Handbook of experimental pharmacology最新文献

In the late 1990s, the antiplatelet agent clopidogrel, a P2Y12 inhibitor, was introduced into clinical practice. Concurrently, several new methods for assessing platelet function emerged, such as the PFA-100 in 1995, marking the beginning of a sustained expansion in platelet function testing. It soon became apparent that patient responses to clopidogrel varied significantly, with some individuals exhibiting high on-treatment platelet reactivity. This variability prompted discussions around the utility of platelet function testing to tailor antiplatelet therapy. Additionally, such testing was proposed for patients preparing for cardiac surgery to better manage the balance between thrombotic risk before surgery and bleeding risk during the perioperative period. This chapter explores widely used platelet function tests in these contexts, particularly those considered point-of-care (POC) or requiring minimal laboratory processing. It also reviews recent guidelines and clinical trial evidence, building on a previously published chapter, regarding the role and effectiveness of platelet function testing in these clinical scenarios.

Hydrogen sulfide (H₂S) is a gasotransmitter that contributes to the regulation of peripheral nervous system (PNS) function. H₂S is produced by several enzymes whose expression changes under different physiological and pathological conditions, influencing how peripheral neurons respond to environmental and internal signals. H₂S modulates neuronal excitability through its actions on ion channels and through interactions with other gasotransmitters, shaping sensory, autonomic, and pain-related pathways. In autonomic circuits, H₂S adjusts sympathetic and parasympathetic activity. Through these actions, it affects cardiovascular control, gastrointestinal motility, and respiratory rhythm. In pain pathways, H₂S can modulate nociception in either direction, with its effectsshaped by the physiological or pathological state. H₂S participates in multiple pain conditions and contributes to changes in peripheral and spinal processing that influence pain sensitivity. Overall, H₂S influences several components of peripheral neurobiology and represents a potential target for strategies aimed at treating autonomic dysfunction and chronic pain.

Perivascular adipose tissue (PVAT) is a metabolically active, endocrine organ that plays a crucial role in regulating blood vessel tone, endothelial function, vascular smooth muscle cell growth, and proliferation and contributes significantly to the onset and progression of cardiovascular diseases. In a healthy state, PVAT displays anticontractile, anti-inflammatory, and antioxidative properties, which are critical for maintaining vascular homeostasis. However, under certain pathophysiological conditions, PVAT exerts pro-contractile effects by decreasing the production of anticontractile and/or increasing that of pro-contractile factors. In this context, recent studies have identified hydrogen sulfide (H₂S) as a key vascular anti-contractile factor released from PVAT. The enzymes responsible for H₂S biosynthesis are differentially expressed in PVAT, depending on the vascular bed and species, and their function can be altered by metabolic and cardiovascular diseases. These alterations can influence H₂S signalling, further contributing to vascular dysfunction. PVAT-derived H₂S may have particular importance in obesity-related vascular disease, hypertension, and diabetes as it has direct paracrine effects on the vasculature. Understanding the role of PVAT-derived H₂S in both healthy and diseased states may provide new insights into preventing vascular dysfunction associated with PVAT changes. The dissection of the specific contributions of each enzyme involved in PVAT-derived H₂S biosynthesis could be relevant to fully understanding the complex role of H₂S in vascular health vs vascular disease. Further research into modulating PVAT-derived H₂S provides an exciting avenue to explore novel pharmacological targets against vascular disease pathogenesis.

