Challenges and Tools for In Vitro Leishmania Exploratory Screening in the Drug Development Process: An Updated Review

Leishmaniases are a group of vector-borne diseases caused by infection with the protozoan parasites Leishmania spp. Some of them, such as Mediterranean visceral leishmaniasis, are zoonotic diseases transmitted from vertebrate to vertebrate by a hematophagous insect, the sand fly. As there is an endemic in more than 90 countries worldwide, this complex and major health problem has different clinical forms depending on the parasite species involved, with the visceral form being the most worrying since it is fatal when left untreated. Nevertheless, currently available antileishmanial therapies are significantly limited (low efficacy, toxicity, adverse side effects, drug-resistance, length of treatment, and cost), so there is an urgent need to discover new compounds with antileishmanial activity, which are ideally inexpensive and orally administrable with few side effects and a novel mechanism of action. Therefore, various powerful approaches were recently applied in many interesting antileishmanial drug development programs. The objective of this review is to focus on the very first step in developing a potential drug and to identify the exploratory methods currently used to screen in vitro hit compounds and the challenges involved, particularly in terms of harmonizing the results of work carried out by different research teams. This review also aims to identify innovative screening tools and methods for more extensive use in the drug development process.

Download Full-text

The 18th FRAME Annual Lecture, October 2019: Human In Silico Trials in Pharmacology

Alternatives to Laboratory Animals ◽

10.1177/0261192919896356 ◽

2019 ◽

Vol 47 (5-6) ◽

pp. 221-227

Author(s):

Blanca Rodriguez

Keyword(s):

Drug Development ◽

In Silico ◽

Drug Testing ◽

Development Process ◽

Computer Modelling ◽

Current Knowledge ◽

Magnetic Resonance Images ◽

Population Heterogeneity ◽

Drug Development Process

Safety and efficacy testing is a crucial part of the drug development process, and several different methods are used to obtain the necessary data (e.g. in vitro testing, animal trials and clinical trials). Our group has been investigating the potential of modelling and simulation as an alternative approach to some of the methods used for testing drugs for cardiac effects. To achieve our goal of developing and promoting novel approaches in drug development, we formed multidisciplinary collaborations that included clinicians, computer scientists and biologists. Our in silico models are based on human data (e.g. magnetic resonance images, electrocardiogram) and on current knowledge of human electrophysiology, thus generating predictions that are directly applicable to humans. Such models are a particularly powerful tool because they encompass different sources of population heterogeneity, which is crucial for drug testing and for assessing how interindividual variability might affect clinical endpoints. Our group has shown that computer modelling can be used to predict the effects of a test drug in a virtual population or in combination with machine learning to predict different phenotypes when a drug is given to a diseased population. Furthermore, our user-friendly drug testing software is freely available and is being adopted by industry in their drug development process. We have been engaging with industry and regulators to show that our models can contribute to the replacement of animals in drug development. Our ambition is to generate models for simulation of different diseases and therapies for investigations from subcellular to whole organ.

Download Full-text

Drug Stereochemistry: A Prodigy For Pharmacology and Drug Development

Current Drug Discovery Technologies ◽

10.2174/1570163816666190502101803 ◽

2020 ◽

Vol 17 (5) ◽

pp. 565-573

Author(s):

Karan Gandhi ◽

Umang Shah ◽

Sandip Patel

Keyword(s):

Side Effects ◽

Literature Review ◽

Drug Development ◽

Development Process ◽

Racemic Mixture ◽

Drug Development Process ◽

Pharmacological Profile ◽

Chiral Drugs ◽

Enantiomer Resolution ◽

Drug Designing

Stereochemistry has evinced the importance of many chiral drugs with respect to drug designing and development. A literature review was conducted for several chiral drugs involving pharmacokinetic and pharmacodynamic parameters of their enantiomers along with their uses in certain diseased conditions. This article mainly includes the pharmacological profile review of some chiral drugs and the aspects due to which the single enantiomer is of importance as compared to the racemic mixture of the drug. This was achieved by moderating the side effects or toxic effects; or by the potentiated activity of the single enantiomer. Resolution deals with the separation of racemic compounds which shows up the credibility to obtain the desired enantiomeric properties. As isomers vary in their pharmacokinetic and pharmacodynamic profiles, chiral drugs have showcased considerable importance in the drug development process. Both the enantiomers have a different pharmacological profile in the treatment of a disease, which differentiates them from drug racemates.

