Insulin biosimilars in clinical practice

Diabetes mellitus (DM) is an important medical and social problem throughout the world due to its high prevalence. At the same time, the majority of patients have type 2 diabetes. The onset of the disease is gradual, with a prolonged asymptomatic preclinical stage. Therefore, it is necessary to conduct screening among patients at risk. Therapy for type 2 diabetes is carried out with oral hypoglycemic drugs. If it is impossible with their help to achieve adequate glycemic control, it is possible to add basal insulin to therapy, and if the own insulin secretion is depleted, an intensive insulin therapy regimen must be prescribed. Insulin preparations differ in the source of receipt, as well as in the duration of action: background, or basal (insulin of medium duration, long-term or ultra-long-acting) and prandial, or food (ultrashort and short insulin). Currently, along with original insulin preparations, their analogues, or biosimilars (biosimilars), appear on the pharmaceutical market. Biosimilar (biosimilar) is a biological product similar in quality, efficacy and safety parameters to a reference biological medicinal product in the same dosage form and having an identical route of administration. Biosimilars are used all over the world, and this applies not only to insulin preparations, but also to other biological preparations. Proof of bioequivalence is a long-term process that ensures comparability and the absence of clinically significant differences between the study and the reference drug, and includes preclinical and clinical studies. The task of studies of biosimilars of insulin is to confirm the comparability with a reference, previously well-studied biological product. The efficacy and safety of domestically produced biosimilars has been studied in a number of clinical studies, during which the bioequivalence of the drugs was shown. These drugs are of high quality and safe, and their pharmacological characteristics, immunogenicity and effectiveness do not differ from the original drugs.

In-silico activity prediction, structure-based drug design, molecular docking and pharmacokinetic studies of selected quinazoline derivatives for their antiproliferative activity against triple negative breast cancer (MDA-MB231) cell line

Background Cancer is a major health threat especially in unindustrialized nations. It surpasses coronary diseases and takes the number one killer position as a result of different global wide influences. Among many breast cancer substrates, triple-negative breast cancer (TNBC) is particularly devastating because it rapidly metastasize to other parts of the body, with a high risk of earlier recession and mortality. Result In this research work, four (4) quantitative structure activity relationship (QSAR) models were developed using a series of quinazoline derivatives with activities against triple negative breast cancer cell line (MDA-MB231), model 1 was selected due to its statistical fitness with the following validation parameters: R2 = 0.875, Q2 = 0.837, R2 − Q2 = 0.038, Next test set = 5, and R2ext = 0.655. Molecular docking studies was performed for the quinazoline series as well as the reference drug (Gefitinib) and the active site of the epidermal growth factor receptor (EGFR) (pdb id = 3ug2). Eight compounds (6, 10, 13, 16, 17, 18, 19 and 20) were observed to have better docking score docking scores relative to Gefitinib. Compound number nineteen from the training set (pred pIC50 = 5.67, Residual = − 0.04 and MolDock score = − 123.238) was identified as the best compound since it has the best Moldock score and was excellently predicted by the selected model with least residual value, Hence was adopted as template for the design of Ten (10) new novel compounds with better activities and better docking scores. The inhibitive activities of the designed compounds were predicted by the selected model and most of them possess an improved activity relative to the template compound (19). The designed compounds were also redocked on to active pocket of the EGFR receptor and it was observed that they displayed better docking scores compared to the Template and the reference drug (Gefitinib) utilized in the design. Furthermore, the designed compounds were subjected to ADMET and drug-likeness studies using SWISSADME and pkCSM online web tools and they were observed to be pharmacologically active, easily synthesized and do not violate the Lipinski’s rule of five. Conclusion Hence, the designed compounds can be employed as inhibitors of MDA-MB231 cell line after passing through in vivo and in vitro evaluation.

