An update on the development on tubulin inhibitors for the treatment of solid tumors.

INTRODUCTION: Microtubules play a vital role in cancer therapeutics. They are implicated in tumorigenesis, thus inhibiting tubulin polymerization in cancer cells, and have now become a significant target for anticancer drug development. A plethora of drug molecules has been crafted to influence microtubule dynamics and presently, numerous tubulin inhibitors are being investigated. This review discusses the recently developed inhibitors including natural products, and also examines the preclinical and clinical data of some potential molecules. AREA COVERED: The current review article summarizes the development of tubulin inhibitors while detailing their specific binding sites. It also discusses the newly designed inhibitors that may be useful in the treatment of solid tumors. EXPERT OPINION: Microtubules play a crucial role in cellular processes, especially in cancer therapy where inhibiting tubulin polymerization holds promise. Ongoing trials signify a commitment to revolutionizing cancer treatment and exploring targeted therapies. Challenges in microtubule modulation, like resistance and off-target effects, demand focused efforts, emphasizing combination therapies and personalized treatments. Beyond microtubules, promising avenues in cancer research include immunotherapy, genomic medicine, CRISPR gene editing, liquid biopsies, AI diagnostics, and stem cell therapy, showcasing a holistic approach for future advancements.

C. elegans: a prominent platform for modeling and drug screening in neurological disorders.

INTRODUCTION: Human neurodevelopmental and neurodegenerative diseases (NDevDs and NDegDs, respectively) encompass a broad spectrum of disorders affecting the nervous system with an increasing incidence. In this context, the nematode C. elegans, has emerged as a benchmark model for biological research, especially in the field of neuroscience. AREAS COVERED: The authors highlight the numerous advantages of this tiny worm as a model for exploring nervous system pathologies and as a platform for drug discovery. There is a particular focus given to describing the existing models of C. elegans for the study of NDevDs and NDegDs. Specifically, the authors underscore their strong applicability in preclinical drug development. Furthermore, they place particular emphasis on detailing the common techniques employed to explore the nervous system in both healthy and diseased states. EXPERT OPINION: Drug discovery constitutes a long and expensive process. The incorporation of invertebrate models, such as C. elegans, stands as an exemplary strategy for mitigating costs and expediting timelines. The utilization of C. elegans as a platform to replicate nervous system pathologies and conduct high-throughput automated assays in the initial phases of drug discovery is pivotal for rendering therapeutic options more attainable and cost-effective.

Efficacy and Mechanisms of Natural Products as Therapeutic Interventions for Chronic Respiratory Diseases.

Chronic respiratory diseases are long-term conditions affecting the airways and other lung components that are characterized by a high prevalence, disability rate, and mortality rate. Further optimization of their treatment is required. Natural products, primarily extracted from organisms, possess specific molecular and structural formulas as well as distinct chemical and physical properties. These characteristics grant them the advantages of safety, gentleness, accessibility, and minimal side effects. The numerous advances in the use of natural products for treating chronic respiratory diseases have provided a steady source of motivation for new drug research and development. In this paper, we introduced the pathogenesis of chronic respiratory diseases and natural products. Furthermore, we classified natural products according to their mechanism for treating chronic respiratory diseases and describe the ways in which these products can alleviate the pathological symptoms. Simultaneously, we elaborate on the signal transduction pathways and biological impacts of natural products' targeting. Additionally, we present future prospects for natural products, considering their combination treatment approaches and administration methods. The significance of this review extends to both the research on preventing and treating chronic respiratory diseases, as well as the advancement of novel drug development in this field.

Paving new roads toward the advancement of broad-spectrum antiviral agents.