Download Full-text

Synthesis, characterization and toxicity studies of pyridinecarboxaldehydes and L-tryptophan derived Schiff bases and corresponding copper (II) complexes

F1000Research ◽

10.12688/f1000research.9226.1 ◽

2016 ◽

Vol 5 ◽

pp. 1921 ◽

Cited By ~ 4

Author(s):

Margarita Malakyan ◽

Nelly Babayan ◽

Ruzanna Grigoryan ◽

Natalya Sarkisyan ◽

Vahan Tonoyan ◽

...

Keyword(s):

Schiff Base ◽

Drug Development ◽

Schiff Bases ◽

Copper Complexes ◽

Development Process ◽

Biological Activities ◽

Drug Development Process ◽

Relationship Analysis

Schiff bases and their metal-complexes are versatile compounds exhibiting a broad range of biological activities and thus actively used in the drug development process. The aim of the present study was the synthesis and characterization of new Schiff bases and their copper (II) complexes, derived from L-tryptophan and isomeric (2-; 3-; 4-) pyridinecarboxaldehydes, as well as the assessment of their toxicity in vitro. The optimal conditions of the Schiff base synthesis resulting in up to 75-85% yield of target products were identified. The structure-activity relationship analysis indicated that the location of the carboxaldehyde group at 2-, 3- or 4-position with regard to nitrogen of the pyridine ring in aldehyde component of the L-tryptophan derivative Schiff bases and corresponding copper complexes essentially change the biological activity of the compounds. The carboxaldehyde group at 2- and 4-positions leads to the higher cytotoxic activity, than that of at 3-position, and the presence of the copper in the complexes increases the cytotoxicity. Based on toxicity classification data, the compounds with non-toxic profile were identified, which can be used as new entities in the drug development process using Schiff base scaffold.

Download Full-text

A non-commercial approach for the generation of transgenicLeishmania tarentolaeand its application in antileishmanial drug discovery

Parasitology ◽

10.1017/s0031182016000585 ◽

2016 ◽

Vol 143 (9) ◽

pp. 1133-1142

Author(s):

TATIANA PINEDA ◽

YESENIA VALENCIA ◽

MARÍA F. FLÓREZ ◽

SERGIO A. PULIDO ◽

IVÁN D. VÉLEZ ◽

...

Keyword(s):

High Throughput ◽

Development Process ◽

Parasitic Infection ◽

Reporter Genes ◽

Drug Development Process ◽

Egfp Gene ◽

Level Ii ◽

High Throughput Technology ◽

Antileishmanial Drug

SUMMARYLeishmaniasis is a parasitic infection caused by several species of the genusLeishmaniathat is considered as a neglected disease. Drug development process requires a robust and updated high-throughput technology to the evaluation of candidate compounds that imply the manipulation of the pathogenic species of the parasite in the laboratory. Therefore, it is restricted to trained personal and level II biosafety environments. However, it has been established the utility ofLeishmania tarentolaeas a model forin vitroscreening of antileishmanial agents without the necessity of level II biosafety setups. In parallel the transfection ofLeishmaniaparasites with reporter genes as the eGFP using non-commercial integration vectors like the pIRmcs3(−) has proved to be a powerful tool for the implementation of semi automatized high-throughput platforms for the evaluation of antileishmanial compounds. Here we report the generation of a newL. tarentolaestrain overexpressing the eGFP gene harboured by the non-commercial vector pIR3(−). We also demonstrate its utility for the semi-automatized screening of antileshmanial compounds in intracellular forms of theL. tarentolaeparasite.

