Investigating side effect modules in the interactome and their use in drug adverse effect discovery

2016 ◽  
Author(s):  
Emre Guney
Keyword(s):  
Side Effects ◽  
Side Effect ◽  
Drug Targets ◽  
Large Scale ◽  
New Drugs ◽  
Drug Side Effects ◽  
Data Set ◽  
Drug Adverse Effect ◽  
Phase Ii And Iii

One of the biggest challenges in drug development is increasing costs of bringing new drugs to the market. Many candidate drugs fail during phase II and III trials due to unexpected side effects and experimental methods remain cost ineffective for large scale discovery of adverse effects. Alternatively, computational methods are used to characterize drug side effects, but they often rely on training predictors based on drug and side effect similarity. Moreover, these methods are typically tailored to the underlying data set and provide little mechanistic insights on the predicted associations. In this study, we investigate the role of network topology in explaining observed side effects of drugs. We find that drug targets are closer in the interactome to the proteins inducing the known side effects of the drug compared to the proteins associated with the rest of the side effects. We show that the interactome based proximity can be used to identify side effects and we highlight a use case in which interactome-based side effect prediction can give insights on drug side effects observed in the clinic.

scholarly journals The Geometric Sparse Matrix Completion Model for Predicting Drug Side effects

2019 ◽  
Author(s):  
Diego Galeano ◽  
Alberto Paccanaro
Keyword(s):  
Clinical Trials ◽  
Side Effects ◽  
Side Effect ◽  
Large Scale ◽  
Learning Algorithm ◽  
Sparse Matrix ◽  
Matrix Completion ◽  
Optimal Solution ◽  
Drug Side Effects ◽  
Chemical Structures

AbstractPair-input associations for drug-side effects are obtained through expensive placebo-controlled experiments in human clinical trials. An important challenge in computational pharmacology is to predict missing associations given a few entries in the drug-side effect matrix, as these predictions can be used to direct further clinical trials. Here we introduce the Geometric Sparse Matrix Completion (GSMC) model for predicting drug side effects. Our high-rank matrix completion model learns non-negative sparse matrices of coefficients for drugs and side effects by imposing smoothness priors that exploit a set of pharmacological side information graphs, including information about drug chemical structures, drug interactions, molecular targets, and disease indications. Our learning algorithm is based on the diagonally rescaled gradient descend principle of non-negative matrix factorization. We prove that it converges to a globally optimal solution with a first-order rate of convergence. Experiments on large-scale side effect data from human clinical trials show that our method achieves better prediction performance than six state-of-the-art methods for side effect prediction while offering biological interpretability and favouring explainable predictions.

scholarly journals Side Effects of mRNA-Based COVID-19 Vaccine: Nationwide Phase IV Study among Healthcare Workers in Slovakia

2021 ◽  
Vol 14 (9) ◽  
pp. 873
Author(s):  
Abanoub Riad ◽  
Barbora Hocková ◽  
Lucia Kantorová ◽  
Rastislav Slávik ◽  
Lucia Spurná ◽  
...  
Keyword(s):  
Side Effects ◽  
Side Effect ◽  
Healthcare Workers ◽  
Large Scale ◽  
Large Population ◽  
Medical Attention ◽  
Cross Sectional Survey ◽  
Cross Sectional ◽  
Post Vaccination ◽  
Phase Iv

mRNA-based COVID-19 vaccines such as BNT162b2 have recently been a target of anti-vaccination campaigns due to their novelty in the healthcare industry; nevertheless, these vaccines have exhibited excellent results in terms of efficacy and safety. As a consequence, they acquired the first approvals from drug regulators and were deployed at a large scale among priority groups, including healthcare workers. This phase IV study was designed as a nationwide cross-sectional survey to evaluate the post-vaccination side effects among healthcare workers in Slovakia. The study used a validated self-administered questionnaire that inquired about participants’ demographic information, medical anamneses, COVID-19-related anamnesis, and local, systemic, oral, and skin-related side effects following receiving the BNT162b2 vaccine. A total of 522 participants were included in this study, of whom 77% were females, 55.7% were aged between 31 and 54 years, and 41.6% were from Banska Bystrica. Most of the participants (91.6%) reported at least one side effect. Injection site pain (85.2%) was the most common local side effect, while fatigue (54.2%), headache (34.3%), muscle pain (28.4%), and chills (26.4%) were the most common systemic side effects. The reported side effects were of a mild nature (99.6%) that did not require medical attention and a short duration, as most of them (90.4%) were resolved within three days. Females and young adults were more likely to report post-vaccination side effects; such a finding is also consistent with what was previously reported by other phase IV studies worldwide. The role of chronic illnesses and medical treatments in post-vaccination side effect incidence and intensity requires further robust investigation among large population groups.

scholarly journals MONITORING OF ANTICONVULSANT DRUG SIDE EFFECTS IN OUTPATIENTS WITH EPILEPSY

