Handbook of experimental pharmacology最新文献

The eye has several dynamic and static barriers in place to limit the entry of foreign substances including therapeutics. As such, efficient drug delivery, especially to posterior segment tissues, has been challenging. This chapter describes the anatomical and physiological challenges associated with ocular drug delivery before discussing constraints with regard to formulation parameters. Finally, it gives an overview of advanced drug delivery technologies with a specific focus on recently marketed and late-stage clinical trial products.

Adjuvants have been extensively and essentially formulated in subunits and certain inactivated vaccines for enhancing and prolonging protective immunity against infections and diseases. According to the types of infectious diseases and the required immunity, adjuvants with various acting mechanisms have been designed and applied in human vaccines. In this chapter, we introduce the advances in vaccine adjuvants based on nanomaterials and small molecules. By reviewing the immune mechanisms induced by adjuvants with different characteristics, we aim to establish structure-activity relationships between the physicochemical properties of adjuvants and their immunostimulating capability for the development of adjuvants for more effective preventative and therapeutic vaccines.

The concept of G protein-coupled receptors initially arose from studies of the β-adrenoceptor, adenylyl cyclase, and cAMP signalling pathway. Since then both canonical G protein-coupled receptor signalling pathways and emerging paradigms in receptor signalling have been defined by experiments focused on adrenoceptors. Here, we discuss the evidence for G protein coupling specificity of the nine adrenoceptor subtypes. We summarise the ability of each of the adrenoceptors to activate proximal signalling mediators including cAMP, calcium, mitogen-activated protein kinases, and protein kinase C pathways. Finally, we highlight the importance of precise spatial and temporal control of adrenoceptor signalling that is controlled by the localisation of receptors at intracellular membranes and in larger protein complexes.

Hypertension is a very prevalent condition associated with high mortality and morbidity, secondary to changes resulting in blood vessels and resultant end-organ damage. Haemodynamic changes, including an initial rise in cardiac output followed by an increase in total peripheral resistance, denote the early changes associated with borderline or stage 1 hypertension, especially in young men. Increased sodium reabsorption leading to kidney damage is another mechanism proposed as one of the initial triggers for essential hypertension. The underlying pathophysiological mechanisms include catecholamine-induced α₁- and ß₁-adrenoceptor stimulation, and renin-angiotensin-aldosterone system activation leading to endothelial dysfunction which is believed to lead to persistent blood pressure elevation.α₁ blockers, α₂ agonists, and ß blockers were among the first oral anti-hypertensives. They are no longer first-line therapy after outcome trials did not demonstrate any benefits over and above other agents, despite similar blood pressure reductions. Angiotensin-converting enzyme inhibitors (or angiotensin receptor blockers), calcium channel blockers, and thiazide-like diuretics are now considered the first line of therapy, although adrenoceptor agents still have a role as second- or third-line therapy. The chapter also highlights hypertension in specific medical conditions such as pregnancy, phaeochromocytoma, hyperthyroidism, portal hypertension, pulmonary arterial hypertension, and ocular hypertension, to provide an overview for clinicians and researchers interested in the role of adrenoceptors in the pathophysiology and management of hypertension.

mRNA and targeted delivery of mRNA carry the promise to enable targeted treatment of undruggable diseases with high unmet medical needs. The transient nature of mRNA opens options for safe influencing of protein biology, immune responses, and complex ailments without impacting DNA heritage. Technical challenges such as mRNA stability and targeted delivery require next generation solutions, which attracted substantial funding and research interests. To build an integrated mRNA value chain and enable the development of novel therapeutics, Merck KGaA Darmstadt, Germany has initiated an internally incubated program, "Targeted mRNA Delivery" (TMD). This collaborative approach brings together scientists, researchers, engineers, and commercial experts from diverse backgrounds to overcome the multidimensional challenges associated with mRNA technology. In this chapter, the multiple opportunities and challenges for the development of mRNA formulations and therapeutics are described comprehensively. Specifically, the TMD program is presented as a use case to show how intrapreneurs were gathered to establish internal mRNA capabilities and foster collaborations for technology development. In the realm of targeted mRNA delivery, partnerships, encompassing internal partnership and external private, public, and hybrid collaborations, play a crucial role in driving innovation and addressing these hurdles. Within multinational pharmaceutical companies, the establishment of "internal startups" is an effective solution to drive innovation to the next level with support from different business sectors, where existing capabilities and positioning are seamlessly blended with the agility and speed of a startup.

