New Active Drugs Research Articles

Experimental model of convulsive syndrome based on phenylcarbamate

Introduction. Carbamates are widely used in the pharmaceutical industry, agriculture, and household chemicals. Being reversible cholinesterase inhibitors, carbamates can cause the development of generalized convulsive syndrome. Untimely treatment contributes to the emergence of persistent neurological disorders. In order to develop and adequately assess in preclinical studies the specific activity of new drugs for the relief of convulsive syndrome in acute intoxication with this group of substances, an easily reproducible experimental model of convulsive carbamate-induced syndrome is required.Objective. Development of an experimental model of generalized convulsive syndrome in rats using phenylcarbamate as a model toxicant for testing in preclinical studies of therapies for poisoning with cholinesterase inhibitors.Materials and methods. The study was performed using mongrel sexually mature male rats, aged 3 months (80 animals), divided into 4 groups (3 experimental and 1 control). At the first stage, the parameters of convulsive syndrome caused by model toxicants were compared: phenylcarbamate 1 mg/kg bw, corazol 65 mg/kg bw, and thiosemicarbazide 8 mg/kg bw. The following parameters were studied: motor activity (open field test), neuromotor functions (grip strength test), cognitive functions (conditioned avoidance responses, CAR), and cardiovascular indicators (ECG and cardiac rhythmogram assessment). The severity of the convulsive syndrome was identified by Racine stages. Additionally, the structure of brain tissues was evaluated by histological methods. second stage, biochemical parameters were studied in three experimental (with toxicants) and control groups. Some biochemical parameters were studied in the blood serum, assessing the function of the liver, kidneys, prooxidant and antioxidant systems. At the third stage, the activity of cholinesterase in the blood and brain was studied in 30 control and 30 experimental rats after phenylcarbamate exposure. Statistical processing of the results was carried out using Statistica v.10.Results. When modeling convulsive syndrome in rats, phenylcarbamate is comparable to corazol in terms of the onset of the latency period, duration and intensity of seizures. When implementing the model, a significant decrease in heart rate was recorded 48 h after administration. The CAR test found that the introduced substance increases the time of the first entry into the dark compartment before training. Significant changes in markers of liver function (ALT, bilirubin, cholesterol, triglycerides), lipid peroxidation and the antioxidant system (MDA, GPx) confirm the complexity of mechanisms responsible for the development of seizures and neurological disorders. The results of histological examination of brain tissues indicate that phenylcarbamate induces pronounced disorders of the brain structure in an experiment on rats.Conclusions. The developed experimental model of phenylcarbamate-based convulsive syndrome in rats is easy to reproduce, thus being recommended for preclinical studies of new drugs for the relief of convulsive syndrome in poisoning with cholinesterase inhibitors.

Extrapolation is not the same as interpolation

We propose a new machine learning formulation designed specifically for extrapolation. The textbook way to apply machine learning to drug design is to learn a univariate function that when a drug (structure) is input, the function outputs a real number (the activity): f(drug) →\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\rightarrow$$\\end{document} activity. However, experience in real-world drug design suggests that this formulation of the drug design problem is not quite correct. Specifically, what one is really interested in is extrapolation: predicting the activity of new drugs with higher activity than any existing ones. Our new formulation for extrapolation is based on learning a bivariate function that predicts the difference in activities of two drugs F(drug1, drug2) →\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\rightarrow$$\\end{document} difference in activity, followed by the use of ranking algorithms. This formulation is general and agnostic, suitable for finding samples with target values beyond the target value range of the training set. We applied the formulation to work with support vector machines , random forests , and Gradient Boosting Machines . We compared the formulation with standard regression on thousands of drug design datasets, gene expression datasets and material property datasets. The test set extrapolation metric was the identification of examples with greater values than the training set, and top-performing examples (within the top 10% of the whole dataset). On this metric our pairwise formulation vastly outperformed standard regression. Its proposed variations also showed a consistent outperformance. Its application in the stock selection problem further confirmed the advantage of this pairwise formulation.

