scholarly journals Inter-individual variability and modeling of electrical activity: a possible new approach to explore cardiac safety?

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Jean-Yves Le Guennec ◽  
Jérôme Thireau ◽  
Aude Ouillé ◽  
Julien Roussel ◽  
Jérôme Roy ◽  
...  
Keyword(s):  
Side Effects ◽  
Computational Models ◽  
Simulation Models ◽  
Human Action ◽  
Individual Variability ◽  
New Drugs ◽  
Channel Blockers ◽  
Nucleotide Polymorphisms ◽  
Cardiac Side Effects ◽  
Drug Candidates

Abstract Safety pharmacology aims to predict rare side effects of new drugs. We explored whether rare pro-arrhythmic effects could be linked to the variability of the effects of these drugs on ion currents and whether taking into consideration this variability in computational models could help to better detect and predict cardiac side effects. For this purpose, we evaluated how intra- and inter-individual variability influences the effect of hERG inhibition on both the action potential duration and the occurrence of arrhythmias. Using two computer simulation models of human action potentials (endocardial and Purkinje cells), we analyzed the contribution of two biological parameters on the pro-arrhythmic effects of several hERG channel blockers: (i) spermine concentration, which varies with metabolic status, and (ii) L-type calcium conductance, which varies due to single nucleotide polymorphisms or mutations. By varying these parameters, we were able to induce arrhythmias in 1 out of 16 simulations although conventional modeling methods to detect pro-arrhythmic molecules failed. On the basis of our results, taking into consideration only 2 parameters subjected to intra- and inter-individual variability, we propose that in silico computer modeling may help to better define the risks of new drug candidates at early stages of pre-clinical development.

scholarly journals The Ethyl Acetate Extraction Obtained from Podocarpus Nagikernel Meal with Anticancer Activity

2021 ◽  
Vol 14 (1) ◽  
pp. 363-366
Author(s):  
Yuchen Xiao ◽  
Jianping Yong ◽  
Yang Yang ◽  
Canzhong Lu
Keyword(s):  
Side Effects ◽  
Anticancer Activity ◽  
Anticancer Drugs ◽  
Biological Activities ◽  
Wide Spectrum ◽  
Public Health Problem ◽  
New Drugs ◽  
Major Public Health Problem ◽  
Drug Candidates

Cancer is a major public health problem worldwide, and it is one of the top three major diseases in terms of mortality. Some small molecular synthesized drugs have been used clinically. However, much side-effects were also appeared during treatment of the cancer patients with the synthesized anticancer drugs in clinical. Some Chinese Traditional Plant Medicines have ever been used for treatment of cancer with the low side-effects. Thus, it is essential to find anticancer drugs or drug candidates from Chinese Traditional Plant Medicines. Podocarpus nagicontains different kinds of biological components together with a wide spectrum of biological activities, and it has ever been used in the folk of Yao Nationality for treatment different diseases. It is essential to study this folk plant medicine to discover new drugs or drug candidates. In this work, we obtained different polar extractions and evaluated their in vitro anticancer activity.

scholarly journals HobPre: accurate prediction of human oral bioavailability for small molecules

2022 ◽  
Vol 14 (1) ◽  
Author(s):  
Min Wei ◽  
Xudong Zhang ◽  
Xiaolin Pan ◽  
Bo Wang ◽  
Changge Ji ◽  
...  
Keyword(s):  
Drug Development ◽  
Small Molecules ◽  
Oral Bioavailability ◽  
Computational Models ◽  
Experimental Tests ◽  
New Drugs ◽  
Drug Candidates ◽  
Drug Molecules ◽  
Key Factor ◽  
Input Variables

AbstractHuman oral bioavailability (HOB) is a key factor in determining the fate of new drugs in clinical trials. HOB is conventionally measured using expensive and time-consuming experimental tests. The use of computational models to evaluate HOB before the synthesis of new drugs will be beneficial to the drug development process. In this study, a total of 1588 drug molecules with HOB data were collected from the literature for the development of a classifying model that uses the consensus predictions of five random forest models. The consensus model shows excellent prediction accuracies on two independent test sets with two cutoffs of 20% and 50% for classification of molecules. The analysis of the importance of the input variables allowed the identification of the main molecular descriptors that affect the HOB class value. The model is available as a web server at www.icdrug.com/ICDrug/ADMET for quick assessment of oral bioavailability for small molecules. The results from this study provide an accurate and easy-to-use tool for screening of drug candidates based on HOB, which may be used to reduce the risk of failure in late stage of drug development. Graphical Abstract

Advances in the application of 1,2,4-triazole-containing hybrids as anti-tuberculosis agents

