Diverse Therapeutic Areas Research Articles

Nanofiber-Based Drug Delivery Systems: A Review on Its Applications, Challenges, and Envisioning Future Perspectives.

Nanomaterials, especially nanofibers, hold considerable promise as drug delivery systems (DDS) by providing targeted administration of drugs due to their unique properties, such as large surface area, high porosity, and mechanical robustness. Nanofibers can be fabricated using various techniques like electrospinning, self-assembly, phase separation, and template synthesis, offering properties such as adjustable size, shape, high precision, and biodegradability. Additionally, features such as multiple target functionalization, controlled release of the drug, and prolonged circulation of the drug make nanofibers particularly suitable for biomedical applications, including drug delivery, tissue regeneration, and biosensing. This comprehensive review explores the characteristics, types, fabrication methods, and applications of nanofibers. Diverse types of polymer nanofibers are used in drug delivery, such as blended nanofibers, core-shell nanofibers, and layer-by-layer assembly, each demonstrating their own advantages in controlled drug release and targeted therapy. Electrospun nanofibers are extensively utilized in biomedical applications due to their superior mechanical performance and high porosity and advancements in coaxial electrospinning enabling the fabrication of core-shell nanofibers, offering controlled drug release kinetics and protection of loaded molecules. These nanofibers demonstrate enhanced bioactivity and biocompatibility and can find application in tissue engineering. Furthermore, this review addresses the challenges associated with nanofiber production, including reproducibility and scalability. Nanofibers exhibit the potential to revolutionize medical treatment across diverse therapeutic areas. Future research directions and challenges in nanofiber-based drug delivery discussed in this review offer guidance for further advancements in this rapidly evolving field.

Innovative approaches in characterizing and developing methods for lipoidal vesicular drug delivery systems

Lipoidal vesicular systems, including liposomes, ethosomes, and transferosomes, represent a significant advancement in targeted drug delivery, offering enhanced bioavailability, controlled release, and specific targeting capabilities. This review discusses the types of lipoidal vesicular systems, their methods of characterization, method development, applications, advantages, challenges, and future perspectives. These systems have shown immense potential in diverse therapeutic areas, including cancer therapy, infectious diseases, gene therapy, and transdermal drug delivery. Despite the challenges in stability, scalability, and targeting, ongoing research and technological advancements promise to expand their applications and improve therapeutic outcomes.

Machine learning in preclinical drug discovery.

Drug-discovery and drug-development endeavors are laborious, costly and time consuming. These programs can take upward of 12 years and cost US $2.5 billion, with a failure rate of more than 90%. Machine learning (ML) presents an opportunity to improve the drug-discovery process. Indeed, with the growing abundance of public and private large-scale biological and chemical datasets, ML techniques are becoming well positioned as useful tools that can augment the traditional drug-development process. In this Perspective, we discuss the integration of algorithmic methods throughout the preclinical phases of drug discovery. Specifically, we highlight an array of ML-based efforts, across diverse disease areas, to accelerate initial hit discovery, mechanism-of-action (MOA) elucidation and chemical property optimization. With advances in the application of ML across diverse therapeutic areas, we posit that fully ML-integrated drug-discovery pipelines will define the future of drug-development programs.

Long-Acting Gel Formulations: Advancing Drug Delivery across Diverse Therapeutic Areas.

This multifaceted landscape of long-acting gels in diverse medical fields, aims to enhance therapeutic outcomes through localized treatment and controlled drug release. The objective involves advancements spanning cancer treatment, immunotherapy, diabetes management, neuroendocrine disorders, ophthalmic applications, contraception, HIV/AIDS treatment, chronic diseases, wound care, and antimicrobial treatments. It explores the potential of long-acting gels to offer sustained and extended drug release, targeted therapy, and innovative administration routes while addressing limitations such as scalability challenges and regulatory hurdles. Future directions focus on personalized therapies, biodegradability, combination therapies, interdisciplinary innovation, regulatory considerations, and patient-centric development. This comprehensive review highlights the pivotal role of long-acting gels in transforming therapeutic approaches and improving patient outcomes across various medical conditions.