AMEERA-4: a randomized, preoperative window-of-opportunity study of amcenestrant versus letrozole in early breast cancer

BackgroundWindow-of-opportunity (WOO) studies provide insights into the clinical activity of new drugs in breast cancer.MethodsAMEERA-4 (NCT04191382) was a WOO study undertaken to compare the pharmacodynamic effects of amcenestrant, a selective estrogen receptor degrader, with those of letrozole in postmenopausal women with newly diagnosed, operable estrogen receptor–positive, human epidermal growth factor receptor 2−negative (ER+/HER2−) breast cancer. Women were randomized (1:1:1) to receive amcenestrant 400 mg, amcenestrant 200 mg, or letrozole 2.5 mg once daily for 14 days before breast surgery. The primary endpoint was change in Ki67 between baseline and Day 15 (i.e., day of surgery).ResultsEnrollment was stopped early because of slow recruitment, in the context of the COVID-19 pandemic. The modified intent-to-treat population consisted of 95 study participants with baseline and post-treatment Ki67 values, whereas the safety population included 104 participants who had received at least one dose of study medication. Relative change from baseline in Ki67 was − 75.9% (95% confidence interval [CI] − 81.9 to − 67.9) for amcenestrant 400 mg, − 68.2% (− 75.7 to − 58.4) for amcenestrant 200 mg, and − 77.7% (− 83.4 to − 70.0) for letrozole (geometric least-squares mean [LSM] estimates). Absolute change in ER H-score from baseline (LSM estimate) was − 176.7 in the amcenestrant 400 mg arm, − 202.9 in the amcenestrant 200 mg arm, and − 32.5 in the letrozole arm. There were no Grade ≥ 3 treatment-related adverse events.ConclusionsBoth amcenestrant and letrozole demonstrated antiproliferative activity in postmenopausal women with previously untreated, operable ER+/HER2− breast cancer and had good overall tolerability.Trial RegistrationClinicalTrials.gov, NCT04191382 https://clinicaltrials.gov/ct2/show/NCT04191382. Registered 9 December 2019.

A Perspective into "TEL"-Tenofovir, Emtricitabine and Lamivudine Antileprotic Activities by Drug Repurposing and Exploring the Possibility of Combination Chemotherapy with Drug Rescued Molecules for a Leprosy Free Mankind.

Since leprosy bacilli cannot grow in vitro, testing for antimicrobial resistance against Mycobacterium leprae or assessing the anti-leprosy activity of new drugs remains hard. Furthermore, developing a new leprosy drug through the traditional drug development process is not economically captivating for pharmaceutical companies. As a result, repurposing existing drugs/approved medications or their derivatives to test their anti-leprotic potency is a promising alternative. It is an accelerated method to uncover different medicinal and therapeutic properties in approved drug molecules. The study aims to explore the binding potential of anti-viral drugs such as Tenofovir, Emtricitabine, and Lamivudine (TEL) against Mycobacterium leprae using molecular docking. The current study evaluated and confirmed the possibility of repurposing antiviral drugs such as TEL (Tenofovir, Emtricitabine, and Lamivudine) by transferring the graphical window of the BIOVIA DS2017 with the Crystal Structure of a phosphoglycerate mutase gpm1 from Mycobacterium leprae (PDB ID: 4EO9). Utilizing the smart minimizer algorithm, the protein's energy was reduced in order to achieve a stable local minima conformation. The protein and molecule energy minimization protocol generated stable configuration energy molecules. The protein 4EO9 energy was reduced from 14264.5 kcal/mol to -17588.1 kcal/mol. The CHARMm algorithm-based CDOCKER run docked all three molecules (TEL) inside the 4EO9 protein binding pocket (Mycobacterium leprae). The interaction analysis revealed that tenofovir had a better binding molecule with a score of - 37.7297 kcal/mol than the other molecules.

