Leveraging malaria vaccines and mRNA technology to tackle the global inequity in pharmaceutical research and production towards disease elimination.

Malaria vaccine introduction in endemic countries is a game-changing milestone in the fight against the disease. This article examines the inequity in the global pharmaceutical research, development, manufacturing, and trade landscape. The role of inequity in hindering progress towards malaria elimination is explored. The analysis finds that transformational changes are required to create an equity-enabling environment. Addressing the inequity is critical to maximizing the public health impact of vaccines and attaining sustainability. Avenues to catalyze progress by leveraging malaria vaccines and messenger ribonucleic acid (mRNA) technology are discussed.

Pull me - push you? The disparate financing mechanisms of drug research in global health.

BACKGROUND: There is an inconsistency in the way pharmaceutical research is financed. While pull mechanisms are predominantly used to incentivize later-stage pharmaceutical research for products with demand in the Global North, so-called neglected diseases are chiefly financed by push funding. This discrepancy has so far been ignored in the academic debate, and any compelling explanation for why we draw the line between push and pull at poor people is lacking. MAIN BODY: Clinical development of new pharmaceuticals is chiefly financed by free market pull mechanisms. Even in cases where markets fail to deliver adequate incentives, demand enhancement mechanisms are used to replicate pull funding artificially, for example, with subscription models for antibiotics. Push funding in clinical research is almost always used when the poverty of patients means that markets fail to create sufficient demand. The general question of whether push or pull generally is the more efficient way to conduct pharmaceutical research arises. CONCLUSIONS: If the state is efficient in directing limited budgets for pharmaceutical research, push funding should be expanded to global diseases. If private industry is the more efficient actor, there would be enormous value in experimenting more aggressively with different approaches to enhance market demand artificially for neglected diseases.

Giant monkey facility could ease U.S. shortage.

Breeder would be the country's largest; locals and animal welfare advocates are concerned.

Recent developments and applications of ambient mass spectrometry imaging in pharmaceutical research: an overview.

The application of ambient mass spectrometry imaging "MSI" is expanding in the areas of fundamental research on drug delivery and multiple phases of the process of identifying and developing drugs. Precise monitoring of a drug's pharmacological workflows, such as intake, distribution, metabolism, and discharge, is made easier by MSI's ability to determine the concentrations of the initiating drug and its metabolites across dosed samples without losing spatial data. Lipids, glycans, and proteins are just a few of the many phenotypes that MSI may be used to concurrently examine. Each of these substances has a particular distribution pattern and biological function throughout the body. MSI offers the perfect analytical tool for examining a drug's pharmacological features, especially in vitro and in vivo effectiveness, security, probable toxic effects, and putative molecular pathways, because of its high responsiveness in chemical and physical environments. The utilization of MSI in the field of pharmacy has further extended from the traditional tissue examination to the early stages of drug discovery and development, including examining the structure-function connection, high-throughput capabilities in vitro examination, and ex vivo research on individual cells or tumor spheroids. Additionally, an enormous array of endogenous substances that may function as tissue diagnostics can be scanned simultaneously, giving the specimen a highly thorough characterization. Ambient MSI techniques are soft enough to allow for easy examination of the native sample to gather data on exterior chemical compositions. This paper provides a scientific and methodological overview of ambient MSI utilization in research on pharmaceuticals.

[Development of a Novel Hepatocyte Model Using Stem Cells for Pharmaceutical Research].

Most drugs are metabolized and detoxified in the liver. Therefore, human hepatocytes are essential for pharmacokinetic and toxicity tests in pharmaceutical research. Although primary human hepatocytes (PHHs) are the main cell source used as a human liver model, major drawbacks include the limited supply of PHHs and their functional deterioration due to long-term culture. Many studies have been conducted to overcome these problems or develop new hepatocyte sources. In particular, stem cells with cell proliferative potential are expected to be useful in pharmaceutical research, as they can supply many homogeneous specific somatic cells through differentiation and maturation. Here, we describe recent advances in the use of hepatocyte-like cells derived from human embryonic stem (ES) cells or induced pluripotent stem (iPS) cells and human liver organoids. The hepatocyte differentiation method from human ES/iPS cells by some strategies has been improved. However, the hepatic functions in human hepatocyte-like cells derived from ES/iPS cells are still lower than those in PHHs. Similarly, although human liver organoids show long-term proliferation, their hepatic functions remain low. Human ES/iPS cells and liver organoids could overcome the limited supply of PHHs, but improving their hepatic function is essential. We believe that stem cell culture technology will be useful for generating a functional hepatocyte source for medical applications.