Broad-spectrum antivirals (BSAs) have the advantageous property of being effective against a wide range of viruses with a single drug, offering a promising therapeutic solution for the largely unmet need in treating both existing and emerging viral infections. In this review, we summarize the current strategies for the development of novel BSAs, focusing on either targeting the commonalities during the replication of multiple viruses or the systemic immunity of humans. In comparison to BSAs that target viral replication, these immuno-modulatory agents possess an expanded spectrum of antiviral activity. However, antiviral immunity is a double-edged sword, and maintaining immune homeostasis ultimately dictates the health status of hosts during viral infections. Therefore, establishing an ideal goal for immuno-modulation in antiviral interventions is crucial. Herein we propose a bionic approach for immuno-modulation inspired by mimicking bats, which possess a more robust immune system for combating viral invasions, compared to humans. In addition, we discuss an empirical approach to treat diverse viral infections using traditional Chinese medicines (TCMs), mainly through bidirectional immuno-modulation to restore the disrupted homeostasis. Advancing our understanding of both the immune system of bats and the mechanisms underlying antiviral TCMs will significantly contribute to the future development of novel BSAs.

From Ocean to Medicine: Harnessing Seaweed's Potential for Drug Development.

Seaweed, a miscellaneous group of marine algae, has long been recognized for its rich nutritional composition and bioactive compounds, being considered nutraceutical ingredient. This revision delves into the promising role of seaweed-derived nutrients as a beneficial resource for drug discovery and innovative product development. Seaweeds are abundant sources of essential vitamins, minerals, polysaccharides, polyphenols, and unique secondary metabolites, which reveal a wide range of biological activities. These bioactive compounds possess potential therapeutic properties, making them intriguing candidates for drug leads in various medical applications and pharmaceutical drug development. It explores their pharmacological properties, including antioxidant, anti-inflammatory, antimicrobial, and anticancer activities, shedding light on their potential as therapeutic agents. Moreover, the manuscript provides insights into the development of formulation strategies and delivery systems to enhance the bioavailability and stability of seaweed-derived compounds. The manuscript also discusses the challenges and opportunities associated with the integration of seaweed-based nutrients into the pharmaceutical and nutraceutical industries. Regulatory considerations, sustainability, and scalability of sustainable seaweed sourcing and cultivation methods are addressed, emphasizing the need for a holistic approach in harnessing seaweed's potential. This revision underscores the immense potential of seaweed-derived compounds as a valuable reservoir for drug leads and product development. By bridging the gap between marine biology, pharmacology, and product formulation, this research contributes to the critical advancement of sustainable and innovative solutions in the pharmaceutical and nutraceutical sectors.

Cardiovascular human organ-on-a-chip platform for disease modeling, drug development, and personalized therapy.

Cardiovascular organ-on-a-chip (OoC) devices are composed of engineered or native functional tissues that are cultured under controlled microenvironments inside microchips. These systems employ microfabrication and tissue engineering techniques to recapitulate human physiology. This review focuses on human OoC systems to model cardiovascular diseases, to perform drug screening, and to advance personalized medicine. We also address the challenges in the generation of organ chips that can revolutionize the large-scale application of these systems for drug development and personalized therapy.

Question-based review for pharmaceutical development: An enhanced quality approach.

Over the last years, the pharmaceutical industry has faced real challenges regarding quality assurance. In this context, the establishment of more holistic approaches to the pharmaceutical development has been encouraged. The emergence of the Quality by Design (QbD) paradigm as systematic, scientific and risk-based methodology introduced a new concept of pharmaceutical quality. In essence, QbD can be interpreted as a strategy to maximize time and cost savings. An in-depth understanding of the formulation and manufacturing process is demanded to optimize the safety, efficacy and quality of a drug product at all stages of development. This innovative approach streamlines the pharmaceutical Research and Development (R&D) process, provides greater manufacturing flexibility and reduces regulatory burden. To assist in QbD implementation, International Conference on Harmonisation (ICH), U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) organized and launched QbD principles in their guidance for industry, identifying key concepts and tools to design and develop a high-quality drug product. Despite the undeniable advantages of the QbD approach, and the widespread information on QbD regulatory expectations, its full implementation in the pharmaceutical field is still limited. The present review aims to establish a crosswise overview on the current application status of QbD within the framework of the ICH guidelines (ICH Q8(R2) - Q14 and ICH Q2(R2)). Moreover, it outlines the way information gathered from the QbD methodology is being harmonized in Marketing Authorization Applications (MAAs) for European market approval. This work also highlights the challenges that hinder the deployment of the QbD strategy as a standard practice.

