safety of Biologics and Small Molecules for Ulcerative Colitis

While participants with inflammatory bowel diseases (IBD) in clinical trials of biologics and small molecule drugs (henceforth, advanced therapies) frequently receive several medications concomitantly, it is unclear how they modify treatment effect. Through an individual patient data pooled analysis of ten clinical trials of advanced therapies for moderate-to-severe ulcerative colitis (UC), we assessed whether concomitant exposure to corticosteroids, immunomodulators, 5-aminosalicylates, proton pump inhibitors (PPIs), histamine receptor antagonists (H2RA), opiates, antidepressants, and antibiotics modified the effect of the intervention on treatment efficacy and safety outcomes, using modified Poisson regression model. Of 6044 patients (4280 receiving intervention, 1764 receiving placebo), several received concomitant corticosteroids (47%), immunomodulators (28%), 5-aminosalicylates (68%), PPIs (14%), H2RAs (2%), opiates (7%), antidepressants (6%), and/or antibiotics (5%). After adjusting for confounders and examining treatment efficacy of intervention vs. placebo, we observed no impact of concomitant exposure to corticosteroids (ratio of relative risk of drug vs. placebo with vs. without concomitant exposure: RRR, 0.81 [95% CI,0.63-1.06], 5-aminosalicylates (RRR, 1.04[0.78-1.39]), PPIs (RRR, 0.87 [0.61-1.22]), H2RAs (RRR, 1.72[0.97-14.29]), opiates (RRR, 0.90[0.54-1.49]), antidepressants (RRR, 1.02[0.57-1.83]), and antibiotics (RRR, 0.72[0.44-1.16]) on likelihood of clinical remission. Concomitant exposure to immunomodulators was associated with lower likelihood of achieving clinical remission (RRR, 0.73[0.55-0.97]), particularly with non-TNF antagonists. In clinical trials of advanced therapies for UC, baseline concomitant exposure to multiple commonly used class of medications does not impact treatment efficacy or safety. These findings directly inform design of regulatory clinical trials with respect to managing concomitant medications at baseline.

Natural History and Clinicopathological Associations of TRPC6-Associated Podocytopathy.

Understanding the genetic basis of human diseases has become integral to drug development and precision medicine. Recent advancements have enabled the identification of molecular pathways driving diseases, leading to targeted treatment strategies. The increasing investment in rare diseases by the biotech industry underscores the importance of genetic evidence in drug discovery and approval processes. Here we studied a monogenic Mendelian kidney disease, TRPC6-associated podocytopathy (TRPC6-AP), to present its natural history, genetic spectrum, and clinicopathological associations in a large cohort of patients with causal variants in TRPC6, in order to help define the specific features of disease and further facilitate drug development and clinical trials design. the study involved 64 individuals from 39 families with TRPC6 causal missense variants. Clinical data, including age of onset, laboratory results, response to treatment, kidney biopsy findings, and genetic information, were collected from multiple centers nationally and internationally. Exome or targeted sequencing was performed and variant classification was based on strict criteria. Structural and functional analyses of TRPC6 variants were conducted to understand their impact on protein function. In depth re-analysis of light and electron microscopy specimens for 9 available kidney biopsies was conducted to identify pathological features and correlates of TRPC6-AP. Large-scale sequencing data did not support causality for TRPC6 protein-truncating variants. We identified 21 unique TRPC6 missense variants, clustering in three distinct regions of the protein, and with different effects on TRPC6 3D protein structure. Kidney biopsy analysis revealed FSGS patterns of injury in most cases, along with distinctive podocyte features including diffuse foot process effacement and swollen cell bodies. The majority of patients presented in adolescence or early adulthood but with ample variation (average 22, SD ± 14 years), with frequent progression to kidney failure but with variability in time between presentation and ESKD. This study provides insights into the genetic spectrum, clinicopathological associations, and natural history of TRPC6-AP.

Global Trends in Oliceridine (TRV130) Research from 2013 to 2024: A Bibliometrics and Knowledge Graph Analysis.

The adverse effects and drug abuse issues associated with opioid drugs have made finding a safe and effective alternative a focus of research. Oliceridine has attracted attention for its lower adverse reactions, such as respiratory depression and gastrointestinal issues, compared to traditional opioids, and is considered a promising candidate for addressing the current limitations in opioid therapy. This article explored the knowledge structure of oliceridine through bibliometric analysis, highlighting its clinical applications in managing acute pain and its mechanisms that may reduce addiction risk. Our bibliometric analysis highlighted hotspots and trends in oliceridine research, guiding future studies on its safety and efficacy in pain management. This study utilized the Web of Science Core Collection database to search for articles related to oliceridine from 2013 to 2024. Systematic analysis was conducted on publication, country, institution, author, journal, references, and keywords. The software Citespace, Vosviewer, and Bibliometrix were employed to visualize bibliometric analysis. From 2013 to 2024, 159 articles on oliceridine were published in 98 journals by 158 institutions from 28 countries. The United States has rapidly developed in this field, providing significant momentum. Keyword clustering analysis revealed that research on oliceridine primarily focused on exploring its molecular and pharmacological mechanisms and conducting clinical studies to evaluate its efficacy and safety in pain management. Analyses of the strongest citation bursts with references and keywords indicated that protein-biased ligands and oliceridine were hotspots. The emergence of divergent views regarding oliceridine's biased agonism will lead to future hotspots focusing on the underlying mechanisms of biased signaling by G protein-coupled receptors and drug design. Bibliometric analysis provides insights into the current hotspots and emerging areas of oliceridine, which can guide future research. The widespread attention and clinical application of oliceridine lay a solid foundation for further drug development and clinical trials.

Administration sequences in single-day chemotherapy regimens for breast cancer: a comprehensive review from a practical perspective.

Breast cancer is one of the most prevalent malignant tumors globally, posing a severe threat to human life and health. Chemotherapy, a cornerstone in the treatment of breast cancer, often overlooks the sequence of drug administration within single-day regimens. This study aims to explore the impact of drug administration order on the efficacy and toxicity of combination chemotherapy protocols for breast cancer. Through a comprehensive review and analysis based on current evidence from evidence-based medicine, we delved into how the order of drug administration affects both efficacy and toxicity. We systematically classified and analyzed commonly used combination drug regimens, providing graded recommendations and a reasoned analysis to offer valuable references for clinical decision-making. Our findings indicate that the sequence of drug administration in complex combination chemotherapy protocols is not arbitrary but necessitates multifaceted considerations. Rational drug sequencing can maximize synergistic effects between drugs, thereby augmenting therapeutic efficacy while effectively mitigating drug-related adverse effects. Additionally, some drug labels and clinical trials have explicitly highlighted the therapeutic benefits of specific drug sequences. This study underscores the importance of considering the sequence of drug administration in clinical practice. It is recommended to prioritize the sequential drug administration according to official drug product labeling, while also considering factors such as the administration sequence from large randomized controlled trials, cell proliferation kinetics specific to cancer types, drug interactions, chronopharmacology, drug irritability, clinical experiences, and patient preferences. By taking these factors into account, the goal is to maximize treatment efficacy and minimize the occurrence of adverse reactions.