INTRODUCTION: Accurate ranking of efficacies and potencies of agonists is essential in the discovery of new selective agonists. For the purpose of system-independent ranking of agonists, the operational model of agonism (OMA) has become a standard. Many receptors function as oligomers which makes functional responses more complex, requiring an extension of the original OMA. AREAS COVERED: Explicit equations of the operational model of agonism of receptor dimers (OMARD) were derived. The OMARD can be applied to any receptor possessing two orthosteric sites. The behavior of OMARD was analyzed to demonstrate its complexity and relation to experimental data. Properties of OMARD and OMA equations were compared to demonstrate their pros and cons. EXPERT OPINION: Extension of OMA by slope factors gives simple equations of functional response that are easy to fit experimental data but results may be inaccurate because of exponentiation of operational efficacy. Also, such equations cannot accommodate bell-shaped curves. Explicit equations of OMARD give accurate results but are complex and tedious to fit experimental data. All operational models use inter-dependent parameters that are a hurdle in the fitting. A good understanding of OMARD behavior helps to overcome such obstacles.
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Combinatory strategies using pharmacology and stem cell therapy have emerged due to their potential in the treatment of retinal pigment epithelium (RPE) cell related diseases, and a variety of different stem cell sources have been evaluated both in animal models and in humans. RPE cells derived from human embryonic stem cells (hESCs) and human induced pluripotent cells (hiPSCs) are already in clinical trials, holding great promise for the treatment of age-related macular disease (AMD) and hereditary RPE-related retinal dystrophies. Highly efficient protocol for RPE generations have been developed, but they are still time-consuming and laborious. Areas covered: The authors review RPE related diseases, as well as the known functions of RPE cells in retinal homeostasis. The authors also discuss small molecules that target RPE in vivo as well as in vitro to aid RPE differentiation from pluripotent stem cells clinically. The authors base this review on literature searches performed through PubMed. Expert opinion: Using high-throughput systems, technology will provide the possibility of identifying and optimizing molecules/drugs that could lead to faster and simpler protocols for RPE differentiation. This could be crucial in moving forward to create safer and more efficient RPE-based personalized therapies.
- MeSH
- buněčná diferenciace fyziologie MeSH
- kombinovaná terapie MeSH
- lidé MeSH
- makulární degenerace patofyziologie terapie MeSH
- nemoci retiny patofyziologie terapie MeSH
- pluripotentní kmenové buňky cytologie MeSH
- retinální pigmentový epitel cytologie MeSH
- rychlé screeningové testy MeSH
- transplantace kmenových buněk metody MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
INTRODUCTION: Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma. The Neuroblastoma New Drug Development Strategy (NDDS) has: 1) established a group with expertise in drug development; 2) prioritised targets and drugs according to tumour biology (target expression, dependency, pre-clinical data; potential combinations; biomarkers), identifying as priority targets ALK, MEK, CDK4/6, MDM2, MYCN (druggable by BET bromodomain, aurora kinase, mTORC1/2) BIRC5 and checkpoint kinase 1; 3) promoted clinical trials with target-prioritised drugs. Drugs showing activity can be rapidly transitioned via parallel randomised trials into front-line studies. Expert opinion: The Neuroblastoma NDDS is based on the premise that optimal drug development is reliant on knowledge of tumour biology and prioritisation. This approach will accelerate neuroblastoma drug development and other poor prognosis childhood malignancies.
- MeSH
- antitumorózní látky škodlivé účinky farmakologie MeSH
- časové faktory MeSH
- cílená molekulární terapie MeSH
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- neuroblastom farmakoterapie patologie MeSH
- preklinické hodnocení léčiv metody MeSH
- prognóza MeSH
- racionální návrh léčiv * MeSH
- randomizované kontrolované studie jako téma MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
While it is true that only a small fraction of fungal species are responsible for human mycoses, the increasing prevalence of fungal diseases has highlighted an urgent need to develop new antifungal drugs, especially for systemic administration. This contribution focuses on the similarities between agricultural fungicides and drugs. Inorganic, organometallic and organic compounds can be found amongst agricultural fungicides. Furthermore, fungicides are designed and developed in a similar fashion to drugs based on similar rules and guidelines, with fungicides also having to meet similar criteria of lead-likeness and/or drug-likeness. Modern approved specific-target fungicides are well-characterized entities with a proposed structure-activity relationships hypothesis and a defined mode of action. Extensive toxicological evaluation, including mammalian toxicology assays, is performed during the whole discovery and development process. Thus modern agrochemical research (design of modern agrochemicals) comes close to drug design, discovery and development. Therefore, modern specific-target fungicides represent excellent lead-like structures/models for novel drug design and development.
- MeSH
- agrochemikálie chemie farmakologie MeSH
- antifungální látky chemie farmakologie MeSH
- fungicidy průmyslové chemie farmakologie MeSH
- houby účinky léků MeSH
- lidé MeSH
- mykózy farmakoterapie MeSH
- objevování léků metody MeSH
- racionální návrh léčiv MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- úvodníky MeSH
INTRODUCTION: Determination of acetylcholinesterase and butyrylcholinesterase activity has become an important tool in drug design and discovery as well as in medicine and toxicology. There are a large number of compounds that are able to modulate cholinesterase activity. These compounds can be used for pharmacological management of various disorders (e.g., Alzheimer's disease, myasthenia Gravis). Moreover, organophosphate poisoning is frequently diagnosed via a cholinesterase activity assay. This broad variety of methods has been developed over the past decades for cholinesterase activity quantification. AREAS COVERED: This review provides a summary of the methods that are based on specific properties of cholinesterases and their interactions with native or artificial substrates. The authors also aim to provide an overview of different techniques used for the determination of quantitative cholinesterase activity. Specifically, the authors describe and discuss the manometric, potentiometric, titrimetric, photometric, fluorometric, and radioisotopic methods. EXPERT OPINION: Existing methods are able to cover most of the problems that arise during cholinesterase activity determination. Colorimetry according to Ellman has proved to be the most useful and versatile approach. It may be used in various protocols for the determination of pesticide or nerve agent exposure or for the development of new drugs. Its possible improvement lies in optimization of hemoglobin-rich samples. The progress of the most common methods (including Ellman) depends on miniaturization and modern physical platforms (e.g., optical fibers, chip methods, or nanotechnologies).
- MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- butyrylcholinesterasa analýza metabolismus MeSH
- chemické bojové látky farmakologie MeSH
- chemické techniky analytické metody MeSH
- cholinesterasové inhibitory farmakologie MeSH
- cholinesterasy analýza metabolismus MeSH
- lidé MeSH
- myasthenia gravis farmakoterapie metabolismus MeSH
- racionální návrh léčiv MeSH
- referenční hodnoty MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