2018 ◽  
Vol 10 (1) ◽  
pp. 303
Author(s):  
Santi Purna Sari ◽  
Natasha Kurnia Salma S ◽  
Alfina Rianti
Keyword(s):  
Valproic Acid ◽  
Side Effects ◽  
Medical Records ◽  
Side Effect ◽  
Anticonvulsant Drug ◽  
Secondary Data ◽  
Drug Side Effects ◽  
Inclusion Criteria ◽  
Descriptive Data ◽  
Effect Monitoring

Objective: This study aimed to monitor the side effects of carbamazepine, phenytoin, and valproic acid, and combinations of these drugs in adultpatients with epilepsy, to raise awareness of the importance of drug side effect monitoring in hospitals.Methods: In this prospective study, descriptive data were collected from patients who met the inclusion criteria of complete samples. Primary datawere obtained using questionnaires, secondary data were collected from medical records, and analyses were performed using the Naranjo algorithm.Results: Among the 54 included patients, 38 (70.37%) of them experienced drug side effects, and the most frequently observed side effect occurredin 48.15% of study subjects.Conclusion: No correlation was identified between side effects and age (p=0.903) or gender (p=1.000).

The Science of Antipsychotics: Mechanistic Insight

CNS Spectrums ◽  
2003 ◽  
Vol 8 (S2) ◽  
pp. 5-9 ◽  
Author(s):  
Carol A. Tamminga
Keyword(s):  
Side Effects ◽  
Tardive Dyskinesia ◽  
Side Effect ◽  
Negative Symptoms ◽  
New Drugs ◽  
Receptor Subtypes ◽  
Side Effect Profile ◽  
Cognitive Symptoms ◽  
Conventional Antipsychotics ◽  
New Antipsychotics

ABSTRACTWith the introduction of conventional antipsychotics in the 1950s, clinicians began to expect effective treatment of positive symptoms of schizophrenia. However, these drugs do not resolve negative and cognitive symptoms of schizophrenia and are also associated with serious side effects, including extrapyramidal side effects (EPS) and tardive dyskinesia. In 1989, clozapine was introduced and labeled the first new antipsychotic owing to its improved efficacy and side-effect profile. Clozapine proved effective in alleviating many of the positive, negative, and cognitive symptoms of schizophrenia, without causing inevitable EPS or tardive dyskinesia. Over the past decade, a number of different new antipsychotics have been developed. These drugs have an affinity for multiple dopamine-receptor subtypes as well as serotonin, norepinephrine, and glutamate receptors, allowing for better treatment outcomes. The antagonism of the 5-HT2A receptor may be responsible for improvement in negative symptoms and decrease in EPS. In addition to providing enhanced efficacy, the affinity of the new drugs for multiple receptors introduces new side effects not seen with the conventional agents, including weight gain. Each new antipsychotic has a unique receptor-binding profile that corresponds to its pharmacologic and side-effect profile. Understanding the differences in mechanisms of action of new antipsychotics will allow physicians to better choose treatment that meets the needs of each individual patient.

scholarly journals Understanding the yeast host cell response to recombinant membrane protein production

2011 ◽  
Vol 39 (3) ◽  
pp. 719-723 ◽  
Author(s):  
Zharain Bawa ◽  
Charlotte E. Bland ◽  
Nicklas Bonander ◽  
Nagamani Bora ◽  
Stephanie P. Cartwright ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Membrane Protein ◽  
Drug Targets ◽  
Large Scale ◽  
Protein Production ◽  
Molecular Mechanisms ◽  
New Drugs ◽  
Host Cells ◽  
Host Cell Response ◽  
Wide Range

Membrane proteins are drug targets for a wide range of diseases. Having access to appropriate samples for further research underpins the pharmaceutical industry's strategy for developing new drugs. This is typically achieved by synthesizing a protein of interest in host cells that can be cultured on a large scale, allowing the isolation of the pure protein in quantities much higher than those found in the protein's native source. Yeast is a popular host as it is a eukaryote with similar synthetic machinery to that of the native human source cells of many proteins of interest, while also being quick, easy and cheap to grow and process. Even in these cells, the production of human membrane proteins can be plagued by low functional yields; we wish to understand why. We have identified molecular mechanisms and culture parameters underpinning high yields and have consolidated our findings to engineer improved yeast host strains. By relieving the bottlenecks to recombinant membrane protein production in yeast, we aim to contribute to the drug discovery pipeline, while providing insight into translational processes.

