Handbook of experimental pharmacology最新文献

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.

Neurocognitive disorders are characterized by a decline in various components of cognitive function, resulting in a high rate of morbidity and mortality. Despite multiple efforts, there is still a lack of practical preventive and therapeutic approaches for these diseases, and current pharmaceuticals have failed to manage their progression. Consequently, this chapter aims to provide a concise overview of the existing preclinical and clinical evidence that explores the impact of plant-based therapies on the prevention and treatment of neurocognitive disorders.We thoroughly searched different web databases to identify preclinical and clinical studies that investigate the effect of plant-based medicines on cognitive function in animal models, as well as individuals who are healthy, those with mild cognitive decline, or those with Alzheimer's disease. We included studies that examined plant extracts, multi-component herbal preparations, and phytochemicals such as Nigella sativa Linn., Rosmarinus officinalis L., Ginkgo biloba, and Melissa officinalis. The neuroprotective effects of these plants were associated with their anticholinesterase, anti-inflammatory, and antioxidative activities. None of the included studies reported severe adverse reactions.In conclusion, the results of the preclinical and clinical studies indicate the potential benefits of plant-based therapies on neurocognitive disorders. However, more extended and comprehensive clinical studies must confirm these findings thoroughly.

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.

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.

Despite more than 200 approved anticancer agents, cancer remains a leading cause of death worldwide due to disease complexity, tumour heterogeneity, drug toxicity, and the emergence of drug resistance. Accordingly, the development of chemotherapeutic agents with higher efficacy, a better safety profile, and the capability of bypassing drug resistance would be a cornerstone in cancer therapy. Natural products have played a pivotal role in the field of drug discovery, especially for the pharmacotherapy of cancer, infectious, and chronic diseases. Owing to their distinctive structures and multiple mechanistic activities, natural products and their derivatives have been utilized for decades in cancer treatment protocols. In this review, we delve into the potential of natural products as anticancer agents by targeting cancer's hallmarks, including sustained proliferative signalling, evading growth suppression, resisting apoptosis and cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. We highlight the molecular mechanisms of some natural products, in vivo studies, and promising clinical trials. This review emphasizes the significance of natural products in fighting cancer and the need for further studies to uncover their fully therapeutic potential.

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.

Parasitic diseases including malaria, leishmaniasis, and trypanosomiasis have received significant attention due to their severe health implications, especially in developing countries. Marine natural products from a vast and diverse range of marine organisms such as sponges, corals, molluscs, and algae have been found to produce unique bioactive compounds that exhibit promising potent properties, including antiparasitic, anti-Plasmodial, anti-Leishmanial, and anti-Trypanosomal activities, providing hope for the development of effective treatments. Furthermore, various techniques and methodologies have been used to investigate the mechanisms of these antiparasitic compounds. Continued efforts in the discovery and development of marine natural products hold significant promise for the future of novel treatments against parasitic diseases.

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.