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Pharmacological Plasticity
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Pharmacological Plasticity

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 46439

Special Issue Editor

Prof. Dr. Michael J. Parnham

E-Mail
Guest Editor
1. Pharmacology Consultant, Bad Soden am Taunus, Germany
2. J.W. Goethe University Frankfurt, Frankfurt am Main, Germany
3. EpiEndo Pharmaceuticals, Seltjarnarnes, Iceland
Interests: inflammation; autoimmunity; respiratory diseases; immunopharmacology; antibiotics; pain and analgesia; drug discovery and development; translational medicine; nutrition

Special Issue Information

Dear Colleagues,

The search for new drugs, the development of robust test conditions, and the assessment of clinical conditions that may affect responses to drugs are all subject to many confounding factors. These interfering variables can markedly influence the desired or expected drug response, leading to pharmacological plasticity. Such influences can arise from poorly controlled conditions, genetic background, ongoing disease processes, or variability within the studied population (cells, animals, or human subjects). Many proposals have been made in recent years to improve the reproducibility and quality of drug testing, enhance translatability to the clinic, and increase understanding of the factors that modify clinical responses to drugs. This Special Issue is collecting articles which reflect the broad spectrum of confounding factors which need to be taken into consideration when evaluating drug responses.

Papers submitted to this Special Issue should be topical reviews or reports on novel results or methods relating to the assessment or evaluation of conditions causing variability or inconsistency in the responses to pharmacological agents in preclinical testing, translational medicine, or clinical studies. These conditions include, but are not limited to, test conditions, epi-/genetic and phenotypic variability, cellular dynamics, tolerance and target sensitivity, environment, diet and microbiota, chronobiology, aging, disease stage, sex, and metabolic processes.

Prof. Dr. Michael J. Parnham
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Drug target dynamics
  • Genetic and phenotypic variability
  • Environmental factors
  • Disease and drug response
  • Tolerance and receptor supersensitivity
  • Chronopharmacology
  • Drugs and aging

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Published Papers (7 papers)