Azolo[1,5-a]pyrimidines and Their Condensed Analogs with Anticoagulant Activity

Hypercytokinemia, or cytokine storm, is one of the severe complications of viral and bacterial infections, involving the release of abnormal amounts of cytokines, resulting in a massive inflammatory response. Cytokine storm is associated with COVID-19 and sepsis high mortality rate by developing epithelial dysfunction and coagulopathy, leading to thromboembolism and multiple organ dysfunction syndrome. Anticoagulant therapy is an important tactic to prevent thrombosis in sepsis and COVID-19, but recent data show the incompatibility of modern direct oral anticoagulants and antiviral agents. It seems relevant to develop dual-action drugs with antiviral and anticoagulant properties. At the same time, it was shown that azolo[1,5-a]pyrimidines are heterocycles with a broad spectrum of antiviral activity. We have synthesized a new family of azolo[1,5-a]pyrimidines and their condensed polycyclic analogs by cyclocondensation reactions and direct CH-functionalization and studied their anticoagulant properties. Five compounds among 1,2,4-triazolo[1,5-a]pyrimidin-7-ones and 5-alkyl-1,3,4-thiadiazolo[3,2-a]purin-8-ones demonstrated higher anticoagulant activity than the reference drug, dabigatran etexilate. Antithrombin activity of most active compounds was confirmed using lipopolysaccharide (LPS)-treated blood to mimic the conditions of cytokine release syndrome. The studied compounds affected only the thrombin time value, reliably increasing it 6.5–15.2 times as compared to LPS-treated blood.

Anti-apoptotic effects of 2-pyrrolidone derivatives in cerebral ischemia

INTRODUCTION: Uncontrolled course of apoptosis reactions underlies a wide range of pathological processes, including ischemic events. AIM: To evaluate the anti-apoptotic properties of some racetams in experimental brain ischemia in rats. MATERIALS AND METHODS: Cerebral ischemia was modeled in Wistar rats by irreversible occlusion of the middle cerebral artery. The test-compounds and the reference drug piracetam were administered per os at a dose of 250 mg/kg. After 72 hours of the ischemic period, the activity of apoptotic systems in the brain tissue was evaluated by determining the concentration of the apoptotic-inducing factor (AIF), caspase-3, ionized calcium, the latent opening time of the mitochondrial transition permeability pore and the zone of brain necrosis. RESULTS: The study showed that the use of the studied compounds contributed to a decrease in the intensity of reactions, both caspase-dependent and caspase-independent apoptosis, which was reflected in a decrease in the concentration of AIF and caspase-3 by 32.4% (p < 0.05); 34.6% (p < 0.05); 31.1% (p < 0.05), and 41.9% (p < 0.05); 39.1% (p < 0.05); 34.5% (p < 0.05) when PirPr, PirAc and PirBut were administered, respectively. Also, the use of the studied substances led to an increase in the latent period of opening the mitochondrial transition permeability pore, a decrease in the concentration of intracellular calcium and the zone of brain necrosis. At the same time, the pharmacological effect of the administration of the compound PirAc exceeded the effect of piracetam and other test substances. CONCLUSIONS: Based on the results obtained, it can be assumed that the studied racetams have neuroprotective action, realized through suppression of the reactions of apoptosis.

The Activities of the Central Nervous System Following Ethyl Acetate Extract of Mucuna pruriens Seed Administration in Male BALB/c Mice

A number of reports showed the beneficial psychotropic effects of many of the Nigerian medicinal plants, but few scientific studies have been carried out as empirical evidence. This study investigated the possible neurobehavioural effects of ethyl acetate extract of Mucuna pruriens (MP) seed in male BALB/c mice. Male BALB/c mice (2½-3 months old) were grouped into 5 (n=6), treated with normal saline (0.1 mL), n-propanol extract of MP (200, 100, 50 mg/kg) or reference drug haloperidol (HP) or diazepam (DZP); thereafter, subjected to diverse behavioural models to evaluate the central nervous system (CNS) effects of the extract. A bolus of MP (200, 100, and 50 mg/kg) decreased the rectal temperature, exploratory activities (locomotion, rearing and grooming), anxiety-like responses (% open-arms time, open-arm entries, and the total number of enclosed arms times). Additionally, a one-shot of intraperitoneal administration of MP decimated the total score of apomorphine-induced stereotyped behaviours. Latency to hexobarbitone-induced sleep increased significantly in the 200 mg/kg MP, unchanged in the 100 mg/kg MP, and decreased in the 50 mg/kg MP treated groups. There was a marked decrease in the markers of convulsion (tonic flexion, extension, clonic convulsion, stupor, and recovery time) following MP treatment, especially the higher doses (200 mg/kg and 100 mg/kg). In conclusion, the CNS effects of systemic administration of MP seed are not unrelated to its hypothermic, hypnotic, anxiolytic, and anticonvulsant effects.