Molecular Docking and Dynamics Simulation Revealed the Potential Inhibitory Activity of New Drugs against Human Topoisomerase I Receptor

Human Topoisomerase I (hTop1p) is a ubiquitous enzyme that relaxes supercoiled DNA through a conserved mechanism involving transient breakage, rotation, and binding. Htop1p is the molecular target of the chemotherapeutic drug camptothecin (CPT). It causes the hTop1p-DNA complex to slow down the binding process and clash with the replicative machinery during the S phase of the cell cycle, forcing cells to activate the apoptotic response. This gives hTop1p a central role in cancer therapy. Recently, two artesunic acid derivatives (compounds c6 and c7) have been proposed as promising inhibitors of hTop1p with possible antitumor activity. We used several computational approaches to obtain in silico confirmations of the experimental data and to form a comprehensive dynamic description of the ligand-receptor system. We performed molecular docking analyses to verify the ability of the two new derivatives to access the enzyme-DNA interface, and a classical molecular dynamics simulation was performed to assess the capacity of the two compounds to maintain a stable binding pose over time. Finally, we calculated the noncovalent interactions between the two new derivatives and the hTop1p receptor in order to propose a possible inhibitory mechanism like that adopted by CPT.

Association between Post-marketing Safety-related Regulatory Actions and Characteristics of New Drugs Approved in Japan between 2005 and 2016

The pharmacovigilance activities of new drugs are usually planned and conducted based on the clinical safety information obtained at approval. Revealing pre- and post-marketing drug characteristics associated with post-marketing safety-related regulatory actions (PSRAs) would help facilitate pharmacovigilance activities as these activities are not sufficient for early detection of safety signals that require warning. Therefore, we investigated the association between PSRAs and characteristics of new drugs in Japan. New active substances approved in Japan between fiscal year 2005 and 2015 were analyzed. PSRAs were defined as "revisions of precautions in drug package insert" instructed by the regulatory authority within the first 5 years after the initial approval (up to 2021). Drug characteristics included therapeutic area, number of Japanese subjects in clinical trials, dose-response study in Japanese subjects, approval lag between Japan and the United States or Europe (US/EU), novelty of the drug, estimated number of target patients, and number of supplemental approvals. Negative binomial regression and path analyses were performed to investigate the association between PSRAs and drug characteristics. PSRAs were more common among antineoplastic agents and drugs with a larger estimated number of target patients and were less common among drugs with a longer approval lag between Japan and the US/EU. Supplemental approval was more common among antineoplastic agents, and there were fewer target patients for novel drugs. For new drugs with the characteristics identified in the present study, it is important to proactively collect post-market safety information by intensifying patient monitoring.

DEVELOPMENT OF A TECHNIQUE FOR MODELING A DEPRESSIVE STATE IN RAT BY STEREOTAXIС INJECTION OF LIPOPOLYSACCHARIDE INTO THE HIPPOCAMPUS

