Handbook of experimental pharmacology最新文献

The application of quantitative systems pharmacology (QSP) has enabled substantial progress and impact in many areas of therapeutic discovery and development. This new technology is increasingly accepted by industry, academia, and solution providers, and is enjoying greater interest from regulators. In this chapter, we summarize key aspects regarding how effective collaboration among institutions and disciplines can support the growth of QSP and expand its application domain. We exemplify these considerations through a selection of successful cross-institutional or cross-functional collaborations, which resulted in reuse, repurposing, or extension of QSP modeling results or infrastructure, with important and novel results.

In this chapter, we envision the future of Quantitative Systems Pharmacology (QSP) which integrates closely with emerging data and technologies including advanced analytics, novel experimental technologies, and diverse and larger datasets. Machine learning (ML) and Artificial Intelligence (AI) will increasingly help QSP modelers to find, prepare, integrate, and exploit larger and diverse datasets, as well as build, parameterize, and simulate models. We picture QSP models being applied during all stages of drug discovery and development: During the discovery stages, QSP models predict the early human experience of in silico compounds created by generative AI. In preclinical development, QSP will integrate with non-animal "new approach methodologies" and reverse-translated datasets to improve understanding of and translation to the human patient. During clinical development, integration with complementary modeling approaches and multimodal patient data will create multidimensional digital twins and virtual populations for clinical trial simulations that guide clinical development and point to opportunities for precision medicine. QSP can evolve into this future by (1) pursuing high-impact applications enabled by novel experimental and quantitative technologies and data types; (2) integrating closely with analytical and computational advancements; and (3) increasing efficiencies through automation, standardization, and model reuse. In this vision, the QSP expert will play a critical role in designing strategies, evaluating data, staging and executing analyses, verifying, interpreting, and communicating findings, and ensuring the ethical, safe, and rational application of novel data types, technologies, and advanced analytics including AI/ML.

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.

The popularity of natural products for the treatment of lower urinary tract symptoms (LUTS) differs considerably between countries. Here we discuss the clinical evidence for efficacy in two indications, male LUTS suggestive of benign prostatic hyperplasia and urinary tract infections, and the mechanistic evidence from experimental studies. Most evidence for male LUTS is based on extracts from saw palmetto berries, stinging nettle roots, and pumpkin seeds, whereas most evidence for urinary tract infection is available for European golden rod and combined preparations although this field appears more fragmented with regard to extract sources. Based on differences in sample collection and extraction, extracts from the same plants are likely to exhibit at least quantitative differences in potential active ingredients, which makes extrapolation of findings with one extract to those of others potentially difficult. While only limited information is available for most individual extracts, some extracts have been compared to placebo and/or active controls in adequately powered trials.

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.

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.

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.

Chronic airway inflammatory diseases like asthma, chronic obstructive pulmonary disease (COPD), and their associated exacerbations cause significant socioeconomic burden. There are still major obstacles to effective therapy for controlling severe asthma and COPD progression. Advances in understanding the pathogenesis of the two diseases at the cellular and molecular levels are essential for the development of novel therapies. In recent years, significant efforts have been made to identify natural products as potential drug leads for treatment of human diseases and to investigate their efficacy, safety, and underlying mechanisms of action. Many major active components from various natural products have been extracted, isolated, and evaluated for their pharmacological efficacy and safety. For the treatment of asthma and COPD, many promising natural products have been discovered and extensively investigated. In this chapter, we will review a range of natural compounds from different chemical classes, including terpenes, polyphenols, alkaloids, fatty acids, polyketides, and vitamin E, that have been demonstrated effective against asthma and/or COPD and their exacerbations in preclinical models and clinical trials. We will also elaborate in detail their underlying mechanisms of action unraveled by these studies and discuss new opportunities and potential challenges for these natural products in managing asthma and COPD.

Bacterial infections are a significant public health concern, and the emergence of antibiotic-resistant bacteria (ARB) has become a major challenge for modern medicine. The overuse and misuse of antibiotics have contributed to the development of ARB, which has led to the need for alternative therapies. Plant-derived natural products (PNPs) have been extensively studied for their potential as alternative therapies for the treatment of bacterial infections. The diverse chemical compounds found in plants have shown significant antibacterial properties, making them a promising source of novel antibacterial agents. The use of PNPs as antibacterial agents is particularly appealing because they offer a relatively safe and cost-effective approach to the treatment of bacterial infections. This chapter aims to provide an overview of the current state of research on PNPs as antibacterial agents. It will cover the mechanisms of action of the main PNPs against bacterial pathogens and discuss their potential to be used as complementary therapies to combat ARB. This chapter will also highlight the most common screening methodologies to discover new PNPs and the challenges and future prospects in the development of these compounds as antibacterial agents.

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.