Cucurbitaceae Glycoside: An In-depth Review on its Source, Structural, and Medicinal Significance

Background: The Cucurbitaceae family has been well-known since ancient times for its use in daily food preparations. Various traditional medicinal systems have also recognized its therapeutic importance. Its significance has also been established by modern techniques. Objective: The current review aims to emphasize the glycosides of the Cucurbitaceae family in terms of their source, structures, extraction media, and bioactivities in various therapeutic areas like anti-inflammatory, anti-bacterial, anti-cancerous, anti-diabetic, and cardiac models. Glycosides of Cucurbitaceae have been studied extensively. However, considering the vastness of the diversity among this family; there are still various avenues in which further research work is needed. Methods: For the present review, we used Elsevier-ScienceDirect, SpringerLink, PubMed, ArticlesPlus, Semantic Scholar, and Google Scholar to conduct a literature search. Results: Cucurbitaceae is enriched with secondary metabolites, mainly glycosides. The occurrence of glycoside with its species, along with plant parts, is crucial and elaborately covered. It also captures the extraction system. The structure of selected glycosides is represented along with respective references. Various studies elaborate on the pharmacological significance of the extracts in diverse therapeutic areas. Conclusion: This review provides extensive aspects about the glycosides of the family Cucurbitaceae and will help in further exploration of extraction, isolation, and bioactivity studies of this important class of compounds from one of the largest families, i.e., Cucurbitaceae. It reiterates the need for further exploration in standardization along with extensive safety and efficacy studies.

A Bird Eye View on Effervescent Drug Delivery System

Effervescent drug delivery systems (EDDS) have gained significant attention in the pharmaceutical industry due to their unique characteristics and potential advantages over conventional dosage forms. This comprehensive review aims to provide an in-depth understanding of EDDS, including their formulation strategies, underlying mechanisms, and diverse applications in drug delivery. EDDS are effervescent dosage forms that release drugs upon water dissolution, leading toward carbon dioxide gas generation. The effervescence, resulting from the reaction between an acid and a base, facilitates rapid drug dissolution and enhances drug bioavailability. The primary components of an EDDS include an active pharmaceutical ingredient (API), effervescent agents (e.g., organic acids and bases), binders, disintegrants, and other excipients. Effervescent tablets, granules, powders, and effervescent-coated dosage forms are commonly employed formulations. Several factors, such as pH, temperature, solubility, and particle size, influence the drug’s effervescence process and subsequent release kinetics. The drug release mechanisms from EDDS can be attributed to various phenomena, including effervescence-driven disintegration, gas evolution, and solubilization. The effervescence-induced carbon dioxide bubbles mechanically disrupt the dosage form, leading to enhanced drug dissolution and subsequent release. Additionally, the carbon dioxide gas acts as a propellant, providing rapid drug delivery and potentially improving patient compliance. EDDS find applications in diverse therapeutic areas, including analgesics, antacids, dietary supplements, and antiviral agents. They offer several advantages, such as improved drug stability, enhanced bioavailability, increased patient convenience, and ease of administration, particularly for populations with swallowing difficulties. Furthermore, EDDS can be tailored to achieve controlled release, targeted drug delivery, and taste masking through appropriate formulation modifications. However, challenges associated with EDDS include their sensitivity to environmental conditions, potential drug degradation during effervescence, and the need for specialized packaging to maintain stability. The selection of suitable effervescent agents, excipients, and manufacturing processes is crucial to overcome these limitations and ensure consistent product performance. In conclusion, effervescent drug delivery

Scutellaria baicalensis: a promising natural source of antiviral compounds for the treatment of viral diseases.

Viruses, the smallest microorganisms, continue to present an escalating threat to human health, being the leading cause of mortality worldwide. Over the decades, although significant progress has been made in the development of therapies and vaccines against viral diseases, the need for effective antiviral interventions remains urgent. This urgency stems from the lack of effective vaccines, the severe side effects associated with current drugs, and the emergence of drug-resistant viral strains. Natural plants, particularly traditionally-used herbs, are often considered an excellent source of medicinal drugs with potent antiviral efficacy, as well as a substantial safety profile. Scutellaria baicalensis, a traditional Chinese medicine, has garnered considerable attention due to its extensive investigation across diverse therapeutic areas and its demonstrated efficacy in both preclinical and clinical trials. In this review, we mainly focused on the potential antiviral activities of ingredients in Scutellaria baicalensis, shedding light on their underlying mechanisms of action and therapeutic applications in the treatment of viral infections.