Introduction: Currently, various mechanisms of the development of depression are known. At the beginning of the 21st century, a new era began in the study of the pathogenesis of this disease. It has been shown that the development of a depressive state is closely associated with neuroinflammation. As a result, it became necessary to develop methods for modeling depression, which will cause inflammation in a strictly defined area of the brain. Purpose of the work: Creation of a model of the depressive state in rats by stereotaxic injection of LPS into the hippocampus. Materials and Methods: Ten female Wistar rats were randomly divided into a control group (n = 3), an LPS-treated group (n = 4), and a sham-operated group (n = 3). LPS was administered at a dose of 30 μg / animal in a volume of 3 μL over 30 min, according to the following stereotaxic coordinates: AP: -3, ML: 2, DV: 3. Depression was assessed in psychopharmacological tests: hole-board test, open field, elevated plus maze, dark-light chamber, Porsolt forced swimming test, sucrose test. The formation of conditioned reflexes of passive avoidance was studied. To assess the localization of the injection, an MRI scan was performed on the 7th day. The result of LPS injection was analyzed on histological preparations. Results: During testing of animals in the setting of a dark-light chamber and an elevated plus maze, it was found that the control and sham-operated groups did not have statistically significant differences. At the same time, the time spent by the rats in the light compartments increased in the experimental group. In the Porsolt forced swimming test, there are statistically significant differences in the time of immobilization of animals. Also, in the rats of the experimental group, the latent period of the onset of reversible actions increased. The study of the formation of a conditioned passive avoidance reflex can be considered not indicative, since two rats from the experimental group and one rat from the group of sham-operated animals did not enter the dark compartment of the installation and did not receive training. In the test for anhedonia, the rats of the experimental group showed a decrease in the consumption of sucrose as compared with the animals of the comparison groups. On histological preparations of the brain at the injection site, the formation of a glial-macrophage "shaft" (hematoxylin-eosin staining) is observed. When analyzing the MRI images, it was proved that the injection was made precisely in the hippocampus of rats. Conclusion: Based on the results of the work, it can be concluded that this method of modeling depression is applicable in fundamental research, since the introduction of lipopolysaccharide into the hippocampus causes neuroinflammation in rats, and as a result, a depression state, and can be used to study the antidepressant activity of new drugs. This work was carried out with the financial support of the Russian Science Foundation grant No. 21-73-20250.

The Use of Fourier Transform Infrared Microspectroscopy for the Determination of Biochemical Anomalies of the Hippocampal Formation Characteristic for the Kindling Model of Seizures.

The animal models of seizures and/or epilepsy are widely used to identify the pathomechanisms of the disease as well as to look for and test the new antiseizure therapies. The understanding of the mechanisms of action of new drugs and evaluation of their safety in animals require previous knowledge concerning the biomolecular anomalies characteristic for the particular model. Among different models of seizures, one of the most widely used is the kindling model that was also applied in our study. To examine the influence of multiple transauricular electroshocks on the biochemical composition of rat hippocampal formation, Fourier transform infrared (FT-IR) microspectrosopy was utilized. The chemical mapping of the main absorption bands and their ratios allowed us to detect significant anomalies in both the distribution and structure of main biomolecules for electrically stimulated rats. They included an increased relative content of proteins with β-sheet conformation (an increased ratio of the absorbance at the wavenumbers of 1635 and 1658 cm–1), a decreased level of cholesterol and/or its esters and compounds containing phosphate groups (a diminished intensity of the massif of 1360–1480 cm–1 and the band at 1240 cm–1), as well as increased accumulation of carbohydrates and the compounds containing carbonyl groups (increased intensity of the bands at 1080 and 1740 cm–1, respectively). The observed biomolecular abnormalities seem to be the consequence of lipid peroxidation promoted by reactive oxygen species as well as the mobilization of glucose that resulted from the increased demand to energy during postelectroshock seizures.

Evaluation of Pirfenidone and Nintedanib in a Human Lung Model of Fibrogenesis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with a poor prognosis and increasing incidence. Pirfenidone and nintedanib are the only approved treatments for IPF but have limited efficacy and their mechanisms of action are poorly understood. Here we have examined the effects of pirfenidone and nintedanib in a human model of lung fibrogenesis, and compared these with the putative anti-fibrotic compounds Lipoxin A4 (LXA4), and senicapoc, a KCa3.1 ion channel blocker. Methods: Early fibrosis was induced in cultured human lung parenchyma using TGFβ1 for 7 days, ± pirfenidone, nintedanib, or LXA4. Pro-fibrotic responses were examined by RT-PCR, immunohistochemistry and soluble collagen secretion. Results: Thirty six out of eighty four IPF and fibrosis-associated genes tested were significantly upregulated by TGFβ1 in human lung parenchyma with a ≥0.5 log2FC (n = 32). Nintedanib (n = 13) reduced the mRNA expression of 14 fibrosis-associated genes including MMPs (MMP1,−4,−13,−14), integrin α2, CXCR4 and PDGFB, but upregulated α-smooth muscle actin (αSMA). Pirfenidone only reduced mRNA expression for MMP3 and −13. Senicapoc (n = 11) previously attenuated the expression of 28 fibrosis-associated genes, including αSMA, several growth factors, collagen type III, and αV/β6 integrins. Pirfenidone and nintedanib significantly inhibited TGFβ1-induced fibroblast proliferation within the tissue, but unlike senicapoc, neither pirfenidone nor nintedanib prevented increases in tissue αSMA expression. LXA4 was ineffective. Conclusions: Pirfenidone and nintedanib demonstrate modest anti-fibrotic effects and provide a benchmark for anti-fibrotic activity of new drugs in human lung tissue. Based on these data, we predict that the KCa3.1 blocker senicapoc will show greater benefit than either of these licensed drugs in IPF.

