scholarly journals Impetigo Animal Models: A Review of Their Feasibility and Clinical Utility for Therapeutic Appraisal of Investigational Drug Candidates

Antibiotics ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 694
Author(s):  
Solomon Abrha ◽  
Andrew Bartholomaeus ◽  
Wubshet Tesfaye ◽  
Jackson Thomas
Keyword(s):  
Animal Models ◽  
In Vivo Studies ◽  
Therapeutic Drug ◽  
Investigational Drug ◽  
Skin Infections ◽  
Drug Candidates ◽  
First Line Therapy ◽  
Superficial Skin

Impetigo (school sores), a superficial skin infection commonly seen in children, is caused by the gram-positive bacteria Staphylococcus aureus and/or Streptococcus pyogenes. Antibiotic treatments, often topical, are used as the first-line therapy for impetigo. The efficacy of potential new antimicrobial compounds is first tested in in vitro studies and, if effective, followed by in vivo studies using animal models and/or humans. Animal models are critical means for investigating potential therapeutics and characterizing their safety profile prior to human trials. Although several reviews of animal models for skin infections have been published, there is a lack of a comprehensive review of animal models simulating impetigo for the selection of therapeutic drug candidates. This review critically examines the existing animal models for impetigo and their feasibility for testing the in vivo efficacy of topical treatments for impetigo and other superficial bacterial skin infections.

Novel Phytochemical Constituents and their Potential to Manage Diabetes

2020 ◽  
Vol 26 ◽  
Author(s):  
Shaik Ibrahim Khalivulla ◽  
Arifullah Mohammed ◽  
Kokkanti Mallikarjuna
Keyword(s):  
Natural Products ◽  
Large Population ◽  
World Health ◽  
In Vivo Studies ◽  
Antidiabetic Activity ◽  
Therapeutic Drug ◽  
Pharmacological Activities ◽  
Chemical Structures

Background: Diabetes is a chronic disease affecting a large population worldwide and stands as one of the major global health challenges to be tackled. According to World Health Organization, about 400 million are having diabetes worldwide and it is the seventh leading cause of deaths in 2016. Plant based natural products had been in use from ancient time as ethnomedicine for the treatment of several diseases including diabetes. As a result of that, there are several reports on plant based natural products displaying antidiabetic activity. In the current review, such antidiabetic potential compounds reported from all plant sources along with their chemical structures are collected, presented and discussed. This kind of reports are essential to pool the available information to one source followed by statistical analysis and screening to check the efficacy of all known compounds in a comparative sense. This kind of analysis can give rise to few numbers of potential compounds from hundreds, whom can further be screened through in vitro and in vivo studies, and human trails leading to the drug development. Methods: Phytochemicals along with their potential antidiabetic property were classified according to their basic chemical skeleton. The chemical structures of all the compounds with antidiabetic activities were elucidated in the present review. In addition to this, the distribution and their other remarkable pharmacological activities of each species is also included. Results: The scrutiny of literature led to identification of 44 plants with antidiabetic compounds (70) and other pharmacological activities. For the sake of information, the distribution of each species in the world is given. Many plant derivatives may exert antidiabetic properties by improving or mimicking the insulin production or action. Different classes of compounds including sulfur compounds (1-4), alkaloids (5-11), phenolic compounds (12-17), tannins (18-23), phenylpropanoids (24-27), xanthanoids (28-31), amino acid (32), stilbenoid (33), benzofuran (34), coumarin (35), flavonoids (36-49) and terpenoids (50-70) were found to be active potential compounds for antidiabetic activity. Of the 70 listed compounds, majorly 17 compounds are from triterpenoids, 13 flavonoids and 7 are from alkaloids. Among all the 44 plant species, maximum number (7) of compounds are reported from Lagerstroemia speciosa followed by Momordica charantia (6) and S. oblonga with 5 compounds. Conclusion: This is the first paper to summarize the established chemical structures of phytochemicals that have been successfully screened for antidiabetic potential and their mechanisms of inhibition. The reported compounds could be considered as potential lead molecules for the treatment of type-2 diabetes. Further, molecular and clinical trials are required to select and establish the therapeutic drug candidates.

