Special Issue:
Challenges and Opportunities in Drug Development
Human Brain Organoids in the Preclinical Phase of Drug Development for Migraine
Parisa Gazerani
Department of Life Sciences and Health, Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway; Department of Health Science and Technology, Faculty of Medicine, Aalborg University, 9260 Gistrup, Denmark
Abstract
Developing drugs for brain disorders poses significant hurdles. These challenges stem from the scarcity of optimal models for preclinical drug testing and the often observed lack of translation from preclinical to human clinical trials. Further complexity arises from the specific targeting required in many brain disorders, with drug delivery often impeded by the necessity to cross the blood-brain barrier (BBB). As such, the search for novel and efficient platforms for preclinical drug development is a vibrant area of research. In acknowledgment of the limitations of animal tests – such as the lack of translation owing to species differences – and in alignment with the principles of reduction, refinement, and replacement (3Rs), the scientific community is moving towards promoting animal-free drug development plans. In this context, human brain organoids are rapidly emerging as potential alternatives to traditional methods. These early-stage in vitro models, mirroring in vivo complexities, hold great promise for preclinical drug testing for brain disorders. Stable organoid phenotypes and the uncovering of disease-specific features could soon elevate them to a valuable strategy in pharmaceutical testing for a range of brain disorders. Recent advancements in assay-ready organoid platforms and microfluidic chips present considerable potential for the application of human brain organoids in drug development. This commentary briefly discusses the generation of human brain organoids and their application in drug development with existing examples, focusing on their potential use in preclinical drug development for migraine, a prevalent, complex, and disabling brain disorder. The associated challenges and opportunities will also be outlined.
Dorothy Maxwell Kazembe
Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa) College of Health Sciences, Addis Ababa University, P.O. Box 9086, Addis Ababa, Ethiopia ; Malawi-Liverpool-Wellcome Trust Clinical Research Programme, P.O. Box 30096, Blantyre, Malawi
Tigist Mesfin, M.D
Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa) College of Health Sciences, Addis Ababa University, P.O. Box 9086, Addis Ababa, Ethiopia; St.Peter Specialized Hospital, Addis Ababa, Ethiopia.
Abigiya Abebe, M.D
Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa) College of Health Sciences, Addis Ababa University, P.O. Box 9086, Addis Ababa, Ethiopia; Department of medicine, St. Paul’s hospital, P.O. Box 1271, Addis Ababa, Ethiopia
Saba Mehari Embaye
Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa) College of Health Sciences, Addis Ababa University, P.O. Box 9086, Addis Ababa, Ethiopia
Esther Nthenya Muthoka
Addis Ababa UniversityCenter for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa) College of Health Sciences, Addis Ababa University, P.O. Box 9086, Addis Ababa, Ethiopia; Tororo General Hospital, Tororo Uganda
Kedir Usmael, M.D
Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa) College of Health Sciences, Addis Ababa University, P.O. Box 9086, Addis Ababa, Ethiopia; Department Of Medicine, College of Medicine and Health Sciences, Dire Dawa University, P.O Box 1362, Dire Dawa, Ethiopia
Mediha Ahmedin
Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa) College of Health Sciences, Addis Ababa University, P.O. Box 9086, Addis Ababa, Ethiopia
Tsegahun Manyazewal, Phd
Abstract
Background: Informed consent provides detailed information to the participants to make informed voluntary and rational decision to participate in a study. It is a communication tool between investigator and the subject to ensure that high research ethical standards are followed. This review paper assessed the level of participants’ understanding of the information given to them by researchers during the clinical research.
Methods: A review approach was used to achieve the study objective.
Results: The findings showed that the level of comprehension varied from study to study. There was a good comprehension in four domains; purpose, voluntariness, benefits and right to withdraw. Poor comprehensions were mostly in risks, side effects, and blinding. Higher level of education, repeated assessments of comprehension, time spent by the researcher explaining and clarifying the information influenced the comprehension.
Conclusion: The study findings point out that comprehension to informed consent is still a challenge that needs to be addressed during the field study. Once the consent is given it becomes a distant memory for most of the participants. This implies that proper tools and cut off points to determine participants’ comprehension need to be developed for standard assessment of such.
Philip H.C. Kremer
Center for Human Drug Research, Leiden, The Netherlands; Leiden Academical Medical Center, Leiden, The Netherlands
Geert Jan Groeneveld
Center for Human Drug Research, Leiden, The Netherlands; Leiden Academical Medical Center, Leiden, The Netherlands
Abstract
With aging populations in many countries, the prevalence of neurodegenerative diseases is expected to increase in the upcoming decades. Currently, no disease modifying therapies for these conditions exist. Advances in genetics and proteomics have identified novel druggable targets for neurodegenerative diseases. Compounds modulating these targets have recently entered clinical trials. These compounds can be orally administered small drug molecules, intravenously dosed antibodies, intrathecally injected antisense oligonucleotides (ASOs), gene therapies, stem cells or viral vectors. For the development of these compounds to be successful, multiple challenges have to be overcome. In this review we discuss advances in drug development for each of the major neurodegenerative diseases, which, when applied to early phase drug studies, increase the chance of successful clinical development. Here we will limit ourselves to: 1) the use of biomarkers for understanding target and pathway engagement at an early stage of development, 2) novel approaches for increasing blood-brain barrier penetration and 3) advances in understanding cerebrospinal fluid flow dynamics in relation to neurodegeneration and target site distribution for intrathecally administered compounds.
Shitang Ma
College of biological and pharmaceutical engineering, West Anhui University, Lu’an, China.
Jiafu Hou
Mudanjiang Medical University, Mudanjiang, China.
Shijuan Liu
Mudanjiang Medical University, Mudanjiang, China.
Fucheng Zhu
College of biological and pharmaceutical engineering, West Anhui University, Lu’an, China.
Peipei Wei
College of biological and pharmaceutical engineering, West Anhui University, Lu’an, China.
Chengtao Feng
Anhui University of Chinese Medicine, Hefei, China.
Naidong Chen
College of biological and pharmaceutical engineering, West Anhui University, Lu’an, China.
Abstract
The need for therapeutics to overcome development of existing diseases research to discover new lead agents. In the face of public health challenges worldwide, natural medicines play a pivotal role in innovative lead drug discovery. Network pharmacology can easily construct complicated poly-pharmacology network based on lead compound, biological function, and bioactive target proteins, which meets the overall feature of natural medicines, and enable to elucidate the action mechanism at molecule-protein level with systematic view. In this work, we first summarized the recent progress delineating lead drug development and its interaction with natural medicines. Second, we focused on the relationship between natural medicines and network pharmacology. Additionally, we discussed current issues and potential prospects for the lead drug discover from natural medicines by network pharmacology. Further investigations should be focus on relevant structural analysis for biological experiment, also the dynamic and quantitative network development. In summary, it is a rational approach for innovative lead drug discovery, and with the development of structure and biology research, this approach makes it a very powerful method for the lead molecules in a high-throughput manner from a comprehensive and powerful special multi-compound to target protein/disease poly pharmacology network.
Pranitha Rayapudi, Pharm.D Paulette Robinson, PhD Ellery D. Mangas, B.S., RAC Andrew Mulberg, MD, FAAP
Senior Vice President, Regulatory Affairs and Quality Assurance Neurogene Inc
Abstract
Drug development in pediatrics is mandated under US and European Union legislation and delays in pediatric studies can impact the appropriate labeling and use of therapeutics for children. Developing medical products for pediatrics is challenging, as there are several critical issues and factors to consider when initiating a pediatric drug development program. The International Conference Harmonisation guideline E11(R1) and criteria under 21 CFR part 50 subpart D define pediatric regulatory standards for drug developers and ensure the safety of pediatric participants in clinical studies.
Adequate adult data are typically required before finalizing pediatric study designs and initiating pediatric studies by virtue of the Pediatric Research Equity Act. It is evolving that the Food and Drug Administration (FDA) is including adolescents in Phase 3 trials. In pediatrics, the lack of coordinated use of extrapolation for safety and efficacy amongst global regulatory agencies impacts the timelines and development of clinical trial designs. First-in-human pediatric trials may be justified if the aspects of 21 CFR 50, subpart D specifically 21 CFR 50.52 are addressed. For example, first-in-human pediatric gene therapy trials have been allowed in spinal muscular atrophy (SMA) using a benefit-risk assessment to justify the conduct of first-in-human trials in children. The statutory requirement to study children in clinical trials is influenced by the nature of the disease that is currently under study and needs to be personalized. These issues are addressed in this perspective on gene therapy treatment in children.
Robert G. Lisziewicz
VERDI Solutions; Vienna, Austria
Felipe Oviedo
Microsoft AI for Good Research Laboratory; Redmond, USA
Andras G. Szasz
VERDI Solutions; Vienna, Austria
Juan L. Ferres
Microsoft AI for Good Research Laboratory; Redmond, USA
Franco Lori
VERDI Solutions; Vienna, Austria/ Research Institute for Genetic and Human Therapy; Milano, Italy
Julianna Lisziewicz
VERDI Solutions, GMBH
Abstract
Background: The COVID-19 pandemic has necessitated the development of efficient diagnostic tools to predict T-cell responses, which are crucial for viral clearance and protection against reinfection. Current diagnostic tests lack the ability to predict the epitope repertoire of an individual that induces T-cell responses.
Methods: We developed VERDI, a new machine learning-based diagnostic tool that leverages the sequence data of all the six HLA class I alleles of an individual to rank all putative epitopes based on their potential to induce T-cell responses. VERDI was trained on a comprehensive clinical dataset of 920 SARS-CoV-2 epitopes and validated using an independent dataset collected for the FDA-approved T-detect COVID test. We compared VERDI’s performance with existing HLA-allele-based models through statistical analyses.
Results: Our findings reveal that VERDI’s top-ranked epitopes accurately represent the individual’s epitope repertoire that participates in T-cell responses. VERDI outperformed current models, improving T-cell response prediction recall by threefold and precision by eightfold. It exhibited exceptional diagnostic accuracy, precision, and recall in predicting the potency of the top 20 epitopes. Despite experimental limitations that allow testing of only 1% of putative epitopes, VERDI accurately predicted 30% of these, implying a potentially higher accuracy if broader testing were feasible. Notably, the mean potency of the top-ranked epitopes predicted by VERDI, which reflects the strength of an individual’s SARS-CoV-2-specific T-cell responses, exhibited a Gaussian distribution.
Conclusions: VERDI is the first diagnostic tool that uses the complete HLA genotype data to predict the breadth and strength of an individual’s T-cell responses to SARS-CoV-2 infection. Its ability to accurately identify the potency of epitopes involved in individual T-cell responses and its superior performance compared to the state-of-the-art make it a new resource for personalized vaccine design and disease management.
Larry L Mweetwa
DDT College of Medicine, Department for Pharmacy and Pharmaceutical Sciences, P.O. Box 70587, Gaborone Botswana, Africa, Tel: +267(0)3904924/5, Cell: +267(0) 77100000 Fax: +267(0)3904935.
