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Experimental Biology and Medicine... Nov 2023The US drug labeling document contains essential information on drug efficacy and safety, making it a crucial regulatory resource for Food and Drug Administration (FDA)...
The US drug labeling document contains essential information on drug efficacy and safety, making it a crucial regulatory resource for Food and Drug Administration (FDA) drug reviewers. Due to its extensive volume and the presence of free-text, conventional text mining analysis have encountered challenges in processing these data. Recent advances in artificial intelligence (AI) for natural language processing (NLP) have provided an unprecedented opportunity to identify key information from drug labeling, thereby enhancing safety reviews and support for regulatory decisions. We developed RxBERT, a Bidirectional Encoder Representations from Transformers (BERT) model pretrained on FDA human prescription drug labeling documents for an enhanced application of drug labeling documents in both research and drug review. RxBERT was derived from BioBERT with further training on human prescription drug labeling documents. RxBERT was demonstrated in several tasks using regulatory datasets, including those involved in the National Institutes of Technology Text Analysis Challenge Dataset (NIST TAC dataset), the FDA Adverse Drug Event Evaluation Dataset (ADE Eval dataset), and the classification of texts from submission packages into labeling sections (US Drug Labeling dataset). For all these tasks, RxBERT reached 86.5 1-scores in both TAC and ADE Eval classification, respectively, and prediction accuracy of 87% for the US Drug Labeling dataset. Overall, RxBERT was shown to be as competitive or have better performance compared to other NLP approaches such as BERT, BioBERT, etc. In summary, we developed RxBERT, a transformer-based model specific for drug labeling that outperformed the original BERT model. RxBERT has the potential to be used to assist research scientists and FDA reviewers to better process and utilize drug labeling information toward the advancement of drug effectiveness and safety for public health. This proof-of-concept study also demonstrated a potential pathway to customized large language models (LLMs) tailored to the sensitive regulatory documents for internal application.
Topics: United States; Humans; Artificial Intelligence; Drug Labeling; Prescription Drugs; Data Mining; Drug-Related Side Effects and Adverse Reactions
PubMed: 38166420
DOI: 10.1177/15353702231220669 -
Lancet (London, England) Mar 2024Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept.
METHODS
The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013-003413-18).
FINDINGS
Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for eligibility and, of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo. During the treatment period, seven (6%) of 110 participants in the abatacept group and 30 (29%) of 103 participants in the placebo group met the primary endpoint. At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92·8% (SE 2·6) in the abatacept group and 69·2% (4·7) in the placebo group. Kaplan-Meier arthritis-free survival plots over 24 months favoured abatacept (log-rank test p=0·044). The difference in restricted mean survival time between groups was 53 days (95% CI 28-78; p<0·0001) at 12 months and 99 days (95% CI 38-161; p=0·0016) at 24 months in favour of abatacept. During treatment, abatacept was associated with improvements in pain scores, functional wellbeing, and quality-of-life measurements, as well as low scores of subclinical synovitis by ultrasonography, compared with placebo. However, the effects were not sustained at 24 months. Seven serious adverse events occurred in the abatacept group and 11 in the placebo group, including one death in each group deemed unrelated to treatment.
INTERPRETATION
Therapeutic intervention during the at-risk phase of rheumatoid arthritis is feasible, with acceptable safety profiles. T-cell co-stimulation modulation with abatacept for 12 months reduces progression to rheumatoid arthritis, with evidence of sustained efficacy beyond the treatment period, and with no new safety signals.
FUNDING
Bristol Myers Squibb.
Topics: Adolescent; Adult; Humans; Abatacept; Arthralgia; Arthritis, Rheumatoid; Pain; Rheumatoid Factor; Synovitis
PubMed: 38364839
DOI: 10.1016/S0140-6736(23)02649-1 -
Gels (Basel, Switzerland) Nov 2023The incorporation of the metal phase into cellulose hydrogels, resulting in the formation of metallogels, greatly expands their application potential by introducing new... (Review)
Review
The incorporation of the metal phase into cellulose hydrogels, resulting in the formation of metallogels, greatly expands their application potential by introducing new functionalities and improving their performance in various fields. The unique antiviral, antibacterial, antifungal, and anticancer properties of metal and metal oxide nanoparticles (Ag, Au, Cu, CuO, ZnO, AlO, TiO, etc.), coupled with the biocompatibility of cellulose, allow the development of composite hydrogels with multifunctional therapeutic potential. These materials can serve as efficient carriers for controlled drug delivery, targeting specific cells or pathogens, as well as for the design of artificial tissues or wound and burn dressings. Cellulose-based metallogels can be used in the food packaging industry to provide biodegradable and biocidal materials to extend the shelf life of the goods. Metal and bimetallic nanoparticles (Au, Cu, Ni, AuAg, and AuPt) can catalyze chemical reactions, enabling composite cellulose hydrogels to be used as efficient catalysts in organic synthesis. In addition, metal-loaded hydrogels (with ZnO, TiO, Ag, and FeO nanoparticles) can exhibit enhanced adsorption capacities for pollutants, such as dyes, heavy metal ions, and pharmaceuticals, making them valuable materials for water purification and environmental remediation. Magnetic properties imparted to metallogels by iron oxides (FeO and FeO) simplify the wastewater treatment process, making it more cost-effective and environmentally friendly. The conductivity of metallogels due to Ag, TiO, ZnO, and AlO is useful for the design of various sensors. The integration of metal nanoparticles also allows the development of responsive materials, where changes in metal properties can be exploited for stimuli-responsive applications, such as controlled release systems. Overall, the introduction of metal phases augments the functionality of cellulose hydrogels, expanding their versatility for diverse applications across a broad spectrum of industries not envisaged during the initial research stages.
