Handbook of experimental pharmacology最新文献

Initiatives to share assets in the life science sector through dedicated partnerships had and still have a multitude of different aspects in the past few decades. The range goes from industry partners, small and big companies, in bilateral agreements with academic institutions up to large privately and publicly funded consortia. In general, the term public-private partnership (PPP) is used when at least one public (non-profit, academic, and/or government) part and one or more private for-profit partners are involved. A Public-Private Partnership is often driven by a public body, i.e. a ministry or a public agency. Their synergism has been described 10 years ago (Dearing, Science 315(19):344-347, 2007; Casty and Wieman, Ther Innov Regul Sci 47(3):375-383, 2013; Stevens et al., Biotechnol Law Rep 34(4):153-165, 2015). So why view this synergism again today? It will be shown that the situation in life science has changed: novel partners acting digital, data expertise being involved on many levels and novel partnering models arising. Success and challenges will be described in this chapter.

Conventional drug delivery systems (DDS) today still face several drawbacks and obstacles. High total doses of active pharmaceutical ingredients (API) are often difficult or impossible to deliver due to poor solubility of the API or undesired clearance from the body caused by strong interactions with plasma proteins. In addition, high doses lead to a high overall body burden, in particular if they cannot be delivered specifically to the target site. Therefore, modern DDS must not only be able to deliver a dose into the body, but should also overcome the hurdles mentioned above as examples. One of these promising devices are polymeric nanoparticles, which can encapsulate a wide range of APIs despite having different physicochemical properties. Most importantly, polymeric nanoparticles are tunable to obtain tailored systems for each application. This can already be achieved via the starting material, the polymer, by incorporating, e.g., functional groups. This enables the particle properties to be influenced not only specifically in terms of their interactions with APIs, but also in terms of their general properties such as size, degradability, and surface properties. In particular, the combination of size, shape, and surface modification allows polymeric nanoparticles to be used not only as a simple drug delivery device, but also to achieve targeting. This chapter discusses to what extent polymers can be designed to form defined nanoparticles and how their properties affect their performance.

In this chapter, we review how ligands, both agonists and antagonists, for the major classes of adrenoreceptors, are utilized in acute care clinical settings. Adrenergic ligands exert their effects by interacting with the three major classes of adrenoceptors. Adrenoceptor agonists and antagonists have important applications, ranging from treatment of hypotension to asthma, and have proven to be extremely useful in a variety of clinical settings of acute care from the operating room to the critical care environment. Continued research interpreting the mechanisms of adrenoreceptors may help the discovery of new drugs with more desirable clinical profiles.

Project-based collaborations between a single academic group and a single pharmaceutical company arguably are the most frequent form of public-private partnership in preclinical research and development of new drugs. This chapter discusses the benefits of such collaborations for both sides and potential challenges that can arise before and during the conduct of a project. This is largely based on a survey of expectations and experience by 134 academic investigators with a history of engagement in a project-based collaboration with a pharmaceutical company as well as unstructured experience directly, and learned through discussions with colleagues, from the authors. Obviously, a key benefit for both sides is achieving goals that neither could easily achieve by itself. Scientific discovery, and publications, may be a shared benefit, while for academics, funding and access to compounds, and for industry, access to assay technology and reputational factors may be important. Major hurdles can be freedom to publish and assignment of intellectual property rights. On pragmatic grounds, reaching a contract can be cumbersome, which is largely attributable to the legal expectations and needs of both parties. However, overall satisfaction with project-based collaborations appears very high for academic investigators.

Transporters of the solute carrier family 12 (SLC12) carry inorganic cations such as Na⁺ and/or K⁺ alongside Cl across the plasma membrane of cells. These tightly coupled, electroneutral, transporters are expressed in almost all tissues/organs in the body where they fulfil many critical functions. The family includes two key transporters participating in salt reabsorption in the kidney: the Na-K-2Cl cotransporter-2 (NKCC2), expressed in the loop of Henle, and the Na-Cl cotransporter (NCC), expressed in the distal convoluted tubule. NCC and NKCC2 are the targets of thiazides and "loop" diuretics, respectively, drugs that are widely used in clinical medicine to treat hypertension and edema. Bumetanide, in addition to its effect as a loop diuretic, has recently received increasing attention as a possible therapeutic agent for neurodevelopmental disorders. This chapter also describes how over the past two decades, the pharmacology of Na⁺ independent transporters has expanded significantly to provide novel tools for research. This work has indeed led to the identification of compounds that are 100-fold to 1000-fold more potent than furosemide, the first described inhibitor of K-Cl cotransport, and identified compounds that possibly directly stimulate the function of the K-Cl cotransporter. Finally, the recent cryo-electron microscopy revolution has begun providing answers as to where and how pharmacological agents bind to and affect the function of the transporters.