Synthesis of 1-oxa-9-azaspiro[5.5]undecane-9-sulfonamides bearing a diverse molecular periphery and a rare zinc-binding group for carbonic anhydrase interrogation

A fundamentally novel type of molecular probes for the recognition by carbonic anhydrase zinc enzymes which constitute promising target family in diverse therapeutic areas has been designed and synthesized. To the best of our knowledge, these molecular tools of 1-oxa-9-azaspiro[5.5]-undecane-9-sulfonamide chemotype for the first time combine in their structure diversely substituted spirocyclic piperidines and an aminosulfamoyl moiety.

Peptides as Pharmacological Carriers to the Brain: Promises, Shortcomings and Challenges.

Central nervous system (CNS) diseases are among the most difficult to treat, mainly because the vast majority of the drugs fail to cross the blood-brain barrier (BBB) or to reach the brain at concentrations adequate to exert a pharmacological activity. The obstacle posed by the BBB has led to the in-depth study of strategies allowing the brain delivery of CNS-active drugs. Among the most promising strategies is the use of peptides addressed to the BBB. Peptides are versatile molecules that can be used to decorate nanoparticles or can be conjugated to drugs, with either a stable link or as pro-drugs. They have been used to deliver to the brain both small molecules and proteins, with applications in diverse therapeutic areas such as brain cancers, neurodegenerative diseases and imaging. Peptides can be generally classified as receptor-targeted, recognizing membrane proteins expressed by the BBB microvessels (e.g., Angiopep2, CDX, and iRGD), "cell-penetrating peptides" (CPPs; e.g. TAT47-57, SynB1/3, and Penetratin), undergoing transcytosis through unspecific mechanisms, or those exploiting a mixed approach. The advantages of peptides have been extensively pointed out, but so far few studies have focused on the potential negative aspects. Indeed, despite having a generally good safety profile, some peptide conjugates may display toxicological characteristics distinct from those of the peptide itself, causing for instance antigenicity, cardiovascular alterations or hemolysis. Other shortcomings are the often brief lifetime in vivo, caused by the presence of peptidases, the vulnerability to endosomal/lysosomal degradation, and the frequently still insufficient attainable increase of brain drug levels, which remain below the therapeutically useful concentrations. The aim of this review is to analyze not only the successful and promising aspects of the use of peptides in brain targeting but also the problems posed by this strategy for drug delivery.

Pharmacogenomics: Relevance and opportunities for clinical pharmacology

Pharmacogenomics: Relevance and opportunities for clinical pharmacology

An Innovative Health Literacy Approach Designed to Improve Patient Understanding of Medication Labeling

ObjectiveLimited health literacy negatively impacts understanding of medication-related information. We describe an innovative methodology designed to optimize user understanding of patient medication labeling through the systematic application of evidence-based health literacy principles, using the Patient Package Insert (PPI) for bezlotoxumab (ZINPLAVA™, Merck & Co., Inc., Kenilworth, NJ, USA) as an example.MethodsWe used a mixed-model, iterative approach consisting of three phases: (1) content development; (2) focus group testing; and (3) comprehension testing. Content development was based on evidence-based health literacy principles and conducted through a collaborative partnership between industry and academia professionals. The PPI was then tested in four focus groups, two in Atlanta and two in Chicago, with an emphasis on collecting feedback from respondents with limited health literacy, evaluated using the Newest Vital Sign (NVS) health literacy assessment tool. Subsequent comprehension testing included patients with C. diff, caregivers, and general population members, with a pre-defined target sample of 25% with limited health literacy identified through two health literacy assessment tools: the Single Item Literacy Screener and the NVS.ResultsContent development of the bezlotoxumab PPI occurred in May 2015. In June 2015, focus group respondents (n = 34) provided generally favorable feedback, with insights revolving around organization and usability; language and comprehension; and volume of information. Comprehension testing of the revised PPI resulted in average comprehension scores of 96% for the overall population (n = 59), 90% for individuals presenting with limited health literacy (n = 14), and 97% for those with adequate health literacy (n = 45). This PPI development approach was similarly effective for subsequent products across diverse therapeutic areas, with comprehension scores ≥ 86% for all participants (n = 1197).ConclusionThis methodology represents a significant advancement for the development of understandable patient medication labeling, especially for people with limited health literacy.

Achieving Efficient Fragment Screening at XChem Facility at Diamond Light Source.