Not Drug-Like, but Like Drugs: Cnidaria Natural Products

Phylum Cnidaria has been an excellent source of natural products, with thousands of metabolites identified. Many of these have not been screened in bioassays. The aim of this study was to explore the potential of 5600 Cnidaria natural products (after excluding those known to derive from microbial symbionts), using a systematic approach based on chemical space, drug-likeness, predicted toxicity, and virtual screens. Previous drug-likeness measures: the rule-of-five, quantitative estimate of drug-likeness (QED), and relative drug likelihoods (RDL) are based on a relatively small number of molecular properties. We augmented this approach using reference drug and toxin data sets defined for 51 predicted molecular properties. Cnidaria natural products overlap with drugs and toxins in this chemical space, although a multivariate test suggests that there are some differences between the groups. In terms of the established drug-likeness measures, Cnidaria natural products have generally lower QED and RDL scores than drugs, with a higher prevalence of metabolites that exceed at least one rule-of-five threshold. An index of drug-likeness that includes predicted toxicity (ADMET-score), however, found that Cnidaria natural products were more favourable than drugs. A measure of the distance of individual Cnidaria natural products to the centre of the drug distribution in multivariate chemical space was related to RDL, ADMET-score, and the number of rule-of-five exceptions. This multivariate similarity measure was negatively correlated with the QED score for the same metabolite, suggesting that the different approaches capture different aspects of the drug-likeness of individual metabolites. The contrasting of different drug similarity measures can help summarise the range of drug potential in the Cnidaria natural product data set. The most favourable metabolites were around 210–265 Da, quite often sesquiterpenes, with a moderate degree of complexity. Virtual screening against cancer-relevant targets found wide evidence of affinities, with Glide scores <−7 in 19% of the Cnidaria natural products.

The main stages of pharmaceutical development of emulgel “Probioskin”

The aim. To conduct research on the pharmaceutical development of a complex preparation with probiotic “Probioskin” in the form of an emulgel for the treatment of infectious and inflammatory dermatological diseases. Methods. Uniformity was determined by visual inspection of the test samples using an XSP-128 ULAB biological microscope. The study of the rheological properties of the samples was carried out using a Rheolab QC rheovisosimeter (Anton Paar, Austria) using a system of coaxial cylinders C-CC27 / SS. Microbiological studies and biotesting on a biological model of ciliates were carried out in aseptic conditions of a laminar box (biological safety cabinet AC2-4E1 “Esco”, Indonesia) of the Department of Biotechnology of the National University of Pharmacy (completely). Pharmacological studies (determination of the parameters of acute toxicity and anti-inflammatory properties on the model of acute exudative inflammation of the foot in rats caused by zymosan and carrageenan) were carried out on the basis of the Central Research Laboratory of the NUPh. Results. On the basis of the complex of the carried out studies, the composition of the complex preparation for skin use “Probioskin” was substantiated. The analysis of the microbiological purity of the developed agent during the proposed shelf life of 12 months showed that the drug meets the requirements of the State Pharmacopoeia Monograph for cutaneous application in terms of the level of microbial contamination by foreign microflora. The complex of pharmacological studies carried out indicates that the drug “Probioskin” can be attributed to group 6 of class and classified as a “relatively harmless” agent. The study of the anti-inflammatory effect of the drug indicates that the drug exhibits moderate anti-inflammatory properties. Under the condition of zymosan inflammation, which is associated with the activation of leukotrienes as inflammatory mediators, the average antiexudative activity of the drug is 33 %. The drug has a moderate antiexudative effect under the condition of carrageenan edema, which is evidence of its effect on exudation processes mediated by prostaglandins. The mean AEA of the study drug was 24 %. Conclusions. For the development of a soft preparation for skin use for the treatment of infectious and inflammatory dermatological diseases, the following components have been selected: active – lactobacilli, dexpanthenol, lactic acid; auxiliary - propylene glycol, peach oil, polysorbate-80, aristophlex, tocopherol, the concentration of which was substantiated on the basis of a complex of organoleptic, physicochemical, pharmacological, microbiological and biological studies. It has been experimentally established that the “Probioskin” emulgel meets the requirements of the SPhU in terms of the level of microbial contamination by extraneous microflora. Pharmacological studies allow the drug to be classified as “relatively harmless” with anti-inflammatory properties at a level not lower than the reference drug

Synthesis and antibacterial activity of 3-arylaminomethyl-1-(2-oxo-2-arylethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a] azepin-1-ium bromides and aryl-(4-R1-phenyl-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-1-ylmethyl)-amines