Effect of wound healing in gels containing tinctures of Alnus glutinosa (L) leaves

BackgroundAlnus glutinosa (L) is a widespread medicinal plant on the territory of the Republic of Belarus. Alnus glutinosa (L) leaves tincture has an anti-inflammatory effect on the diseases of the throat, intestines, in rheumatism and gout. Water extracts from collective fruit, leaves and bark are used for gargling in stomatitis and gum bleeding. The purpose of the research was to establish wound healing activity of gels based on alcohol extracts from Alnus glutinosa (L) leaves on the model of a surface full flap skin wound on laboratory animals.MethodsRegenerating action of new drugs (gels) based on tinctures of Alnus glutinosa (L) leaves was studied on a model of planar full-layer skin wound in laboratory animals. Wounds were treated daily with gels applied to complete healing. The wound area was measured planometrically to assess the effectiveness of drugs and then the percentage of area reduction was calculated. Regenerative action of the gels developed was compared to widely used in medical practice 4% Dexpanthenol Gel and Reparef-2 Ointment. 15 g of Reparef-2 Ointment contains 1200 mg of bien and 75 mg of dioxidine.ResultsWound healing activity of gels containing tinctures of Alnus glutinosa (L) leaves based on 30% and 60% alcohol as to the rate of healing and the area of wounds epithelialization has been proved. Wound area treated with the gel based on Alnus glutinosa (L) extract containing 60% alcohol on day 13 of the experiment decreased by 95.59% ± 0.9% (p ≤ 0.05); based on the tincture containing 30% alcohol - by 92.93% ± 1.11%. Medicinal preparations with proved wound healing activity were compared: Reparef-2 Ointment (reduction percentage of wound area on day 13 of the experiment made 92.24% ± 2.21%) and Dexpanthenol Gel (reduction percentage of wound area on day 13 of the experiment made 83.09% ± 3.41%).Compared with the control group the gel based on 60% tincture of Alnus glutinosa (L) leaves showed a decrease in the epithelialization period by 29.5%; based on 30% tincture - by 24.6%; Reparef-2 Ointment - by 23.6% and Dexpanthenol Gel - by 13.8%.ConclusionsThe results of this study showed that the developed gels based on Alnus glutinosa (L) have a regenerating action and can be used to treat wound processes taking into account previously established antimicrobial activity.

Determination of modification degree of polysialylated therapeutic proteins using 1H-NMR spectroscopy

Water soluble polymers and their derivatives bound to proteins can dramatically favor the biological activity of new drugs and vaccines. Quantification of the modification degree of the protein is crucial during the development and licensing phase and later in order to monitor the industrial production process and to match product specification. In this work, we describe an innovative way to measure directly the modification degree of polysialylated proteins using proton NMR (Nuclear Magnetic Resonance) spectroscopy. Following a calibration step, the modification degree can be easily deduced by the integration ratio of a separate signal from the polymer and selected signals from the protein. In fact, the upfield-shifted signals of methyl groups from Valine, Leucine and Isoleucine can be used as an internal calibration reference for the integration. In this paper recombinant factor VIII (rFVIII) and recombinant factor IX (rFIX) proteins modified by polysialic acid (PSA) are used to illustrate the accuracy, reproducibility and ease of the method that may replace or complement wet-chemistry approaches.