2021 ◽  
Author(s):  
Yingdong Cao ◽  
Hong Lu
Keyword(s):  
Side Effects ◽  
Rational Design ◽  
Communicable Disease ◽  
Mechanisms Of Action ◽  
New Drugs ◽  
Current Status ◽  
Potential Drug ◽  
Antitubercular Agents ◽  
Drug Candidates ◽  
Privileged Structure

Tuberculosis is a deadly communicable disease caused by the bacillus Mycobacterium tuberculosis (MTB), and pulmonary tuberculosis accounts for over 80% of the total cases. The 1,2,4-triazole is a privileged structure in the discovery of new drugs, and its derivatives act on various targets in MTB. In particular, 1,2,4-triazole hybrids can not only exert dual or multiple antitubercular mechanisms of action but also have the potential to enhance efficacy and reduce side effects. The present work aims to summarize the current status of 1,2,4-triazole hybrids as potential antitubercular agents, covering articles published between 2010 and 2020, to aid the further rational design of novel potential drug candidates endowed with higher efficacy, better compliance and fewer side effects.

Recent Advances in the Development of Antimicrobial Peptides (AMPs): Attempts for Sustainable Medicine?

2018 ◽  
Vol 25 (21) ◽  
pp. 2503-2519 ◽  
Author(s):  
Anne Kokel ◽  
Marianna Torok
Keyword(s):  
Side Effects ◽  
Antimicrobial Peptides ◽  
Potential Drug ◽  
Green Technologies ◽  
Specific Antibodies ◽  
Structural Modifications ◽  
Drug Candidates ◽  
Induce Resistance ◽  
Conventional Antibiotics

Background: Since the first isolation of antimicrobial peptides (AMPs) they have attracted extensive interest in medicinal chemistry. However, only a few AMP-based drugs are currently available on the market. Despite their effectiveness, biodegradability, and versatile mode of action that is less likely to induce resistance compared to conventional antibiotics, AMPs suffer from major issues that need to be addressed to broaden their use. Notably, AMPs can lack selectivity leading to side effects and cytotoxicity, and also exhibit in vivo instability. Several strategies are being actively considered to overcome the limitations that restrain the success of AMPs. Methods: In the current work, recent strategies reported for improving AMPs in the context of drug design and delivery were surveyed, and also their possible impact on patients and the environment was assessed. Results: As a major advantage AMPs possess an easily tunable skeleton offering opportunities to improve their properties. Strategic structural modifications and the beneficial properties of cyclic or branched AMPs in term of stability have been reported. The conjugation of AMPs with nanoparticles has also been explored to increase their in vivo stability. Other techniques such as the coupling of AMPs with specific antibodies aim to increase the selectivity of the potential drug towards the target. These strategies were evaluated for their effect on the environment highlighting green technologies. Conclusion: Although further research is needed taking into account both environmental and human health consequences of novel AMPs, several of these compounds are promising drug candidates for use in sustainable medicine.

scholarly journals Cardiooncology—dealing with modern drug treatment, long-term complications, and cancer survivorship

2021 ◽  
Author(s):  
Claudia de Wall ◽  
Johann Bauersachs ◽  
Dominik Berliner
Keyword(s):  
Side Effects ◽  
Checkpoint Inhibitors ◽  
Heart Diseases ◽  
Tumor Therapy ◽  
Treatment Strategies ◽  
Tumor Treatment ◽  
Cardiac Side Effects ◽  
Cardiovascular Side Effects ◽  
Modern Drug

AbstractModern treatment strategies have improved prognosis and survival of patients with malignant diseases. The key components of tumor treatment are conventional chemotherapy, radiotherapy, targeted therapies, and immunotherapy. Cardiovascular side-effects may occur in the early phase of tumor therapy or even decades later. Therefore, knowledge and awareness of acute and long-lasting cardiac side effects of anti-cancer therapies are essential. Cardiotoxicity impairs quality of life and overall survival. The new cardiologic subspecialty ‘cardio-oncology’ deals with the different cardiovascular problems arising from tumor treatment and the relationship between cancer and heart diseases. Early detection and treatment of cardiotoxicity is of crucial importance. A detailed cardiac assessment of patients prior to administration of cardiotoxic agents, during and after treatment should be performed in all patients. The current review focusses on acute and long-term cardiotoxic side effects of classical cytotoxic and selected modern drug treatments such as immune checkpoint inhibitors and discusses strategies for the diagnosis of treatment-related adverse cardiovascular effects in cancer patients.