Derrick D Tlhoiwe
DDT College of Medicine, Department for Pharmacy and Pharmaceutical Sciences, P.O. Box 70587, Gaborone Botswana, Africa, Tel: +267(0)3904924/5, Cell: +267(0) 77100000 Fax: +267(0)3904935.
Tumelo Tlhoiwe
DDT College of Medicine, Department for Pharmacy and Pharmaceutical Sciences, P.O. Box 70587, Gaborone Botswana, Africa, Tel: +267(0)3904924/5, Cell: +267(0) 77100000 Fax: +267(0)3904935.
Kabo Osmas Tshiamo
DDT College of Medicine, Department for Pharmacy and Pharmaceutical Sciences, P.O. Box 70587, Gaborone Botswana, Africa, Tel: +267(0)3904924/5, Cell: +267(0) 77100000 Fax: +267(0)3904935.
Sody Mweetwa Munsaka
University of Zambia, School of Health Sciences, P. O. Box 32379 Lusaka, Africa.
Thatoyaone J Kenaope
Department of Pharmacy, Boitekanelo College, Plot 5824 Masetlheng Rd, Gaborone 00000, Botswana.
Getrude Mothibe
Department of Pharmacy, Boitekanelo College, Plot 5824 Masetlheng Rd, Gaborone 00000, Botswana.
Ogorogile Mokate
DDT College of Medicine, Department for Pharmacy and Pharmaceutical Sciences, P.O. Box 70587, Gaborone Botswana, Africa, Tel: +267(0)3904924/5, Cell: +267(0) 77100000 Fax: +267(0)3904935.
Emmanuel T Oluwabusola
DDT College of Medicine, Department for Pharmacy and Pharmaceutical Sciences, P.O. Box 70587, Gaborone Botswana, Africa, Tel: +267(0)3904924/5, Cell: +267(0) 77100000 Fax: +267(0)3904935.
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) or Coronavirus was initially detected in Wuhan China in December 2019 and has subsequently resulted in the COVID-19 pandemic. The disease presents asymptomatically in some of individuals yet also causes symptoms ranging from those associated with influenza and pneumonia, acute respiratory distress syndrome (ARDS) and even death. The world is currently relying on physical (social) distancing, hygiene and repurposed medicines; however, it was predicted that an effective vaccine will be necessary to ensure comprehensive protection against COVID-19. There was a global effort to develop an effective vaccine against SARS-CoV-2 with approximately 300 vaccines in clinical trials, and over 200 more in different stages of development and anticipated that their success will change research clinical trials processes. Although every one of these vaccines comes with its own particular set of characteristics and difficulties, they were all developed as a direct result of research and development efforts that were carried out on a scale that had never been seen before. It is the first time in the history of vaccination that a worldwide immunization campaign has begun during a time of severe pandemic activity that is defined by high virus transmission. This achievement marks an important milestone in the history of vaccination. More than anything else, the most important aspect of the new game change in drug design is that the traditional drug discovery rules have been rewritten. This is especially significant for the development of vaccines, as it is possible for all clinical trials to be accelerated, which would bring a vaccine or drug molecule to market within a year rather than the traditional fifteen years for each phase of drug clinical trials. This review provides insight in respect to first generation COVID-19 vaccines, which were in clinical use as of December 2020 and focused on the Pfizer/ BioNTech/Fosun, Moderna mRNA-1273, Johnson and Johnson and AstraZeneca/Oxford AZD1222 vaccines.
Stephen Bevan Shrewsbury, MBChB
Impel Pharmaceuticals Inc., Seattle, WA, USA
Greg Davies, BSc (Hons)
Impel Pharmaceuticals Inc, Seattle, WA, USA
Lisa McConnachie, PhD
Impel Pharmaceuticals Inc, Seattle, WA, USA
John Hoekman, PhD
Impel Pharmaceuticals Inc, Seattle, WA, USA
Abstract
Nasal drug delivery presents a potential opportunity for achieving rapid, extensive drug absorption via a nonoral route by 1) avoiding degradation within the gastrointestinal tract and first-pass metabolism in the liver and 2) facilitating faster onset via rapid absorption into the bloodstream. However, the site of drug deposition within the nasal cavity may impact drug pharmacokinetics. Precision Olfactory Delivery (POD®) by Impel Pharmaceuticals Inc. is a new technology that provides handheld, manually actuated, propellant-powered drug delivery to the upper nasal space for rapid and efficient absorption. Rapid onset of effect can be a major advantage in many clinical applications where quick and effective administration is needed (eg, alleviating agitation in emergency settings or reducing debilitating migraine symptoms). Here, we review the pharmacokinetic profile of INP105, which is being developed to deliver olanzapine (OLZ) by POD to treat agitation in patients with autism. Because formulation can play a large role in the pharmacokinetic profile of a nasally administered drug, we provide a comprehensive review of both published and previously unpublished preclinical data outlining how the INP105 formulation was developed and optimized for study in humans. Multiple formulation carriers and excipients were tested to find a stable INP105 formulation with a desirable nasal absorption profile. Because the nasal architecture in nonhuman primates (NHPs) is similar to humans, the pharmacokinetics and tolerability of an INP105 combination product (NHP-INP105) using a clinical formulation combined with a device specifically designed for NHPs has been investigated in preclinical NHP studies, providing translational data for human studies and the pathway for testing novel products and formulations. The pharmacokinetics and tolerability of INP105 were then evaluated in an early clinical study in humans, demonstrating favorable pharmacokinetic and pharmacodynamic profiles. In this review, we aim to illustrate how delivery of therapeutics to the upper nasal space using POD, such as with agents like INP105, has the potential to optimize nasal delivery and unlock the potential of delivery-limited drugs to provide patients with rapid onset of effect, ease of use, and convenience.
Ronald P. Evens, B.S. Pharm, Pharm.D., FCCP
Adjunct Research Professor, Tufts University; President, M.A,P,S. 4 Biotec, Inc
Abstract
Biotechnology (the science and the business) has revolutionized product development and healthcare worldwide over the past 40 years with novel molecules, new companies, and major advances in disease mitigation. The revolution has continued and even accelerated as can be observed in comparing the last 20 years (2000-2019) versus first 20 years (1980-1999), and the recent years of 2020 and 2021 as well. This biotech review addresses the many product categories, indications, research, companies, business changes, and product sales, especially comparing these two time periods and demonstrating the substantial growth and impact of biotechnology and continuing the revolution through the last two years (2020-2021). Over 500 biotech products are available worldwide in 10 different categories of molecules for over 460 indications with over 160 biotech and pharma companies marketing the products. Biosimilar products (close duplicates of marketed products) have become commonplace in last 15 years. The top companies in biotech research and sales over these 40 years include Roche, Amgen, and Novo Nordisk, along with all the pharma companies becoming engaged. Twenty plus of the leading biotech companies have been acquired over these times. All of pharma is now dedicated to biotech molecule development independently and mostly in extensive collaboration with biotech companies. Clinical research has expanded with the top 90 biotech companies that spend at least $100 million in one year totaling over $50 billion in 2020, along with tens of billions from pharma companies for biotech research & development. Over 600 molecules are being studied in phase three clinical trials. Worldwide biotech sales grew to $327 million in 2020 from $35 billion in 2001 with biotech over 25% of all drug sales. The biotech revolution is alive and well and continuing with novel molecules from exiting and more new biotech and pharma companies for further advances in healthcare.
Abstract
The emergence and spread of a novel coronavirus designated as SARS-CoV-2 in late 2019 undeniably precipitated the greatest public health disaster of this new millennium. In absence of an available vaccine or virus-specific anti-viral drug, global health authorities issued several public advisories at the beginning of the pandemic and recommended mitigation measures based on the accumulating evidence and growing knowledge of the spread of this respiratory virus largely through airborne droplets and fomites. The recommended measures emphasized practicing respiratory, hand, and surface hygiene to break the chain of infection and reduce transmission of the virus. As a result of these recommendations, consumer products such as soap bars, liquid cleansers, alcohol-based hand sanitizers, oral rinses, and surface cleaners, in addition to masks (surgical, N95, etc) became the most sought-after commodities in markets across the globe. Beyond the public health recommendations, it was incumbent upon the manufacturers of such consumer products to substantiate their product efficacy against the SARS-CoV-2 virus, and later variants as they emerged, to ensure that the public confidence in the effectiveness of these products was not misplaced. In this article we will review the standard test methodologies and their scientific robustness to determine virucidal efficacy, as well as their relevance to consumer usage; discuss the contributory ingredients in each class of personal care formulations and their mechanisms of virucidal action; and establish the importance of the fully formulated products to ensure they are efficacious under consumer habit-oriented usage. Additionally, we will highlight the impact of hand, body, and oral hygiene practices and compliance in infection control for COVID-19 and their relevance for future outbreaks. Last but not the least, we will provide an overview of the existing regulatory challenges for claiming virucidal benefits from personal care formulations and propose ways in which opportunities to disclose proven benefits of these formulations would be beneficial to the public at large in sustaining efforts towards personal hygiene practices for infection prevention.
Meghan Cook
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Meghan Ferguson
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Alma Garcia
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Katie Konieczny
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Kevin Bumanglag
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Thi Tran
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Robert B. Campbell
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Abstract
Neuroblastoma is a solid malignancy observed in pediatric patients developing when neuroblasts are unable to mature, leading to unregulated proliferation and tumor formation. Neuroblastoma is heterogeneous and aggressive in nature, leading to high treatment failure, morbidity, and mortality rates. Lewis family glycans, as part of the Core 2 O-glycans, play a key role in neuroblastoma malignant cell behavior in MYCN-amplified cell lines. Current treatment approaches for neuroblastoma include chemotherapy, surgery, and radiation. These approaches are faced with physiological and cellular barriers, including the less understood role of glycosylation in development and treatment. Studies have confirmed that the inhibition of mucin glycosylation has improved effectiveness of cytotoxic drug agents employed against solid malignancies such as with pancreatic cancer, yet little research is available regarding the influence of glycosylated proteins for other diseases. This article explores genetic defects associated with neuroblastoma such MYCN gene amplification at the time of diagnosis, as well as clinical approaches and therapeutic challenges encountered during treatment. Additionally, the article reviews experimental and clinical evidence in support of the influence of glycosylation in neuroblastoma development, and possible unfavorable impact of glycosylation on drug therapy.
Bellet M
Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Braunstein G
Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Verweij P
Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Danaietash P
Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Iglarz M
Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Flamion B
Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Abstract
Dose selection plays a critical role in the clinical development of a drug. This current review highlights the lessons learned from previous dose finding studies (DFSs) of antihypertensive drugs and from the recent example of aprocitentan, a novel endothelin receptor antagonist for the treatment of resistant hypertension. Based on these, the authors provide 10 key recommendations for an efficient DFS for a new antihypertensive medication. These recommendations respect critical comments repeatedly made by the U.S. Food and Drug Administration (FDA) Division of Cardiology and Nephrology over the last 5 decades and go beyond the more limited recommendations made in the 2016 Committee for Medicinal Products for Human Use (CHMP) guideline on the development of new antihypertensive medications. The added value of a dose-response modelling approach enriches prior regulatory advice on DFSs.