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Research

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14 pages, 1536 KiB  
Article
Sustainable Stabilizer-Free Nanoparticle Formulations of Valsartan Using Eudragit® RLPO
by Eszter Hajba-Horváth, Andrea Fodor-Kardos, Nishant Shah, Matthias G. Wacker and Tivadar Feczkó
Int. J. Mol. Sci. 2021, 22(23), 13069; https://doi.org/10.3390/ijms222313069 - 2 Dec 2021
Cited by 4 | Viewed by 2728
Abstract
The bioavailability of the antihypertensive drug valsartan can be enhanced by various microencapsulation methods. In the present investigation, valsartan-loaded polymeric nanoparticles were manufactured from Eudragit® RLPO using an emulsion–solvent evaporation method. Polyvinyl alcohol (PVA) was found to be a suitable stabilizer for [...] Read more.
The bioavailability of the antihypertensive drug valsartan can be enhanced by various microencapsulation methods. In the present investigation, valsartan-loaded polymeric nanoparticles were manufactured from Eudragit® RLPO using an emulsion–solvent evaporation method. Polyvinyl alcohol (PVA) was found to be a suitable stabilizer for the nanoparticles, resulting in a monodisperse colloid system ranging in size between 148 nm and 162 nm. Additionally, a high encapsulation efficiency (96.4%) was observed. However, due to the quaternary ammonium groups of Eudragit® RLPO, the stabilization of the dispersion could be achieved in the absence of PVA as well. The nanoparticles were reduced in size (by 22%) and exhibited similar encapsulation efficiencies (96.4%). This more cost-effective and sustainable production method reduces the use of excipients and their expected emission into the environment. The drug release from valsartan-loaded nanoparticles was evaluated in a two-stage biorelevant dissolution set-up, leading to the rapid dissolution of valsartan in a simulated intestinal medium. In silico simulations using a model validated previously indicate a potential dose reduction of 60–70% compared to existing drug products. This further reduces the expected emission of the ecotoxic compound into the environment. Full article
(This article belongs to the Special Issue Pharmacological Plasticity)
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20 pages, 2505 KiB  
Article
NMDARs Containing NR2B Subunit Do Not Contribute to the LTP Form of Hippocampal Plasticity: In Vivo Pharmacological Evidence in Rats
by Abdallah Ahnaou, Kobe Heleven, Ria Biermans, Nikolay V. Manyakov and Wilhelmus H. Drinkenburg
Int. J. Mol. Sci. 2021, 22(16), 8672; https://doi.org/10.3390/ijms22168672 - 12 Aug 2021
Cited by 3 | Viewed by 2936
Abstract
Synaptic plasticity is the key to synaptic health, and aberrant synaptic plasticity, which in turn impairs the functioning of large-scale brain networks, has been associated with neurodegenerative and psychiatric disorders. The best known and most studied form of activity-dependent synaptic plasticity remains long-term [...] Read more.
Synaptic plasticity is the key to synaptic health, and aberrant synaptic plasticity, which in turn impairs the functioning of large-scale brain networks, has been associated with neurodegenerative and psychiatric disorders. The best known and most studied form of activity-dependent synaptic plasticity remains long-term potentiation (LTP), which is controlled by glutamatergic N-methyl-d-aspartate) receptors (NMDAR) and considered to be a mechanism crucial for cellular learning and memory. Over the past two decades, discrepancies have arisen in the literature regarding the contribution of NMDAR subunit assemblies in the direction of NMDAR-dependent synaptic plasticity. Here, the nonspecific NMDAR antagonist ketamine (5 and 10 mg/kg), and the selective NR2B antagonists CP-101606 and Ro 25-6981 (6 and 10 mg/kg), were administered intraperitoneally in Sprague Dawley rats to disentangle the contribution of NR2B subunit in the LTP induced at the Schaffer Collateral-CA1 synapse using the theta burst stimulation protocol (TBS). Ketamine reduced, while CP-101606 and Ro 25-6981 did not alter the LTP response. The administration of CP-101606 before TBS did not influence the effects of ketamine when administered half an hour after tetanization, suggesting a limited contribution of the NR2B subunit in the action of ketamine. This work confirms the role of NMDAR in the LTP form of synaptic plasticity, whereas specific blockade of the NR2B subunit was not sufficient to modify hippocampal LTP. Pharmacokinetics at the doses used may have contributed to the lack of effects with specific antagonists. The findings refute the role of the NR2B subunit in the plasticity mechanism of ketamine in the model. Full article
(This article belongs to the Special Issue Pharmacological Plasticity)
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27 pages, 3107 KiB  
Article
Drugs and Epigenetic Molecular Functions. A Pharmacological Data Scientometric Analysis
by Dario Kringel, Sebastian Malkusch and Jörn Lötsch
Int. J. Mol. Sci. 2021, 22(14), 7250; https://doi.org/10.3390/ijms22147250 - 6 Jul 2021
Cited by 12 | Viewed by 4540
Abstract
Interactions of drugs with the classical epigenetic mechanism of DNA methylation or histone modification are increasingly being elucidated mechanistically and used to develop novel classes of epigenetic therapeutics. A data science approach is used to synthesize current knowledge on the pharmacological implications of [...] Read more.
Interactions of drugs with the classical epigenetic mechanism of DNA methylation or histone modification are increasingly being elucidated mechanistically and used to develop novel classes of epigenetic therapeutics. A data science approach is used to synthesize current knowledge on the pharmacological implications of epigenetic regulation of gene expression. Computer-aided knowledge discovery for epigenetic implications of current approved or investigational drugs was performed by querying information from multiple publicly available gold-standard sources to (i) identify enzymes involved in classical epigenetic processes, (ii) screen original biomedical scientific publications including bibliometric analyses, (iii) identify drugs that interact with epigenetic enzymes, including their additional non-epigenetic targets, and (iv) analyze computational functional genomics of drugs with epigenetic interactions. PubMed database search yielded 3051 hits on epigenetics and drugs, starting in 1992 and peaking in 2016. Annual citations increased to a plateau in 2000 and show a downward trend since 2008. Approved and investigational drugs in the DrugBank database included 122 compounds that interacted with 68 unique epigenetic enzymes. Additional molecular functions modulated by these drugs included other enzyme interactions, whereas modulation of ion channels or G-protein-coupled receptors were underrepresented. Epigenetic interactions included (i) drug-induced modulation of DNA methylation, (ii) drug-induced modulation of histone conformations, and (iii) epigenetic modulation of drug effects by interference with pharmacokinetics or pharmacodynamics. Interactions of epigenetic molecular functions and drugs are mutual. Recent research activities on the discovery and development of novel epigenetic therapeutics have passed successfully, whereas epigenetic effects of non-epigenetic drugs or epigenetically induced changes in the targets of common drugs have not yet received the necessary systematic attention in the context of pharmacological plasticity. Full article
(This article belongs to the Special Issue Pharmacological Plasticity)
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17 pages, 13367 KiB  
Article
Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway
by Xiaohe Li, Ling Ma, Kai Huang, Yuli Wei, Shida Long, Qinyi Liu, Deqiang Zhang, Shuyang Wu, Wenrui Wang, Guang Yang, Honggang Zhou and Cheng Yang
Int. J. Mol. Sci. 2021, 22(4), 1985; https://doi.org/10.3390/ijms22041985 - 17 Feb 2021
Cited by 17 | Viewed by 3676
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway. Full article
(This article belongs to the Special Issue Pharmacological Plasticity)
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Review