The approval of mRNA-containing lipid nanoparticles (LNPs) for use in a vaccine against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the clinical utility of RNA-loaded nanocapsules has stimulated a rapid acceleration in research in this area. The development of mRNA-containing LNP vaccines has been rapid, not only because of regulatory adjustments, but also to the advances made in nucleic acid delivery as the result of efforts by many basic researchers. RNA functions, not only in the nucleus and cytoplasm, but also in mitochondria, which have their own genomic apparatus. Mitochondrial diseases caused by mutations or defects in the mitochondrial genome, mitochondrial DNA (mtDNA) are intractable and are mainly treated symptomatically, but gene therapy as a fundamental treatment is expected to soon be a reality. To realize this therapy, a drug delivery system (DDS) that delivers nucleic acids including RNA to mitochondria is required, but efforts in this area have been limited compared to research targeting the nucleus and cytoplasm. This contribution provides an overview of mitochondria-targeted gene therapy strategies and discusses studies that have attempted to validate mitochondria-targeted RNA delivery therapies. We also present the results of 'RNA delivery to mitochondria' based on the use of our mitochondria-targeted DDS (MITO-Porter) that was developed in our laboratory.

This chapter provides a short history of adrenoceptor research starting from the initial discovery of adrenaline. It covers the evolving classification of adrenoceptor subtypes, the cloning of these subtypes from multiple species, and factors such as adrenoceptor regulation, inverse agonism and biased agonism. More details on many of these aspects are provided in other chapters of this volume of Handbook of Experimental Pharmacology.

Adrenoceptors are class A G-protein-coupled receptors grouped into three families (α₁-, α₂-, and β-adrenoceptors), each one including three members. All nine corresponding adrenoceptor genes display genetic variation in their coding and adjacent non-coding genomic region. Coding variants, i.e., nucleotide exchanges within the transcribed and translated receptor sequence, may result in a difference in amino acid sequence thus altering receptor function and signaling. Such variants have been intensely studied in vitro in overexpression systems and addressed in candidate-gene studies for distinct clinical parameters. In recent years, large cohorts were analyzed in genome-wide association studies (GWAS), where variants are detected as significant in context with specific traits. These studies identified two of the in-depth characterized 18 coding variants in adrenoceptors as repeatedly statistically significant genetic risk factors - p.Arg389Gly in the β₁- and p.Thr164Ile in the β₂-adrenoceptor, along with 56 variants in the non-coding regions adjacent to the adrenoceptor gene loci, the functional role of which is largely unknown at present. This chapter summarizes current knowledge on the two coding variants in adrenoceptors that have been consistently validated in GWAS and provides a prospective overview on the numerous non-coding variants more recently attributed to adrenoceptor gene loci.

The CLC family encompasses two functional categories of transmembrane proteins: chloride conducting channels and proton-chloride antiporters. All members in this chloride channel/transporter family consist of two identical protein subunits, and each subunit forms an independent ion-transport pathway, a structural architecture known as "double barrel." These CLC proteins serve biological functions ranging from membrane excitability and cell volume regulation to acidification of endosomes. Despite their ubiquitous expression, physiological significance, and resolved molecular structures of some of the family members, the mechanisms governing these molecules' biophysical functions are still not completely settled. However, a series of functional and structural studies have brought insights into interesting questions related to these proteins. This chapter explores the functional peculiarities underlying CLC channels aided by information observed from the chloride-proton antiporters in the CLC family. The overall structural features of these CLC proteins will be presented, and the biophysical functions will be addressed. Finally, the mechanism of pharmacological agents that interact with CLC channels will also be discussed.

In the evolving landscape of biomedical research, the convergence of molecular biology and translational medicine has ushered in a new era of pharmaceutical innovation. This paradigm shift, characterized by significant advances in targeted therapies and gene editing, emphasizes the critical role of integrating academic research - and academic researchers - within industry settings. Contemporary innovation models are moving beyond traditional, corporation-centered frameworks, adopting more open, collaborative approaches. Here, we discuss the challenges and solutions brought about by this new direction in pharma innovation and describe the BioMed X innovation model, a unique open innovation approach that has been growing continuously over the past ten years.