scholarly journals In vitro evaluation of ivermectin, moxidectin, albendazole and pyrantel against cyathostomins of horses

2017 ◽  
Vol 27 (1) ◽  
pp. 90-93 ◽  
Author(s):  
Marcelo Beltrão Molento ◽  
Ricardo José Canever
Keyword(s):  
Multidrug Resistance ◽  
Drug Monitoring ◽  
Drug Efficacy ◽  
Effective Concentration ◽  
Coefficient Of Determination ◽  
Infective Stage ◽  
Drug Candidates ◽  
Alternative Drug

Abstract Cyathostomins are the most prevalent nematodes of horses, and multidrug resistance has been reported worldwide. There is a need to implement alternative drug monitoring analytical tests. The objective of this study was to determine the consistency (5 repetitions) of the larval migration on agar test (LMAT) using ivermectin, moxidectin, pyrantel or albendazole against cyathostomin infective-stage larvae in eight different concentrations. LMAT showed a strong coefficient of determination (R2 > 0.91), between the test repetitions (n=5). The average 50% effective concentration (EC50) for ivermectin, moxidectin, pyrantel and albendazole were 0.0404, 0.0558, 0.0864 and 0.0988 nMol, respectively. The results of the EC50 for albendazole showed the greatest range of concentration. Ivermectin and moxidectin had the lowest in between-test variation. In the future, internationally certified susceptible isolates could be used for screening new drug candidates, or to follow up the pattern of drug efficacy from field populations.

scholarly journals Development of anEx VivoLymph Node Explant Model for Identification of Novel Molecules Active against Leishmania major

2013 ◽  
Vol 58 (1) ◽  
pp. 78-87 ◽  
Author(s):  
Alex G. Peniche ◽  
Yaneth Osorio ◽  
Adam R. Renslo ◽  
Doug E. Frantz ◽  
Peter C. Melby ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Drug Efficacy ◽  
Peritoneal Macrophages ◽  
Effective Concentration ◽  
Content Type ◽  
Drug Candidates ◽  
New Drug ◽  
Vector Borne

ABSTRACTLeishmaniasis is a vector-borne zoonotic infection affecting people in tropical and subtropical regions of the world. Current treatments for cutaneous leishmaniasis are difficult to administer, toxic, expensive, and limited in effectiveness and availability. Here we describe the development and application of a medium-throughput screening approach to identify new drug candidates for cutaneous leishmaniasis using anex vivolymph nodeexplantculture (ELEC) derived from the draining lymph nodes ofLeishmania major-infected mice. The ELEC supported intracellular amastigote proliferation and contained lymph node cell populations (and their secreted products) that enabled the testing of compounds within a system that mimicked the immunopathological environment of the infected host, which is known to profoundly influence parasite replication, killing, and drug efficacy. The activity of known antileishmanial drugs in the ELEC system was similar to the activity measured in peritoneal macrophages infectedin vitrowithL. major. Using the ELEC system, we screened a collection of 334 compounds, some of which we had demonstrated previously to be active againstL. donovani, and identified 119 hits, 85% of which were confirmed to be active by determination of the 50% effective concentration (EC50). We found 24 compounds (7%) that had aninvitrotherapeuticindex (IVTI; 50% cytotoxic/effective concentration [CC50]/EC50) > 100; 19 of the compounds had an EC50below 1 μM. According to PubChem searchs, 17 of those compounds had not previously been reported to be active againstLeishmania. We expect that this novel method will help to accelerate discovery of new drug candidates for treatment of cutaneous leishmaniasis.

scholarly journals In Vitro Antibacterial Activity of Selected Palestinian Medicinal Plants against Chlamydia trachomatis

2021 ◽  
Vol 12 (3) ◽  
pp. 656-662
Author(s):  
Omar Hamarsheh ◽  
Ahmad Amro ◽  
Munir A. Al-Zeer
Keyword(s):  
Plant Extracts ◽  
Bacterial Resistance ◽  
Multidrug Resistant ◽  
World Health ◽  
Chlamydia Infection ◽  
Drug Candidates ◽  
Cell Defense ◽  
Wide Range ◽  
Alternative Drug