Differentiating Behavioral Disturbances of Dementia From Drug Side Effects

1997 ◽  
Vol 8 (S3) ◽  
pp. 429-434 ◽  
Author(s):  
John H. Eastham ◽  
Dilip V. Jeste
Keyword(s):  
Side Effects ◽  
Behavioral Problems ◽  
Patient Management ◽  
Cost Of Care ◽  
New Drugs ◽  
Behavioral Disturbance ◽  
Drug Side Effects ◽  
Comorbid Conditions ◽  
Behavioral Disturbances

Patients with dementia may be treated with several drugs because of comorbid conditions or symptoms related to the dementia itself. Such drug treatment can complicate patient management because many drugs may cause side effects, such as depression and Parkinsonism, that also are considered behavioral disturbances of dementia. Distinguishing between drug side effects and behavioral problems is difficult but necessary for several reasons. Attributing the behavioral disturbance to an incorrect cause can affect the type of treatment selected and the patient's response to it. It also can increase the overall cost of care and adversely affect the patient's quality of life. Making this distinction has theoretical importance as well, including the development of new drugs that have fewer behavioral side effects.

scholarly journals In Vivo Large Scale Mapping Of Protein Turnover In The Human Cerebrospinal Fluid

2019 ◽  
Author(s):  
Sylvain Lehmann ◽  
Christophe Hirtz ◽  
Jérôme Vialaret ◽  
Maxence Ory ◽  
Guillaume Gras Combes ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Drug Targets ◽  
Large Scale ◽  
Large Data ◽  
Clinical Samples ◽  
Sample Collection ◽  
Data Set ◽  
Disease Etiology ◽  
System Physiology

SummaryThe extraction of accurate physiological parameters from clinical samples provides a unique perspective to understand disease etiology and evolution, including under therapy. We introduce a new proteomics framework to map patient proteome dynamics in vivo, either proteome wide or in large targeted panels. We applied it to ventricular cerebrospinal fluid (CSF) and could determine the turnover parameters of almost 200 proteins, whereas a handful were known previously. We covered a large number of neuron biology- and immune system-related proteins including many biomarkers and drug targets. This first large data set unraveled a significant relationship between turnover and protein origin that relates to our ability to investigate the central nervous system physiology precisely in future studies. Our data constitute a reference in CSF biology as well as a repertoire of peptides for the community to design new proteome dynamics analyses. The disclosed methods apply to other fluids or tissues provided sequential sample collection can be performed.

Separation of Powers, Treaty-Making, and Treaty Withdrawal

2019 ◽  
pp. 134-155
Author(s):  
Pierre-Hugues Verdier ◽  
Mila Versteeg
Keyword(s):  
Large Scale ◽  
Legal Status ◽  
Separation Of Powers ◽  
Original Data ◽  
Comparative Perspective ◽  
Data Set ◽  
Constitutional Review ◽  
Alternative Procedures ◽  
Domestic Law

This chapter examines from a comparative perspective the national legal regimes that govern treaty-making and treaty withdrawal, functions that in many countries were traditionally vested in the executive. Drawing from an original data set that covers 101 countries for the period 1815–2013, the chapter identifies several large-scale trends. First, it confirms a sustained trend toward greater parliamentary involvement in treaty-making. Second, it shows that many countries recognize executive agreements and other alternative procedures through which the executive can conclude internationally binding agreements without parliamentary approval, but that these “workarounds” are typically subject to significant constraints affecting the executive’s discretion and the domestic legal status of the resulting agreements. Third, it shows that in recent years several countries have introduced constraints on the executive’s ability to withdraw from treaties without parliamentary approval. Finally, it draws attention to the little-noticed role of national judiciaries in treaty-making, by showing that in many legal systems treaties are subject to constitutional review prior to ratification. The chapter discusses the implications of these four trends, all of which represent moves away from the executive-dominated world of traditional treaty relations. It hypothesizes that these trends respond to growing separation of powers concerns as treaties increasingly shape domestic law.

scholarly journals Indirect Taxis on a Fluctuating Environment

Mathematics ◽  
2020 ◽  
Vol 8 (11) ◽  
pp. 2052
Author(s):  
Andrey Morgulis ◽  
Konstantin Ilin
Keyword(s):  
Side Effects ◽  
Pattern Formation ◽  
Large Scale ◽  
Food Resource ◽  
Small Scale ◽  
Fluctuating Environment ◽  
Environmental Fluctuations ◽  
Sea Currents ◽  
Homogeneous Environment

In this article, we study a Patlak–Keller–Siegel (PKS) model of a community of two species placed in the inhomogeneous environment. We employ PKS law for modeling tactic movement due to interspecific taxis and in response to the environmental fluctuations. These fluctuations can arise for natural reasons, e.g., the terrain relief, the sea currents and the food resource distribution, and there are artificial ones. The main result in the article elucidates the effect of the small-scale environmental fluctuations on the large-scale pattern formation in PKS systems. This issue remains uncharted, although numerous studies have addressed the pattern formation while assuming an homogeneous environment. Meanwhile, exploring the role of the fluctuating environment is substantial in many respects, for instance, for predicting the side effects of human activity or for designing the control of biological systems. As well, it is necessary for understanding the roles played in the dynamics of trophic communities by the natural environmental inhomogeneities—those mentioned above, for example. We examined the small-scale environmental inhomogeneities in the spirit of Kapitza’s theory of the upside-down pendulum, but we used the homogenization instead of classical averaging. This approach is novel for the dynamics of PKS systems (though used commonly for other areas). Employing it has unveiled a novel mechanism of exerting the effect from the fluctuating environment on the pattern formation by the drift of species arising upon the homogenization of the fluctuations.

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