scholarly journals Preclinical in vivo Neurotoxicity Studies of Drug Candidates

2020 ◽  
Vol 10 (3) ◽  
pp. 164-176
Author(s):  
N. V. Eremina ◽  
L. G. Kolik ◽  
R. U. Ostrovskaya ◽  
A. D. Durnev
Keyword(s):  
Cognitive Functions ◽  
New Drugs ◽  
Laboratory Animals ◽  
Preclinical Studies ◽  
Early Assessment ◽  
Factors Affecting ◽  
Early Stages ◽  
Wide Range ◽  
Neurotoxic Effects

Neurotoxic effects are one of the common reasons for discontinuation of preclinical and/or clinical studies. Preclinical evaluation of neurotoxic effects is complicated due to a wide range of manifestations and degrees of severity. Current experimental approaches to neurotoxicity assessment are cumbersome, laborious and not adapted enough for preclinical studies in the early stages of drug development. The aim of the study was to review existing approaches to experimental assessment of neurotoxic potential of new drugs and to discuss the need for and feasibility of developing and using integrated rapid neurotoxicity tests for early assessment of a pharmacological project’s potential. The authors reviewed scientific literature and guidance documents and analysed current approaches to chemical compound neurotoxicity assessment in laboratory animals. The paper analyses the main issues of neurotoxicity assessment for new drugs and compares Irwin tests with the functional observation battery. It analyses issues related to assessment of drugs’ effects on the development and maturation of central nervous system functions at pre- and postnatal stages. It was determined that the current practice is not sufficient for assessment of potential adverse effects on cognitive functions. The authors assessed factors affecting cognitive functions of rodents during studies. The “Acute suppression of the exploratory and orientation response” and “Extrapolation escape task” tests were proposed for validation as potential rapid tests for detection of an array of organic and functional neurotoxic disorders at early stages of preclinical studies.

scholarly journals Foeniculum vulgareMill: A Review of Its Botany, Phytochemistry, Pharmacology, Contemporary Application, and Toxicology

2014 ◽  
Vol 2014 ◽  
pp. 1-32 ◽  
Author(s):  
Shamkant B. Badgujar ◽  
Vainav V. Patel ◽  
Atmaram H. Bandivdekar
Keyword(s):  
Traditional Medicine ◽  
Scientific Evidence ◽  
New Drugs ◽  
Future Research ◽  
Foeniculum Vulgare ◽  
Wide Range ◽  
Research Findings ◽  
Valuable Compounds

Foeniculum vulgareMill commonly called fennel has been used in traditional medicine for a wide range of ailments related to digestive, endocrine, reproductive, and respiratory systems. Additionally, it is also used as a galactagogue agent for lactating mothers. The review aims to gather the fragmented information available in the literature regarding morphology, ethnomedicinal applications, phytochemistry, pharmacology, and toxicology ofFoeniculum vulgare. It also compiles available scientific evidence for the ethnobotanical claims and to identify gaps required to be filled by future research. Findings based on their traditional uses and scientific evaluation indicates thatFoeniculum vulgareremains to be the most widely used herbal plant. It has been used for more than forty types of disorders. Phytochemical studies have shown the presence of numerous valuable compounds, such as volatile compounds, flavonoids, phenolic compounds, fatty acids, and amino acids. Compiled data indicate their efficacy in severalin vitroandin vivopharmacological properties such as antimicrobial, antiviral, anti-inflammatory, antimutagenic, antinociceptive, antipyretic, antispasmodic, antithrombotic, apoptotic, cardiovascular, chemomodulatory, antitumor, hepatoprotective, hypoglycemic, hypolipidemic, and memory enhancing property.Foeniculum vulgarehas emerged as a good source of traditional medicine and it provides a noteworthy basis in pharmaceutical biology for the development/formulation of new drugs and future clinical uses.

scholarly journals Development of a Fluorescent Assay to Search New Drugs Using Stable tdTomato-Leishmania, and the Selection of Galangin as a Candidate With Anti-Leishmanial Activity

2021 ◽  
Vol 11 ◽  
Author(s):  
María Fernanda García-Bustos ◽  
Agustín Moya Álvarez ◽  
Cecilia Pérez Brandan ◽  
Cecilia Parodi ◽  
Andrea Mabel Sosa ◽  
...  
Keyword(s):  
Active Compound ◽  
Wild Strain ◽  
Fluorescence Assay ◽  
New Drugs ◽  
Lipid Inclusion ◽  
Screening Assay ◽  
Meglumine Antimoniate ◽  
Wide Range