Cancer drug repurposing in autism spectrum disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with uncertain origins. Understanding of the mechanisms underlying ASD remains limited, and treatments are lacking. Genetic diversity complicates drug development. Given the complexity and severity of ASD symptoms and the rising number of diagnoses, exploring novel therapeutic strategies is essential. Here, we focus on shared molecular pathways between ASD and cancer and highlight recent progress on the repurposing of cancer drugs for ASD treatment, such as mTOR inhibitors, histone deacetylase inhibitors, and anti-inflammatory agents. We discuss how to improve trial design considering drug dose and patient age. Lastly, the discussion explores the critical aspects of side effects, commercial factors, and the efficiency of drug-screening pipelines; all of which are essential considerations in the pursuit of repurposing cancer drugs for addressing core features of ASD.

Pharmacohistory of Cannabis Use-A New Possibility in Future Drug Development for Gastrointestinal Diseases.

Humans have employed cannabis for multiple uses including medicine, recreation, food, and fibre. The various components such as roots, flowers, seeds, and leaves have been utilized to alleviate pain, inflammation, anxiety, and gastrointestinal disorders like nausea, vomiting, diarrhoea, and inflammatory bowel diseases (IBDs). It has occupied a significant space in ethnomedicines across cultures and religions. Despite multi-dimensional uses, the global prohibition of cannabis by the USA through the introduction of the Marijuana Tax Act in 1937 led to prejudice about the perceived risks of cannabis, overshadowing its medicinal potential. Nevertheless, the discovery of tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, and the endocannabinoid system renewed scientific interest in understanding the role of cannabis in modulating different conditions, including gastrointestinal disorders. Preparations combining cannabidiol and THC have shown promise in mitigating gut symptoms through anti-inflammatory and motility-enhancing effects. This review revisits the ethnomedicinal use of cannabis in gastrointestinal diseases and emphasizes the need for further research to determine optimal dosages, formulations, and safety profiles of cannabis-based medicines. It also underscores the future potential of cannabinoid-based therapies by leveraging the role of the expanded endocannabinoid system, an endocannabinoidome, in the modulation of gastrointestinal ailments.

Natural products in non-alcoholic fatty liver disease (NAFLD): Novel lead discovery for drug development.

With changing lifestyles, non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease worldwide. A substantial increase in the incidence, mortality, and associated burden of NAFLD-related advanced liver disease is expected. Currently, the initial diagnosis of NAFLD is still based on ultrasound and there is no approved treatment method. Lipid-lowering drugs, vitamin supplementation, and lifestyle improvement treatments are commonly used in clinical practice. However, most lipid-lowering drugs can produce poor patient compliance and specific adverse effects. Therefore, the exploration of bio-diagnostic markers and active lead compounds for the development of innovative drugs is urgently needed. More and more studies have reported the anti-NAFLD effects and mechanisms of natural products (NPs), which have become an important source for new drug development to treat NAFLD due to their high activity and low side effects. At present, berberine and silymarin have been approved by the US FDA to enter clinical phase IV studies, demonstrating the potential of NPs against NAFLD. Studies have found that the regulation of lipid metabolism, insulin resistance, oxidative stress, and inflammation-related pathways may play important roles in the process. With the continuous updating of technical means and scientific theories, in-depth research on the targets and mechanisms of NPs against NAFLD can provide new possibilities to find bio-diagnostic markers and innovative drugs. As we know, FXR agonists, PPARα agonists, and dual CCR2/5 inhibitors are gradually coming on stage for the treatment of NAFLD. Whether NPs can exert anti-NAFLD effects by regulating these targets or some unknown targets remains to be further studied. Therefore, the study reviewed the potential anti-NAFLD NPs and their targets. Some works on the discovery of new targets and the docking of active lead compounds were also discussed. It is hoped that this review can provide some reference values for the development of non-invasive diagnostic markers and new drugs against NAFLD in the clinic.

Pharmaceutical Development Challenges in a Beyond Rule of Five Prodrug: Case Study of ABBV-167, Phosphate Prodrug of Venetoclax.