Transplantation of Adipose-derived Cells for Periodontal Regeneration: A Systematic Review

2019 ◽  
Vol 14 (6) ◽  
pp. 504-518 ◽  
Author(s):  
Dilcele Silva Moreira Dziedzic ◽  
Bassam Felipe Mogharbel ◽  
Priscila Elias Ferreira ◽  
Ana Carolina Irioda ◽  
Katherine Athayde Teixeira de Carvalho
Keyword(s):  
Systematic Review ◽  
Animal Models ◽  
Platelet Rich Plasma ◽  
Periodontal Regeneration ◽  
In Vitro Studies ◽  
In Vivo Studies ◽  
Cell Sources ◽  
Study Designs

This systematic review evaluated the transplantation of cells derived from adipose tissue for applications in dentistry. SCOPUS, PUBMED and LILACS databases were searched for in vitro studies and pre-clinical animal model studies using the keywords “ADIPOSE”, “CELLS”, and “PERIODONTAL”, with the Boolean operator “AND”. A total of 160 titles and abstracts were identified, and 29 publications met the inclusion criteria, 14 in vitro and 15 in vivo studies. In vitro studies demonstrated that adipose- derived cells stimulate neovascularization, have osteogenic and odontogenic potential; besides adhesion, proliferation and differentiation on probable cell carriers. Preclinical studies described improvement of bone and periodontal healing with the association of adipose-derived cells and the carrier materials tested: Platelet Rich Plasma, Fibrin, Collagen and Synthetic polymer. There is evidence from the current in vitro and in vivo data indicating that adipose-derived cells may contribute to bone and periodontal regeneration. The small quantity of studies and the large variation on study designs, from animal models, cell sources and defect morphology, did not favor a meta-analysis. Additional studies need to be conducted to investigate the regeneration variability and the mechanisms of cell participation in the processes. An overview of animal models, cell sources, and scaffolds, as well as new perspectives are provided for future bone and periodontal regeneration study designs.

scholarly journals Predicting Absorption-Distribution Properties of Neuroprotective Phosphine-Borane Compounds Using In Silico Modeling and Machine Learning

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2505
Author(s):  
Raheem Remtulla ◽  
Sanjoy Kumar Das ◽  
Leonard A. Levin
Keyword(s):  
Machine Learning ◽  
Neural Networks ◽  
In Silico ◽  
Disulfide Bonds ◽  
Oral Absorption ◽  
In Vivo Studies ◽  
Drug Candidates ◽  
In Silico Methods

Phosphine-borane complexes are novel chemical entities with preclinical efficacy in neuronal and ophthalmic disease models. In vitro and in vivo studies showed that the metabolites of these compounds are capable of cleaving disulfide bonds implicated in the downstream effects of axonal injury. A difficulty in using standard in silico methods for studying these drugs is that most computational tools are not designed for borane-containing compounds. Using in silico and machine learning methodologies, the absorption-distribution properties of these unique compounds were assessed. Features examined with in silico methods included cellular permeability, octanol-water partition coefficient, blood-brain barrier permeability, oral absorption and serum protein binding. The resultant neural networks demonstrated an appropriate level of accuracy and were comparable to existing in silico methodologies. Specifically, they were able to reliably predict pharmacokinetic features of known boron-containing compounds. These methods predicted that phosphine-borane compounds and their metabolites meet the necessary pharmacokinetic features for orally active drug candidates. This study showed that the combination of standard in silico predictive and machine learning models with neural networks is effective in predicting pharmacokinetic features of novel boron-containing compounds as neuroprotective drugs.

A review on Remdesivir: A broad-spectrum antiviral molecule for possible COVID-19 treatment

2021 ◽  
Vol 21 ◽  
Author(s):  
Jabeena Khazir ◽  
Tariq Maqbool ◽  
Bilal Ahmad Mir
Keyword(s):  
Clinical Trials ◽  
Broad Spectrum ◽  
Ebola Virus ◽  
Controlled Trial ◽  
In Vivo Studies ◽  
Therapeutic Drug ◽  
Viral Agent ◽  
Double Blind

: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel coronavirus strain and the causative agent of COVID-19 was identified to have emerged in Wuhan, China, in December 2019 [1]. This pandemic situation and magnitude of suffering has led to global effort to find out effective measures for discovery of new specific drugs and vaccines to combat this deadly disease. In addition to many initiatives to develop vaccines for protective immunity against SARS-CoV-2, some of which are at various stages of clinical trials researchers worldwide are currently using available conventional therapeutic drugs with potential to combat the disease effectively in other viral infections and it is believed that these antiviral drugs could act as a promising immediate alternative. Remdesivir (RDV), a broad-spectrum anti-viral agent, initially developed for the treatment of Ebola virus (EBOV) and known to show promising efficiency in in vitro and in vivo studies against SARS and MERS coronaviruses, is now being investigated against SARS-CoV-2. On May 1, 2020, The U.S. Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) for RDV to treat COVID-19 patients [2]. A number of multicentre clinical trials are on-going to check the safety and efficacy of RDV for the treatment of COVID-19. Results of published double blind, and placebo-controlled trial on RDV against SARS-CoV-2, showed that RDV administration led to faster clinical improvement in severe COVID-19 patients compared to placebo. This review highlights the available knowledge about RDV as a therapeutic drug for coronaviruses and its preclinical and clinical trials against COVID-19.