Role of the norepinephrine transporter polymorphisms in atomoxetine treatment: From response to side effects in children with ADHD

2021 ◽  
pp. 026988112110152
Author(s):  
Melike Kevser Gul ◽  
Elif Funda Sener ◽  
Muge Gulcihan Onal ◽  
Esra Demirci
Keyword(s):  
Side Effects ◽  
Treatment Response ◽  
Large Population ◽  
Norepinephrine Transporter ◽  
Response To Treatment ◽  
Nucleotide Polymorphisms ◽  
Children With Adhd ◽  
Real Time Quantitative Pcr ◽  
Treatment Side Effects ◽  
Adhd Treatment

Objective: Atomoxetine (ATX), one of the most commonly used drugs after stimulants in attention deficit hyperactivity disorder (ADHD) treatment, is an inhibitor of the norepinephrine transporter ( NET/SLC6A2), which is also associated with the etiology of ADHD. In this study, we aimed to investigate the effect of NET gene polymorphisms on response to ATX treatment and to find the answers to the questions about whether there is a relationship between the severity of the disorder and the observed side effects in children with ADHD. Method: About 100 children with ADHD and 80 healthy controls (HCs) were included in this study. The dose of ATX was started at 0.5 mg/kg/day and titrated at 1.2 mg/kg/day. Response to treatment of 78 patients was evaluated 2 months after the beginning of the treatment. After whole blood samples were obtained, DNAs were isolated, and samples were stored at −80°C. Two single-nucleotide polymorphisms (SNPs) (rs12708954 and rs3785143) were analyzed by real-time quantitative PCR (qRT-PCR). Results: The patients with both rs12708954 and rs3785143 heterozygous genotype had better treatment response and more side effects than patients with wild type. There was not found any association between any of the investigated NET polymorphisms and ADHD severity. Conclusion: It was, however, found that the NET rs12708954 and rs3785143 genotypes affect the treatment response to ATX in our study; thus, further studies with a large population are needed to understand the effects of NET polymorphisms on treatment, side effects, and also the severity of ADHD.

scholarly journals Prospects for new drugs to treat binge-eating disorder: Insights from psychopathology and neuropharmacology

2021 ◽  
pp. 026988112110324
Author(s):  
David J Heal ◽  
Sharon L Smith
Keyword(s):  
Eating Disorder ◽  
Binge Eating ◽  
Binge Eating Disorder ◽  
Clinical Findings ◽  
New Drugs ◽  
Dopaminergic Neurotransmission ◽  
Drug Candidates ◽  
Product Profile ◽  
Proven Efficacy ◽  
New Treatments

Background: Binge-eating disorder (BED) is a common psychiatric condition with adverse psychological and metabolic consequences. Lisdexamfetamine (LDX) is the only approved BED drug treatment. New drugs to treat BED are urgently needed. Methods: A comprehensive review of published psychopathological, pharmacological and clinical findings. Results: The evidence supports the hypothesis that BED is an impulse control disorder with similarities to ADHD, including responsiveness to catecholaminergic drugs, for example LDX and dasotraline. The target product profile (TPP) of the ideal BED drug combines treating the psychopathological drivers of the disorder with an independent weight-loss effect. Drugs with proven efficacy in BED have a common pharmacology; they potentiate central noradrenergic and dopaminergic neurotransmission. Because of the overlap between pharmacotherapy in attention deficit hyperactivity disorder (ADHD) and BED, drug-candidates from diverse pharmacological classes, which have already failed in ADHD would also be predicted to fail if tested in BED. The failure in BED trials of drugs with diverse pharmacological mechanisms indicates many possible avenues for drug discovery can probably be discounted. Conclusions: (1) The efficacy of drugs for BED is dependent on reducing its core psychopathologies of impulsivity, compulsivity and perseveration and by increasing cognitive control of eating. (2) The analysis revealed a large number of pharmacological mechanisms are unlikely to be productive in the search for effective new BED drugs. (3) The most promising areas for new treatments for BED are drugs, which augment noradrenergic and dopaminergic neurotransmission and/or those which are effective in ADHD.

scholarly journals Differences in subcortico-cortical interactions identified from connectome and microcircuit models in autism

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Bo-yong Park ◽  
Seok-Jun Hong ◽  
Sofie L. Valk ◽  
Casey Paquola ◽  
Oualid Benkarim ◽  
...  
Keyword(s):  
Data Exchange ◽  
Computational Models ◽  
Simulation Models ◽  
Autism Diagnostic Observation Schedule ◽  
Supervised Machine Learning ◽  
Global Network ◽  
Imaging Data ◽  
Phenotypic Data ◽  
Severity Scores ◽  
High Level

AbstractThe pathophysiology of autism has been suggested to involve a combination of both macroscale connectome miswiring and microcircuit anomalies. Here, we combine connectome-wide manifold learning with biophysical simulation models to understand associations between global network perturbations and microcircuit dysfunctions in autism. We studied neuroimaging and phenotypic data in 47 individuals with autism and 37 typically developing controls obtained from the Autism Brain Imaging Data Exchange initiative. Our analysis establishes significant differences in structural connectome organization in individuals with autism relative to controls, with strong between-group effects in low-level somatosensory regions and moderate effects in high-level association cortices. Computational models reveal that the degree of macroscale anomalies is related to atypical increases of recurrent excitation/inhibition, as well as subcortical inputs into cortical microcircuits, especially in sensory and motor areas. Transcriptomic association analysis based on postmortem datasets identifies genes expressed in cortical and thalamic areas from childhood to young adulthood. Finally, supervised machine learning finds that the macroscale perturbations are associated with symptom severity scores on the Autism Diagnostic Observation Schedule. Together, our analyses suggest that atypical subcortico-cortical interactions are associated with both microcircuit and macroscale connectome differences in autism.