In fragment-based drug discovery, hundreds or often thousands of compounds smaller than ~300 Da are tested against the protein of interest to identify chemical entities that can be developed into potent drug candidates. Since the compounds are small, interactions are weak, and the screening method must therefore be highly sensitive; moreover, structural information tends to be crucial for elaborating these hits into lead-like compounds. Therefore, protein crystallography has always been a gold-standard technique, yet historically too challenging to find widespread use as a primary screen. Initial XChem experiments were demonstrated in 2014 and then trialed with academic and industrial collaborators to validate the process. Since then, a large research effort and significant beamtime have streamlined sample preparation, developed a fragment library with rapid follow-up possibilities, automated and improved the capability of I04-1 beamline for unattended data collection, and implemented new tools for data management, analysis and hit identification. XChem is now a facility for large-scale crystallographic fragment screening, supporting the entire crystals-to-deposition process, and accessible to academic and industrial users worldwide. The peer-reviewed academic user program has been actively developed since 2016, to accommodate projects from as broad a scientific scope as possible, including well-validated as well as exploratory projects. Academic access is allocated through biannual calls for peer-reviewed proposals, and proprietary work is arranged by Diamond's Industrial Liaison group. This workflow has already been routinely applied to over a hundred targets from diverse therapeutic areas, and effectively identifies weak binders (1%-30% hit rate), which both serve as high-quality starting points for compound design and provide extensive structural information on binding sites. The resilience of the process was demonstrated by continued screening of SARS-CoV-2 targets during the COVID-19 pandemic, including a 3-week turn-around for the main protease.

Advances in the Development Ubiquitin-Specific Peptidase (USP) Inhibitors

Ubiquitylation and deubiquitylation are reversible protein post-translational modification (PTM) processes involving the regulation of protein degradation under physiological conditions. Loss of balance in this regulatory system can lead to a wide range of diseases, such as cancer and inflammation. As the main members of the deubiquitinases (DUBs) family, ubiquitin-specific peptidases (USPs) are closely related to biological processes through a variety of molecular signaling pathways, including DNA damage repair, p53 and transforming growth factor-β (TGF-β) pathways. Over the past decade, increasing attention has been drawn to USPs as potential targets for the development of therapeutics across diverse therapeutic areas. In this review, we summarize the crucial roles of USPs in different signaling pathways and focus on advances in the development of USP inhibitors, as well as the methods of screening and identifying USP inhibitors.

Abstract SP113: The making of an ADC

Abstract Targeted treatment using antibody therapeutics has proved successful for the development of meaningful treatments in diverse therapeutic areas. However, despite strong advances, many patients still fail to respond or become resistant to targeted treatment and novel innovative approaches to improve therapy are therefore required. Genetic and chemical engineering of antibodies, fueled by recent molecular insights, is providing important opportunities for the development of more potent antibody therapeutics. Antibody-drug conjugates (ADC), which combine the tumor-targeting capacity of monoclonal antibodies with the antitumor activity of cytotoxic agents, received much attention. In the road-map to developing an ADC, understanding target biology and selecting the most optimal antibody, linker and toxic payload represent critical parameters. This talk will provide an overview of this thought process in the context of the development of two ADCs currently in the clinic, tisotumab vedotin and enapotamab vedotin. Citation Format: PWHI Parren. The making of an ADC [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP113.

Activation of carbonic anhydrase isoforms involved in modulation of emotional memory and cognitive disorders with histamine agonists, antagonists and derivatives

Carbonic anhydrases (CAs, EC 4.2.1.1) activators were shown to be involved in memory enhancement and learning in animal models of cognition. Here we investigated the CA activating effects of a large series of histamine based compounds, including histamine receptors (H1R – H4R) agonists, antagonists and other derivatives of this autacoid. CA activators may be thus useful for improving cognition as well as in diverse therapeutic areas (phobias, obsessive-compulsive disorder, generalised anxiety, post-traumatic stress disorders), for which activation of this enzyme was recently shown to be involved.

Recent advances in supramolecular antidotes.

Poisons always have fascinated humankind. Initially considered as deleterious or hazardous substances, the modern era has witnessed the controlled utilization of dangerous poisons in medicine and cosmetics. Simultaneously, antidotes have become crucial as reversal agents to counteract the effects of a poison, and they are also used today to positively cancel the benefits of a poison after use. Currently, the majority of poisons are composed of small molecules. This review focuses on recent developments to reverse or prevent toxic effects of poisons by encapsulation in host molecules. Cyclodextrins, cucurbiturils, acyclic cucurbituril derivatives, calixarenes, and pillararenes, have been reported to largely impact the effects of toxic compounds, thus extending the current paradigm of small molecule antidotes by adding a new family of macrocyclic compounds to the current arsenal of antidotes. Along this line of research, endogenous "harmful" species are also sequestered by one or more of these supramolecular host molecules, expanding the potential of supramolecular antidotes to diverse therapeutic areas.

