Handbook of experimental pharmacology最新文献

Atherosclerosis is a common cardiovascular disease closely associated with factors such as hyperlipidaemia and chronic inflammation. Among them, endothelial dysfunction serves as a major predisposing factor. Vascular endothelial dysfunction is manifested by impaired endothelium-dependent vasodilation, enhanced oxidative stress, chronic inflammation, leukocyte adhesion and hyperpermeability, endothelial senescence, and endothelial-mesenchymal transition (EndoMT). Flavonoids are known for their antioxidant activity, eliminating oxidative stress induced by reactive oxygen species (ROS), thereby preventing the oxidation of low-density lipoprotein (LDL) cholesterol, reducing platelet aggregation, alleviating ischemic damage, and improving vascular function. Flavonoids have also been shown to possess anti-inflammatory activity and to protect the cardiovascular system. This review focuses on the protective effects of these naturally-occuring bioactive flavonoids against the initiation and progression of atherosclerosis through their effects on endothelial cells including, but not limited to, their antioxidant, anti-inflammatory, anti-thrombotic, and lipid-lowering properties. However, more clinical evidences are still needed to determine the exact role and optimal dosage of these compounds in the treatment of atherosclerosis.

Cannabis sativa is one of the oldest medicinal plants in human history. Even ancient physicians from hundreds of years ago used Cannabis sativa to treat several conditions like pain. In the modern era, the research community, including health-care providers, have witnessed wide-scale changes in cannabis policy, legislation, and marketing, with a parallel increase in patient interest. A simple search in PubMed using "cannabis and pain" as keywords provides more than 2,400 articles, about 80% of which were published in the last 8-10 years. Several advancements have been achieved in understanding the complex chemistry of cannabis along with its multiple pharmacological activities. Preclinical data have demonstrated evidence for the promising potential of cannabis for pain management, and the continuous rise in the prevalence of pain increases the urgency to translate this into clinical practice. Despite the large body of cannabis literature, researchers still need to find rigorous answers for the questions about the efficacy and safety of cannabis in treatment of certain disorders such as pain. In the current chapter, we seek to present a critical overview about the current knowledge on cannabis with special emphasis on pain-related disorders.

Metabolic syndrome (MetS) is a prevalent health condition that requires significant attention and intervention due to its multifaceted nature. It encompasses a variety of ailments such as diabetes mellitus, hypertension, obesity, and dyslipidemia. Despite extensive research, the underlying pathophysiology of MetS is not entirely understood, and current synthetic drugs used to treat it have adverse effects and can be expensive. Therefore, natural products are being investigated as a potential alternative treatment for MetS. This chapter provides an overview of studies on natural products as a treatment for MetS. The available evidence suggests that bioactive phytochemicals and herbal medicines, such as curcumin, resveratrol, Nigella sativa, Hibiscus sabdariffa, and Theobroma cacao, have the potential to treat MetS effectively. Furthermore, natural products can be explored as a novel drug discovery approach for MetS. However, it is imperative to conduct well-designed randomized controlled trials with large sample sizes to confirm these findings. Based on our review, we conclude that natural products could be a promising alternative for treating MetS. Further research is warranted to explore this potential fully. The use of natural products for MetS treatment could reduce the reliance on synthetic drugs, many of which have harmful side effects and are costly. The development of natural products as a treatment for MetS could have significant implications for public health, and we encourage further research in this area.

Maintaining good vascular health is a major component in healthy ageing as it reduces the risk of cardiovascular diseases. Endothelial dysfunction, in particular, is a key mechanism in the development of major cardiovascular diseases including hypertension, atherosclerosis and diabetes. Recently, endothelial senescence has emerged as a pivotal early event in age-related endothelial dysfunction. Endothelial function is characterized by an imbalance between the endothelial formation of vasoprotective mechanisms, including the formation of nitric oxide (NO) and endothelium-dependent hyperpolarization responses, and an increased level of oxidative stress involving several pro-oxidant enzymes such as NADPH oxidases and, often also, the appearance of cyclooxygenase-derived vasoconstrictors. Pre-clinical studies have indicated that natural products, in particular several polyphenol-rich foods, can trigger activating pathways in endothelial cells promoting an increased formation of NO and endothelium-dependent hyperpolarization. In addition, some can even exert beneficial effects on endothelial senescence. Moreover, some of these products have been associated with the prevention and/or improvement of established endothelial dysfunction in several experimental models of cardiovascular diseases and in humans with cardiovascular diseases. Therefore, intake of certain natural products, such as dietary and plant-derived polyphenol-rich products, appears to be an attractive approach for a healthy vascular system in ageing.

Quantitative systems pharmacology (QSP) is a modeling approach employed in drug research and development that combines mechanistic representations of biological processes with drug pharmacology to deepen biological understanding and predict the responses to novel drugs or protocols. QSP has evolved from and is related to other modeling approaches, but has a number of unique attributes and applications. Here, we clarify the definition of QSP and its key features, trace its evolution, briefly compare it to other approaches, and explain why and how it can be used to reduce risk and improve efficiency in drug research and development.

Despite an increasing number of clinical trials, cancer is one of the leading causes of death worldwide in the past decade. Among all complex diseases, clinical trials in oncology have among the lowest success rates, in part due to the high intra- and inter-tumoral heterogeneity. There are more than a thousand cancer drugs and treatment combinations being investigated in ongoing clinical trials for various cancer subtypes, germline mutations, metastasis, etc. Particularly, treatments relying on the (re)activation of the immune system have become increasingly present in the clinical trial pipeline. However, the complexities of the immune response and cancer-immune interactions pose a challenge to the development of these therapies. Quantitative systems pharmacology (QSP), as a computational approach to predict tumor response to treatments of interest, can be used to conduct in silico clinical trials with virtual patients (and emergent use of digital twins) in place of real patients, thus lowering the time and cost of clinical trials. In line with improved mechanistic understanding of the human immune system and promising results from recent cancer immunotherapy, QSP models can play critical roles in model-informed drug development in immuno-oncology. In this chapter, we discuss how QSP models were designed to serve different study objectives, including hypothesis testing, dose optimization, and efficacy prediction, via case studies in immuno-oncology.

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.

Proteins and peptides are highly desirable as therapeutic agents, being highly potent and specific. However, there are myriad challenges with processing them into patient-friendly formulations: they are often unstable and have a tendency to aggregate or degrade upon storage. As a result, the vast majority of protein actives are delivered parenterally as solutions, which has a number of disadvantages in terms of cost, accessibility, and patient experience. Much work has been undertaken to develop new delivery systems for biologics, but to date this has led to relatively few products on the market. In this chapter, we review the challenges faced when developing biologic formulations, discuss the technologies that have been explored to try to overcome these, and consider the different delivery routes that can be applied. We further present an overview of the currently marketed products and assess the likely direction of travel in the next decade.

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.