Chlamydia spp. are intracellular pathogens of humans and animals that cause a wide range of diseases such as blinding trachoma and sexually transmitted infections. According to the World Health Organization (WHO), there are more than 127 million new infections each year worldwide. Chlamydial urogenital infections can cause cervicitis, urethritis, pelvic inflammatory disease and infertility. From within an intracellular niche, termed an inclusion, the Chlamydiae complete their life cycle shielded from host defenses. The host cell defense response used to eliminate the pathogen must subvert this protective shield and is thought to involve the gamma interferon-inducible family of immunity related GTPase proteins and nitric oxide. Typically, azithromycin and doxycycline are the first line drugs for the treatment of chlamydial infections. Although C. trachomatis is sensitive to these antibiotics in vitro, currently, there is increasing bacterial resistance to antibiotics including multidrug-resistant C. trachomatis, which have been described in many instances. Therefore, alternative drug candidates against Chlamydia should be assessed in vitro. In this study, we tested and quantified the activity of plant extracts against Chlamydia-infected HeLa cells with C. trachomatis inclusions. The in vitro results show that post-treatment with Artemisia inculta Delile extract significantly inhibits Chlamydia infection compared to DMSO-treated samples. In conclusion, plant extracts may contain active ingredients with antichlamydial activity potential and can be used as alternative drug candidates for treatment of Chlamydia infection which has significant socio-economic and medical impact.

scholarly journals Histone deacetylase inhibitors with high in vitro activities against Plasmodium falciparum isolates collected from Gabonese children and adults

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Erik Koehne ◽  
Andrea Kreidenweiss ◽  
Rella Zoleko Manego ◽  
Matthew McCall ◽  
Ghyslain Mombo-Ngoma ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Drug Efficacy ◽  
Human Cells ◽  
Drug Candidates ◽  
Lower Drug ◽  
Reduced Toxicity

AbstractHistone deacetylase (HDAC) enzymes are targets for the development of antimalarial drugs with a different mode of action to established antimalarials. Broad-spectrum HDAC-inhibitors show high potency against Plasmodium falciparum, but displayed some toxicity towards human cells. Inhibitors of human HDAC6 are new drug candidates with supposed reduced toxicity to human cells and favorable activities against laboratory P. falciparum strains. We investigated the potency of 12 peptoid-based HDAC-inhibitors against asexual stages of P. falciparum clinical isolates. Parasites representing different genetic backgrounds were isolated from adults and children with uncomplicated malaria in Gabon. Clinical studies on (non-HDAC-inhibitors) antimalarials, moreover, found lower drug efficacy in children, mainly attributed to acquired immunity with age in endemic areas. Therefore, we compared the in vitro sensitivity profiles of adult- and child-derived isolates to antimalarials (HDAC and standard drugs). All HDAC-inhibitors showed 50% inhibitory concentrations at nanomolar ranges with higher activities than the FDA approved reference HDAC-inhibitor SAHA. We propose peptoid-based HDAC6-inhibitors to be lead structures for further development as antimalarial chemotherapeutics. Our results further suggest no differences in activity of the tested antimalarials between P. falciparum parasites isolated from children and adults.

scholarly journals Drug Efficacy Comparison of 3D Forming and Preforming Sphere Models with a Micropillar and Microwell Chip Platform

2019 ◽  
Vol 24 (4) ◽  
pp. 476-483 ◽  
Author(s):  
Il Doh ◽  
Yong-Jun Kwon ◽  
Bosung Ku ◽  
Dong Woo Lee
Keyword(s):  
High Throughput Screening ◽  
Drug Efficacy ◽  
High Sensitivity ◽  
Chemotherapeutic Agents ◽  
Cell Culture Model ◽  
Drug Candidates ◽  
Tumor Microenvironments ◽  
Culture Model

Hepatocellular carcinoma (HCC), a major histological subtype of liver cancer, is the third most common cause of cancer-related death worldwide. Currently, many curative standard treatments using target-specific chemotherapeutic agents are being developed. However, drug efficacy tests based on the 2D monolayer cell culture model do not effectively screen the best drug candidates because they do not accurately reflect in vivo tumor microenvironments. Thus, to select the best drug candidates or repositioning drugs, we developed new 3D in vitro hepatic tumor models, including 3D forming and preformed sphere models. A micropillar and microwell chip platform was used for the 3D in vitro liver cell-based model for high-throughput screening. We measured the efficacy of 60 drugs and sorted the most efficacious drugs by comparing the drug response of the 2D monolayer model with the 3D forming and preformed sphere models. Among the 60 drugs, 17 drugs (28.3%) showed a significant high efficacy in the 3D preformed sphere model, while 45 drugs (75%) showed an efficacy in the 2D model. We also calculated the IC50 values of the 17 drugs and found that 7 drugs exhibited a high sensitivity in HCC, which was in agreement with previous studies.