Abstract
Background: Hormone receptor positive, human epidermal growth factor receptor negative Luminal A breast cancer subtype responds to targeted endocrine therapy, signal transduction inhibitors and cyclin dependent kinase inhibitors. Estrogen and progesterone receptor mediated signal transduction involves receptor-DNA binding and transcriptional activation of downstream target genes. In addition to hormone receptor signaling, cellular metabolism of estradiol and progesterone exhibit distinct roles in cancer growth modulation. Targeted therapy is associated with systemic toxicity, therapy resistance and emergence of chemo-resistant cancer initiating stem cells. These limitations emphasize identification of testable drug candidates for therapy resistant breast cancer. Cellular metabolism of ovarian steroid hormones generates oxidative metabolites with distinct growth modulating effects. Anti-proliferative metabolites may represent potential drug candidates.
Objectives: The objectives of the present review are to provide i) Systematic discussion of published evidence relevant to the role of ovarian steroid hormone metabolism in growth modulatory effects on cancer progression, ii) Evidence for applicability of Luminal A breast cancer and drug-resistant cancer stem cell models to identify mechanistic leads for efficacy of anti-proliferative hormone metabolites, and iii) Future research directions for clinical translatability of patient derived preclinical data.
Conclusions: Contrasting growth modulatory effects ovarian steroid hormones, anti-proliferative effects of individual metabolites of ovarian steroid hormones, growth inhibitory efficacy of nutritional herbs via altered cellular metabolism of estradiol and development of drug-resistant cancer stem cell model represent salient features of this review. Collectively, present evidence validates experimental approaches to identify growth inhibitory hormone metabolites and bioactive agent from nutritional herbs as potential drug candidates for therapy-resistant breast cancer.
Future Research: This review provides a rationale for future investigations to evaluate stem cell targeted efficacy of anti-proliferative hormone metabolites and herbal bioactive agents. These directions may include functional significance of estrogen receptor-β, and telomerase expression. Furthermore, investigations using patient-derived tumor explant and tumor organoid models from therapy-resistant breast cancer may facilitate experimental approaches to expand preclinical evidence for its clinical relevance and translational potential.
Gudepalya Renukaiah Rudramurthy
Foundation for Neglected Disease Research (FNDR), Plot No. 20A, KIADB Industrial Area, Bengaluru – 561203, Karnataka, India
Radha Krishan Shandil
Foundation for Neglected Disease Research (FNDR), Plot No. 20A, KIADB Industrial Area, Bengaluru – 561203, Karnataka, India
Shridhar Narayanan
Foundation for Neglected Disease Research (FNDR), Plot No. 20A, KIADB Industrial Area, Bengaluru – 561203, Karnataka, India
Abstract
The current pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) demands rapid identification of new antiviral molecules from the existing drugs. Drug repurposing is a significant alternative for pandemics and emerging diseases because of the availability of preclinical data, documented safety in clinic and possibility of immediate production and scalable capacity and supply. Several drugs such as ivermectin and hydroxy chloroquine have been repurposed as anti-SARS-CoV-2 agents, but the effect of these compounds in treating the COVID-19 patients remains sub-optimal. In the present study repurposed drug libraries consisting of 560 compounds from two different sources have been screened against SARS-CoV-2 isolate USA-WA1/2020 in Vero-E6 cell line and 24 compounds were found active. The SARS-CoV-2 virus propagated in Vero E6 cell line and used in screening the drug libraries was sequenced by Next Generation Sequencing to identify any mutations that may have accumulated in the virus genome. The whole genome sequencing data of SARS-CoV-2 showed 9 and 6 single nucleotide polymorphisms in spike protein with reference to Wuhan-Hu-1(NC045512.2) and USA/WA-CDC-WA1/2020 (MN985325.1) isolates respectively. The present study identified 24 compounds active against SARS-CoV-2 isolate USA-WA1/2020 out of 560 repurposed drugs from two libraries. The IC-50 values of the identified hits range from 0.4 µM to 16 µM. Further studies on the repurposed drugs identified in the present screen may be helpful in the rapid development of antiviral drugs against SARS-CoV-2.
Vijay Sharma
Cellular Pathology, Liverpool Clinical Laboratories, Royal Liverpool Hospital, School of Medicine and Department of Molecular and Clinical Cancer Medicine, Department of Molecular and Cancer Medicine, Institute of Systems
Abstract
The biological behaviour of breast cancer is remarkably heterogeneous and it is essential to have tools which can provide the necessary risk stratification to plan clinical management. Breast cancer prediction and prognosis needs to be holistic, and account for multiple levels of organisation. The histological classification and grading of the tumour itself presents valuable predictive and prognostic information. Hormone receptor status remains a mainstay, but roles may emerge for assessment of the intrinsic molecular subtype, for a molecular subclassification of triple negative carcinomas, and for whole genome sequencing. The recent discovery that antibody drug conjugates are effective in patients with weak HER-2 protein expression has led to the definition of the HER-2 low group.
There has been a proliferation in predictive and prognostic models, numbering over 900, but the majority are at high risk of bias and tend to perform less well when applied to populations beyond the development cohort. The Nottingham Prognostic Index is a notable exception. Of the molecular risk stratification tools currently available, Oncotype Dx is the most widely recommended and used, but the question as to which test is superior remains unanswerable with current data. There is growing interest in omics-based approaches from which a number of biomarkers are being developed.
It is well established that the microenvironment of the tumour is key to the tumour’s behaviour. Some components contain and destroy the cancer, whereas others are co-opted by the tumour and aid in its progression; the current evidence is reviewed, including the current status of tumour infiltrating lymphocyte assessment and immune checkpoint inhibition in breast cancer. The use of the liquid biopsy to achieve early detection of tumours and to manage tumour evolution is receiving intense attention; approaches include circulating tumour cells and circulating tumour DNA. Specific assessment of tumour giant cells may also provide the ability to anticipate tumour evolution. The influence of the gut microbiome on breast cancer is an intriguing development which requires further intensive study. There is a paucity of biomarkers in the setting of hereditary breast cancer. The use of polygenic risk scores in this setting is an interesting development requiring further study.
The greatest challenge of all is to pull from such complexity key decision nodes that are clear enough to guide treatment decisions without losing the depth and richness of the information that underlies them. Seeking and finding this balance has been and will continue to be the holy grail of all endeavours in this field.
Ronald P. Evens, B.S. Pharm., Pharm.D., FCCP
Research Professor, Center for the Study of Drug Development, School of Medicine, Tufts University, Boston, MA President, M.A.P.S. Biotech Consulting Inc, Napa, CA
Abstract
What is the commitment of the pharma industry to biotechnology in its research, products, and business practices? Five issues demonstrate the pharma companies’ extensive engagement with and embrace of biotechnology as a primary focus in their business practices (marketing, sales, acquisitions) and research over the timeframe of 2000 through 2022. Overall trends for biotechnology [1980 to 2000 to 2022] are explored for context and display the overall extent of biotech impact on products approved (number and types), their breadth of indications, and extent of utilization/sales. Discovery of biotech molecules addresses pharma versus biotech companies’ results, significantly favoring biotech companies. The top 100 biotech products and drugs are discussed for 2001 versus 2011 versus 2021, especially changes over time, with pharma growth exceeding biotech companies. The top pharma & biotech companies are examined for marketing of biotech products, again showing dramatic expansion of pharma engagement. Mergers and acquisitions of biotech companies by pharma companies is presented, especially the extensive investments and breadth and depth of pharma companies engaged. All these parameters (products, companies, research, sales, company acquisitions) well documents the movement of pharma companies collectively to substantially incorporate biotech products into their research pipelines and product portfolios.
Dr. U. Ubaidulla
Associate professor, Department of pharmaceutics, Cresent school of pharmacy, B.S. Abdur Rahman cresent institute of science and technology, India.
Dr. Sandhiya V
Associate professor, Department of pharmaceutics, Faculty of pharmacy, Sree Balaji Medical college and hospital campus, BIHER, Chennai-44
Dr. T. Purushoth Prabhu
Professor and Head, Department of pharmacognosy, C.L.Baid metha college of pharmacy, thoraipakkam ,Chennai-97
Dr. N. Deepa
Dean, Department of pharmacognosy, Faculty of pharmacy, Sree Balaji Medical college and hospital campus, BIHER, Chennai-44
Dr. Arulprakasam K C
Professor, JKKMMRF’s Annai JKK Sampoorani Ammal College of Pharmacy, Komarapalayam, India.
Senthilkumar Balakrishnan
Professor, JKKMMRF’s Annai JKK Sampoorani Ammal College of Pharmacy, Komarapalayam, India.
Velayutham Suresh
Professor, JKKMMRF’s Annai JKK Sampoorani Ammal College of Pharmacy, Komarapalayam, India.
Abstract
The urgent need for a novel way to replicate human drug reactions in preclinical research has motivated the development of organ-on-a-chip (OoC) systems. These difficulties are not recognized during preclinical trials, owing to ineffective screening technologies that mimic the complexities of human tissues and provide quick, accurate screening readouts. Microfluidics and microfabrication are powerful methods for creating numerous systems with high spatiotemporal precision to simulate in vivo microenvironments for drug delivery, discovery, development, and screening. This method might be used to investigate cell responses to pharmacological and mechanical stimuli in a more physiologically effective way. In this paper, we examine current achievements in OoC with an emphasis on biomimicry, functionality, and characteristics, as well as multi-organ platforms that attempt to replicate the essential aspects of integrated human physiology. Finally, we explore future prospects and limits that must be addressed in order to get OoC systems closer to clinical translation.
Marcos A. Sanchez-Gonzalez
Lake Erie College of Osteopathic Medicine, Bradenton, FL, USA; Research & Development, Aventura Pulmonary Institute, Miami, FL, USA
Jonna B. Westover
Institute for Antiviral Research, Utah State University, Logan, Utah, USA
Syed A A Rizvi
Department of Pharmaceutical Sciences, Hampton University School of Pharmacy, Hampton, VA, USA
Joselit Torres
Institute of Immunodiagnosis. Urb. El Rosal, Caracas, Venezuela
Gustavo A. Ferrer, MD
Research & Development, Aventura Pulmonary Institute, Miami, FL, USA
Abstract
Recently, the nasal cavity has been highlighted as an ideal route of administration for interventions as it is the portal of entry of the severe acute respiratory syndrome coronavirus (SARS-CoV-2). The present study aimed to demonstrate the feasibility and efficacy of intranasally administered Chlorpheniramine Maleate (CPM) spray to treat coronavirus disease 2019 (COVID-19).