FATTY LIVER DYSTROPHY MODELING BY USING STRONTIUM SULFATE

In recent years, the problem of the increasing number of the hepatobiliary system disorders has acquired particular importance for veterinary medicine. These disorders have negative impact on normal physiology of an animal's body. It is important to continue the search for effective hepatoprotective agents. To test the pharmaceutical activity of new drugs, methods of modeling hepatopathies are constantly being improved. The study suggested a model of fatty liver dystrophy using strontium sulfate.

COVID-19: The question of genetic diversity and therapeutic intervention approaches.

Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2), is the largest pandemic in modern history with very high infection rates and considerable mortality. The disease, which emerged in China’s Wuhan province, had its first reported case on December 29, 2019, and spread rapidly worldwide. On March 11, 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a pandemic and global health emergency. Since the outbreak, efforts to develop COVID-19 vaccines, engineer new drugs, and evaluate existing ones for drug repurposing have been intensively undertaken to find ways to control this pandemic. COVID-19 therapeutic strategies aim to impair molecular pathways involved in the virus entrance and replication or interfere in the patients’ overreaction and immunopathology. Moreover, nanotechnology could be an approach to boost the activity of new drugs. Several COVID-19 vaccine candidates have received emergency-use or full authorization in one or more countries, and others are being developed and tested. This review assesses the different strategies currently proposed to control COVID-19 and the issues or limitations imposed on some approaches by the human and viral genetic variability.

ATP citrate lyase inhibitor Bempedoic Acid alleviate long term HFD induced NASH through improvement in glycemic control, reduction of hepatic triglycerides & total cholesterol, modulation of inflammatory & fibrotic genes and improvement in NAS score

Non-alcoholic fatty liver disease (NAFLD) and Non-alcoholic steatohepatitis (NASH) are chronic liver disorders, the prevalence of which is increasing worldwide. Long term High Fat Diet (HFD) induced NASH animal models closely mimic the characteristics of human NASH and hence used by investigators as a model system for studying the mechanism of action of new drugs. Bempedoic acid (ETC-1002), a ATP citrate lyase (ACLY) inhibitor that lowers the LDL cholesterol was recently approved by US FDA for the treatment of heterozygous familial hypercholesterolemia (HeFH) and established atherosclerotic cardiovascular disease (ASCVD). ACLY is one of the genes modulated in NASH patients and hence we studied the effect of ACLY inhibitor Bempedoic acid in long term HFD induced NASH animal model to understand the pharmacological benefits and the associated mechanism of action of this newly approved drug in NASH. Mice fed with 60% Kcal High Fat Diet for 32 weeks were used for the study and the animals were given Bempedoic acid for 5 weeks at doses of 10 ​mg ​kg−1, po, qd, and 30 ​mg ​kg−1, po, qd. Bempedoic acid treatment resulted in inhibition of body weight gain and improved the glycemic control. Bempedoic acid treated group showed statistically significant reduction in plasma ALT, AST, hepatic triglycerides (TG) and total cholesterol (TC), along with statistically significant reduction in steatosis score by histological analysis. Hepatic gene expression analysis showed significant reduction in inflammatory and fibrotic genes such as Mcp-1/Ccl2, Timp-1 &Col1α1. Histological analysis showed significant improvement in NAS score. Overall, Bempedoic acid alleviated HFD induced Non-Alcoholic Steatohepatitis through inhibition of body weight gain, improvement in glycemic control, reduction of hepatic triglycerides & total cholesterol, modulation of inflammatory & fibrotic genes, and improvement in NAS score. Hence, Bempedoic acid can be a potential therapeutic option for metabolic syndrome and NASH.