The aim of this work is to develop methods of synthesis of 3-arylaminomethyl-1-(2-oxo-2-arylethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-1-ium bromides and aryl-(4-R1-phenyl-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-1-ylmethyl)-amines and to study their antimicrobial activity against strains of gram-positive and gram-negative bacteria as well as yeast fungi. Materials and methods. 1Н NMR spectra were recorded on Bruker 400 spectrometer operating at frequency of 400 MHz. Antimicrobial activity of the compounds synthesized was evaluated by their minimum inhibitory concentration (MIC) values. Results and discussion. The interaction of 3-arylaminomethyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepines with substituted phenacyl bromides produced novel 3-arylaminomethyl-1-(2-oxo-2-arylethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-1-ium bromides. The latter when refluxed in 10 % solution of NaOH gave aryl-(4-R1-phenyl-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulen-1-ylmethyl)-amines. The study of antimicrobial activity of the compounds obtained allowed to find derivatives which are active against С. albicans and S. aureus strains. Among the compounds tested 3-[(41-bromophenylamino)-methyl]-1-[2-(4-methoxyphenyl)-2-oxoethyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-1-ium bromide 5cd appeared to be more active than the reference drug Cefixime and displayed close antimicrobial activity as the antibiotic Linezolid. Conclusions. It was found out that derivatives of 3-arylaminomethyl-1-(2-oxo-2-arylethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-1-ium bromides display broad spectrum of antimicrobial activity and are able to inhibit growth of both bacteria and fungi. S. aureus and C. albicans turned out to be the most sensitive strains to the compounds tested, MIC was in the range of 6.2-25.0 mg/mL. Gram-negative strains of microorganisms were less sensitive to the compounds evaluated and 5fа was the most active derivative displaying antimicrobial activity at the concentration of 50.0 mg/mL. Antimicrobial activity of triazoloazepinium bromide derivatives was similar to that one of Linezolid and Fluconazole reference drugs and more pronounced than the activity of Cefixime. Hence, the data gathered evidence the feasibility of further study of the antimicrobial properties of the most active compounds in in vivo experiments aiming at assessment of the prospects for the creation of new effective and safe antimicrobial drugs based on them

Antipyretic activity of Calotropis gigantea, Vernonia cinerea,and Cissampelos pareiraextractsonlipopolysaccharide-induced pyrexia in rabbits

This study aims to evaluate the antipyretic activity of Calotropis gigantea (CG), Vernonia cinerea (VC), and Cissampelos pareira (CP)extracts. Rabbits were received an intravenous lipopolysaccharide (LPS) after being orally administered with the plant extracts or paracetamol, a reference drug. The treatment of CG and VC ethanolic extract (125 and 250 mg/kg) and paracetamol (150 mg/kg) significantly reduced LPS-induced pyrexia. Moreover, ethyl acetate fraction (50 mg/kg) of CG showed a more significant effect in lowering the hyperthermia than dichloromethane, n-butanol fraction, or water residue. In conclusion, this study demonstrated that CG and VC ethanolic extract possess antipyretic activity. Besides, the components in the ethyl acetate fraction of CG play an important role in the antipyretic property of this herb

Pharmacological Effect of Verapamil on Brain Oxidative Parameters and Mania-Like Behaviour in Paradoxical Sleep Deprived Mice

Although the implication of calcium signalling in the aetiology of anxiety remains elusive, drugs modulating calcium (like calcium channel blockers) have been discovered to be some worth beneficial as treatment option for anxiety related disorders. This study was therefore undertaken to assess probable ameliorative potential of verapamil against manic-like (stereotype behaviour) and anxiety-like symptoms in mice exposed to sleep deprivation. Mice were allotted into five treatment groups (n=5): group 1 and 2 received 10 mL/kg distilled water, groups 3 and 4 verapamil (25 and 50 mg/kg) while group 5 received astaxanthin (50 mg/kg) which served as the reference drug. Treatment was for 7 days and animals were sleep-deprived on the final 72 hours. Various behavioural tests to determine degree of stereotypical behaviour and locomotor activity were carried out. Anxiety test was done via the aid of a light/dark box and plus maze while stereotype behaviour was assess utilizing an open field box. Oxidative stress parameters; malondialdehyde and glutathione were assessed. Histopathological perturbations in the caudate putamen were also recorded. Data were subjected to ANOVA at α0.05. The results obtained suggest that verapamil significantly suppressed stereotyped behaviour and reduced the incidence of manic-like behaviour which was induced by paradoxical sleep deprivation. Verapamil also significantly restored antioxidant levels and protected against loss of caudate neurons. In conclusion, verapamil ameliorates manic-like symptoms and anxiety in mice derived of sleep, while protecting brain neurons against oxidative stress damage induced by sleep deprivation.