scholarly journals Synthesis of oxadiazole-2-oxide derivatives as potential drug candidates for schistosomiasis targeting SjTGR

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Gongming Li ◽  
Qingqing Guo ◽  
Chao Feng ◽  
Huan Chen ◽  
Wenjiao Zhao ◽  
...  
Keyword(s):  
Schistosoma Japonicum ◽  
Inhibitory Activity ◽  
Pyridine Ring ◽  
New Drugs ◽  
Wild Type ◽  
Drug Candidates ◽  
Structure Activity ◽  
Docking Method ◽  
Antigen Protein ◽  
Thioredoxin Glutathione Reductase

Abstract Background Schistosomiasis is a chronic parasitic disease that affects millions of people’s health worldwide. Because of the increasing drug resistance to praziquantel (PZQ), which is the primary drug for schistosomiasis, developing new drugs to treat schistosomiasis is crucial. Oxadiazole-2-oxides have been identified as potential anti-schistosomiasis reagents targeting thioredoxin glutathione reductase (TGR). Methods In this work, one of the oxadiazole-2-oxides derivatives furoxan was used as the lead compound to exploit a series of novel furoxan derivatives for studying inhibitory activity against both recombinant Schistosoma japonicum TGR containing selenium (rSjTGR-Sec) and soluble worm antigen protein (SWAP) containing wild-type Schistosoma japonicum TGR (wtSjTGR), in order to develop a new leading compound for schistosomiasis. Thirty-nine novel derivatives were prepared to test their activity toward both enzymes. The docking method was used to detect the binding site between the active molecule and SjTGR. The structure–activity relationship (SAR) of these novel furoxan derivatives was preliminarily analyzed. Results It was found that several new derivatives, including compounds 6a–6d, 9ab, 9bd and 9be, demonstrated greater activity toward rSjTGR-Sec or SWAP containing wtSjTGR than did furoxan. Interestingly, all intermediates bearing hydroxy (6a–6d) showed excellent inhibitory activity against both enzymes. In particular, compound 6d with trifluoromethyl on a pyridine ring was found to have much higher inhibition toward both rSjTGR-Sec (half-maximal inhibitory concentration, IC50,7.5nM) and SWAP containing wtSjTGR (IC50 55.8nM) than furoxan. Additionally, the docking method identified the possible matching sites between 6d and Schistosoma japonicum TGR (SjTGR), which theoretically lends support to the inhibitory activity of 6d. Conclusion The data obtained herein showed that 6d with trifluoromethyl on a pyridine ring could be a valuable leading compound for further study.

scholarly journals What the Cardiologist Needs to Consider in the Management of Oncologic Patients with STEMI-Like Syndrome; A Case Report and Literature Review

2021 ◽  
Vol 14 (6) ◽  
pp. 563
Author(s):  
Aneta Aleksova ◽  
Giulia Gagno ◽  
Alessandro Pierri ◽  
Carla Todaro ◽  
Alessandra Lucia Fluca ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Case Report ◽  
Side Effects ◽  
Single Agent ◽  
St Segment Elevation ◽  
Cardiac Catheterization Laboratory ◽  
Cardiac Side Effects ◽  
Coronary Syndrome ◽  
St Segment ◽  
Oncologic Patients

In pre-hospital care, an accurate and quick diagnosis of ST-segment elevation myocardial infarction (STEMI) is imperative to promptly kick-off the STEMI network with a direct transfer to the cardiac catheterization laboratory (cath lab) in order to reduce myocardial infarction size and mortality. Aa atherosclerotic plaque rupture is the main mechanism responsible for STEMI. However, in a small percentage of patients, emergency coronarography does not reveal any significant coronary stenosis. The fluoropyrimidine agents such as 5-Fluorouracil (5-FU) and capecitabine, widely used to treat gastrointestinal, breast, head and neck cancers, either as a single agent or in combination with other chemotherapies, can cause potentially lethal cardiac side effects. Here, we present the case of a patient with 5-FU cardiotoxicity resulting in an acute coronary syndrome (ACS) with recurrent episodes of chest pain and ST-segment elevation.. Our case report highlights the importance of widening the knowledge among cardiologists of the side effects of chemotherapeutic drugs, especially considering the rising number of cancer patients around the world and that fluoropyrimidines are the main treatment for many types of cancer, both in adjuvant and advanced settings.

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