Methods: The present study used a two-phase, non-clinical to clinical approach. The non-clinical phase evaluated CPM’s antiviral activity against SARS-CoV-2 delta (B.1.617.2) strain via a highly differentiated three-dimensional in vitro model of normal, human-derived tracheal/bronchial epithelial cells. CPM was tested in duplicate inserts of the tissue models of the human airway. Virus yield reduction assays measured antiviral activity on day six after infection. For the clinical phase, COVID-19 symptomatic (polymerase chain reaction positive) patients were recruited and assigned to a 7-day CPM treatment (n=32) or placebo (PLB; n=13). Close safety monitoring of all patients was conducted before and after administering the drug. The primary outcomes monitored were time to symptom resolution (days), progression to hospitalization, emergency room visits, and symptoms of the severity of the disease using a visual analog scale (VAS) on a scale of 1-10 (no symptoms to worst symptoms).
Results: The virus yielded a reduction in the assay such that the CPM solution log reduction value was 2.69 and Remdesivir 0.12, demonstrating much high antiviral activity of CPM. Results of the clinical phase demonstrate that VAS scores between the groups were evident after using CPM for two days (day 3). The CPM group VAS were significantly lower (P<0.001) starting from day three compared with day one. In contrast, there were no statistically significant (P>0.05) changes in the PLB during the 7-day treatment window. No subjects in the intervention group were hospitalized, while two in the PLB required hospitalization (15.4%; X2=5.15, P=0.023). Besides some mild discomfort felt by subjects immediately after applying the spray, the participants reported neither adverse reactions nor side effects.
Conclusion: If taken together, the results of the present two-phase study point towards the conclusion that CPM is an antiviral agent that can be administered intranasally to treat COVID-19 effectively.
Wamae PM
Climate and Human Health Research Unit, Centre for Global Health Research, Kenya Medical Research Institute (KEMRI). P.O Box 1578-40100 Kisumu, Kenya; Department of Community Health, School of Public Health, Kenyatta University. P.O Box 43844-00100 Nairobi, Kenya
Otieno GO
Department of Community Health, School of Public Health, Kenyatta University. P.O Box 43844-00100 Nairobi, Kenya
Kabiru EW
Department of Community Health, School of Public Health, Kenyatta University. P.O Box 43844-00100 Nairobi, Kenya
Munga S
Division of Malaria Control (DOMC), Ministry of Public Health and Sanitation, Kenya. P.O Box 19982-00202 Nairobi, Kenya
Kibet SJ
Division of Malaria Control (DOMC), Ministry of Public Health and Sanitation, Kenya. P.O Box 19982-00202 Nairobi, Kenya
Duombia SO
Malaria Research and Training Centre, Faculty of Medicine. University of Mali, Bamako. P.O Box 1805 Bamako, Mali
Githeko AK
Climate and Human Health Research Unit, Centre for Global Health Research, Kenya Medical Research Institute (KEMRI). P.O Box 1578-40100 Kisumu, Kenya
Abstract
Malaria heterogeneity in the highlands is due to range of factors including seasonal weather changes, climate variability, land-use changes, topography, drug resistance, and malaria control programs. High coverage of long lasting insecticide treated nets is the basis of vector control in epidemic prone western Kenya highlands. Long lasting insecticide treated nets have effectively controlled malaria in the hypo-endemic zones, but not in meso-endemic and hyper-endemic zones where significant residue of transmission remains despite control efforts.
Inadequate policy on integrated vector management application for ecologically heterogeneous ecosystems hinders effective malaria control. Advances in ecological and epidemiological studies have improved our understanding on vector distribution determinants and malaria transmission enabling us to effectively integrate indoor residual spraying into the existing long lasting insecticide treated nets programme.
Data on malaria vector abundance and parasite prevalence for different malaria ecosystems within western Kenya highlands before and after mass insecticide treated bed-net distribution campaigns was gathered to assess the efficacy of the long lasting insecticide treated nets based control efforts. Field tests were carried out to determine the impact of combined indoor residual spray and long lasting insecticide treated nets on vector indoor resting densities in zones where insecticide treated nets alone had limited efficacy or zero efficacy was observed.
Female An. gambiae s.l resting densities of 0.1 mosquitoes/ house/night were associated with a plasmodium falciparum (pf) prevalence rate of 10% or below. This observation enabled the development of a framework for the inclusion of indoor residual spray in integrated vector management with the suggestion that IRS should be applied in malaria eco-epidemiological zones where An. gambiae s.l resting densities exceeds 0.1 females/ house/ night.
Similarly, only those houses with a resting density of 0.1 females An. gambiae s.l and above should be targeted during spraying. Such an approach would significantly reduce the cost associated with indoor residual spray and provides a rationale for judicious integration of indoor residual spray within existing long lasting insecticide treated nets control programmes.
Annamaria Bosi, MD
Section of Respiratory Diseases, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, University Hospital of Modena, 41124 Modena, Italy.
Maria Serena Simeone, MD
Section of Respiratory Diseases, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, University Hospital of Modena, 41124 Modena, Italy.
Federica Ghinassi, MD
Section of Respiratory Diseases, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, University Hospital of Modena, 41124 Modena, Italy.
Serena Baroncini, MD
Section of Respiratory Diseases, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, University Hospital of Modena, 41124 Modena, Italy.
Valentina Ruggieri, PhD
Section of Respiratory Diseases, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, University Hospital of Modena, 41124 Modena, Italy.
Bianca Beghe, MD, PhD
Section of Respiratory Diseases, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, University Hospital of Modena, 41124 Modena, Italy.
Abstract
Asthma is a common and heterogeneous disease whose treatment has considerably changed over the last decades. While inhaled therapies based on inhaled corticosteroids and long acting β2 agonists are effective in controlling asthma in the majority of patients, about 5% of asthmatics poorly respond to inhaled steroids or inhaled steroids/long acting β2 agonists combinations. These patients are affected by “severe asthma”, which is associated with need of oral corticosteroids, progression of the disease, increased use of healthcare services, deterioration of quality of life, and a significant economic burden on society. Asthma is no longer considered a single disease, but a respiratory syndrome with complex biological network of distinct and interrelating inflammatory and remodeling pathways (endotypes) that are associated with different clinical manifestations (phenotypes) both in the lungs (asthma) and other organs (e.g. nose and skin). Severe asthma endotypes may be broadly regarded as Type 2-high and Type 2-low, a model that has become central to asthma management with the development of novel treatments for the Type 2-high endotypes. The hallmark feature of Type 2-high asthma is eosinophilic inflammation, often associated with increased serum IgE, increased exhaled nitric oxide (FeNO) and blood eosinophilia. The discovery of the main key drivers of Type 2-high inflammation (IgE, cytokines such as interleukin IL-5, -4 and -13) enabled the development of new biological agents directed towards specific molecular targets. These advances have shifted the existing paradigm “one drug fits all” to “patient-tailored” novel therapies. The monoclonal antibodies direct to IgE (omalizumab), IL-5 and IL-5 receptor (mepolizumab, benralizumab, reslizumab), and to the α chain of the IL-4 and IL-13 combined receptor (dupilumab), and more recently, to the thymic stromal lymphopoietin (tezepelumab) have been shown in both clinical trials and real-life studies to control symptoms, reduce asthma exacerbations and improve lung function in severe asthmatics not controlled by full inhalation therapies. More recently, the Single Inhaler Triple Therapy (SITT) containing inhaled steroids, long acting β2 agonists and muscarinic antagonists has been developed, slightly improving the effectiveness/safety of the inhalation therapy. This report aims to review available therapeutic opportunities for patients with severe asthma focusing on patients with Type 2-high severe asthma and how to position these new therapeutic alternatives in clinical practice.
Yaochao Zheng
Regenerative Bioscience Center, Department of Animal and Dairy Science, College of Agricultural and Environmental Science, University of Georgia, Athens, GA 30602, USA
Rachel Hankin
Regenerative Bioscience Center, Department of Animal and Dairy Science, College of Agricultural and Environmental Science, University of Georgia, Athens, GA 30602, USA
Yao Yao
Regenerative Bioscience Center, Department of Animal and Dairy Science, College of Agricultural and Environmental Science, University of Georgia, Athens, GA 30602, USA
Abstract
Amyotrophic lateral sclerosis (ALS) remains an untreatable neurodegenerative disease without a cure or effective treatment, mainly due to elusive underlying mechanisms. ALS is primarily characterized by motor neuron dysfunction in the brain and spinal cord. However, it also exhibits non-motor symptoms such as executive, behavioral, and language dysfunction, making it challenging to establish informative disease models for relevant preclinic and clinical research. The discovery of ALS-causing genes has paved the way for the development of various animal models. Among these models, rodents have emerged as particularly valuable, demonstrating unique ALS-related behavioral defects in multiple behavioral tests. These models enable further understanding of disease mechanisms and provide sensitive and precise functional assessments for drug development. Given the intricate nature of ALS pathology, it is crucial and challenging to select appropriate behavioral tests as functional exploratory readouts, mainly due to the diverse array of ALS rodent models exhibiting distinct behavioral paradigms. Therefore, this report endeavors to present an overview of various behavioral assessments, encompassing motion ability tests, cognitive evaluations, sensory analyses, and other paradigms described in rodent models of ALS. Our goal is to summarize and compare the behavioral alterations observed in diverse rodent models of ALS with distinct gene mutations, thus providing comprehensive references and guidance for advancing pathogenic and therapeutic research in ALS.
Oscar Cobar
Pharmacogenomics and Nutrigenomics Research Laboratory, School of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.; Biomedical Sciences, Ph.D. Program, School of Medical Sciences, University of San Carlos, Guatemala.
Stella Cobar
School of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.
Abstract
Background: One of the major problems in drug design is to enhance the drug’s potency against genetic variants, for which adding a suitable pharmacophore to a newly designed molecule is preferred.
RNA-dependent RNA polymerase (RdRp) is the SARS-CoV-2 enzyme responsible for genome replication and gene transcription into the human cell.
Cryogenic Electron Microscopy resolved the first structure of the RdRp complex of SARS-CoV-2 in April 2020, followed by two other studies that reported similar structures that same year.
The RdRp complex is built up from several nonstructural proteins included nsp12, nsp7, and nsp8.
The protein nsp12 represents the core component and the catalytic subunit of RdRp, while nsp7 and nsp8 are accessory factors that increase the binding and processivity of the RdRp template.
The nsp12 subunit contains an N-terminal nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain, an interface domain and a C-terminal RdRp domain.
Subunits nsp7 and nsp8 bind to the thumb, and an additional copy of nsp8 binds to the fingers domain.
During replication, the active site of RdRp is responsible for incorporating free nucleotides into the daughter RNA strand of the replication complex.
RdRp inhibitors, once metabolized, compete with the viral ATP molecules for incorporation into the nascent RNA strand.
Once the RdRp drug replaces ATP in the new strand, the RNA synthesis process is terminated, thereby preventing further replication of the virus from occurring.
In several studies reviewed in this manuscript, Molecular Docking simulations was employed to screen inhibitors that showed binding interaction with the conserved residues of RdRp.
