Prospects for intranasal drug delivery systems with Ginkgo biloba in the treatment of cerebral circulatory disorders

Purpose: To analyze the range of currently available nasal medicines, and to study extant information on the use of Ginkgo biloba herbal complexes for the treatment of cerebral circulatory disorders of different etiologies. The study dwelt on the features and prospects of intranasal drug administration. Currently, intranasal administration is used primarily for the treatment of local symptoms. However, it has a much higher potential: the mucous membrane of the nasal cavity offers an opportunity for noninvasive treatment using systemic administration. Methods: The study involved the analysis of materials from information-retrieval systems, library databases, patent databases, and scientific information repositories such as e-Library. PubMed, Scopus, Google Scholar, as well as materials from the websites of manufacturers of herbal medicinal products and other herbal substances. Results: Herbal medicinal products have great potential in terms of intranasal administration. This is especially true of herbal medicines obtained through extraction of leaves of Ginkgo biloba, which have a broad spectrum of action, i.e., anti-aggregatory, venotonic, nootropic, anti-hypoxic, antioxidant, antiinflammatory, membrane-stabilizing, and capillary-protective effects. The range of Ginkgo biloba-based medicines calls for expansion, and this testifies to a good potential of these products in terms of further research and use. The analysis of literature and technical information showed the existence of a wide range of nasal medicines currently in use. However, only few drugs are used for the treatment of cerebrovascular diseases. Furthermore, there are no herbal medicines among these drugs, despite obvious advantages of herbal products such as ease of use, high bioavailability, and systemic action potential. Conclusion: The current status of research on nasal dosage forms of Ginkgo biloba herbal complexes warrants further development involving biopharmaceutical and pharmacological studies

Sequential localization of a complex electron fluid

Complex and correlated quantum systems with promise for new functionality often involve entwined electronic degrees of freedom. In such materials, highly unusual properties emerge and could be the result of electron localization. Here, a cubic heavy fermion metal governed by spins and orbitals is chosen as a model system for this physics. Its properties are found to originate from surprisingly simple low-energy behavior, with two distinct localization transitions driven by a single degree of freedom at a time. This result is unexpected, but we are able to understand it by advancing the notion of sequential destruction of an SU(4) spin-orbital-coupled Kondo entanglement. Our results implicate electron localization as a unified framework for strongly correlated materials and suggest ways to exploit multiple degrees of freedom for quantum engineering.Comment: 21 pages, 4 figures (preprint format

Inhibitors in the Management of Patients with Atherosclerotic Cardiovascular Diseases: Guidelines and Reimbursement Issues

Current guidelines for the management of patients with dyslipidemia define low-density lipoprotein cholesterol (LDL-C) as the primary target in addressing lipid-lowering therapy. The target level of LDL-C in real clinical practice is achieved in no more than a third of patients who have undergone a coronary event and receive high-intensity lipid-lowering therapy. Achieving the goals of lipid-lowering therapy in a significant proportion of patients with atherosclerotic cardiovascular diseases (ACVD) is impossible with the use of even high doses of statins, which requires its enhancement by other drugs. The article considers the place of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in the prevention of cardiovascular diseases in patients with ACVD in accordance with the latest Russian and international guidelines. A modern decision-making algorithm for the initiation of PCSK9 inhibitors therapy in patients with ACVD is presented. The authors provide a clear understanding about the patient populations that will benefit most from the taking of PCSK9 inhibitors. Particular attention is paid to Guidelines for the management of dyslipidemias developed by European Society of Cardiology and European Atherosclerosis Society in 2019. The issues of patients provision with PCSK9 inhibitors with reference to Russian conditions are described in details in accordance with the requirements for territorial programs of state guarantees. Further improvement in the provision of PCSK9 inhibitors to patients with indications for this therapy is necessary, considering the potential of these drugs in reducing cardiovascular morbidity and mortality in patients with ACVD

Comparative evaluation of recommendations for preclinical studies of transporter-mediated drug–drug interactions

Scientific relevance. Sound recommendations for preclinical studies of transporter- mediated pharmacokinetic interactions of medicinal products can help increase the likelihood of identifying potentially nephrotoxic and hepatotoxic medicinal products at the development and authorisation stages. However, overly strict requirements for the number of studies to be performed may lead to a significant increase in the cost of finished medicinal products.Aim. The aim was to compare regulatory documents on studying transporter-mediated drug–drug interactions (DDIs).Discussion. This review examines changes in regulatory requirements for studying DDIs in chronological order from the first guidelines that appeared in 1997. As exemplified in this article, the multiplicity of transporters and the lack of specific inhibitors pose significant challenges in assessing the role of a particular transporter in drug distribution and drug–drug interactions. This comparative review shows that extrapolating from in vitro transporter inhibition studies to in vivo pharmacokinetics can be misleading.Conclusions. A unified approach to studying transporter-mediated DDIs will increase the likelihood of identifying potentially toxic agents at the stage of new molecule screening. At the same time, it is advisable to limit the number of in vitro and in vivo transporter studies and recommend conducting these studies only for medicinal products with a narrow therapeutic index

Experimental Cell Line Models for Nephrotoxicity Screening

The aim of the study was to review literature data on cell models for experimental assessment of drug nephrotoxicity in vitro. Because of nephrotoxicity, 2% of new investigational medicinal products are discarded at the stage of preclinical in vivo studies in laboratory animals, and 19%—after phase 3 clinical trials. Prediction of toxicity in cell models could make drug development more cost-effective and help to reduce/avoid animal testing. At present, there are no official international guidelines for assessment of nephrotoxicity in vitro, but there is a lot of research underway. The main toxicity target in kidneys is renal proximal tubule epithelial cells, therefore the main research is focused on the development of renal proximal tubule epithelial cell lines with stable functional characteristics. Another important aspect in nephrotoxicity modeling is the choice of relevant test methods and end points which would reflect potential toxicity mechanisms. The paper reviews existing human renal proximal tubule epithelial cell lines and current test methods for assessing cytotoxicity. Promising areas for future development of cell models for nephrotoxicity assessment— are optimisation and standardisation of in vitro systems that would help to make preclinical predictions of drug nephrotoxicity in vivo