Significance of Premature Vertebral Mineralization in Zebrafish Models in Mechanistic and Pharmaceutical Research on Hereditary Multisystem Diseases.

Zebrafish are increasingly becoming an important model organism for studying the pathophysiological mechanisms of human diseases and investigating how these mechanisms can be effectively targeted using compounds that may open avenues to novel treatments for patients. The zebrafish skeleton has been particularly instrumental in modeling bone diseases as-contrary to other model organisms-the lower load on the skeleton of an aquatic animal enables mutants to survive to early adulthood. In this respect, the axial skeletons of zebrafish have been a good read-out for congenital spinal deformities such as scoliosis and degenerative disorders such as osteoporosis and osteoarthritis, in which aberrant mineralization in humans is reflected in the respective zebrafish models. Interestingly, there have been several reports of hereditary multisystemic diseases that do not affect the vertebral column in human patients, while the corresponding zebrafish models systematically show anomalies in mineralization and morphology of the spine as their leading or, in some cases, only phenotype. In this review, we describe such examples, highlighting the underlying mechanisms, the already-used or potential power of these models to help us understand and amend the mineralization process, and the outstanding questions on how and why this specific axial type of aberrant mineralization occurs in these disease models.

Current Pharmaceutical Research on the Significant Pharmacophore Mannich bases in Drug Design.

A multitude of distinct Mannich bases have been synthesized and evaluated as potential therapeutics for a wide variety of diseases and medical conditions, either in the form of prodrugs or as molecules that trigger a biological response from specific targets. The Mannich reaction has been utilized to enhance the biological activity of numerous compounds, resulting in notable progress in various areas such as anticonvulsant, antimalarial, anticancer, anti-inflammatory, antiproliferative, antibacterial, antimicrobial, antitubercular, antiprotozoal, topoisomerases I and II inhibition, α-glucosidase inhibition, carbonic anhydrase inhibition, as well as research related to anti-Alzheimer's disease and anti-Parkinson's disease. Bioactive semisynthetic Mannich bases derived from natural compounds such as chalcone, curcumin, and thymol have also been identified. Pharmaceutical compounds characterized by low solubility may encounter challenges related to their oral bioavailability, half-life, distribution within tissues, rapid metabolism, toxicity, and various other relevant variables. Mannich bases have the ability to undergo protonation under physiological circumstances, facilitating interactions between ligands and receptors, and enhancing their solubility in water. The experimental findings indicate that the solubility of Mannich base prodrugs is higher compared to that of the parent compound. The use of the multicomponent Mannich reaction has been established as a valuable synthetic methodology for the construction of multifunctional compounds through the application of diverse synthetic strategies under varying reaction conditions. The continuous investigation of synthetic techniques for Mannich reactions involves several approaches, such as employing protocols in aquatic environments, utilizing catalysts that are both biodegradable and reusable, exploring the use of ionic liquids, investigating solvent-free and/or catalyst-free media, and exploring reaction conditions involving microwave and ultrasound irradiation. Consequently, the Mannich reaction has emerged as a powerful technique in the field of medicinal chemistry. It is utilized for the creation of new chemical compounds that possess diverse and attractive biologic features. Additionally, this reaction is employed to alter the physicochemical properties of a potential drug candidate, thereby influencing its bioavailability, efficacy, and pharmacological activity. Due to their favorable bioactivities and synthesis techniques, Mannich bases remain a subject of ongoing attention in the field of medicinal/pharmaceutical chemistry.