Aim: The purpose of the Review is to present a literature review from January 1, 2023, to April 30, 2024, on the advances in SARS-CoV-2 RdRp inhibitors as a therapeutic approach against the virus, emphasizing on the structure of the enzime, the non-structural proteins that comprises, in particular nsp12, nsp 8 and nsp 7, the mechanisms that underlie the antiviral activity of RdRp inhibitory substances, the structure of the nucleoside analogs that have demonstrated RdRp inhibition in structural biology and computational research studies, and examine the current understanding of the molecular mechanisms underlying the action of these nucleoside analogs.
Materials and Methods: Original scientific articles published in Medline, Pubmed, Science Direct, Web of Science, Scopus, EBSCO and BioMed Central databases, official health organizations (World Health Organization, U.S. Centers for Disease Control and Prevention, European Centre for Disease Prevention and Control) electronic publications, and specialized media in the subject, were electronically searched to accomplish the aim of the study. Articles published in any language were included from January 1, 2023, to April 30, 2024, using a variety of keywords in combination. The studies relevant to our review were analyzed and compared.
Results and Discussion:
Inhibition of RdRp´s has been an integral approach for managing various viral infections such as dengue, influenza, Hepatitis C (HCV), Bovine Viral Diarrhea Virus (BVDV), among others. Inhibition of the SARS-CoV-2 RdRp is currently rigorously explored for the treatment of COVID-19. Consequently, the importance of RdRp in developing anti-viral agents against this viral disease, has been discussed by the scientific community in the last four years. The structure activity relationship profile and binding conformations of the reported inhibitors are essential features to elucidate some hypothesis for the designing of further SARS-CoV-2 RdRp inhibitors.
The search on scientific literature on these inhibitors, the analyses of the interaction characteristics, together with the examination of the inhibitors chemical structure, it would guide the rational design of antiviral medications and research into viral transcriptional mechanisms.
Conclusions: Several RdRp inhibitors have shown promising results for their use in treating the SARS-CoV-2 virus.
While work must still be conducted to fully understand the mechanisms responsible for reducing the antiviral activity of SARS-CoV-2, their potential in healing infected individuals is extremely valuable.
The development of SARS-CoV-2 RdRp inhibitors, to relieve the severity of an infection for a SARS-CoV-2 variants that could emerge in the near future, it is an essential task for the scientific community.
The analyses of inhibitors chemical structure-RdRp, besides the analyses of the inhibitors-RdRp interactions, it would guide the rational design of antiviral medications and research into SARS-CoV-2 transcriptional mechanisms.
This review summarizes recent progress in studies of RdRp inhibitors, 87 compounds was tested, focusing on the chemical structure of the inhibitors and the interactions between these inhibitors and the enzyme complex.
Kauther I. Layas
Libyan Oxygen Medical Centre, Tripoli, Libya
Prabal K. Chatterjee
Centre for Precision Health and Translational Medicine, School of applied Sciences, University of Brighton, Lewes Road, Brighton, BN2 4GJ, UK
Ananth S. Pannala
Centre for Precision Health and Translational Medicine, School of applied Sciences, University of Brighton, Lewes Road, Brighton, BN2 4GJ, UK
Abstract
Acute kidney injury is characterised by abrupt failure of kidney function, sometimes leading to chronic kidney disease, and is associated with significant morbidity and mortality. However, there is no clear effective therapeutic solution and treatment is mainly based on either alleviation or removal of the possible cause and/or renal replacement therapy. Oxidative stress has been indicated as one of the main pathophysiological pathways in the development of acute kidney injury. Various treatments including antioxidants, inflammatory mediators and genetic modifiers have been proposed to for the treatment of this condition. Epidemiological studies show lower incidence of kidney failure with higher consumption of antioxidants. However, the data is inconclusive due to their physicochemical properties, bioavailability or toxicity. Novel drug delivery systems such as liposomes and nanoparticles have been proposed to overcome the pharmacodynamic and pharmacokinetic barriers. This review provides a brief introduction to acute kidney injury and the different factors involved in its pathology, focusing on oxidative stress. It also covers details of antioxidant use as preventive and/or treatment option. It will summarise their limitations as free drugs and the possible improvement in their bioavailability by two main novel drug delivery systems: liposomes and polymeric nanoparticles. Other therapies such as inflammatory mediators and genetic modifiers are also discussed briefly.
Stephen E. Nadeau, MD
1 Neurology Service and the Brain Rehabilitation Research Center, Malcom Randall VA Medical Center and the Department of Neurology, University of Florida College of Medicine.
Richard A. Lawhern, PhD
Independent healthcare writer and patient advocate.
Abstract
Introduction: In a previous paper, we inquired into the root causes of the two opioid crises our nation is facing, one evolved from the effects of political and psychosocial forces, one manufactured by the Centers for Disease Control and Prevention. This inquiry led us to suspect that the very different opioid consumption patterns of various groups of people were driven by very different motivations related to the opioid experience. Here we explore four potential motivations or disincentives: analgesia, euphoria, dysphoria, and the search for oblivion. We particularly focus on two populations more likely to be motivated by the search for oblivion: people addicted to opioids and terminal cancer patients, and the problem of tolerance.
Methods: Analytic review of the scientific literature.
Results and Discussion: Essentially all patients managed in American clinics, including many patients with cancer, are motivated by a simple desire for analgesia. A search for euphoria almost certainly motivates the population of people who use mind-altering drugs, including opioids, for recreation. Dysphoria is a feeling of unpleasantness associated with a particular opioid sufficient to motivate a patient to refuse the drug. It represents a common challenge in managing patients in chronic pain. The search for oblivion appears to be the primary motivation for people with opioid addiction. It may also be a motivating factor in certain patients with terminal cancer who suffer not just pain but also agonizing existential crisis.
Conclusion: A greater appreciation on the part of clinicians, scientists and policy makers of the different factors that motivate use of opioids could have major implications for how we handle different people consuming opioids. It could disabuse us of the suspicion that every patient in pain is seeking euphoria rather than analgesia and help us to understand their vanishingly small risk of drug abuse or addiction. It could lead to serious study of the mechanisms of dysphoria and the development of means to circumvent it. It could lead to improved approaches to patients with pain from terminal cancer and optimal strategies for dealing with the addiction crisis in the streets.
Stephen Bevan Shrewsbury
Impel Pharmaceuticals
Abstract
In this imperfect world, given that humans often need to treat or prevent disease by delivering medicine to the target cells earlier and for longer than previously possible, certain optimum requirements should be met. Treatment, or prevention, by a therapeutic molecule should be delivered at the right time, at the right dose, to the right target cell, by the safest, most convenient, inexpensive and effective method of delivery.
Most new drugs go through a phase, usually in early development, when they are administered by intravenous delivery, but many of these products end up being delivered by a different modality later, and locally acting drugs for local disease may benefit from topical administration to the epithelium, or adjacent tissue, of interest. With many of the newer medicines being proteins or peptides, oral delivery is not an option due to their degradation in the gut, so non-oral formulations are becoming even more important.
This editorial highlights some of the challenges facing developers when considering how to deliver their products. It focuses on a new route of administration that recently received approval that may represent an opportunity for non-invasive delivery of acutely needed medications.
Minesh Patel
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Eric Conte
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Nan Luo
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Virali Patel
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Ashley Varela Martinez
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Hae Chan Kim
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Naga Goli
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Robert B. Campbell
Department of Pharmaceutical Sciences, MCPHS University Worcester, MA 01608, USA; Professor of Pharmaceutics, MCPHS University, Department of Pharmaceutical Sciences, 19 Foster Street, Worcester, MA 01608, USA
Abstract
Retinoblastoma is the most common type of eye cancer in infants and children. Probability of saving vision and survival depends upon two main factors: progression of the disease from unilateral to bilateral and severity of the disease. In order to effectively treat retinoblastoma and retain vision, it is crucial to focus treatment options on reducing toxicity and nonspecific targeting while enhancing drug delivery, cellular uptake, and accumulation of chemotherapeutic agents to their specific target sites. Rapid elimination from blood circulation is the greatest obstacle that conventional chemotherapeutic agents face on journey to their target sites. Target specific nanoparticles have proven to be a useful tool in efforts to overcome challenges typically encountered by targeting strategies. Development of nanoparticles loaded with chemotherapeutic agents can allow for more selective tumor targeting, extended drug circulation times, and reduced drug-associated toxicity. Nanoparticles can significantly improve the treatment efficacy in retinoblastoma. The purpose of this review is to discuss the important characteristics and differences of nano delivery systems used against cellular and in vivo models of retinoblastoma, particularly as they relate to the popular Y79 retinoblastoma cell line.
Stephen E. Nadeau, MD
Neurology Service and the Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, and the Department of Neurology, University of Florida College of Medicine.
Richard A. Lawhern, PhD
Independent healthcare writer and patient advocate.
Abstract
Introduction: In a previous paper, we inquired into the root causes of the two opioid crises our nation is facing, one evolved from the effects of political and psychosocial forces, one manufactured by the Centers for Disease Control and Prevention. This inquiry led us to suspect that the very different opioid consumption patterns of various groups of people were driven by very different motivations related to the opioid experience. Here we explore four potential motivations or disincentives: analgesia, euphoria, dysphoria, and the search for oblivion. We particularly focus on two populations more likely to be motivated by the search for oblivion: people addicted to opioids and terminal cancer patients, and the problem of tolerance.
Methods: Analytic review of the scientific literature.
Results and Discussion: Essentially all patients managed in American clinics, including many patients with cancer, are motivated by a simple desire for analgesia. A search for euphoria almost certainly motivates the population of people who use mind-altering drugs, including opioids, for recreation. Dysphoria is a feeling of unpleasantness associated with a particular opioid sufficient to motivate a patient to refuse the drug. It represents a common challenge in managing patients in chronic pain. The search for oblivion appears to be the primary motivation for people with opioid addiction. It may also be a motivating factor in certain patients with terminal cancer who suffer not just pain but also agonizing existential crisis.
Conclusion: A greater appreciation on the part of clinicians, scientists and policy makers of the different factors that motivate use of opioids could have major implications for how we handle different people consuming opioids. It could disabuse us of the suspicion that every patient in pain is seeking euphoria rather than analgesia and help us to understand their vanishingly small risk of drug abuse or addiction. It could lead to serious study of the mechanisms of dysphoria and the development of means to circumvent it. It could lead to improved approaches to patients with pain from terminal cancer and optimal strategies for dealing with the addiction crisis in the streets.
Stephen Bevan Shrewsbury
Impel Pharmaceuticals
Abstract
In this imperfect world, given that humans often need to treat or prevent disease by delivering medicine to the target cells earlier and for longer than previously possible, certain optimum requirements should be met. Treatment, or prevention, by a therapeutic molecule should be delivered at the right time, at the right dose, to the right target cell, by the safest, most convenient, inexpensive and effective method of delivery.
Most new drugs go through a phase, usually in early development, when they are administered by intravenous delivery, but many of these products end up being delivered by a different modality later, and locally acting drugs for local disease may benefit from topical administration to the epithelium, or adjacent tissue, of interest. With many of the newer medicines being proteins or peptides, oral delivery is not an option due to their degradation in the gut, so non-oral formulations are becoming even more important.
