PCSK9 Antagonists: Clinical Efficacy and Main Trends in the Development of New Medicines

Scientific relevance. Cardiovascular diseases (CVD) are the leading cause of death worldwide. Dyslipidemia, as the pathophysiological basis of atherosclerosis, is the most important cause of CVD. Among the factors that modify this pathology, the World Health Organisation lists statins, which effectively reduce the cholesterol level. However, statin treatment compliance is not sufficient to achieve population-based lipid targets. This is a powerful stimulus for the creation of fundamentally new groups of lipid-lowering agents, in particular, antagonists of proprotein convertase subtilisin/kexin type 9 (PCSK9).Aim. The study aimed to review innovative approaches to developing a new generation of lipid-lowering agents, PCSK9 antagonists, and to evaluate the effectiveness, safety, and clinical potential of these medicines.Discussion. PCSK9 antagonists significantly increase the effectiveness of lipid-lowering therapy when combined with statins and are an effective monotherapy in patients with contraindications for statins. PCSK9 monoclonal antibodies, as well as inclisiran, have a favourable risk–benefit ratio. However, the high cost of commercially available PCSK9 antagonists limits their clinical use. A number of promising directions exist for developing new PCSK9 antagonists that have fundamentally different mechanisms of action, such as adnectins; genome editing with CRISPR/Cas9; combining small molecules with low molecular weight PCSK9 inhibitors; PCSK9 vaccines; and antisense oligonucleotides. Medicinal products from these groups are currently at various stages of preclinical and clinical development.Conclusions. Therefore, new lipid-lowering agents can be developed by synthesising high and low molecular weight PCSK9 ligands and by altering the genetic mechanisms of PCSK9 synthesis. The innovative medicines considered in this review are highly effective, and most have shown no signs of toxicity at the pre-authorisation stage

Dosis facit venenum

The article presents the history of the exploration of arrow poisons, used in Asia, Africa and South America. The active ingredients of these poisonswere widely used and continue to apply currently in traditional and official medicine. Methodology for development of new drugs based on arrow poisons has determined tendencies of drug design in modern pharmacology

Transformation of views on the teratogenic effects of antiepileptic drugs

This review presents information on pharmaceuticals that have the properties of inverse agonists. The article describes the features of the interaction of the ligand - receptor with constitutive conformational changes. Many of ligands, assumed to be neutral antagonists, behave as inverse agonists displaying negative efficacy in experimental systems. This suggests that their therapeutic actions may involve not only receptor blockade, but also the decrease of spontaneous receptor activity. Examples of inverse agonists that influence the processes of excitation of adrenergic, histaminergic, opioid and benzodiazepine receptors are presented. The existence of constitutive activity in vivo and its pathophysiological relevance are also discusse

Inductively Coupled Plasma-Atomic Emission Spectrometry for the Analysis of Heavy Metals and Arsenic in Tinctures

To ensure the safety of herbal medicinal products, particularly in liquid dosage forms, it is necessary to control environmental toxins to acceptable levels. However, there is no methodology for individual elemental impurities in tinctures. The aim of the study was to select sample preparation conditions for quantitative determination of heavy metals and arsenic in tinctures. Materials and methods: the study used tinctures of anomalous peony, motherwort and valerian sampled from pharmacies. Sample preparation involved microwave-assisted digestion of pre-concentrated aliquots. Quantitative determination of 16 elemental impurities (As, Cd, Co, Cr, Cu, Fe, Mn, Mo, Ni, Pb, Sb, Sr, Ti, V, Zn, Hg) was carried out using inductively coupled plasma–atomic emission spectrometry. Results: according to the study results, quantitative analysis of most elemental impurities requires sample concentration at the preparation step. Due to the method sensitivity, direct quantification of individual elements in a sample is possible only at levels of not less than 0.1 mg/kg. The optimal volume of a tincture for concentration is 25 ml, both in terms of time efficiency and recovery of toxic elements. Conclusions: the proposed procedure showed the possibility of quantification of 16 elemental impurities in the tinctures. The concentrations of heavy metals and arsenic in the tinctures of anomalous peony, motherwort and valerian did not exceed 0.722 mg/kg. Zinc and manganese were the most abundant elemental impurities in the studied samples