Hydrogen sulfide (H₂S) is an endogenous gasotransmitter able to exert a pivotal role in different organs and systems, strongly influencing cardiovascular health. It is an endowed antioxidant, a vasorelaxant, and has cardioprotective properties, thanks to the activation of different classes of potassium channels and the interaction with several pathways including those involving sirtuins, nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor kappa B (NF-κB), and nitric oxide (NO) production. Alterations in the homeostasis of H₂S represent an etiopathogenetic factor in the onset and progression of cardiovascular diseases, such as hypertension, atherosclerosis, and vascular diabetic complications, highlighting the therapeutic potential of exogeneous H₂S-donors in H₂S-poor diseases. Several natural H₂S-donor compounds, or their precursors, derive from plants belonging to the Alliaceae (e.g., garlic and onion), Brassicaceae (e.g., broccoli and rocket salad), or Moringaceae (e.g., moringa) families. Preclinical studies demonstrated the antioxidant, vasoprotective, and anti-hypertensive properties of both plant extracts and isolated polysulfides or isothiocyanates (ITCs). In fact, polysulfides and ITCs are able to exert vascular effects superimposable to those induced by H₂S. Preclinical and clinical studies successfully demonstrated that garlic extracts decrease systolic and diastolic blood pressure and contrast endothelial dysfunction and atherosclerosis. Similarly, preclinical studies highlighted the anti-inflammatory, anti-hypertensive, and vasoprotective properties of ITCs. However, clinical studies only demonstrated the improvement of the lipid profile in healthy patients, with no effects on systolic or diastolic blood pressure. Taken together, these findings suggest that natural H₂S-donors could restore H₂S homeostasis, therefore preventing and/or contrasting cardiovascular diseases.

Type 2 diabetes (T2D) is a disease that occurs when cells do not respond normally to insulin, a condition called insulin resistance, which leads to high blood glucose levels. Although it can be treated pharmacologically, dietary habits beyond carbohydrate restriction can be highly relevant in the management of T2D. Emerging evidence supports the possibility that natural products (NPs) could contribute to managing blood glucose or counteract the undesirable effects of hyperglycemia and insulin resistance. This chapter summarizes the relevant preclinical evidence involving the flavonoid (-)-epicatechin (EC) in the optimization of glucose homeostasis, reducing insulin resistance and/or diabetes-associated disorders. Major effects of EC are observed on (i) intestinal functions, including digestive enzymes, glucose transporters, microbiota, and intestinal permeability, and (ii) redox homeostasis, including oxidative stress and inflammation. There is still a need for further clinical studies to confirm the in vitro and rodent data, allowing recommendations for EC, particularly in prediabetic and T2D patients. The collection of similar data and the lack of clinical evidence for EC is also applicable to other NPs.

Congenital disorders of glycosylation (CDG) constitute an increasing group of inborn metabolic disorders, with more than 170 described diseases to date. A disturbed glycosylation process characterizes them, with molecular defects localized in distinct cell compartments. In CDG, N-glycosylation, O-glycosylation, glycosylation of lipids (including phosphatidylinositol) as well as the glycosaminoglycan synthesis can be affected. Owing to the importance of glycosylation for the function of concerned proteins and lipids, glycosylation defects have diverse clinical consequences. CDG affected individuals often present with a non-specific multivisceral syndrome including neurological involvement, intellectual disability, dysmorphia, and hepatopathy. As CDG are rare diseases frequently lacking distinctive symptoms, biochemical and genetic testing bear important and complementary diagnostic roles.After an introduction on glycosylation and CDG, we review current biomarkers and analytical techniques in the field. Furthermore, we illustrate their interests in the follow-up of proven therapeutic approaches including D-mannose in MPI-CDG, D-galactose in PGM1-CDG, and manganese (MnSO₄) in TMEM165-CDG.

Glycosaminoglycans (GAG) are polysaccharides that are ubiquitous on the surface of all mammalian cells, interacting with a multitude of proteins and orchestrating essential physiological and pathological processes. Among various GAG structures, heparan sulfate (HS) stands out for its intricate structure, positioning it as a significant cell-surface molecule capable of regulating wide range of cellular functions. Consequently, investigating the structure-activity relationships (SARs) with well-defined HS ligands emerges as an attractive avenue advancing drug discovery and biosensors. This chapter outlines a modular divergent strategy for synthesizing HS oligosaccharides to elucidate SARs. Here, we provide a literature overview on the synthesis of disaccharide building blocks, employing different orthogonal protecting groups, promoters, and optimization conditions to improve their suitability for subsequent oligosaccharide synthesis. Further, we highlight the synthesis of universal disaccharide building blocks derived from natural polysaccharides. We also provide insights of one-pot method and automated solid-phase synthesis of HS oligosaccharides. Finally, we review the status of SARs of popular heparan sulfate binding proteins (HSBPs).