Building a nonclinical pathology laboratory of the future for pharmaceutical research excellence.

We describe a roadmap for a fully digital artificial intelligence (AI)-augmented nonclinical pathology laboratory across three continents. Underpinning the design are Good Laboratory Practice (GLP)-validated laboratory information management systems (LIMS), whole slide-scanners (WSS), image management systems (IMS), and a digital microscope intended for use by the nonclinical pathologist. Digital diagnostics are supported by tools that include AI-based virtual staining and deep learning-based decision support. Implemented during the COVID-19 pandemic, the initial digitized workflow largely mitigated disruption of pivotal nonclinical studies required to support pharmaceutical clinical testing. We believe that this digital transformation of our nonclinical pathology laboratories will promote efficiency and innovation in the future and enhance the quality and speed of drug development decision making.

Utilization of 3D bioprinting technology in creating human tissue and organoid models for preclinical drug research - State-of-the-art.

Rapid development of tissue engineering in recent years has increased the importance of three-dimensional (3D) bioprinting technology as novel strategy for fabrication functional 3D tissue and organoid models for pharmaceutical research. 3D bioprinting technology gives hope for eliminating many problems associated with traditional cell culture methods during drug screening. However, there is a still long way to wider clinical application of this technology due to the numerous difficulties associated with development of bioinks, advanced printers and in-depth understanding of human tissue architecture. In this review, the work associated with relatively well-known extrusion-based bioprinting (EBB), jetting-based bioprinting (JBB), and vat photopolymerization bioprinting (VPB) is presented and discussed with the latest advances and limitations in this field. Next we discuss state-of-the-art research of 3D bioprinted in vitro models including liver, kidney, lung, heart, intestines, eye, skin as well as neural and bone tissue that have potential applications in the development of new drugs.

Surgical management of peritoneal metastasis: Opportunities for pharmaceutical research.

Cytoreductive surgery (CRS) has emerged as a survival-extending treatment of peritoneal metastasis (PM); recent advances include using intraperitoneal chemotherapy (IPC) at normothermic or hyperthermic temperatures, or under pressure (CRS + IPC). Clinical CRS + IPC research has established its highly variable efficacy and suggested tumor size, tumor locations and presence of ascites as potential determinants. On the other hand, there is limited knowledge on the effects of pharmaceutical properties on treatment outcomes. The present study investigated the inter-subject variability of paclitaxel binding to proteins in patient ascites because some PM patients show accumulation of ascites and because activity and transport of highly protein-bound drugs such as paclitaxel are affected by protein binding. Ascites samples were collected from 26 patients and investigated for their protein contents using LC/MS/MS proteomics analysis and for the concentrations of total proteins and two major paclitaxel-binding proteins (human serum albumin or HSA and α-1-acid glycoprotein or AAG). The association constants of paclitaxel to HSA and AAG and the extent of protein binding of paclitaxel in patient ascites were studied using equilibrium dialysis. Proteomic analysis of four randomly selected samples revealed 288 proteins, >90% of which are also present in human plasma. Between 72% - 94% of paclitaxel was bound to proteins in patient ascites. The concentrations of HSA and AAG in ascites showed substantial inter-subject variations, ranging from 14.7 - 46.3 mg/mL and 0.13-2.56 mg/mL, respectively. The respective paclitaxel association constants to commercially available HSA and AAG were âˆ¼ 3.5 and âˆ¼ 120 mM. Calculation using these constants and the HSA and AAG concentrations in individual patient ascites indicated that these two proteins accounted for >85% of the total protein-binding of paclitaxel in ascites. The extensive drug binding to ascites proteins, by reducing the pharmacologically active free fraction, may lead to the diminished CRS efficacy in PM patients with ascites. Clinical advances in CRS + IPC have outpaced current knowledge of pharmaceutical properties in this setting. IPC, as a locally acting therapy, is subjected to processes different from those governing systemic treatments. This study, to our knowledge, is the first to illustrate the implications of drug properties in the CRS + IPC efficacy against PM. While drugs are now an integral part of PM patient management, there is limited pharmaceutical research in this treatment setting (e.g., effects of hyperthermia or pressure on drug transport or release from delivery systems, pharmacokinetics, pharmacodynamics). Hence, CRS + IPC of PM represents an area where additional pharmaceutical research can assist further development and optimization.