This editorial highlights some of the challenges facing developers when considering how to deliver their products. It focuses on a new route of administration that recently received approval that may represent an opportunity for non-invasive delivery of acutely needed medications.
Minesh Patel
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Eric Conte
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Nan Luo
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Virali Patel
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Ashley Varela Martinez
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Hae Chan Kim
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Naga Goli
MCPHS University, School of Pharmacy, Department of Pharmaceutical Sciences, Worcester, MA 01608, USA
Robert B. Campbell
Department of Pharmaceutical Sciences, MCPHS University Worcester, MA 01608, USA; Professor of Pharmaceutics, MCPHS University, Department of Pharmaceutical Sciences, 19 Foster Street, Worcester, MA 01608, USA
Abstract
Retinoblastoma is the most common type of eye cancer in infants and children. Probability of saving vision and survival depends upon two main factors: progression of the disease from unilateral to bilateral and severity of the disease. In order to effectively treat retinoblastoma and retain vision, it is crucial to focus treatment options on reducing toxicity and nonspecific targeting while enhancing drug delivery, cellular uptake, and accumulation of chemotherapeutic agents to their specific target sites. Rapid elimination from blood circulation is the greatest obstacle that conventional chemotherapeutic agents face on journey to their target sites. Target specific nanoparticles have proven to be a useful tool in efforts to overcome challenges typically encountered by targeting strategies. Development of nanoparticles loaded with chemotherapeutic agents can allow for more selective tumor targeting, extended drug circulation times, and reduced drug-associated toxicity. Nanoparticles can significantly improve the treatment efficacy in retinoblastoma. The purpose of this review is to discuss the important characteristics and differences of nano delivery systems used against cellular and in vivo models of retinoblastoma, particularly as they relate to the popular Y79 retinoblastoma cell line.
Fatima Khwaja
Department of Preventive Medicine, Stony Brook University, Stony Brook, New York
Robert A. Honkanen
Department of Ophthalmology, Stony Brook University, Stony Brook, New York
Basil Rigas
Department of Preventive Medicine, Stony Brook University, Stony Brook, New York; Department of Ophthalmology, Stony Brook University, Stony Brook, New York
Abstract
Dry eye disease (DED), a multifactorial disorder of the ocular surface and tear film, affects 5-50% of the global population. Currently, no satisfactory treatments of DED exist. Ongoing efforts to identify novel therapeutic agents are handicapped by the limitations of its preclinical animal models, which to some extent reflect the pathophysiological complexities of DED.. A plethora of DED models employing multiple animal species (mice, rats, cats, rabbits, dogs, and non-human primates) has been reported, each aiming to capture components of DED that appear to determine its pathophysiology and response to novel treatments. Here, we review the main animal models of DED and attempt to place each in the context of drug discovery. We also discuss a nascent method for ex vivo culture of human conjunctival cells that may abbreviate early screening of candidate therapeutics. Despite the remaining challenges, there is justified optimism that with the contribution of these preclinical models, the development of an efficacious and safe treatment of DED will be forthcoming.
Paula Martín Lillo
Research students. Faculty of Medicine. University of Zaragoza. Spain
Juan Solchaga
Research students. Faculty of Medicine. University of Zaragoza. Spain
Irene Rodríguez, MD
Head of Pathology Department in Madrid. Analiza. Madrid. Spain
Bárbara Angulo, BD, PhD
Molecular Diagnostic Department. Analiza. Madrid. Spain
Javier Azua-Romeo, MD, PhD
Operational Chief of Pathology. Analiza. Madrid. Spain. Professor and Senior researcher. University of Zaragoza. Spain
Abstract
Lung cancer is one of the most commonly diagnosed cancers worldwide. It is the leading cause of cancer-related deaths in both men and women.
In 2020, there were an estimated 2.2 million new cases of lung cancer and 1.8 million deaths due to the disease.
Historically, lung cancer has been more common in men, but the gap has been closing.
Smoking tobacco is the leading cause of lung cancer. Survival rates for lung cancer vary greatly depending on the stage at diagnosis and other factors. Overall, the prognosis for lung cancer is often poor, with a relatively low five-year survival rate compared to some other cancers.
In this work, we aim to show new paths in the diagnosis of lung cancer, through the study of several mutations and proteins, mostly detected by Next-generation sequencing (NGS) which has significantly transformed our understanding of cancer, by providing high-throughput and cost-effective methods for analyzing genomic information. In the context of lung cancer, NGS has played a crucial role in advancing our knowledge of the disease, improving diagnosis and treatment, and guiding personalized medicine approaches. key points highlighting the importance of next-generation sequencing in lung cancer:
Comprehensive Genomic Profiling
Identification of Driver Mutations
Stratification of Patients
Predicting Treatment Response
Monitoring Disease Progression
Clinical Trials and Drug Development
Early Detection and Prognosis
A large meta-analysis has been done, as well as a detailed study of 86 patients diagnosed with lung cancer in the ANALIZA laboratory. In this sense the most frequently implicated mutations in this tumor have been analyzed, ALK, ROS1 and EGFR, the positions they occupy in the genes, in addition to the programmed death ligand 1 (PD-L1), an immune control protein, which is expressed in activated immune cells and in tumor cells, and how its identification allows us to direct treatment in a more optimal way.
In summary, next-generation sequencing has revolutionized the field of lung cancer research and clinical practice. By providing detailed insights into the genomic landscape of tumors, NGS facilitates personalized treatment approaches, early detection, and ongoing monitoring, ultimately leading to improved patient outcomes.
Angelo Azzi
Tufts University, Boston, MA, USA, School of Graduate Biomedical Pharmacology and Drug Development Program
Abstract
Oxidative stress refers to an imbalance between the production of reactive oxygen species and the ability of the body to detoxify or repair the resulting damage. However, it will be shown that the term “oxidative stress” is often used instead of the correct “oxidative damage”. The term “eustress” has been used for describing beneficial signaling by small amounts of reactive oxygen species, but it will be shown that reactive oxygen species signaling can also promote cancer cell growth. The term “oxidative distress” has been created to describe the negative effects produced on cells, organs, and the entire body by large amounts of reactive oxygen species. However, if the reactive oxygen species are used to kill infectious microorganisms, the result is beneficial. Measurements of oxidative stress in body fluids or tissue specimens are a measure of oxidative damage potentially occurring simultaneously in different cells, tissues, and organs; they only provide a sum of non-separable events, possibly with opposite effects. There is no officially approved therapy to prevent or treat oxidative stress or oxidative damage. This implies that while oxidative stress issues are already a complex challenge for basic biological sciences, in a clinical setting oxidative stress is only a term of convenience with no diagnostic or therapeutic value. A critical appraisal of oxidative stress terminology, quantification, and therapeutic attempts is presented.
Ricardo Borges, MD, PhD
Pharmacology Unit. Dept of Physical Medicine and Pharmacology. Medical School. Universidad de La Laguna. Tenerife. Spain
Abstract
Marketed drugs are known to possess both therapeutic (primary) effects and side (secondary) effects. Occasionally, during the course of treating a specific disease, unexpected beneficial outcomes, referred to as “tertiary effects,” may emerge. These tertiary effects have shown great potential for drug repurposing, particularly in the context of rare diseases. Unfortunately, the observation of such effects often falls to physicians, nurses, and pharmacists who lack a proper system for effectively communicating these findings to the healthcare community. In this proposal, I suggest the development of an innovative solution called the “Orange Card,” which aims to facilitate the reporting of suspected unexpected beneficial effects associated with a particular treatment. This system would leverage the existing well-established framework employed by most countries for reporting side effects, enabling seamless integration and enhancing communication within the healthcare system.
Jingjing Ye
Global Statistics and Data Sciences (GSDS), BeiGene USA, Fulton, MD
Haitao Pan
Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN
Gregory Reaman
National Cancer Institute (NCI), National Institute of Health (NIH)
Satrajit Roychoudhury
Statistical Research and Innovation, Pfizer Inc.
Chengxing Lu
Oncology Biometrics, AstraZeneca, Waltham, Massachusetts
Lindsay A. Renfro
Division of Biostatistics, University of Southern California and Children’s Oncology Group, Los Angeles, CA
Yuan Ji
University of Chicago, Chicago, IN
Rong Liu
Biostatistics and Data Management, Regeneron Pharmaceuticals, Tarrytown NY 10591
Ying Yuan
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
Weidong Zhang
Sana Biotechnology, Cambridge, Massachusetts
Abstract
Pediatric cancer consists of a diverse group of rare diseases. Due to limited patient populations, standard randomized and controlled trials are often infeasible. As a result, single-arm trials are common in pediatric oncology and the use of external controls is often desirable or necessary to help generate actionable evidence and contextualize trial results. In this paper, we illustrate unique features in pediatric oncology clinical trials and describe their impact on the use of external controls. Various types of relevant external control data sources are described in terms of their utility and drawbacks. Statistical methodologies and design implications with external control are discussed. Two recent case studies using external controls to support pediatric oncology drug development are described in detail.
Stephen E Nadeau, MD
Neurology Service and the Brain Rehabilitation Research Center, Malcom Randall VA Medical Center and the Department of Neurology, University of Florida College of Medicine.
Richard A Lawhern, PhD
Independent healthcare writer and patient advocate
Abstract
Introduction: The United States currently faces two opioid crises, an evolved crisis currently manifesting as widespread abuse of illicit opioids, and a crisis in pain management largely manufactured by the Centers for Disease Control and Prevention 2016 Guideline. Our goal in this paper is to identify root causes, trace the trajectory of forces unleashed over time, and define potential solutions to these crises.
Methods: Analytic review of the scientific, socioeconomic, and historical literature.
Results: The evolved crisis reflects a socioeconomic rift in American society that began in the 1970s and has resulted in disintegration of lives and rising levels of desperation, particularly among the under-educated, rendering them susceptible to the lure of illicit opioids. Present manifestations of that crisis reflect a complex series of events starting with a consensus in the late1990s that opioids were fully acceptable in the management of chronic noncancer pain. This was followed by vast opportunism by pill mills, drug distributors, and the manufacturers that supplied them; aggressive actions by state governments to rein in the pill mills; and ultimately, the development of an enormous black market in heroin and fentanyl. The manufactured crisis reflects intrusion into the medical care of patients in chronic pain by the Centers for Disease Control that had been politicized decades earlier and that, in 2016, issued a Guideline that reflected serious mis-construal of the causes of the opioid crisis. We trace this history and review the literature on treatment of addiction, including medically assisted therapy, treatment of depression, psychosocial interventions, 12-step programs, programs that seek to address the causes of desperation, supervised injection facilities, decriminalization, legalization, and the impact of the comprehensive approach taken by Portugal. We also analyze the problems affecting the Centers for Disease Control that led to the publication of its ill-advised 2016 Guideline.
Discussion: We conclude that many approaches currently being taken to treat addiction are well supported by scientific evidence but that the overall efficacy of treatment programs is not optimal and only a small fraction of all patients actually enter such programs. We also conclude that the Centers for Disease Control should have no future role in the regulation of patient care.