Antimonials continue to be considered the first-line treatment for leishmaniases, but its use entails a wide range of side effects and serious reactions. The search of new drugs requires the development of methods more sensitive and faster than the conventional ones. We developed and validated a fluorescence assay based in the expression of tdTomato protein by Leishmania, and we applied this method to evaluate the activity in vitro of flavonoids and reference drugs. The pIR1SAT/tdTomato was constructed and integrated into the genome of Leishmania (Leishmania) amazonensis. Parasites were selected with nourseothricin (NTC). The relation of L. amaz/tc3 fluorescence and the number of parasites was determined; then the growth in vitro and infectivity in BALB/c mice was characterized. To validate the fluorescence assay, the efficacy of miltefosine and meglumine antimoniate was compared with the conventional methods. After that, the method was used to assess in vitro the activity of flavonoids; and the mechanism of action of the most active compound was evaluated by transmission electron microscopy and ELISA. A linear correlation was observed between the emission of fluorescence of L. amaz/tc3 and the number of parasites (r2 = 0.98), and the fluorescence was stable in the absence of NTC. No differences were observed in terms of infectivity between L. amaz/tc3 and wild strain. The efficacy of miltefosine and meglumine antimoniate determined by the fluorescence assay and the microscopic test showed no differences, however, in vivo the fluorescence assay was more sensitive than limiting dilution assay. Screening assay revealed that the flavonoid galangin (GAL) was the most active compound with IC50 values of 53.09 µM and 20.59 µM in promastigotes and intracellular amastigotes, respectively. Furthermore, GAL induced mitochondrial swelling, lipid inclusion bodies and vacuolization in promastigotes; and up-modulated the production of IL-12 p70 in infected macrophages. The fluorescence assay is a useful tool to assess the anti-leishmanial activity of new compounds. However, the assay has some limitations in the macrophage-amastigote model that might be related with an interfere of flavanol aglycones with the fluorescence readout of tdTomato. Finally, GAL is a promising candidate for the development of new treatment against the leishmaniasis.

scholarly journals Characterization of the phototoxicity, chemigenetic profile, and mutational signatures of the chemotherapeutic CX-5461 in Caenorhabditis elegans

2019 ◽  
Author(s):  
Frank B. Ye ◽  
Akil Hamza ◽  
Tejomayee Singh ◽  
Stephane Flibotte ◽  
Philip Hieter ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Cancer Therapeutics ◽  
Copy Number Variations ◽  
Factors Affecting ◽  
C Elegans ◽  
Dna Damaging Agents ◽  
Wide Range ◽  
Anti Cancer ◽  
Exogenous Factors

ABSTRACTNew anti-cancer therapeutics require extensive in vivo characterization to identify endogenous and exogenous factors affecting efficacy, to measure toxicity and mutagenicity, and to determine genotypes resulting in therapeutic sensitivity or resistance. We used Caenorhabditis elegans as a platform with which to characterize properties of anti-cancer therapeutic agents in vivo. We generated a map of chemigenetic interactions between DNA damage response mutants and common DNA damaging agents. We used this map to investigate the properties of the new anti-cancer therapeutic CX-5461. We phenocopied the photoreactivity observed in CX-5461 clinical trials and found that CX-5461 generates reactive oxygen species when exposed to UVA radiation. We demonstrated that CX-5461 is a mutator, resulting in both large copy number variations and a high frequency of single nucleotide variations (SNVs). CX-5461-induced SNVs exhibited a distinct mutational signature. Consistent with the wide range of CX-5461-induced mutation types, we found that multiple repair pathways were needed for CX-5461 tolerance. Together, the data from C. elegans demonstrate that CX-5461 is a multimodal DNA damaging agent with strong similarity to ellipticines, a class of antineoplastic agents, and to anthracycline-based chemotherapeutics.

Isolated hemoperfused heart model of slaughterhouse pigs

2001 ◽  
Vol 24 (4) ◽  
pp. 215-221 ◽  
Author(s):  
D. Modersohn ◽  
S. Eddicks ◽  
C. Grosse-Siestrup ◽  
I. Ast ◽  
S. Holinski ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Heart Function ◽  
Animal Experiments ◽  
Laboratory Animals ◽  
Coronary Perfusion ◽  
Balloon Catheters ◽  
Wide Range ◽  
Infusion Of Norepinephrine