P0554IN VITRO ASSESSMENT OF HA330 CARTRIDGE ADSORPTION CAPACITY REALTED TO VANCOMYCIN

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Anna Lorenzin ◽  
Llaria Godi ◽  
Massimo De Cal ◽  
Claudio Ronco
Keyword(s):  
Adsorption Isotherm ◽  
In Vitro Study ◽  
Potential Interaction ◽  
Blood Purification ◽  
Reduction Ratio ◽  
In Vivo Studies ◽  
Adsorptive Capacity ◽  
Therapeutic Drug

Abstract Background and Aims The rationale for blood purification as adjunctive therapy during sepsis involved the capacity in removing endogenous and exogenous toxins, but currently no recommendations exists [1]. A critical point may be the potential interaction with antimicrobial therapy, which remains the mainstay of sepsis treatment. HA330 cartridge (Jafron, Zhuhai City, China), widely used in China and actually available in Europe, is used in hemoperfusion for blood purification in septic patients.The aim of this in vitro study was to investigate the adsorptive capacity of HA330 related to vancomycin (VAN). Reference: 1. Rhodes A et al. Crit Care Med 45:486-552. 2017 Method This is an experimental study, simulating an hemoperfusion treatment with HA330. We circulated (250 ml/min) in a closed loop 500 ml of normal saline solution enriched with VAN, stirred and maintained at 37°C. We spiked 100 mg of VAN every 15 minutes to increase the antibiotic load until reaching 1500 mg, the last injection was 500 mg to get a total amount of 2 g. Samples were collected from the inlet line at each VAN adjunct, after system stabilization. Measured VAN concentrations were used to get the adsorption isotherm: for each VAN load, the adsorbed amount of VAN was obtained by multiplying VAN reduction ratio and the quantity of VAN injected. Results Figure 1 shows VAN adsorption isotherm obtained with HA330 cartridge. We observed that, at each injection, after 15 minutes VAN was almost entirely adsorbed by the cartridge, with an average reduction ratio of 0.96. Interestingly, this was confirmed even adding 500 mg at once. Even increasing the VAN load to 500 mg at once, the reduction ratio was maintained. Conclusion In our study, simulating hemoperfusion using HA330, a rapid and clinically relevant removal of VAN has been shown. A significant amount of VAN (2g) was adsorbed without reaching membrane saturation nor reducing its adsorptive capacity. In a clinical setting, we recommend a therapeutic drug monitoring to optimize VAN levels during blood purification with HA330 and a VAN loading dose may be considered. Further in vivo studies are warranted to confirm these findings.

scholarly journals Immune responses to azacytidine in animal models of inflammatory disorders: a systematic review

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Sija Landman ◽  
Chiel van der Horst ◽  
Piet E. J. van Erp ◽  
Irma Joosten ◽  
Rob de Vries ◽  
...  
Keyword(s):  
Animal Models ◽  
Risk Of Bias ◽  
New Drugs ◽  
In Vivo Studies ◽  
Common Mechanism ◽  
Solid Organ ◽  
Inflammatory Disorders ◽  
Organ Rejection

AbstractInflammatory disorders like diabetes, systemic lupus erythematodes, inflammatory lung diseases, rheumatoid arthritis and multiple sclerosis, but also rejection of transplanted organs and GvHD, form a major burden of disease. Current classes of immune suppressive drugs to treat these disorders are never curative and side effects are common. Therefore there is a need for new drugs with improved and more targeted modes of action. Potential candidates are the DNA methyl transferase inhibitor 5-azacytidine (Aza) and its derivative 5-aza 2′deoxycitidine (DAC). Aza and DAC have been tested in several pre-clinical in vivo studies. In order to obtain an overview of disorders for which Aza and/or DAC can be a potential treatment, and to find out where information is lacking, we systematically reviewed pre-clinical animal studies assessing Aza or DAC as a potential therapy for distinct inflammatory disorders. Also, study quality and risk of bias was systematically assessed. In the 35 identified studies, we show that both Aza and DAC do not only seem to be able to alleviate a number of inflammatory disorders, but also prevent solid organ rejection and GvHD in in vivo pre-clinical animal models. Aza/DAC are known to upregulate FOXP3, a master transcription factor for Treg, in vitro. Seventeen studies described the effect on Treg, of which 16 studies showed an increase in Treg. Increasing Treg therefore seems to be a common mechanism in preventing inflammatory disorders by Aza/DAC. We also found, however, that many essential methodological details were poorly reported leading to an unclear risk of bias. Therefore, reported effects might be an overestimation of the true effect.