Adrianna D. Jensen, MD
The Pacific Center for Oculofacial and Aesthetic Plastic Surgery PC; The Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, United States
Stuart R. Seiff, MD
The Pacific Center for Oculofacial and Aesthetic Plastic Surgery PC; The Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, United States
Abstract
Thyroid-associated orbitopathy (TAO) is a disfiguring and in severe cases debilitating autoimmune disease that has been the subject of much recent drug development and investigation. This condition is characterized by an acute inflammatory phase followed by a resolving, cicatricial phase. There has been a search to find an effective agent to address the acute inflammatory phase of this disease, which would hopefully minimize end stage disfigurement, overall morbidity, and the need for surgery. The advent of antibody-based immunologic therapies has shown promise in this regard. Herein we discuss the current biologic therapeutic landscape, including agents targeting the insulin-like growth factor-1 receptor (IGF-1R, teprotumumab) and the interleukin-6 receptor (IL-6R, tocilizumab), and provide additional insight and opinion from our group practice that is highly experienced in treating a large number of TAO patients. Notably, though teprotumumab is effective, and we regularly prescribe this agent with good success, we feel that tocilizumab should be regarded as another first-line therapy that may be a more appropriate choice for certain patients with active inflammatory TAO.
Eliana Zeballos
USDA Economic Research Service, Food Economic Division, Washington, D.C., USA
Wilson Sinclaira
USDA Economic Research Service, Food Economic Division, Washington, D.C., USA
Keenan Marchesia
USDA Economic Research Service, Food Economic Division, Washington, D.C., USA
Abstract
The U.S. government’s efforts in response to the pandemic included the development, manufacturing, and distribution of safe and effective COVID-19 vaccines. By the end of 2020, the Food and Drug Administration issued Emergency Use Authorizations for the Pfizer-BioNTech COVID-19 and the Moderna COVID-19 vaccine. Following this authorization, on December 14, 2020, each State received allocations of vaccines and devised individual distribution plans. This study investigates the impact of COVID-19 vaccination on U.S. food spending at home and away from home in 2021 employing fixed-effects regression analysis on quarterly State-level data. The results reveal that higher vaccination rates—measured by the share of the population that is fully vaccinated—are associated with a decrease in food-at-home sales and an increase in food-away-from-home sales. Further analysis reveals nuanced shifts between full-service and limited-service restaurants, indicating increased sales at full-service establishments and decreased sales at limited-service ones, suggesting a trade-off effect between the two restaurant types. The results of this study provide valuable insights for policymakers and industry stakeholders seeking to understand the heterogenous impacts of vaccinations on food spending.
Daria Lahoda
Doctor of Philosophy in Medicine (PhD), Assistant Professor of the Department of Family Medicine and Polyclinic Therapy, Odesa National Medical University, ave. 2 Valikhovskyi St., Odesa, Ukraine 65000, 0966419743
Abstract
Diseases of the respiratory tract occupy one of the leading places among pathologies in people of working age in the world. According to the data of world studies, it can be considered that these two comorbidities are mutually aggravating, but scientists do not have a unanimous opinion about whether this is a simple coincidence or whether these pathologies are pathogenetically related. There is considerable evidence that asthma patients do not achieve adequate asthma control worldwide. Yes, according to Maria Sandra Magnoni et al. 77.8% of patients with asthma have an uncontrolled course of asthma, although 68.4% of them believe that they have sufficient asthma control, and their treatment does not require correction. Therefore, taking into account all of the above and taking into account the low level of asthma control in patients with comorbid pathology who often suffer from bacterial and viral diseases, we believe that a more detailed study of the immunological status of these individuals is necessary in order to optimize treatment and prevention measures. Aim: to investigate the effectiveness of alternative ways of asthma control in patients with bronchial asthma against the background of overweight or obesity. Materials and methods. At the I stage, 255 patients with BA were examined. According to the study design, patients were selected according to the “inclusion/exclusion” criteria at this stage. The study was randomized. Allocation of patients into groups was carried out by the method of simple randomization with elements of stratification. Groups are statistically significant. Statistical processing of the results was carried out using parametric and non-parametric analysis methods. Resalts. Overweight or obese patients had a more severe course of bronchial asthma than patients with a normal body mass index. Overweight or obese patients were found to have higher levels of systemic inflammation, namely eosinophilic cationic protein levels and erythrocyte sedimentation rate, than patients with a normal body mass index. In addition, a close direct correlation was established between the severity of the course of bronchial asthma and indicators of eosinophil cationic protein (r=0.97; p˂0.001). After pharmacological correction, there was an increase in asthma control in patients with different severity of the course (р˂0.001; p˂0.001; p˂0.001, respectively), a decrease in the frequency of exacerbations (p˂0.05), a reduction in the number of hospitalizations (p˂0, 05) and the number of acute respiratory diseases (p˂0.05) in patients with bronchial asthma against the background of excess body weight or obesity. The use of the developed treatment-prophylactic complex using the drug bacterial lysate and inosine pranobex together with training in the Asthma School and standard treatment contributes to increasing asthma control and compliance with the doctor, reducing the number of exacerbations and hospitalizations per year in patients with bronchial asthma against the background overweight or obesity.
Michael Gronow, PhD (Cantab)
Cambridge Cancer Research Fund, CB25 9FA, UK
Abstract
This review is concerned with the role of various thiol constituents of the eukaryote cellular thiolome, particularly the part they play in the metabolism of tumour cells. The thiolome can be divided into two sections of high and low molecular weight thiol moieties and these are discussed. The impact of the discovery of high concentrations of a new unknown low molecular weight thiol in a tumour thiolome is also discussed. Its presence may have important ramifications in the search for new and more effective chemotherapeutic drugs to treat metastatic tumour cell growths.
Georg Ferber, PhD
Statistik Georg Ferber GmbH, Riehen, Switzerland
Dilshat Djumanov, PhD
Richmond Pharmacology Limited, London, UK
Ulrike Lorch, MD, FFPM
Richmond Pharmacology Limited, London, UK
Edward Jackson, BSc, MSc, PhD, MBChB
Richmond Pharmacology Limited, London, UK
Joao Almeida Melo, MD
Richmond Pharmacology Limited, London, UK
James Rickard, MPharm
King’s College London, UK, Richmond Research Institute – St George’s University of London, UK
Jorg Taubel, MD, FFPM, FESC
Richmond Pharmacology Limited, London, UK; St George’s University of London, UK, Statistik Georg Ferber GmbH, Riehen, Switzerland; King’s College London, UK; Richmond Research Institute – St George’s University of London, UK
Abstract
The electrical activity of the heart, characterised by the QT interval on an electrocardiogram (ECG), serves as a crucial parameter for evaluating cardiac health. Variations in the QT interval, particularly when corrected for heart rate using Fridericia’s formula (QTcF), have long been of interest in cardiology and play a pivotal role in assessing cardiac safety in clinical trials. Understanding the influence of meals given at different times on QTcF intervals is essential for the accurate execution of Thorough QT (TQT) studies. Moreover, it has been proposed that this meal-related QT interval shortening could serve as a valuable indicator of assay sensitivity in TQT studies or even as a potential integration of TQT investigations into in Phase I/II studies.
This study explores the impact of meals on QTcF intervals, specifically in the context of pharmacodynamic studies and TQT investigations. The primary goal is to gain insights into how different meals and baseline calculations affect QTcF changes and their potential implications for cardiac health and the risk of arrhythmias. Recent research has begun shedding light on the intricate relationship between meal composition, timing, and QTcF alterations. Several studies have investigated the effects of various nutrients, such as carbohydrates, fats, and proteins, on QTcF duration, as well as the implications of postprandial changes. These investigations have unveiled the complex interplay between dietary components and the cardiovascular system, raising essential questions about how our dietary choices may influence cardiac electrophysiology.
In this comprehensive meta-analysis, we analyse data from nine studies, all conducted in accordance with Good Clinical Practice and ethical standards. These studies were approved by Ethics Committees and Regulatory authorities. Our analysis focuses on ECG assessments, involving the use of 12-lead ECGs recorded electronically and evaluated by certified cardiologists. We apply the Fridericia formula for QT correction (QTcF), as it has been shown to provide more accurate results across different heart rates compared to other correction methods.
Our findings confirm existing literature into the impact of meals on QTcF intervals. We observe a consistent shortening of QTcF following breakfast, exceeding 5 milliseconds, which aligns with the positive control requirement defined by ICH E14, thus demonstrating the validity of our approach. In contrast, the effect of lunch is consistently less than 5 milliseconds across various timepoints and studies, indicating differences in the meal-related QTcF changes.
Furthermore, our analysis incorporates gender-based assessments, showing that women exhibit a smaller effect than men, which is significant for breakfast and the fasted condition. These results suggest that the observed QTcF effect post-breakfast is a combination of the meal itself and factors unique to the initial day of a study. This insight holds potential for improving the design and interpretation of cardiac safety studies, particularly in Phase I investigations, and may offer the opportunity to explore the removal of positive control agents like Moxifloxacin, thereby reducing exposure to harmful challenge agents and contributing to the global effort to combat antimicrobial resistance (AMR).
In conclusion, this meta-analysis advances our understanding of meal-induced QTcF changes and their significance in cardiac safety assessment, offering the prospect of more efficient and patient-focused drug development practices. This not only contributes to enhanced safety but also supports the reduction of antibiotic consumption, a key element in the global fight against AMR.
M. Sawkat Anwer, PhD, DMVH
Distinguished Professor Emeritus Department of Comparative Pathophysiology Cummings School of Veterinary Medicine at Tufts University 200 Westboro Road North Grafton, MA 01536
Abstract
Artificial Intelligent (AI)-powered technology is expected to significantly alter the way healthcare is delivered. Artificial Intelligence tools, such as machine learning and deep learning, have shown promise in supporting diagnostic assessments, recommending treatments, guiding surgical care, monitoring patients, supporting population health management, and enhancing drug development research. These tools at varying stages of maturity can also reduce provider burden and increase efficiency by recording digital notes, optimizing operational processes, and automating laborious tasks. Challenges surrounding AI tools include high-quality data access, potentially biased data, inadequate transparency, and uncertainty over liability. Fundamental changes in governmental oversight of health care, industry-hospital communication, the patient-provider relationship, and human-AI cooperation will be necessary to take advantage of the opportunities and overcome the challenges. We need to be critical and at the same time receptive as we embrace AI tools to deliver healthcare. It would be important to maintain human oversight and control to avoid unintended consequences of runaway machines making life and death decisions.