Cryo-EM: The Resolution Revolution and Drug Discovery.

Single-particle cryogenic electron microscopy (cryo-EM) has been elevated to the mainstream of structural biology propelled by technological advancements in numerous fronts, including imaging analysis and the development of direct electron detectors. The drug discovery field has watched with (initial) skepticism and wonder at the progression of the technique and how it revolutionized the molecular understanding of previously intractable targets. This article critically assesses how cryo-EM has impacted drug discovery in diverse therapeutic areas. Targets that have been brought into the realm of structure-based drug design by cryo-EM and are thus reviewed here include membrane proteins like the GABAA receptor, several TRP channels, and G protein-coupled receptors, and multiprotein complexes like the ribosomes, the proteasome, and eIF2B. We will describe these studies highlighting the achievements, challenges, and caveats.

PKIS deep dive yields a chemical starting point for dark kinases and a cell active BRSK2 inhibitor

The Published Kinase Inhibitor Set (PKIS) is a publicly-available chemogenomic library distributed to more than 300 laboratories by GlaxoSmithKline (GSK) between 2011 and 2015 and by SGC-UNC from 2015 to 2017. Screening this library of well-annotated, published kinase inhibitors has yielded a plethora of data in diverse therapeutic and scientific areas, funded applications, publications, and provided impactful pre-clinical results. GW296115 is a compound that was included in PKIS based on its promising selectivity following profiling against 260 human kinases. Herein we present more comprehensive profiling data for 403 wild type human kinases and follow-up enzymatic screening results for GW296115. This more thorough investigation of GW296115 has confirmed it as a potent inhibitor of kinases including BRSK1 and BRSK2 that were identified in the original panel of 260 kinases as well as surfaced other kinases that it potently inhibits. Based on these new kinome-wide screening results, we report that GW296115 is an inhibitor of several members of the Illuminating the Druggable Genome (IDG) list of understudied dark kinases. Specifically, our results establish GW296115 as a potent lead chemical tool that inhibits six IDG kinases with IC50 values less than 100 nM. Focused studies establish that GW296115 is cell active, and directly engages BRSK2. Further evaluation showed that GW296115 downregulates BRSK2-driven phosphorylation and downstream signaling. Therefore, we present GW296115 as a cell-active chemical tool that can be used to interrogate the poorly characterized function(s) of BRSK2.

The emerging role of exosomes as novel therapeutics: Biology, technologies, clinical applications, and the next.

The extracellular vesicles (EVs) research area has grown rapidly because of their pivotal roles in intercellular communications and maintaining homeostasis of individual organism. As a subtype of EVs, exosomes are made via unique biogenesis pathway and exhibit disparate functional and phenotypic characteristics. Functionally, exosomes transfer biological messages from donor cell to recipient cell, which makes exosomes as a novel therapeutic platform delivering therapeutic materials to the target tissue/cell. Currently, both academia and industry try to develop exosome platform‐based therapeutics for disease management, some of which are already in clinical trials. In this review, we will discuss focusing on therapeutic values of exosomes, recent advances in therapeutic exosome platform development, and late development of exosome therapeutics in diverse therapeutic areas.

Azo benzimidazole - A biologically active scaffold

Azo compounds are a very unique class of chemical compounds, drawing considerations in scientific research. Azo compounds are studied as class of organic colorants which have at least a conjugated chromophore azo (-N=N-) group in fusion with one or more aromatic or heterocyclic ring system. Benzimidazole derivatives are privileged intermediates for the development of molecules of pharmaceutical or biological interest. Benzimidazole derivatives have gathered wide applications in diverse therapeutic areas such as antiulcer, anticancer agents, and anthelmintic species to name just a few. Although many azo derivatives of benzimidazole nucleus has been reported in literature but only few of them have been evaluated for their biological potencies. This review focuses primarily on those derivatives which are evaluated as anticancer, antibacterial, antifungal, antitubercular, and other medicinal agents. This review may be helpful for the investigators on the basis of substitution pattern on the nucleus with an objective to assist medicinal chemists for developing an SAR on azo benzimidazoles or similar compounds.