Handbook of experimental pharmacology最新文献

The mineralocorticoid aldosterone is produced in the zona glomerulosa of the adrenal cortex. Its synthesis is regulated by the serum concentrations of the peptide hormone angiotensin II and potassium. The primary role of aldosterone is to control blood volume and electrolytes. The autonomous production of aldosterone (primary aldosteronism, PA) is considered the most frequent cause of secondary hypertension. Aldosterone-producing adenomas and (micro-)nodules are frequent causes of PA and often carry somatic mutations in ion channels and transporters. Rare familial forms of PA are due to germline mutations. Both somatic and germline mutations in the chloride channel gene CLCN2, encoding ClC-2, have been identified in PA. Clinical findings and results from cell culture and animal models have advanced our knowledge about the role of anions in PA. The zona glomerulosa of the adrenal gland has now been firmly established as a tissue in which anions play a significant role for signaling. In this overview, we aim to summarize the current knowledge and highlight novel concepts as well as open questions.

Distress, or negative stress, is known to considerably increase the incidence of several diseases, including cancer. There is indeed evidence from pre-clinical models that distress causes a catecholaminergic overdrive that, mainly through the activation of β-adrenoceptors (β-ARs), results in cancer cell growth and cancer progression. In addition, clinical studies have evidenced a role of negative stress in cancer progression. Moreover, plenty of data demonstrates that β-blockers have positive effects in reducing the pro-tumorigenic activity of catecholamines, correlating with better outcomes in some type of cancers as evidenced by several clinical trials. Among β-ARs, β2-AR seems to be the main β-AR subtype involved in tumor development and progression. However, there are data indicating that also β1-AR and β3-AR may be involved in certain tumors. In this chapter, we will review current knowledge on the role of the three β-AR isoforms in carcinogenesis as well as in cancer growth and progression, with particular emphasis on recent studies that are opening new avenues in the use of β-ARs as therapeutic targets in treating tumors.

Asthma has been recognised as a respiratory disorder for millennia and the focus of targeted drug development for the last 120 years. Asthma is one of the most common chronic non-communicable diseases worldwide. Chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality worldwide, is caused by exposure to tobacco smoke and other noxious particles and exerts a substantial economic and social burden. This chapter reviews the development of the treatments of asthma and COPD particularly focussing on the β-agonists, from the isolation of adrenaline, through the development of generations of short- and long-acting β-agonists. It reviews asthma death epidemics, considers the intrinsic efficacy of clinical compounds, and charts the improvement in selectivity and duration of action that has led to our current medications. Important β2-agonist compounds no longer used are considered, including some with additional properties, and how the different pharmacological properties of current β2-agonists underpin their different places in treatment guidelines. Finally, it concludes with a look forward to future developments that could improve the β-agonists still further, including extending their availability to areas of the world with less readily accessible healthcare.

Public-private partnerships in drug R&D have great potential for driving innovation. They can bridge between excellent fundamental research and development and commercialization of innovative medicines to address unmet needs for the therapy of severe diseases in the interest of public health and human welfare. Therefore, public-private partnerships in drug R&D are promoted and publicly funded by governments and the European Commission. Nonetheless, they need to comply with legal requirements, particularly stemming from State aid law and competition law. Those requirements do not only protect a fair competition, but rather also further open information exchange as well as fair sharing of risks and fair participation in gains and results with the goal of having a successful collaboration and increasing the chance of successful commercialization of pharmaceutical innovations.

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.

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.