scholarly journals Critical Considerations for the Design of Multi-Organ Microphysiological Systems (MPS)

2021 ◽  
Vol 9 ◽  
Author(s):  
Mridu Malik ◽  
Yang Yang ◽  
Parinaz Fathi ◽  
Gretchen J. Mahler ◽  
Mandy B. Esch
Keyword(s):  
Animal Models ◽  
Drug Toxicity ◽  
New Drugs ◽  
Drug Candidate ◽  
Preclinical Studies ◽  
Toxicity Screening ◽  
Drug Candidates ◽  
Microphysiological Systems

Identification and approval of new drugs for use in patients requires extensive preclinical studies and clinical trials. Preclinical studies rely on in vitro experiments and animal models of human diseases. The transferability of drug toxicity and efficacy estimates to humans from animal models is being called into question. Subsequent clinical studies often reveal lower than expected efficacy and higher drug toxicity in humans than that seen in animal models. Microphysiological systems (MPS), sometimes called organ or human-on-chip models, present a potential alternative to animal-based models used for drug toxicity screening. This review discusses multi-organ MPS that can be used to model diseases and test the efficacy and safety of drug candidates. The translation of an in vivo environment to an in vitro system requires physiologically relevant organ scaling, vascular dimensions, and appropriate flow rates. Even small changes in those parameters can alter the outcome of experiments conducted with MPS. With many MPS devices being developed, we have outlined some established standards for designing MPS devices and described techniques to validate the devices. A physiologically realistic mimic of the human body can help determine the dose response and toxicity effects of a new drug candidate with higher predictive power.

The effects of PDE inhibitors on multiple sclerosis: a review of in vitro and in vivo models

2021 ◽  
Vol 27 ◽  
Author(s):  
Alexandra Ainatzoglou ◽  
Eleni Stamoula ◽  
Ioannis Dardalas ◽  
Spyridon Siafis ◽  
Georgios Papazisis
Keyword(s):  
Multiple Sclerosis ◽  
Animal Models ◽  
In Vivo Studies ◽  
Pde4 Inhibitor ◽  
Neuroprotective Effects ◽  
In Vivo Models ◽  
Pde Inhibitors ◽  
Ms Therapy

Background: Multiple sclerosis (MS) is a chronic inflammatory and immune-mediated disease, whose current therapeutic means are mostly effective in the relapsing-remitting form of MS, where inflammation is still prominent, but fall short of preventing long term impairment. However, apart from inflammation-mediated demyelination, autoimmune mechanisms play a major role in MS pathophysiology, constituting a promising pharmacological target. Phosphodiesterase (PDE) inhibitors have been approved for clinical use in psoriasis and have undergone trials suggesting their neuroprotective effects, rendering them eligible as an option for accessory MS therapy. Objective: In this review, we discuss the potential role of PDE inhibitors as a complementary MS therapy. Methods: We conducted a literature search through which we screened and comparatively assessed papers on the effects of PDE inhibitor use, both in vitro and in animal models of MS, taking into account a number of inclusion and exclusion criteria. Results: In vitro studies indicated that PDE inhibitors promote remyelination and axonal sustenance, while curbing inflammatory cell infiltration, hindering oligodendrocyte and neuronal loss and suppressing cytokine production. In vivo studies underlined that these agents alleviate symptoms and reduce disease scores in MS animal models. Conclusion: PDE inhibitors proved to be effective in addressing various aspects of MS pathogenesis both in vitro and in vivo models. Given the latest clinical trials proving that the PDE4 inhibitor Ibudilast exerts neuroprotective effects in patients with progressive MS, research on this field should be intensified and selective PDE4 inhibitors with enhanced safety features should be seriously considered as prospective complementary MS therapy.

scholarly journals HGG-23. IN VITRO AND IN VIVO PRECLINICAL DRUG SCREENING OF PROMISING THERAPEUTICS FOR DIFFUSE MIDLINE GLIOMA (DMG)