ABBV-167, a phosphate prodrug of BCL-2 inhibitor venetoclax, was recently progressed into the clinic as an alternative means of reducing pill burden for patients in high-dose indications. The dramatically enhanced aqueous solubility of ABBV-167 allowed for high drug loading within a crystalline tablet and, when administered in phase I clinical study, conferred venetoclax exposure commensurate with the equivalent dose administered as an amorphous solid dispersion. In enabling the progression into the clinic, we performed a comprehensive evaluation of the CMC development aspects of this beyond the rule of five (bRo5) prodrug. Adding a phosphate moiety resulted in excessively complex chemical speciation and solid form landscapes with significant physical-chemical stability liabilities. A combination of experimental and computational methods including microelectron diffraction (MicroED), total scattering, tablet colorimetry, finite element, and molecular dynamics modeling were used to understand CMC developability across drug substance and product manufacture and storage. The prodrug's chemical structural characteristics and loose crystal packing were found to be responsible for the loss of crystallinity during its manufacturing, which in turn led to high solid-state chemical reactivity and poor shelf life stability. The ABBV-167 case exemplifies key CMC development challenges for complex chemical matter such as bRo5 phosphate prodrugs with significant ramifications during drug substance and drug product manufacturing and storage.

Development of Anterior Segment Focused Biologic Therapies to Regenerate Corneal Tissue for the Treatment of Disease: Drug Development Experience.

On February 24-27, 2021, the Association for Ocular Pharmacology and Therapeutics (AOPT) held its 15th biennial scientific meeting online. The meeting was organized by Dr. Sanjoy Bhattacharya of the University of Miami in conjunction with the board of trustees of the AOPT. The 3-day conference was attended by academic scientists, clinicians, and industry and regulatory professionals. The theme of the meeting was Restoring Vision through Regeneration and it was sponsored, in part, by the National Institutes of Health, Bright Focus, Regeneron, and Santen (USA). During the 3 days of the meeting, presentations from several sessions explored different aspects of regenerative medicine in ophthalmology, including optic nerve regeneration, drugs and devices in glaucoma, retinal neuroprotection and plasticity, visual perception, and degeneration of trabecular meshwork. This article summarizes the proceedings of the session on corneal regenerative medicine research and discusses emerging concepts in drug development for corneal epithelial and endothelial regeneration. Since the meeting in 2021, several of these concepts have advanced to clinical-stage therapies, but so far as of 2023, none has been approved by regional regulatory authorities in the United States. One form of corneal endothelial cell therapy has been approved in Japan and only for bullous keratopathy. Ongoing work is proceeding in the United States and other countries. Clinical Registration No: National Clinical Trials 04894110, 04812667; Japan Registry for Clinical Trials a031210199.

Molecular docking as a tool for the discovery of molecular targets of nutraceuticals in diseases management.

Molecular docking is a computational technique that predicts the binding affinity of ligands to receptor proteins. Although it has potential uses in nutraceutical research, it has developed into a formidable tool for drug development. Bioactive substances called nutraceuticals are present in food sources and can be used in the management of diseases. Finding their molecular targets can help in the creation of disease-specific new therapies. The purpose of this review was to explore molecular docking's application to the study of dietary supplements and disease management. First, an overview of the fundamentals of molecular docking and the various software tools available for docking was presented. The limitations and difficulties of using molecular docking in nutraceutical research are also covered, including the reliability of scoring functions and the requirement for experimental validation. Additionally, there was a focus on the identification of molecular targets for nutraceuticals in numerous disease models, including those for sickle cell disease, cancer, cardiovascular, gut, reproductive, and neurodegenerative disorders. We further highlighted biochemistry pathways and models from recent studies that have revealed molecular mechanisms to pinpoint new nutraceuticals' effects on disease pathogenesis. It is convincingly true that molecular docking is a useful tool for identifying the molecular targets of nutraceuticals in the management of diseases. It may offer information about how nutraceuticals work and support the creation of new therapeutics. Therefore, molecular docking has a bright future in nutraceutical research and has a lot of potentials to lead to the creation of brand-new medicines for the treatment of disease.

[Application and development of systems biology in computer-aided drug design].