A model of hemoperfused slaughterhouse pighearts is described providing a wide range of applications which leads to a reduction in animal experiments. The size of a pigheart, heart rate, coronary perfusion, metabolism, etc. are more comparable to conditions in patients than those in hearts of small laboratory animals. Global heart function can be assessed either by measuring stroke volume, ejection fraction, Emaxetc. in the working model or by measuring intraventricular pressure with balloon catheters in the isovolumetric model. Regional cardiac function can be measured by sonomicrometry and ischemic and non-ischemic areas can be compared. Local metabolic changes are measurable as well with microdialysis. Cardiac function can be kept on any given functional level by infusion of norepinephrine in spite of the fact that functional parameters are lower without adrenergic drive in vitro than in vivo. Stable heart function can be maintained for several hours with only 500 to 1000 ml of blood because the blood is permanently regenerated by a special dialysis system. This model can be applied in many research projects dealing with reperfusion injuries, inotropic, antiarrhythmic or arrhythmogenic effects of certain drugs, immunological rejection, evaluation of imaging systems (NMR, echocardiography etc.) or cardiac assist devices.

Prospects for the application of lignin containing sorbents in veterinary medicine

2020 ◽  
pp. 29-30
Author(s):  
Anastasiya A. Moroz ◽  
◽  
Svetlana A. Schislenko ◽  
Keyword(s):  
Veterinary Medicine ◽  
Laboratory Animals ◽  
Gastrointestinal Infections ◽  
Animal Products ◽  
High Sorption Capacity ◽  
E Coli ◽  
Wide Range ◽  
High Sorption ◽  
Acute Form

Vaccines against colibacillosis are mainly used, containing only one specific variant of pathogenic E. coli with a preventive purpose among the livestock of stationary dysfunctional farms in conditions of Krasnoyarsk region. For therapeutic purposes, veterinarians usually use wide range of antimicrobial preparations to combat outbreaks of gastrointestinal infections. Many researchers point to the high variability of E. coli bacteria. Use of such preparations, in addition to the formation of high resistance in opportunistic microorganisms to the latter, provoke the accumulation of antibacterial drugs in animal products. Authors conducted studies of the possibility of the practical use of lignin-containing sorbents for therapeutic and prophylactic purposes in field of veterinary medicine in the period from 2001 to 2020. Authors proposed to use the residues after extraction, formed during the complex processing of larch bark, as an enterosorbent. Authors studied the therapeutic and prophylactic effect of enterosorbent from larch bark in case of gastrointestinal infections in experiments in vivo. It was found that the use of the sorbent for therapeutic purposes for 2 days ensured the safety of laboratory animals in the acute form of colibacillosis infection. Preservation was ensured by preventing the penetration of microbial toxins into the tissues of the gastrointestinal tract. The prophylactic and therapeutic efficacy of the investigated type of enterosorbent is associated with angioprotective, antitoxic effects due to the high sorption capacity of the drugs.

scholarly journals Magnetic Resonance Imaging for Translational Research in Oncology

2019 ◽  
Vol 8 (11) ◽  
pp. 1883 ◽  
Author(s):  
Maria Felicia Fiordelisi ◽  
Carlo Cavaliere ◽  
Luigi Auletta ◽  
Luca Basso ◽  
Marco Salvatore
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Small Animal ◽  
Laboratory Animals ◽  
Resonance Imaging ◽  
Preclinical Research ◽  
Ongoing Research ◽  
Wide Range

The translation of results from the preclinical to the clinical setting is often anything other than straightforward. Indeed, ideas and even very intriguing results obtained at all levels of preclinical research, i.e., in vitro, on animal models, or even in clinical trials, often require much effort to validate, and sometimes, even useful data are lost or are demonstrated to be inapplicable in the clinic. In vivo, small-animal, preclinical imaging uses almost the same technologies in terms of hardware and software settings as for human patients, and hence, might result in a more rapid translation. In this perspective, magnetic resonance imaging might be the most translatable technique, since only in rare cases does it require the use of contrast agents, and when not, sequences developed in the lab can be readily applied to patients, thanks to their non-invasiveness. The wide range of sequences can give much useful information on the anatomy and pathophysiology of oncologic lesions in different body districts. This review aims to underline the versatility of this imaging technique and its various approaches, reporting the latest preclinical studies on thyroid, breast, and prostate cancers, both on small laboratory animals and on human patients, according to our previous and ongoing research lines.