State-of-the-art Application of Artificial Intelligence to Transporter-centered Functional and Pharmaceutical Research.

Protein transporters not only have essential functions in regulating the transport of endogenous substrates and remote communication between organs and organisms, but they also play a vital role in drug absorption, distribution, and excretion and are recognized as major determinants of drug safety and efficacy. Understanding transporter function is important for drug development and clarifying disease mechanisms. However, the experimental-based functional research on transporters has been challenged and hinged by the expensive cost of time and resources. With the increasing volume of relevant omics datasets and the rapid evolution of artificial intelligence (AI) techniques, next-generation AI is becoming increasingly prevalent in the functional and pharmaceutical research of transporters. Thus, a comprehensive discussion on the state-of-the-art application of AI in three cutting-edge directions was provided in this review, which included (a) transporter classification and function annotation, (b) structure discovery of membrane transporters, and (c) drug-transporter interaction prediction. This study provides a panoramic view of AI algorithms and tools applied to the field of transporters. It is expected to guide a better understanding and utilization of AI techniques for in-depth studies of transporter-centered functional and pharmaceutical research.

Three-Dimensional Cell Co-Culture Liver Models and Their Applications in Pharmaceutical Research.

As the primary site for the biotransformation of drugs, the liver is the most focused on organ type in pharmaceutical research. However, despite being widely used in pharmaceutical research, animal models have inherent species differences, while two-dimensional (2D) liver cell monocultures or co-cultures and three-dimensional (3D) liver cell monoculture in vitro liver models do not sufficiently represent the complexity of the human liver's structure and function, making the evaluation results from these tools less reliable. Therefore, there is a pressing need to develop more representative in vitro liver models for pharmaceutical research. Fortunately, an exciting new development in recent years has been the emergence of 3D liver cell co-culture models. These models hold great promise as in vitro pharmaceutical research tools, because they can reproduce liver structure and function more practically. This review begins by explaining the structure and main cell composition of the liver, before introducing the potential advantages of 3D cell co-culture liver models for pharmaceutical research. We also discuss the main sources of hepatocytes and the 3D cell co-culture methods used in constructing these models. In addition, we explore the applications of 3D cell co-culture liver models with different functional states and suggest prospects for their further development.

Commentary: Reconsidering Pharmaceutical Research and Development Investments.

Following Lee and colleagues' (2023) article explaining how Canadians are being shortchanged by drug companies when it comes to investments in research and development (R&D), this rejoinder adds context and appends two other very problematic elements in the debate between wishful narratives over the industry's contribution in R&D and actual numbers. First, even the current stricter definition of R&D investment might simply be too large considering that elements such as seeding trials - a well-known marketing device - can be accounted for as R&D expenditures. Second, this rejoinder identifies how Statistics Canada acted in concert with Innovative Medicines Canada to reinforce the industry's preferred narratives around R&D expenditures. This situation puts into question the trustworthiness of Canada's statistical agency.

Pharmaceutical Methods for Enhancing the Dissolution of Poorly Water-Soluble Drugs.

Low water solubility is the main hindrance in the growth of pharmaceutical industry. Approximately 90% of newer molecules under investigation for drugs and 40% of novel drugs have been reported to have low water solubility. The key and thought-provoking task for the formulation scientists is the development of novel techniques to overcome the solubility-related issues of these drugs. The main intention of present review is to depict the conventional and novel strategies to overcome the solubility-related problems of Biopharmaceutical Classification System Class-II drugs. More than 100 articles published in the last 5 years were reviewed to have a look at the strategies used for solubility enhancement. pH modification, salt forms, amorphous forms, surfactant solubilization, cosolvency, solid dispersions, inclusion complexation, polymeric micelles, crystals, size reduction, nanonization, proliposomes, liposomes, solid lipid nanoparticles, microemulsions, and self-emulsifying drug delivery systems are the various techniques to yield better bioavailability of poorly soluble drugs. The selection of solubility enhancement technique is based on the dosage form and physiochemical characteristics of drug molecules.