Prognostički značaj vrednosti serumskog feritina pri inicijalnoj dijagnozi kod bolesnika sa akutnom mijeloidnom leukemijom

Introduction/Aim: Acute myeloid leukemia (AML) is a heterogenous malignant disease whose course and outcome are influenced by a number of prognostic factors. Serum ferritin (SF) is often elevated in oncology patients, and it has been shown that it strongly influences an unfavorable outcome in various malignancies. The aim of this study is to assess the effect of high SF values on overall survival and disease-free survival, as well as to assess the correlation of SF values with other prognostic markers, such as clinical and laboratory parameters. Methods: Retrospective analysis included 108 patients diagnosed with AML at the Clinic for Hematology of the Clinical Center of Serbia (CCS), in Belgrade, in the period 2017 - 2019. Patients with acute promyelocytic leukemia, acute mixed lineage leukemia, secondary AML and patients treated with palliative therapy were excluded from the study. Patients were grouped based on the SF cutoff value of 800 µg/L. Results: Patients with higher SF values had a significantly higher incidence of early death (p = 0.020), sepsis in the induction phase of therapy (p < 0.010), and significantly lower initial hemoglobin levels (p = 0.040), as compared to patients with lower SF values. SF at diagnosis appeared to be a significant independent predictive factor of overall survival (p = 0.019) and of disease-free survival (p = 0.040). Conclusion: Our study showed a significant association of high SF values with sepsis in induction, early death, mean hemoglobin, overall survival, and disease-free survival. Identification of SF as an independent prognostic factor and a potential target site of the action of new drugs could contribute to a better prognosis of AML patients.

An in vitro model of hepatic steatosis using lipid loaded induced pluripotent stem cell derived hepatocyte like cells.

Hepatic steatosis is a metabolic disease, characterized by selective and progressive accumulation of lipids in liver, leading to progressive non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and cirrhosis. The existing in vitro models of hepatic steatosis to elucidate the molecular mechanisms behind the onset of hepatic steatosis and to profile small molecule modulators uses lipid loaded primary hepatocytes, and cell lines like HepG2. The limitation of these models includes high variability between the different donor samples, reproducibility, and translatability to physiological context. An in vitro human hepatocyte derived model that mimics the pathophysiological changes seen in hepatic steatosis may provide an alternative tool for pre-clinical drug discovery research. We report the development of an in vitro experimental model of hepatic steatosis using human induced pluripotent stem cell (iPSC) derived hepatocytes like cells (HLC), loaded with lipids. Our data suggests that HLC carry some of the functional characteristics of primary hepatocytes and are amenable for development of an in vitro steatosis model using lipid loading method. The in vitro experimental model of hepatic steatosis was further characterized using biomarker analysis and validated using telmisartan. With some refinement and additional validation, our in vitro steatosis model system may be useful for profiling small molecule inhibitors and studying the mechanism of action of new drugs.

Analysis of the Differences in the Expression of mRNAs and miRNAs Associated with Drug Resistance in Endometrial Cancer Cells Treated with Salinomycin.

It is important to understand the molecular mechanisms involved in cancer drug resistance and to study the activity of new drugs, e.g. salinomycin. The purpose of the study was to analyze changes in the expression of genes associated with drug resistance in the Ishikawa endometrial cancer cell line when treated with salinomycin. In addition, changes in the level of miRNA potentially regulating these mRNAs were evaluated. Endometrial cancer cells were treated with 1 μM of salinomycin for 12, 24 and 48 hours periods. Untreated cells were a control culture. The molecular analysis consists of mRNA and miRNA microarray analysis and the RTqPCR technique. The following was observed about the number of mRNAs differentiating the cell culture exposed to the drug compared to a control culture: H-12 vs. C - 9 mRNAs, H_24 vs. C - 6 mRNAs, and H_48 vs. C - 1 mRNA. It was noted that 4 of the 9 differentiating mRNAs were characteristic for 12 hours of exposure to salinomycin and they correspond to the following genes: TUFT1, ABCB1, MTMR11, and MX2. After 24 hours, 2 mRNAs were characteristic for this time of incubation cells with salinomycin: TUFT1 and MYD88 and after 48 hours, SLC30A5 could also be observed. The highest differences in expression were indicated for TUFT1, MTMR11, and SLC30A5. The highest influence probability was determined between TUFT1 and hsa- miR-3188 (FC + 2.48), MTMR11and has-miR-16 (FC -1.74), and between SLC30A5 and hsa-miR-30d (FC -2.01). Salinomycin induces changes in the activity of mRNA and miRNA participating in drug resistance; however, the observed changes in character are the expected result of anti-cancer treatment.