Download Full-text

Drug Interaction Studies in the Drug Development Process: Studies In Vitro

Handbook of Drug Metabolism ◽

10.1201/9780429190315-16 ◽

2019 ◽

pp. 429-466

Author(s):

R. Scott Obach ◽

Kimberly Lapham

Keyword(s):

Drug Interaction ◽

Drug Development ◽

Development Process ◽

Drug Development Process ◽

Interaction Studies ◽

Process Studies

Download Full-text

Intelligent Drug Development

10.1093/oso/9780199974580.001.0001 ◽

2014 ◽

Author(s):

Michael Tansey

Keyword(s):

Clinical Trials ◽

Cost Effectiveness ◽

Drug Development ◽

Clinical Research ◽

Development Process ◽

Drug Development Process ◽

Individual Trial ◽

Specific Technology

Clinical research is heavily regulated and involves coordination of numerous pharmaceutical-related disciplines. Each individual trial involves contractual, regulatory, and ethics approval at each site and in each country. Clinical trials have become so complex and government requirements so stringent that researchers often approach trials too cautiously, convinced that the process is bound to be insurmountably complicated and riddled with roadblocks. A step back is needed, an objective examination of the drug development process as a whole, and recommendations made for streamlining the process at all stages. With Intelligent Drug Development, Michael Tansey systematically addresses the key elements that affect the quality, timeliness, and cost-effectiveness of the drug-development process, and identifies steps that can be adjusted and made more efficient. Tansey uses his own experiences conducting clinical trials to create a guide that provides flexible, adaptable ways of implementing the necessary processes of development. Moreover, the processes described in the book are not dependent either on a particular company structure or on any specific technology; thus, Tansey's approach can be implemented at any company, regardless of size. The book includes specific examples that illustrate some of the ways in which the principles can be applied, as well as suggestions for providing a better context in which the changes can be implemented. The protocols for drug development and clinical research have grown increasingly complex in recent years, making Intelligent Drug Development a needed examination of the pharmaceutical process.

Download Full-text

Toxicity Protocols for Natural Products in the Drug Development Process

Poisonous Plants and Phytochemicals in Drug Discovery ◽

10.1002/9781119650034.ch9 ◽

2020 ◽

pp. 189-212

Author(s):

Tamirat Bekele Beressa ◽

Amanjot Annu ◽

Andrew G. Mtewa

Keyword(s):

Natural Products ◽

Drug Development ◽

Development Process ◽

Drug Development Process

Download Full-text

Microphysiological systems: What it takes for community adoption

Experimental Biology and Medicine ◽

10.1177/15353702211008872 ◽

2021 ◽

pp. 153537022110088

Author(s):

Passley Hargrove-Grimes ◽

Lucie A Low ◽

Danilo A Tagle

Keyword(s):

Rare Diseases ◽

Development Process ◽

Emerging Technology ◽

National Institutes Of Health ◽

Drug Development Process ◽

Microphysiological Systems ◽

Pediatric Populations ◽

Neural Disorders ◽

Future Path

Microphysiological systems (MPS) are promising in vitro tools which could substantially improve the drug development process, particularly for underserved patient populations such as those with rare diseases, neural disorders, and diseases impacting pediatric populations. Currently, one of the major goals of the National Institutes of Health MPS program, led by the National Center for Advancing Translational Sciences (NCATS), is to demonstrate the utility of this emerging technology and help support the path to community adoption. However, community adoption of MPS technology has been hindered by a variety of factors including biological and technological challenges in device creation, issues with validation and standardization of MPS technology, and potential complications related to commercialization. In this brief Minireview, we offer an NCATS perspective on what current barriers exist to MPS adoption and provide an outlook on the future path to adoption of these in vitro tools.

Download Full-text