Zebrafish, a biological model for pharmaceutical research for the management of anxiety.

The zebrafish (Danio rerio) is a valuable animal model rapidly becoming more commonly used in pharmaceutical studies. Due to its low-cost maintenance and high breeding potential, the zebrafish is a suitable substitute for most adult rodents (mice and rats) in neuroscience research. It is widely used in various anxiety models. This species has been used to develop a conceptual framework for anxiety behavior studies with broad applications in the laboratory, including the study of herbal and chemical drugs. This review discusses the latest studies of anxiety-related behavior in the zebrafish model.

What Procedural Ethics Can Learn from the Quest for Moral Justification for the "Rule of Rescue".

In this issue, Sirrs and colleagues (2023) provide a very informative picture of the value and cost of policies to promote orphan drug development. They examine the influence of these policies on pharmaceutical research and development, the proliferation of rare diseases, the prohibitive costs and the loopholes of these policies. One section of the paper identifies the ethical issues and proposes a response to the challenge of integrating the utility perspectives of pharmacoeconomic analyses with those of treatment access claims formulated from a deontological perspective. Their proposal is essentially that of procedural ethics. I enter the ethical debate obliquely by looking at the rule of rescue phenomenon observed by Albert R. Jonsen (Jonsen 1986). I explore the twists and turns of the discussion on this subject and assume the perspective of authors who give significant weight to the symbolic value of respecting it. In conclusion, I take up the symbolic question by arguing that the challenge of preserving the aura of legitimacy that must surround political decisions sometimes requires distancing oneself from sound recommendations, which, even if they are the result of an ideal procedure, will nevertheless be perceived as unjust and insensitive.

Professor Raj Suryanarayanan: Scientist, Educator, Mentor, Family Man and Giant in Pharmaceutical Research.

This special edition of the Journal of Pharmaceutical Sciences is dedicated to Professor Raj Suryanarayanan (Professor and William & Mildred Peters Endowed Chair, University of Minnesota, School of Pharmacy) and honors his extensive and distinguished career as a scientist, educator and mentor. The goal of this commentary is to provide an overview of Professor Suryanarayanan's noteworthy career path and summarize his key research contributions. The commentary concludes with the personal summaries by guest editors.

Postbiotics as the new frontier in food and pharmaceutical research.

Food is the essential need of human life and has nutrients that support growth and health. Gastrointestinal tract microbiota involves valuable microorganisms that develop therapeutic effects and are characterized as probiotics. The investigations on appropriate probiotic strains have led to the characterization of specific metabolic byproducts of probiotics named postbiotics. The probiotics must maintain their survival against inappropriate lethal conditions of the processing, storage, distribution, preparation, and digestion system so that they can exhibit their most health effects. Conversely, probiotic metabolites (postbiotics) have successfully overcome these unfavorable conditions and may be an appropriate alternative to probiotics. Due to their specific chemical structure, safe profile, long shelf-life, and the fact that they contain various signaling molecules, postbiotics may have anti-inflammatory, immunomodulatory, antihypertensive properties, inhibiting abnormal cell proliferation and antioxidative activities. Consequently, present scientific literature approves that postbiotics can mimic the fundamental and clinical role of probiotics, and due to their unique characteristics, they can be applied in an oral delivery system (pharmaceutical/functional foods), as a preharvest food safety hurdle, to promote the shelf-life of food products and develop novel functional foods or/and for developing health benefits, and therapeutic aims. This review addresses the latest postbiotic applications with regard to pharmaceutical formulations and commercial food-based products. Potential postbiotic applications in the promotion of host health status, prevention of disease, and complementary treatment are also reviewed.