With the advances in medicine, people have deeply understood the complex pathogenesis of diseases. Revealing the mechanism of action and therapeutic effect of drugs from an overall perspective has become the top priority of drug design. However, the traditional drug design methods cannot meet the current needs. In recent years, with the rapid development of systems biology, a variety of new technologies including metabolomics, genomics, and proteomics have been used in drug research and development. As a bridge between traditional pharmaceutical theory and modern science, computer-aided drug design(CADD) can shorten the drug development cycle and improve the success rate of drug design. The application of systems biology and CADD provides a methodological basis and direction for revealing the mechanism and action of drugs from an overall perspective. This paper introduces the research and application of systems biology in CADD from different perspectives and proposes the development direction, providing reference for promoting the application.

Physiologically based pharmacokinetic (PBPK) modelling of oral drug absorption in older adults - an AGePOP review.

The older population consisting of persons aged 65 years or older is the fastest-growing population group and also the major consumer of pharmaceutical products. Due to the heterogenous ageing process, this age group shows high interindividual variability in the dose-exposure-response relationship and, thus, a prediction of drug safety and efficacy is challenging. Although physiologically based pharmacokinetic (PBPK) modelling is a well-established tool to inform and confirm drug dosing strategies during drug development for special population groups, age-related changes in absorption are poorly accounted for in current PBPK models. The purpose of this review is to summarise the current state-of-knowledge in terms of physiological changes with increasing age that can influence the oral absorption of dosage forms. The capacity of common PBPK platforms to incorporate these changes and describe the older population is also discussed, as well as the implications of extrinsic factors such as drug-drug interactions associated with polypharmacy on the model development process. The future potential of this field will rely on addressing the gaps identified in this article, which can subsequently supplement in-vitro and in-vivo data for more robust decision-making on the adequacy of the formulation for use in older adults and inform pharmacotherapy.

Synthesis, Quality Control and Preliminary Activity Evaluation of a New Compound HM475.

Based on the principle of molecular splicing and theory of traditional Chinese medicine pairs, a new multi-active compound (HM475) was synthesized by connecting metformin with honokiol, and its structure was characterized, which not only reduced the toxicity of raw materials, but also maintained the original activity, and had a certain significance in research and innovation. At the same time, quality control and preliminary activity evaluation were carried out, and the effect of HM475 on neuroinflammation was further explored, which provided a new idea for drug development of neurodegenerative diseases.

[Live biotherapeutic products: the forefront of innovative drug development driven by biotechnology].

As human microbiome research advances, a large body of evidence shows that microorganisms are closely related to human health. Probiotics were discovered and used as foods or dietary supplements with health benefits in the last century. Microorganisms have shown broader application prospects in human health since the turn of the century, owing to the rapid development of technologies such as microbiome analysis, DNA synthesis and sequencing, and gene editing. In recent years, the concept of "next-generation probiotics" has been proposed as new drugs, and microorganisms are considered as "live biotherapeutic products (LBP)". In a nutshell, LBP is a living bacterial drug that can be used to prevent or treat certain human diseases and indications. Because of its distinct advantages, LBP has risen to the forefront of drug development research and has very broad development prospects. This review introduces the varieties and research advances on LBP from a biotechnology standpoint, followed by summarizing the challenges and opportunities for LBP clinical implementations, with the aim to facilitate LBP development.

Drug development, Brazilian biodiversity and political choices: Where are we heading?