Flavonoids as P-gp Inhibitors: A Systematic Review of SARs

2019 ◽  
Vol 26 (25) ◽  
pp. 4799-4831 ◽  
Author(s):  
Jiahua Cui ◽  
Xiaoyang Liu ◽  
Larry M.C. Chow
Keyword(s):  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Drug Candidates ◽  
Chemical Structures ◽  
Transporter Family ◽  
Promising Area ◽  
New Generation ◽  
Nontoxic Inhibitors

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

2019 ◽  
Vol 22 (8) ◽  
pp. 509-520
Author(s):  
Cauê B. Scarim ◽  
Chung M. Chin
Keyword(s):  
Drug Discovery ◽  
Chagas Disease ◽  
Drug Candidates ◽  
Lead Compounds ◽  
New Drug ◽  
Compound Libraries ◽  
Screening Assays ◽  
Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

scholarly journals Targeting RON receptor tyrosine kinase for treatment of advanced solid cancers: antibody–drug conjugates as lead drug candidates for clinical trials

2020 ◽  
Vol 12 ◽  
pp. 175883592092006
Author(s):  
Hang-Ping Yao ◽  
Sreedhar Reddy Suthe ◽  
Xiang-Min Tong ◽  
Ming-Hai Wang
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Targeted Therapeutics ◽  
Antibody Drug Conjugates ◽  
Drug Candidates ◽  
Drug Conjugates ◽  
Ron Receptor ◽  
Antibody Drug

The recepteur d’origine nantais (RON) receptor tyrosine kinase, belonging to the mesenchymal-to-epithelial transition proto-oncogene family, has been implicated in the pathogenesis of cancers derived from the colon, lung, breast, and pancreas. These findings lay the foundation for targeting RON for cancer treatment. However, development of RON-targeted therapeutics has not gained sufficient attention for the last decade. Although therapeutic monoclonal antibodies (TMABs) targeting RON have been validated in preclinical studies, results from clinical trials have met with limited success. This outcome diminishes pharmaceutical enthusiasm for further development of RON-targeted therapeutics. Recently, antibody–drug conjugates (ADCs) targeting RON have drawn special attention owing to their increased therapeutic activity. The rationale for developing anti-RON ADCs is based on the observation that cancer cells are not sufficiently addicted to RON signaling for survival. Thus, TMAB-mediated inhibition of RON signaling is ineffective for clinical application. In contrast, anti-RON ADCs combine a target-specific antibody with potent cytotoxins for cancer cell killing. This approach not only overcomes the shortcomings in TMAB-targeted therapies but also holds the promise for advancing anti-RON ADCs into clinical trials. In this review, we discuss the latest advancements in the development of anti-RON ADCs for targeted cancer therapy including drug conjugation profile, pharmacokinetic properties, cytotoxic effect in vitro, efficacy in tumor models, and toxicological activities in primates.

scholarly journals Simple Thalidomide Analogs in Melanoma: Synthesis and Biological Activity

2021 ◽  
Vol 11 (13) ◽  
pp. 5823
Author(s):  
Alexia Barbarossa ◽  
Alessia Catalano ◽  
Jessica Ceramella ◽  
Alessia Carocci ◽  
Domenico Iacopetta ◽  
...  
Keyword(s):  
Anticancer Agent ◽  
Ring System ◽  
In Vitro Assays ◽  
Tubulin Polymerization ◽  
Cytotoxic Effects ◽  
Ongoing Research ◽  
Drug Candidates ◽  
Small Series ◽  
Clinical Interest