PubMed: 37998968
DOI: 10.3390/gels9110878 -
Journal of Oncology Pharmacy Practice :... Dec 2023The handling of antineoplastic drugs should follow strict supervision and safety rules to minimize the occupational exposure risks to professionals involved. The...
INTRODUCTION
The handling of antineoplastic drugs should follow strict supervision and safety rules to minimize the occupational exposure risks to professionals involved. The external surface contamination of drug vials is recognized as a health risk. So, our goal was to determine if there is residual contamination on the vials and containers surface of the antineoplastic drugs doxorubicin (DOX) and cyclophosphamide (CP).
METHODS
A cross-sectional study was conducted. Samples were collected using a uniform sampling procedure on the inner surfaces of the packages/boxes and the outer surfaces of the vials. The analyzes were executed by high-performance liquid chromatography/mass spectrometry (UHPLC-MS/MS).
RESULTS
A total of 209 samples were analyzed, 66 of CP and 143 of DOX. CP levels were detected in nine samples (13.63%), three were below the lower limit of quantification (LLQ) and the other six had contamination levels ranging from 1.24 to 28.04 ng/filter. DOX levels were detected in 36 samples (25.17%), two were below the LLQ and the others had levels between 1.32 and 664.84 ng/filter. The majority of samples with residual contamination were in vials (80.0%), however, boxes also showed contamination.
CONCLUSIONS
The results revealed the presence of residual contamination in the vials and packages of CP and DOX drugs. Although the residues found in each sample are small, special care should be taken in the handling and disposal of the antineoplastic drugs. The use of personal protective equipment is fundamental while handling the vials and packaging of cytotoxic drugs.
Topics: Humans; Tandem Mass Spectrometry; Cross-Sectional Studies; Antineoplastic Agents; Cyclophosphamide; Doxorubicin; Drug Packaging; Occupational Exposure; Equipment Contamination; Environmental Monitoring; Drug Contamination
PubMed: 36659825
DOI: 10.1177/10781552231151693 -
International Journal of Molecular... Mar 2024Antidepressant drugs play a crucial role in the treatment of mental health disorders, but their efficacy and safety can be compromised by drug degradation. Recent... (Review)
Review
Antidepressant drugs play a crucial role in the treatment of mental health disorders, but their efficacy and safety can be compromised by drug degradation. Recent reports point to several drugs found in concentrations ranging from the limit of detection (LOD) to hundreds of ng/L in wastewater plants around the globe; hence, antidepressants can be considered emerging pollutants with potential consequences for human health and wellbeing. Understanding and implementing effective degradation strategies are essential not only to ensure the stability and potency of these medications but also for their safe disposal in line with current environment remediation goals. This review provides an overview of degradation pathways for amitriptyline, a typical tricyclic antidepressant drug, by exploring chemical routes such as oxidation, hydrolysis, and photodegradation. Connex issues such as stability-enhancing approaches through formulation and packaging considerations, regulatory guidelines, and quality control measures are also briefly noted. Specific case studies of amitriptyline degradation pathways forecast the future perspectives and challenges in this field, helping researchers and pharmaceutical manufacturers to provide guidelines for the most effective degradation pathways employed for minimal environmental impact.