Oxygen uptake of developing eggs of Cancer pagurus (Crustacea: Decapoda: Cancridae) and consequent behaviour of the ovigerous females

1999 ◽  
Vol 79 (2) ◽  
pp. 305-315 ◽  
Author(s):  
J.K. Naylor ◽  
E.W. Taylor ◽  
D.B. Bennett
Keyword(s):  
Oxygen Uptake ◽  
Egg Mass ◽  
Seasonal Temperature ◽  
Mean Values ◽  
Factors Affecting ◽  
Cancer Pagurus ◽  
Partial Pressures ◽  
Ambient Oxygen ◽  
Wide Range

This study investigated factors affecting the metabolic rate of Cancer pagurus eggs. The oxygen uptake of portions of the egg mass and recently hatched zoeae was measured. Oxygen uptake of the eggs of an individual animal was found to vary widely, with measured mean values under normoxic conditions ranging from 38 to 250 μmoles O2 kg−1 min−1. Mean values for the oxygen uptake of zoeae ranged from 958 to 1168 μmoles O2 kg−1 min−1. Mean rates of oxygen uptake of the eggs generally increased with increasing seasonal temperature and advancing developmental stage. Rates of oxygen uptake were maintained over a wide range of ambient oxygen partial pressures. As oxygen partial pressure in the seawater surrounding the eggs fell from a critical value (Pc) of between 60 and 90 mm Hg, the oxygen uptake of the eggs also declined. Mean values for ambient oxygen partial pressures within the egg mass in vivo ranged from 34 to 98 mm Hg. Adult female C. pagurus appear to be able to detect conditions within the egg mass and adjust their egg ventilation behaviour accordingly. Active egg mass ventilation by the adult increased as the eggs became more developed and their oxygen demands increased.

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.

scholarly journals Evolution of Antibacterial Drug Screening Methods: Current Prospects for Mycobacteria

2021 ◽  
Vol 9 (12) ◽  
pp. 2562
Author(s):  
Clara M. Bento ◽  
Maria Salomé Gomes ◽  
Tânia Silva
Keyword(s):  
Rapid Development ◽  
Drug Susceptibility Testing ◽  
New Drugs ◽  
Host Cells ◽  
Screening Methods ◽  
Antibacterial Drug ◽  
Efficient Treatment ◽  
Wide Range

The increasing resistance of infectious agents to available drugs urges the continuous and rapid development of new and more efficient treatment options. This process, in turn, requires accurate and high-throughput techniques for antimicrobials’ testing. Conventional methods of drug susceptibility testing (DST) are reliable and standardized by competent entities and have been thoroughly applied to a wide range of microorganisms. However, they require much manual work and time, especially in the case of slow-growing organisms, such as mycobacteria. Aiming at a better prediction of the clinical efficacy of new drugs, in vitro infection models have evolved to closely mimic the environment that microorganisms experience inside the host. Automated methods allow in vitro DST on a big scale, and they can integrate models that recreate the interactions that the bacteria establish with host cells in vivo. Nonetheless, they are expensive and require a high level of expertise, which makes them still not applicable to routine laboratory work. In this review, we discuss conventional DST methods and how they should be used as a first screen to select active compounds. We also highlight their limitations and how they can be overcome by more complex and sophisticated in vitro models that reflect the dynamics present in the host during infection. Special attention is given to mycobacteria, which are simultaneously difficult to treat and especially challenging to study in the context of DST.

Potential repurposing of drugs with anti-SARS-CoV-2 activity in preclinical trials: a systematic review

2020 ◽  
Vol 27 ◽  
Author(s):  
Yasmim Mendes Rocha ◽  
Gabriel Acácio de Moura ◽  
Juliana Ramos de Oliveira ◽  
Larissa Deadame de Figueiredo Nicolete ◽  
Roberto Nicolete
Keyword(s):  
Control Measures ◽  
New Drugs ◽  
Preclinical Studies ◽  
New Techniques ◽  
Major Threat ◽  
Preclinical Trials ◽  
In Silico Analyses ◽  
Potential Tool

: COVID-19 is an emerging outbreak similar to previous pandemics caused by Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). Till date, SARS-CoV-2 infection is still spreading, representing a major threat to public health, where several control measures are being practiced in order to culminate its spread. The research and development of new drugs require a lot of funding in addition to being a slow and costly process. As a result, new techniques have been proposed to streamline this process. The repositioning or repurposing of drugs represents an attractive strategy, presenting a promising way to introduce new drugs. Currently, numerous reused drugs are already available in the market and are in practice. In this review, it was observed that the antiviral drugs Entricitabine and Tenofovir display potential therapeutic efficacy in preclinical studies. Therefore, in silico analyses were considered a potential tool for predicting the effectiveness of drugs, mainly as an effective approach to encourage a complementary in vitro and in vivo antiviral evaluation.

Sign in / Sign up

Export Citation Format

Share Document