Quantitative Systems Pharmacology (QSP) models offer a promising approach to extrapolate drug efficacy across different patient populations, particularly in rare diseases. Unlike conventional empirical models, QSP models can provide a mechanistic understanding of disease progression and therapeutic response by incorporating current disease knowledge into the descriptions of biomarkers and clinical endpoints. This allows for a holistic representation of the disease and drug response. The mechanistic nature of QSP models is well suited to pediatric extrapolation concepts, providing a quantitative method to assess disease and drug response similarity between adults and pediatric patients. The application of a QSP-based assessment of the disease and drug similarity in adult and pediatric patients in the clinical development program of olipudase alfa, a treatment for Acid Sphingomyelinase Deficiency (ASMD), illustrates the potential of this approach.

Quantitative systems toxicology (QST) is emerging as an independent field of model-informed drug development (MIDD) with a focus on predicting toxicity endpoints. To enable toxicological predictions, QST models require incorporation of mechanistic details specific to safety applications including the ability to accurately model supratherapeutic doses and appropriately represent safety endpoints. Unique to the field of toxicology, mechanistic knowledge is often described through the use of adverse outcome pathways (AOPs), which formally represent existing knowledge about mechanisms of toxicity. The toxicities represented by QST models can arise from exaggerated or adverse pharmacological effects of engaging the drug's intended target (on-target toxicity) or from adverse events due to modulation of additional targets beyond the primary target (off-target toxicity). In cases of on-target toxicity, QST models can be considered as a type of Quantitative Systems Pharmacology (QSP) model that incorporates safety biomarkers and often includes simulations performed outside the therapeutic dose range to explore potential adverse consequences of exaggerated pharmacology in a pre-clinical or clinical setting. QST models assessing off-target toxicities can be considered distinct from QSP models in that they are typically applicable across molecules of a given modality which can (and often do) have different primary therapeutic targets. Off-target QST models commonly focus on the interrogation of general (e.g. pan-compound) toxicity mechanisms, often within a specific organ system. It can be difficult to categorize a model as purely QSP or QST (given that some models can be considered as both a QSP and a QST model), and therefore, we encourage readers to refer to a model based on its context of use and application. Thus, throughout this chapter, we refer to models as QST models when the context of use is to understand safety-related questions. To illustrate QST modeling approaches, examples of QST model applications for on-target and off-target toxicities at different stages of the drug discovery and development pipeline are presented and discussed. Additionally, contexts of use, triggers, key objectives, and potential impacts of QST models including the types of decisions QST applications can inform across drug discovery and development are reviewed. The chapter concludes with an overview of key challenges and future perspectives in the field of QST.

The use of Cannabis sativa by humans dates back to the third millennium BC, and it has been utilized in many forms for multiple purposes, including production of fibre and rope, as food and medicine, and (perhaps most notably) for its psychoactive properties for recreational use. The discovery of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) as the main psychoactive phytocannabinoid contained in cannabis by Gaoni and Mechoulam in 1964 (J Am Chem Soc 86, 1646-1647), was the first major step in cannabis research; since then the identification of the chemicals (phytocannabinoids) present in cannabis, the classification of the pharmacological targets of these compounds and the discovery that the body has its own endocannabinoid system (ECS) have highlighted the potential value of cannabis-derived compounds in the treatment of many diseases, such as neurological disorders and cancers. Although the use of Δ⁹-THC as a therapeutic agent is constrained by its psychoactive properties, there is growing evidence that non-psychoactive phytocannabinoids, derived from both Cannabis sativa and other plant species, as well as non-cannabinoid compounds found in Cannabis sativa, have real potential as therapeutics. This chapter will focus on the possibilities for using these compounds in the prevention and treatment of cardiovascular disease and related metabolic disturbances.