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12 pages, 276 KiB  
Review
Factors Determining Plasticity of Responses to Drugs
by Michael J. Parnham and Jennifer A. Kricker
Int. J. Mol. Sci. 2022, 23(4), 2068; https://doi.org/10.3390/ijms23042068 - 13 Feb 2022
Cited by 3 | Viewed by 2002
Abstract
The plasticity of responses to drugs is an ever-present confounding factor for all aspects of pharmacology, influencing drug discovery and development, clinical use and the expectations of the patient. As an introduction to this Special Issue of the journal IJMS on pharmacological plasticity, [...] Read more.
The plasticity of responses to drugs is an ever-present confounding factor for all aspects of pharmacology, influencing drug discovery and development, clinical use and the expectations of the patient. As an introduction to this Special Issue of the journal IJMS on pharmacological plasticity, we address the various levels at which plasticity appears and how such variability can be controlled, describing the ways in which drug responses can be affected with examples. The various levels include the molecular structures of drugs and their receptors, expression of genes for drug receptors and enzymes involved in metabolism, plasticity of cells targeted by drugs, tissues and clinical variables affected by whole body processes, changes in geography and the environment, and the influence of time and duration of changes. The article provides a rarely considered bird’s eye view of the problem and is intended to emphasize the need for increased awareness of pharmacological plasticity and to encourage further debate. Full article
(This article belongs to the Special Issue Pharmacological Plasticity)
36 pages, 3526 KiB  
Review
Comprehensive Survey of Recent Drug Discovery Using Deep Learning
by Jintae Kim, Sera Park, Dongbo Min and Wankyu Kim
Int. J. Mol. Sci. 2021, 22(18), 9983; https://doi.org/10.3390/ijms22189983 - 15 Sep 2021
Cited by 73 | Viewed by 16302
Abstract
Drug discovery based on artificial intelligence has been in the spotlight recently as it significantly reduces the time and cost required for developing novel drugs. With the advancement of deep learning (DL) technology and the growth of drug-related data, numerous deep-learning-based methodologies are [...] Read more.
Drug discovery based on artificial intelligence has been in the spotlight recently as it significantly reduces the time and cost required for developing novel drugs. With the advancement of deep learning (DL) technology and the growth of drug-related data, numerous deep-learning-based methodologies are emerging at all steps of drug development processes. In particular, pharmaceutical chemists have faced significant issues with regard to selecting and designing potential drugs for a target of interest to enter preclinical testing. The two major challenges are prediction of interactions between drugs and druggable targets and generation of novel molecular structures suitable for a target of interest. Therefore, we reviewed recent deep-learning applications in drug–target interaction (DTI) prediction and de novo drug design. In addition, we introduce a comprehensive summary of a variety of drug and protein representations, DL models, and commonly used benchmark datasets or tools for model training and testing. Finally, we present the remaining challenges for the promising future of DL-based DTI prediction and de novo drug design. Full article
(This article belongs to the Special Issue Pharmacological Plasticity)
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22 pages, 914 KiB  
Review
The Impact of Diet and Exercise on Drug Responses
by Ellen Niederberger and Michael J. Parnham
Int. J. Mol. Sci. 2021, 22(14), 7692; https://doi.org/10.3390/ijms22147692 - 19 Jul 2021
Cited by 27 | Viewed by 13114
Abstract
It is well known that lifestyle changes can alter several physiological functions in the human body. For exercise and diet, these effects are used sensibly in basic therapies, as in cardiovascular diseases. However, the physiological changes induced by exercise and a modified diet [...] Read more.
It is well known that lifestyle changes can alter several physiological functions in the human body. For exercise and diet, these effects are used sensibly in basic therapies, as in cardiovascular diseases. However, the physiological changes induced by exercise and a modified diet also have the capacity to influence the efficacy and toxicity of several drugs, mainly by affecting different pharmacokinetic mechanisms. This pharmacological plasticity is not clinically relevant in all cases but might play an important role in altering the effects of very common drugs, particularly drugs with a narrow therapeutic window. Therefore, with this review, we provide insights into possible food–drug and exercise–drug interactions to sharpen awareness of the potential occurrence of such effects. Full article
(This article belongs to the Special Issue Pharmacological Plasticity)
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