Motor excitability measurements in early stage familial amyloid polyneuropathy: The influence of tafamidis treatment

To test motor fiber excitability in early affected patients with transthyretin (TTR)-type familial amyloid polyneuropathy (TTR-FAP) before and during tafamidis treatment. We examined the left median nerve of 21 healthy-matched controls and 10 early affected TTR-FAP patients using the automated threshold-tracking program, QTRAC. TTR-FAP patients were tested one day before the initiation of tafamidis treatment, 3 and 6 months later. The drug was well-tolerated in all patients; there was no drop-out. No statistical difference was found between healthy controls and TTR-FAP patients at study entry. On treatment, both stimulus intensity for 50% of the maximal motor response and rheobase increased significantly from entry to the last evaluation at 6 months (P<0.05). Strength duration time constant decreased significantly from the 3rd to the 6th month of evaluation (P<0.05). There was also a "fanning-out" effect on the late depolarization phase (TEd 90-100ms) as well as a shortened relative refractory period from study entry to the 6th month of evaluation. Threshold-tracking of median nerve motor fibers is not a helpful technique for the early diagnosis of TTR-FAP patients. Tafamidis was well-tolerated. We observed possible membrane hyperpolarization during treatment. Threshold tracking can contribute to documenting the action of new drugs to treat neuropathies. Tafamidis may change nerve electrical properties by reducing the burden of amyloid fibrils.

TOPOISOMERASE PREPARATIONS K‑19, DECOVIN AND K‑20, OBTAINED ON THE BASIS OF COLCHICINE AND COLCHAMINE: MITOTIC ACTIVITY, ALKYLATING ACTION AND EFFECT

New drugs derived from colchicine K‑19, decovin and K‑20, have high antitumor activity and the ability to potentiate the effects of radiation. The elements of the mechanism of action of new drugs: mitotic activity,alkylating action, effects on topoisomerases I and II were studied.

A Comprehensive Review on the Screening Models for the Pharmacological Assessment of Antiulcer Drugs.

Due to inappropriate diet, smoking, alcohol consumption, regular use of drugs like NSAIDs and sedentary lifestyle, one may feel upper abdominal pain which may be the predictor of the gastrointestinal disorder called Peptic Ulcer. When an imbalance occurs between the defensive factor and aggressive factor of the stomach, ulcer formation in the esophageal lining, stomach, or duodenum takes place. This leads to the formation of small sores that cause pain. Another condition that synergizes the abdominal pain is vomiting materials which look like coffee grounds, blood in the stool, black or tarry stools. This pain may increase after lunch or dinner. This problem persists, that often leads to the gastroenterologist's consultation. There are many antiulcer screening models present for the determination of antiulcer activity of the drug molecule. The main objective of this study is to find which model is best for the determination of antiulcer activity. A literature search was conducted on the databases namely Science direct and PubMed with the help of different keywords such as "Anti-ulcer", "In-vitro models" and "In-vivo models". The search was customized by applying the appropriate filters so as to get the most relevant articles to meet the objective of this review article. There are different research and review papers based on the antiulcer screening models for the determination of antiulcer activity of new drug molecules. On the basis of our study, we found some useful models for the antiulcer activity of drugs and suggested that, if we use in-vitro and in-vivo methods together, then we may obtain the most relevant result in our research area.