Rate Setting for Labour Costs Related to Pharmacovigilance System Inspections

The inspection of pharmacovigilance systems is regulated by the Good Pharmacovigilance Practices (GVP) and local laws and regulations. Inspections may be carried out by audit teams of competent authorities as part of regulatory activities or business agreements. So far, there have been no studies dealing with rate setting for competent authorities labour costs in connection with onsite or documentary inspections of pharmacovigilance systems.The aim of the study was to develop scientifically valid rate setting criteria for labour costs related to onsite or documentary inspections of pharmacovigilance systems.Materials and methods: the assessment of labour costs was carried out by surveying experts of two Eurasian Economic Union (EAEU) countries who have experience in preparing and conducting evaluation and inspection of pharmacovigilance systems. The calculation of the experts’ time costs was performed automatically using the CrocoTime software. The expected workload for experts in 2022 was estimated based on the reports over the last 5 years (2016–2020) containing information on the number of foreign marketing authorisations, and the number of medicines under development according to national registers of medicinal products of the EAEU member states.Results: the study calculated the average expert labour costs and estimated workload for the EAEU competent authorities in 2022. It was demonstrated that the average labour costs are comparable in EAEU member states, however, estimated amount of labour may change (both increase or decrease).Conclusions: further study of rate setting for labour costs related to pharmacovigilance documentary inspections and study of competent authorities staffing could be performed by a dedicated division, e.g. of the Eurasian Academy of Good Practices. A constructive discussion of approaches to the improvement of control over pharmacovigilance systems will increase availability of efficacious and safe medicines of assured quality for the population and help pharmaceutical companies and regulatory authorities manage financial and reputational risks

On the safety of acetaminophen

Acetaminophen is one of the most commonly used analgesics /anti pyretics. However, taking into account the existing risk of hepatotoxicity,regulatory bodies of a number of the countries made additional adjustments tothe recommendations on the use of this drug. In the article the possible reasonsfor recourse to acetaminophen are discusse

ON THE IMPACT OF DRUG NAMES AND LABELS ON THE RISK OF MEDICATION ERRORS

In this article authors analyze the influence of a label on drugpackage on the risk of medication errors and propose methods of their prevention.Analysis of the corresponding data published by regulators EMA and FDA hasprovided an opportunity to find examples of phonetic and graphic similaritieswith drugs identificatio

Nicotine dependence and neuropsychotic effects of varenicline

Varenicline is a partial agonist of nicotinic acetylcholine receptors for the therapy of nicotine addiction. The efficacy and safety of the use of varenicline in the treatment of nicotine dependence have been demonstrated in clinical trial EAGLES. These studies describe adverse reactions such us mental disorders: depression, suicidal thoughts, suicidal behavior. However, data on the increase in the incidence of these adverse reactions during longer treatment with varenicline was not obtained. In 2016, the FDA has been presented with information about the risk of development the following serious neuropsychiatric adverse reactions on the using of varenicline: depression, manic syndrome, psychosis, hallucinations, delusions, homicidal ideation, aggression, agitation, anxiety, panic, suicidal ideation, attempt of suicide. These adverse reactions were observed in patients with and without psychiatric disorders

THE EFFICACY AND SAFETY PROFILE OF ADVANCED THERAPY MEDICINAL PRODUCTS IN THE TREATMENT OF AGE-RELATED MACULAR DEGENERATION

Age-related macular degeneration is the main cause of loss of sight in the world. This review presents a current view on modern drugs used for the treatment of macular degeneration. A comparison effectiveness and safety profile of bevacizumab, ranibizumab, and pegaptanib aflibercept enables us to conclude that each of these compounds has its own advantages and disadvantages. Further study will develop rational schemes of their application

Nanoparticle albumin-bound paclitaxel – first step of nanotechnology into clinical practice

Paclitaxel is an effective antitumor agent used for treatment of breast cancer, lung, stomach and pancreas. However, its own adverse effects and the use of toxic Cremophor EL as the solvent limit the application range of this drug. Associated with the albumin-bound nanoparticle paclitaxel (paclitaxel SAN) specifically transported into tumor tissue. This leads to an increase in the antitumor effect, and it reduces the severity of side effects