The autonomic nervous system plays a crucial role in the innervation of the eye. Consequently, it comes as no surprise that catecholamines and their corresponding receptors have been extensively studied and characterized in numerous ocular structures, including the cornea, conjunctiva, lacrimal gland, trabecular meshwork, uvea, and retina. These investigations have unveiled substantial clinical implications, particularly in the context of treating glaucoma, a progressive neurodegenerative disorder responsible for irreversible vision loss on a global scale. The primary therapeutic approaches for glaucoma frequently involve the modulation of α₁-, α₂-, and β-adrenoceptors, making them pivotal targets. In this chapter, we offer a comprehensive overview of the expression, distribution, and functional roles of adrenoceptors within various components of the eye and its associated structures. Additionally, we delve into the pivotal role of adrenoceptors in the pathophysiology of glaucoma. Furthermore, we provide a concise historical perspective on adrenoceptor research, examine the distinct contributions of individual adrenoceptor subtypes to the treatment of various ocular conditions, and propose potential future avenues of exploration in this field.

Adrenoceptors (ARs) throughout the brain are stimulated by noradrenaline originating mostly from neurons of the locus coeruleus, a brainstem nucleus that is ostensibly the earliest to show detectable pathology in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The α₁-AR, α₂-AR, and β-AR subtypes expressed in target brain regions and on a range of cell populations define the physiological responses to noradrenaline, which includes activation of cognitive function in addition to modulation of neurometabolism, cerebral blood flow, and neuroinflammation. As these heterocellular functions are critical for maintaining brain homeostasis and neuronal health, combating the loss of noradrenergic tone from locus coeruleus degeneration may therefore be an effective treatment for both cognitive symptoms and disease modification in neurodegenerative indications. Two pharmacologic approaches are receiving attention in recent clinical studies: preserving noradrenaline levels (e.g., via reuptake inhibition) and direct activation of target adrenoceptors. Here, we review the expression and role of adrenoceptors in the brain, the preclinical studies which demonstrate that adrenergic stimulation can support cognitive function and cerebral health by reversing the effects of noradrenaline depletion, and the human data provided by pharmacoepidemiologic analyses and clinical trials which together identify adrenoceptors as promising targets for the treatment of neurodegenerative disease.

Solute carrier family 26 (SLC26) is a family of functionally diverse anion transporters found in all kingdoms of life. Anions transported by SLC26 proteins include chloride, bicarbonate, and sulfate, but also small organic dicarboxylates such as fumarate and oxalate. The human genome encodes ten functional homologs, several of which are causally associated with severe human diseases, highlighting their physiological importance. Here, we review novel insights into the structure and function of SLC26 proteins and summarize the physiological relevance of human members.

Sphingolipids are crucial molecules in the respiratory airways. As in most other tissues and organs, in the lung sphingolipids play an essential role as structural constituents as they regulate barrier function and fluidity of cell membranes. A lung-specific feature is the occurrence of sphingolipids as minor structural components in the surfactant. However, sphingolipids are also key signaling molecules involved in airway cell signaling and their dynamical formation and metabolism are important for normal lung physiology. Dysregulation of sphingolipid metabolism and signaling is involved in altering lung tissue and initiates inflammatory processes promoting the pathogenesis of pulmonal diseases including cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and asthma.In the present review, the important role of specific sphingolipid species in pulmonal diseases will be discussed. Only such an understanding opens up the possibility of developing new therapeutic strategies with the aim of correcting the imbalance in sphingolipid metabolism and signaling. Such delivery strategies have already been studied in animal models of these lung diseases, demonstrating that targeting the sphingolipid profile represents new therapeutic opportunities for lung disorders.

Respiratory diseases are a major concern in public health, impacting a large population worldwide. Despite the availability of therapies that alleviate symptoms, selectively addressing the critical points of pathopathways remains a major challenge. Innovative formulations designed for reaching these targets within the airways, enhanced selectivity, and prolonged therapeutic effects offer promising solutions. To provide insights into the specific medical requirements of chronic respiratory diseases, the initial focus of this chapter is directed on lung physiology, emphasizing the significance of lung barriers. Current treatments involving small molecules and the potential of gene therapy are also discussed. Additionally, we will explore targeting approaches, with a particular emphasis on nanoparticles, comparing targeted and non-targeted formulations for pulmonary administration. Finally, the potential of inhaled sphingolipids in the context of respiratory diseases is briefly discussed, highlighting their promising prospects in the field.