Topics: Humans; Amitriptyline; Antidepressive Agents, Tricyclic; Drug Packaging; Environmental Pollutants; Environmental Restoration and Remediation
PubMed: 38612638
DOI: 10.3390/ijms25073822 -
Molecular Pharmaceutics Feb 2024Female reproductive health has traditionally been an underrepresented area of research in the drug delivery sciences. This disparity is also seen in the emerging field... (Review)
Review
Female reproductive health has traditionally been an underrepresented area of research in the drug delivery sciences. This disparity is also seen in the emerging field of mRNA therapeutics, a class of medicines that promises to treat and prevent disease by upregulating protein expression in the body. Here, we review advances in mRNA therapies through the lens of improving female reproductive health. Specifically, we begin our review by discussing the fundamental structure and biochemical modifications associated with mRNA-based drugs. Then, we discuss various packaging technologies, including lipid nanoparticles, that can be utilized to protect and transport mRNA drugs to target cells in the body. Last, we conclude our review by discussing the usage of mRNA therapy for addressing pregnancy-related health and vaccination against sexually transmitted diseases in women. Of note, we also highlight relevant clinical trials using mRNA for female reproductive health while also providing their corresponding National Clinical Trial identifiers. In undertaking this review, our aim is to provide a fundamental background understanding of mRNA therapy and its usage to specifically address female health issues with an overarching goal of providing information toward addressing gender disparity in certain aspects of health research.
Topics: Pregnancy; Humans; Female; Reproductive Health; RNA, Messenger; Sexually Transmitted Diseases
PubMed: 38189262
DOI: 10.1021/acs.molpharmaceut.3c00803 -
Journal of Thrombosis and Haemostasis :... Dec 2023Remarkably, it has been 40 years since the isolation of the 2 genes involved in hemophilia A (HA) and hemophilia B (HB), encoding clotting factor (F) VIII (FVIII) and... (Review)
Review
Remarkably, it has been 40 years since the isolation of the 2 genes involved in hemophilia A (HA) and hemophilia B (HB), encoding clotting factor (F) VIII (FVIII) and FIX, respectively. Over the years, these advances led to the development of purified recombinant protein factors that are free of contaminating viruses from human pooled plasma for hemophilia treatments, reducing the morbidity and mortality previously associated with human plasma-derived clotting factors. These discoveries also paved the way for modified factors that have increased plasma half-lives. Importantly, more recent advances have led to the development and Food and Drug Administration approval of a hepatocyte-targeted, adeno-associated viral vector-mediated gene transfer approach for HA and HB. However, major concerns regarding the durability and safety of HA gene therapy remain to be resolved. Compared with FIX, FVIII is a much larger protein that is prone to misfolding and aggregation in the endoplasmic reticulum and is poorly secreted by the mammalian cells. Due to the constraint of the packaging capacity of adeno-associated viral vector, B-domain deleted FVIII rather than the full-length protein is used for HA gene therapy. Like full-length FVIII, B-domain deleted FVIII misfolds and is inefficiently secreted. Its expression in hepatocytes activates the cellular unfolded protein response, which is deleterious for hepatocyte function and survival and has the potential to drive hepatocellular carcinoma. This review is focused on our current understanding of factors limiting FVIII secretion and the potential pathophysiological consequences upon expression in hepatocytes.
Topics: Animals; Humans; Factor VIII; Hemophilia A; Blood Coagulation Factors; Genetic Therapy; Hemophilia B; Mammals
PubMed: 37839613
DOI: 10.1016/j.jtha.2023.10.005 -
Scientific Reports Aug 2023The authentic SARS-CoV-2 requires to be handled in Biosafety Level 3 laboratories, which restrains investigation by the broader scientific community. Here, we report the...
The authentic SARS-CoV-2 requires to be handled in Biosafety Level 3 laboratories, which restrains investigation by the broader scientific community. Here, we report the development of a novel SARS-CoV-2 viral vector composed of all 4 SARS-CoV-2 structural proteins, the packaging signal sequence of SARS-CoV-2, a reporter gene, and an RNA amplification component of Venezuelan equine encephalitis virus (VEEV). This VEE-SARS-CoV-2 viral vector transduces target cells in an ACE2-dependent manner, and all 4 structural proteins of SARS-CoV-2 are indispensable for its transduction activity. Comparative studies show that the incorporation of the VEEV self-amplification mechanism increases the gene expression level by ~ 65-fold and extends the transgene expression up to 11 days in transduced cells. Additionally, we demonstrated the significant applications of this new VEE-SARS-CoV-2 vector for neutralizing antibody quantification and antiviral drug testing. The VEE-SARS-CoV-2 vectors developed will be an important and versatile tool for investigating SARS-CoV-2 molecular virology, developing antiviral agents targeting receptor binding, and studying RNA genome packaging and function of the essential but not well studied structural proteins of SARS-CoV-2.
Topics: Animals; Horses; SARS-CoV-2; COVID-19; Encephalitis Virus, Venezuelan Equine; Antibodies, Neutralizing; RNA; Antiviral Agents
PubMed: 37567900
DOI: 10.1038/s41598-023-40370-8