Thalidomide is an old well-known drug that is still of clinical interest, despite its teratogenic activities, due to its antiangiogenic and immunomodulatory properties. Therefore, efforts to design safer and effective thalidomide analogs are continually ongoing. Research studies on thalidomide analogs have revealed that the phthalimide ring system is an essential pharmacophoric fragment; thus, many phthalimidic compounds have been synthesized and evaluated as anticancer drug candidates. In this study, a panel of selected in vitro assays, performed on a small series of phthalimide derivatives, allowed us to characterize compound 2k as a good anticancer agent, acting on A2058 melanoma cell line, which causes cell death by apoptosis due to its capability to inhibit tubulin polymerization. The obtained data were confirmed by in silico assays. No cytotoxic effects on normal cells have been detected for this compound that proves to be a valid candidate for further investigations to achieve new insights on possible mechanism of action of this class of compounds as anticancer drugs.

scholarly journals The Repurposed Drugs Suramin and Quinacrine Cooperatively Inhibit SARS-CoV-2 3CLpro In Vitro

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 873
Author(s):  
Raphael J. Eberle ◽  
Danilo S. Olivier ◽  
Marcos S. Amaral ◽  
Ian Gering ◽  
Dieter Willbold ◽  
...  
Keyword(s):  
Binding Mode ◽  
Drug Candidates ◽  
Main Protease ◽  
Ic50 Values ◽  
Repurposed Drugs ◽  
Antiparasitic Drugs ◽  
Inhibitory Potential ◽  
Dynamics Simulations ◽  
Micromolar Range

Since the first report of a new pneumonia disease in December 2019 (Wuhan, China) the WHO reported more than 148 million confirmed cases and 3.1 million losses globally up to now. The causative agent of COVID-19 (SARS-CoV-2) has spread worldwide, resulting in a pandemic of unprecedented magnitude. To date, several clinically safe and efficient vaccines (e.g., Pfizer-BioNTech, Moderna, Johnson & Johnson, and AstraZeneca COVID-19 vaccines) as well as drugs for emergency use have been approved. However, increasing numbers of SARS-Cov-2 variants make it imminent to identify an alternative way to treat SARS-CoV-2 infections. A well-known strategy to identify molecules with inhibitory potential against SARS-CoV-2 proteins is repurposing clinically developed drugs, e.g., antiparasitic drugs. The results described in this study demonstrated the inhibitory potential of quinacrine and suramin against SARS-CoV-2 main protease (3CLpro). Quinacrine and suramin molecules presented a competitive and noncompetitive inhibition mode, respectively, with IC50 values in the low micromolar range. Surface plasmon resonance (SPR) experiments demonstrated that quinacrine and suramin alone possessed a moderate or weak affinity with SARS-CoV-2 3CLpro but suramin binding increased quinacrine interaction by around a factor of eight. Using docking and molecular dynamics simulations, we identified a possible binding mode and the amino acids involved in these interactions. Our results suggested that suramin, in combination with quinacrine, showed promising synergistic efficacy to inhibit SARS-CoV-2 3CLpro. We suppose that the identification of effective, synergistic drug combinations could lead to the design of better treatments for the COVID-19 disease and repurposable drug candidates offer fast therapeutic breakthroughs, mainly in a pandemic moment.

A rare case of hypokalaemia and hypophosphataemia secondary to geophagia

2021 ◽  
Vol 14 (5) ◽  
pp. e239322
Author(s):  
Charmaine Schmidt ◽  
Jonathan Oxley Oxland ◽  
Robert Freercks
Keyword(s):  
Creatine Kinase ◽  
Iron Deficiency ◽  
Phosphate Binder ◽  
Rare Case ◽  
Potassium Level ◽  
Serum Potassium Level ◽  
Electrolyte Abnormality ◽  
Distal Muscle

We report a case of severe hypokalaemia and moderate hypophosphataemia from clay ingestion. A 60-year-old woman presented with flaccid paralysis. Investigations revealed a serum potassium level of 1.8 mmol/L, phosphate level of 0.56 mmol/L and creatine kinase level of 30 747 IU/L. She had marked proximal and distal muscle weakness due to severe hypokalaemia and concurrent hypophosphataemia, which likely contributed to the onset of rhabdomyolysis. The patient subsequently admitted to significant pica, most likely secondary to an associated iron deficiency. We conclude that the ingested clay acted as a potassium and phosphate binder. Although we did not investigate the content of the clay in this case, it has been reported that clay can bind potassium in vitro and is rich in minerals such as aluminium that could play a role in the binding of phosphate, although the exact mechanism remains unclear. The patient recovered fully and outpatient follow-up at 6 months and again at 40 months confirmed no electrolyte abnormality, myopathy nor any further geophagia.

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