The aim of this review was to (i) acknowledge structural advantages of natural products (NPs) for designing therapeutic drugs; (ii) emphasize how wildlife conservation is socially and economically necessary for scientific and commercial progress in Brazilian regions; and (iii) show how decisions by governmental regulations exert damaging effects on safeguarding of biodiversity. Natural products (NPs) from animals (e.g.: bufadienolides as marinobufagin), plants (diterpenes: casearin X and paclitaxel; triterpenes: betulinic acid) and microorganisms (depsipeptides: geodiamolides; antraciclines: doxorubicin) are the main source of oral drugs and have innate advantages for enteral and parenteral drug design, synthesis and combinational chemistry using novel techniques, including green chemistry. NPs possess high chemical diversity, binding flexibility to biological targets, chiral centers, aliphatic systems, hydrogen-bond acceptors and donors, and/or heteroatoms, and broad-spectrum pharmacological properties, including against malign disorders. Nonetheless, all Brazilian biomes and connected ecosystems have been systemically threatened since 2019 by the following fire, deforestation, monocultures, cattle raising, mining and/or oil spills mainly as consequence of financial cuts in key institutions which oversee environmental stability for terrestrial and marine Brazilian fauna and flora. Nevertheless, natural chemical entities, broad traditional knowledge on agrobiodiversity, fishing, fire management, and pioneering processes of economic interest play a vital role for "Science of Biodiversity," which arises as business bioeconomy opportunities to convert Brazil into a self-sufficient country for production of pharmaceutical supplies, cosmeticsand foods. Hence, Brazil needs sustainable development projects supported by government and scientific input if one wishes to use the chemical and biological biodiversity to treat individuals and improve the quality of life.

Role of three-dimensional cell culture in therapeutics and diagnostics: an updated review.

Drug development and testing are a tedious and expensive process with a high degree of uncertainty in the clinical success and preclinical validation of manufactured therapeutic agents. Currently, to understand the drug action, disease mechanism, and drug testing, most therapeutic drug manufacturers use 2D cell culture models to validate the drug action. However, there are many uncertainties and limitations with the conventional use of 2D (monolayer) cell culture models for drug testing that are primarily attributed due to poor mimicking of cellular mechanisms, disturbance in environmental interaction, and changes in structural morphology. To overcome such odds and difficulties in the preclinical validation of therapeutic medications, newer in vivo drug testing cell culture models with higher screening efficiencies are required. One such promising and advanced cell culture model reported recently is the "three-dimensional cell culture model." The 3D cell culture models are reported to show evident benefits over conventional 2D cell models. This review article outlines and describes the current advancement in cell culture models, their types, significance in high-throughput screening, limitations, applications in drug toxicity screening, and preclinical testing methodologies to predict in vivo efficacy.

Assessing Definitions and Incentives Adopted for Innovation for Pharmaceutical Products in Five High-Income Countries: A Systematic Literature Review.

BACKGROUND: The concept of health care innovation varies across organizations and countries. Harmonizing the definitions of innovation can augment the discovery of new therapies, minimize costs, and streamline drug development and approval processes. A systematic literature review (SLR) was conducted to gather insights surrounding different elements of innovation in the USA, the UK, France, Germany, and Japan. The SLR identified studies that have defined innovation and captured the types of incentives provided to promote innovation. METHODS: The MEDLINE, Embase, and EconLit databases were searched via the OVID SP platform on October 22, 2020. A secondary desk search literature review was performed to identify additional information of interest in regional languages: French, German, and Japanese. All the relevant literature in English was screened using the Linguamatics natural language processing (NLP) tool, except for articles from EconLit, which were screened manually using structured search strategies. Articles that describe a definition of innovation or refer to a definition of innovation published were included. All full-text articles were reviewed manually, and two reviewers independently screened the full texts for eligibility. RESULTS: After screening, 90 articles were considered to meet the SLR objectives. The most common dimension of innovation identified was therapeutic benefit as a measure of innovation, followed by newness and novelty aspects of innovations. Incentives around exclusivities were found to be the most prevalent in the data set, followed by rewards and premiums. Among the different therapy areas, the largest number of innovations was targeted at oncology. CONCLUSIONS: This SLR highlights the lack of a unified definition of innovation among regulatory authorities and health technology assessment bodies in five countries, and variation in the types of incentives associated with innovation. The targeted countries cover different dimensions of definition and incentives of innovation at varying levels, with a few focused on specific therapy areas. Harmonization and consensus for innovation would be needed across countries because drug development is a global undertaking. This SLR envisages a more holistic approach to evaluation, wherein the value provided to patients and health systems is accounted for. The results of this SLR will help to promote broader discussion among different stakeholders and decision makers across countries to identify gaps in policies and develop sustainable strategies to promote innovation for pharmaceutical products.