Helena Yusuf-Makagiansar
Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047; Mapp Biopharmaceutical Inc., 6160 Lusk Blvd. # C105, San Diego, CA 92121
Tatyana V. Yakovleva
Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1225 Center Drive, Gainesville, FL 32610
Meagan Weldele
Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047; Johnson County Community College, 12345 College Blvd, Overland Park, KS 66210
Rucha Mahadik
Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047
Teruna J. Siahaan
Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047
Abstract
Interactions between vascular endothelial cells and inflammatory leukocytes are intermediated via cell adhesion molecules and they become one of the key events for vascular cell injury and development of atherosclerosis. This study evaluated the effects of MTX-peptide conjugates as anti-inflammatory agents on human coronary artery endothelial cells (HCAEC) and Molt-3 T cells. Cyclic peptides, cLABL and cLBEL, were derived from the a- and b-subunits of leukocyte function-associated antigen-1 (LFA-1), respectively. They interact with intercellular adhesion molecule-1 (ICAM-1) to inhibit LFA-1/ICAM-1-mediated homotypic or heterotypic T-cell adhesion. cLABL and cLBEL were linked to the anti-inflammatory drug, methotrexate (MTX), to produce MTX-cLABL and MTX-cLBEL conjugates. This study showed that peptides and MTX-peptide conjugates inhibited T cell adhesion to HCAEC monolayers while MTX alone did not. The conjugates, but not MTX, inhibited binding of anti-ICAM-1 monoclonal antibody (mAb) to ICAM-1 on the HCAEC. This indicates that conjugation of MTX to cLABL and cLBEL peptides did not dramatically change their binding properties to ICAM-1. The conjugates had relatively lower toxicity to cells compared to MTX alone, while they were more toxic than the parent peptides. At low concentrations, MTX, MTX-cLABL and MTX-cLBEL decreased production of IL-6 and IL-8 as inflammatory cytokines. In contrast, higher concentrations of the parent peptides compared to the conjugates were required to inhibit IL-6 and IL-8 productions. Overall, both MTX-cLABL and MTX-cLBEL were more active than both free-peptides. In addition, the conjugates were less toxic than MTX alone. In conclusion, the conjugate can selectively target MTX to ICAM-1-expressing cells to increase cell targeting and to lower MTX toxicity.
Paula Martín Lillo
Research students. Faculty of Medicine. University of Zaragoza. Spain
Juan Solchaga
Research students. Faculty of Medicine. University of Zaragoza. Spain
Irene Rodríguez, MD
Head of Pathology Department in Madrid. Analiza. Madrid. Spain
Bárbara Angulo, BD, PhD
Molecular Diagnostic Department. Analiza. Madrid. Spain
Javier Azua-Romeo, MD, PhD
Operational Chief of Pathology. Analiza. Madrid. Spain. Professor and Senior researcher. University of Zaragoza. Spain
Abstract
Lung cancer is one of the most commonly diagnosed cancers worldwide. It is the leading cause of cancer-related deaths in both men and women.
In 2020, there were an estimated 2.2 million new cases of lung cancer and 1.8 million deaths due to the disease.
Historically, lung cancer has been more common in men, but the gap has been closing.
Smoking tobacco is the leading cause of lung cancer. Survival rates for lung cancer vary greatly depending on the stage at diagnosis and other factors. Overall, the prognosis for lung cancer is often poor, with a relatively low five-year survival rate compared to some other cancers.
In this work we aim to show new paths in the diagnosis of lung cancer, through the study of several mutations and proteins, mostly detected by Next-generation sequencing (NGS) which has significantly transformed our understanding of cancer, by providing high-throughput and cost-effective methods for analyzing genomic information. In the context of lung cancer, NGS has played a crucial role in advancing our knowledge of the disease, improving diagnosis and treatment, and guiding personalized medicine approaches. key points highlighting the importance of next-generation sequencing in lung cancer:
Comprehensive Genomic Profiling
Identification of Driver Mutations
Stratification of Patients
Predicting Treatment Response
Monitoring Disease Progression
Clinical Trials and Drug Development
Early Detection and Prognosis
A large meta-analysis has been done, as well as a detailed study of 86 patients diagnosed with lung cancer in the ANALIZA laboratory. In this sense the most frequently implicated mutations in this tumor have been analyzed, ALK, ROS1 and EGFR, the positions they occupy in the genes, in addition to the programmed death ligand 1 (PD-L1), an immune control protein, which is expressed in activated immune cells and in tumor cells, and how its identification allows us to direct treatment in a more optimal way.
In summary, next-generation sequencing has revolutionized the field of lung cancer research and clinical practice. By providing detailed insights into the genomic landscape of tumors, NGS facilitates personalized treatment approaches, early detection, and ongoing monitoring, ultimately leading to improved patient outcomes.
Angelo Azzi
Tufts University, Boston, MA, USA, School of Graduate Biomedical Pharmacology and Drug Development Program
Abstract
Oxidative stress refers to an imbalance between the production of reactive oxygen species and the ability of the body to detoxify or repair the resulting damage. However, it will be shown that the term “oxidative stress” is often used instead of the correct “oxidative damage”. The term “eustress” has been used for describing beneficial signaling by small amounts of reactive oxygen species, but it will be shown that reactive oxygen species signaling can also promote cancer cell growth. The term “oxidative distress” has been created to describe the negative effects produced on cells, organs, and the entire body by large amounts of reactive oxygen species. However, if the reactive oxygen species are used to kill infectious microorganisms, the result is beneficial. Measurements of oxidative stress in body fluids or tissue specimens are a measure of oxidative damage potentially occurring simultaneously in different cells, tissues, and organs; they only provide a sum of non-separable events, possibly with opposite effects. There is no officially approved therapy to prevent or treat oxidative stress or oxidative damage. This implies that while oxidative stress issues are already a complex challenge for basic biological sciences, in a clinical setting oxidative stress is only a term of convenience with no diagnostic or therapeutic value. A critical appraisal of oxidative stress terminology, quantification, and therapeutic attempts is presented.
Ricardo Borges, MD, PhD
Pharmacology Unit. Dept of Physical Medicine and Pharmacology. Medical School. Universidad de La Laguna. Tenerife. Spain
Abstract
Marketed drugs are known to possess both therapeutic (primary) effects and side (secondary) effects. Occasionally, during the course of treating a specific disease, unexpected beneficial outcomes, referred to as “tertiary effects,” may emerge. These tertiary effects have shown great potential for drug repurposing, particularly in the context of rare diseases. Unfortunately, the observation of such effects often falls to physicians, nurses, and pharmacists who lack a proper system for effectively communicating these findings to the healthcare community. In this proposal, I suggest the development of an innovative solution called the “Orange Card,” which aims to facilitate the reporting of suspected unexpected beneficial effects associated with a particular treatment. This system would leverage the existing well-established framework employed by most countries for reporting side effects, enabling seamless integration and enhancing communication within the healthcare system.
Jingjing Ye
Global Statistics and Data Sciences (GSDS), BeiGene USA, Fulton, MD
Haitao Pan
Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN
Gregory Reaman
National Cancer Institute (NCI), National Institute of Health (NIH)
Satrajit Roychoudhury
Statistical Research and Innovation, Pfizer Inc.
Chengxing Lu
Oncology Biometrics, AstraZeneca, Waltham, Massachusetts
Lindsay A. Renfro
Division of Biostatistics, University of Southern California and Children’s Oncology Group, Los Angeles, CA
Yuan Ji
University of Chicago, Chicago, IN
Rong Liu
Biostatistics and Data Management, Regeneron Pharmaceuticals, Tarrytown NY 10591
Ying Yuan
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
Weidong Zhang
Sana Biotechnology, Cambridge, Massachusetts
Abstract
Pediatric cancer consists of a diverse group of rare diseases. Due to limited patient populations, standard randomized and controlled trials are often infeasible. As a result, single-arm trials are common in pediatric oncology and the use of external controls is often desirable or necessary to help generate actionable evidence and contextualize trial results. In this paper, we illustrate unique features in pediatric oncology clinical trials and describe their impact on the use of external controls. Various types of relevant external control data sources are described in terms of their utility and drawbacks. Statistical methodologies and design implications with external control are discussed. Two recent case studies using external controls to support pediatric oncology drug development are described in detail.
Stephen E Nadeau, MD
Neurology Service and the Brain Rehabilitation Research Center, Malcom Randall VA Medical Center and the Department of Neurology, University of Florida College of Medicine.
Richard A Lawhern, PhD
Independent healthcare writer and patient advocate
Abstract
Introduction: The United States currently faces two opioid crises, an evolved crisis currently manifesting as widespread abuse of illicit opioids, and a crisis in pain management largely manufactured by the Centers for Disease Control and Prevention 2016 Guideline. Our goal in this paper is to identify root causes, trace the trajectory of forces unleashed over time, and define potential solutions to these crises.
Methods: Analytic review of the scientific, socioeconomic, and historical literature.
Results: The evolved crisis reflects a socioeconomic rift in American society that began in the 1970s and has resulted in disintegration of lives and rising levels of desperation, particularly among the under-educated, rendering them susceptible to the lure of illicit opioids. Present manifestations of that crisis reflect a complex series of events starting with a consensus in the late1990s that opioids were fully acceptable in the management of chronic noncancer pain. This was followed by vast opportunism by pill mills, drug distributors, and the manufacturers that supplied them; aggressive actions by state governments to rein in the pill mills; and ultimately, the development of an enormous black market in heroin and fentanyl. The manufactured crisis reflects intrusion into the medical care of patients in chronic pain by the Centers for Disease Control that had been politicized decades earlier and that, in 2016, issued a Guideline that reflected serious mis-construal of the causes of the opioid crisis. We trace this history and review the literature on treatment of addiction, including medically assisted therapy, treatment of depression, psychosocial interventions, 12-step programs, programs that seek to address the causes of desperation, supervised injection facilities, decriminalization, legalization, and the impact of the comprehensive approach taken by Portugal. We also analyze the problems affecting the Centers for Disease Control that led to the publication of its ill-advised 2016 Guideline.
Discussion: We conclude that many approaches currently being taken to treat addiction are well supported by scientific evidence but that the overall efficacy of treatment programs is not optimal and only a small fraction of all patients actually enter such programs. We also conclude that the Centers for Disease Control should have no future role in the regulation of patient care.
Adrianna D. Jensen, MD
The Pacific Center for Oculofacial and Aesthetic Plastic Surgery PC; The Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, United States
Stuart R. Seiff, MD
The Pacific Center for Oculofacial and Aesthetic Plastic Surgery PC; The Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, United States
Abstract
Thyroid-associated orbitopathy (TAO) is a disfiguring and in severe cases debilitating autoimmune disease that has been the subject of much recent drug development and investigation. This condition is characterized by an acute inflammatory phase followed by a resolving, cicatricial phase. There has been a search to find an effective agent to address the acute inflammatory phase of this disease, which would hopefully minimize end stage disfigurement, overall morbidity, and the need for surgery. The advent of antibody-based immunologic therapies has shown promise in this regard. Herein we discuss the current biologic therapeutic landscape, including agents targeting the insulin-like growth factor-1 receptor (IGF-1R, teprotumumab) and the interleukin-6 receptor (IL-6R, tocilizumab), and provide additional insight and opinion from our group practice that is highly experienced in treating a large number of TAO patients. Notably, though teprotumumab is effective, and we regularly prescribe this agent with good success, we feel that tocilizumab should be regarded as another first-line therapy that may be a more appropriate choice for certain patients with active inflammatory TAO.