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i21-i22
Author(s):  
Chiara Cianciolo Cosentino ◽  
Sandra Laternser ◽  
Justyna M Przystal ◽  
Sridevi Yadavilli ◽  
Jie Zhang ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Tumor Biology ◽  
In Vivo Studies ◽  
Continuous Exposure ◽  
Intrinsic Resistance ◽  
Drug Candidates ◽  
Zebrafish Larvae ◽  
Wide Range

Abstract Introduction Diffuse midline gliomas (DMGs) are amongst the most unforgiving pediatric brain tumors, characterized by an intrinsic resistance to therapy. Despite major advances in understanding of tumor biology, the prognosis remains exceedingly poor, and treatment options are limited. New therapeutics are being evaluated at a fast rate by different laboratories. In order to prioritize effective drug candidates for DMG treatment, we comprehensively characterized a panel of promising therapeutic agents in in vitro and in different vivo systems. Methods We determined the sensitivity of primary DMG cell lines to a panel of small molecule inhibitors targeting known DMG targets and pathways. Dose response curves were generated for more than 20 different compounds and possible synergistic effects were investigated by SynergieFinder. In an effort to highlight potential toxicities and associated mechanisms at a large scale, we performed a preclinical toxicity evaluation in zebrafish larvae, with a slightly modified version of the official Fish Embryo Acute Toxicity (FET) test. Drug toxicity was tested by continuous exposure of zebrafish larvae to increasing concentrations of the different compounds. Survival curves, morphological analyses and behavioral tests were performed at a maximum tolerated dose (MTD). To confirm the findings obtained in zebrafish, we further performed in vivo studies in mice for promising candidates. Results Among the tested drugs in vitro we found 10 drugs showing promising dose- dependent reduction in cell viability with IC50 in nM to µM range. These were further evaluated for toxicity in zebrafish. The zebrafish larvae toxicities observations strongly correlated with the findings in murine in vivo studies, reinforcing the importance of zebrafish as an accurate investigative toxicology model to assess acute toxicity of molecules in preclinical studies. Conclusions By testing a wide range of drugs, targeting different pathways on DMG cells and in different in vivo systems we identified promising drug candidates for clinical management of children diagnosed with DMG.

scholarly journals Structure-Based Virtual Screening and Molecular Dynamics of Phytochemicals Derived from Saudi Medicinal Plants to Identify Potential COVID-19 Therapeutics

2020 ◽  
Author(s):  
MUBARAK ALAMRI ◽  
Ali Altharawi ◽  
Alhumaidi B. Alabbas ◽  
Manal A. Alossaimi ◽  
Safar M. Alqahtani
Keyword(s):  
Virtual Screening ◽  
Medicinal Plants ◽  
In Vivo Studies ◽  
Effective Vaccine ◽  
Traditional Medicines ◽  
Drug Candidates ◽  
Computational Screening ◽  
Novel Coronavirus

Coronavirus disease 2019 (COVID-19) has affected almost every country in the world by causing a global pandemic with a high mortality rate. Lack of an effective vaccine and/or antiviral drugs against SARS-CoV-2, the causative agent, has severely hampered the response to this novel coronavirus. Natural products have long been used in traditional medicines to treat various diseases, and purified phytochemicals from medicinal plants provide a valuable scaffold for the discovery of new drug leads. In the present study, we performed a computational screening of an in-house database composed of ~1000 phytochemicals derived from traditional Saudi medicinal plants with recognised antiviral activity. Structure-based virtual screening was carried out against three druggable SARS-CoV-2 targets, viral RNAdependent RNA polymerase (RdRp), 3-chymotrypsin-like cysteine protease (3CLpro) and papain like protease (PLpro) to identify putative inhibitors that could facilitate the development of potential anti-COVID-19 drug candidates. Computational analyses identified three compounds inhibiting each target, with binding affinity scores ranging from-9.9 to -6.5 kcal/mol. Among these, luteolin 7-rutinoside, chrysophanol 8-(6-galloylglucoside) and kaempferol 7-(6’’-galloylglucoside) bound efficiently to RdRp, while chrysophanol 8-(6galloylglucoside), 3,4,5-tri-O-galloylquinic acid and mulberrofuran G interacted strongly with 3CLpro, and withanolide A, isocodonocarpine and calonysterone bound tightly to PLpro. These potential drug candidates will be subjected to further in vitro and in vivo studies and may assist the development of effective anti-COVID-19 drugs.

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