Blood schizontocidal activity of azithromycin and its combination with α/β arteether against multi-drug resistant Plasmodium yoelii nigeriensis, a novel MDR parasite model for antimalarial screening

Parasitology ◽  
2005 ◽  
Vol 131 (3) ◽  
pp. 295-301 ◽  
Author(s):  
R. TRIPATHI ◽  
S. DHAWAN ◽  
G. P. DUTTA
Keyword(s):  
Antimalarial Activity ◽  
Wide Spectrum ◽  
Oral Route ◽  
Plasmodium Yoelii ◽  
Drug Resistant ◽  
Curative Effect ◽  
Resistant Lines ◽  
High Doses ◽  
New Compounds

Many different drug-resistant lines of rodent malaria are available as screening models. It is obligatory to screen new compounds for antimalarial activity against a series of resistant lines in order to identify a compound with potential for the treatment of multi-drug resistant (MDR) malaria infections. Instead of using a battery of resistant lines, a single MDR Plasmodium yoelii nigeriensis strain that shows a wide spectrum of drug resistance to high doses of chloroquine, mepacrine, amodiaquine, mefloquine, quinine, quinidine, halofantrine as well as tetracyclines, fluoroquinolines and erythromycin, was used to assess the blood schizontocidal efficacy of a new macrolide azithromycin and other antibiotics. The present study shows that only azithromycin has the potential to control an MDR P. y. nigeriensis infection in Swiss mice, provided the treatment with a dose of 50–100 mg/kg/day by oral route is continued for a period of 7 days. Tetracycline, oxytetracycline, doxycyline, erythromycin, ciprofloxacin and norfloxacin, although active in vitro, failed to protect the mice. Tetracycline, ciprofloxacin and norfloxacin combinations with chloroquine did not control the infection. Additionally, the antimalarial efficacy of azithromycin can be potentiated with the addition of arteether, which is an ethyl ether derivative of artemisinin. A total (100%) curative effect has been obtained with a shorter regimen of 4 days only.

Antimalarial interaction of quinine and quinidine with clarithromycin

Parasitology ◽  
2012 ◽  
Vol 140 (3) ◽  
pp. 406-413 ◽  
Author(s):  
SWAROOP KUMAR PANDEY ◽  
HEMLATA DWIVEDI ◽  
SARIKA SINGH ◽  
WASEEM AHMAD SIDDIQUI ◽  
RENU TRIPATHI
Keyword(s):  
Antimalarial Activity ◽  
Plasmodium Yoelii ◽  
Drug Resistant ◽  
Cyp3a4 Activity ◽  
Curative Effect ◽  
Poor Patient ◽  
Poor Patient Compliance ◽  
Synergistic Response ◽  
Antimalarial Action

SUMMARYQuinine (QN) and quinidine (QND) have been commonly used as effective and affordable antimalarials for over many years. Quinine primarily is used for severe malaria treatment. However, plasmodia resistance to these drugs and poor patient compliance limits their administration to the patients. The declining sensitivity of the parasite to the drugs can thus be dealt with by combining with a suitable partner drug. In the present study QN/QND was assessed in combination with clarithromycin (CLTR), an antibiotic of the macrolide family. In vitro interactions of these drugs with CLTR against Plasmodium falciparum (P. falciparum) have shown a synergistic response with mean sum fractional inhibitory concentrations (ΣFICs) of ⩽1 (0·85 ± 0·11 for QN + CLTR and 0·64 ± 0·09 for QND + CLTR) for all the tested combination ratios. Analysis of this combination of QN/QND with CLTR in mouse model against Plasmodium yoelii nigeriensis multi-drug resistant (P. yoelii nigeriensis MDR) showed that a dose of 200 mg/kg/day for 4 days of QN or QND produces 100% curative effect with 200 mg/kg/day for 7 days and 150 mg/kg/day for 7 days CLTR respectively, while the same dose of individual drugs could produce only up to a maximum 20% cure. It is postulated that CLTR, a CYP3A4 inhibitor, might have caused reduced CYP3A4 activity leading to increased plasma level of the QN/QND to produce enhanced antimalarial activity. Further, parasite apicoplast disruption by CLTR synergies the antimalarial action of QN and QND.

Synthesis and antimalarial activity of novel bicyclic and tricyclic aza-peroxides

RSC Advances ◽  
2016 ◽  
Vol 6 (28) ◽  
pp. 23718-23725 ◽  
Author(s):  
Lalit Yadav ◽  
Mohit K. Tiwari ◽  
Bharti Rajesh Kumar Shyamlal ◽  
Manas Mathur ◽  
Ajit K. Swami ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Oral Route ◽  
Plasmodium Yoelii ◽  
Swiss Mice

Bicyclic and tricyclic aza-peroxides were synthesized and assessed for theirin vitroandin vivoantimalarial activities againstPlasmodium falciparum(3D7 strain) andPlasmodium yoelii nigeriensisin Swiss mice by an oral route, respectively.

scholarly journals Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivax

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Letícia Tiburcio Ferreira ◽  
Juliana Rodrigues ◽  
Gustavo Capatti Cassiano ◽  
Tatyana Almeida Tavella ◽  
Kaira Cristina Peralis Tomaz ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
In Silico ◽  
Antimalarial Activity ◽  
Drug Repositioning ◽  
Dna Gyrase ◽  
Plasmodium Yoelii ◽  
Computer Assisted ◽  
Content Type

ABSTRACT Widespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks, and time-to-market. Herein, we have used this strategy to identify novel antimalarial hits. We used a comparative in silico chemogenomics approach to select Plasmodium falciparum and Plasmodium vivax proteins as potential drug targets and analyzed them using a computer-assisted drug repositioning pipeline to identify approved drugs with potential antimalarial activity. Among the seven drugs identified as promising antimalarial candidates, the anthracycline epirubicin was selected for further experimental validation. Epirubicin was shown to be potent in vitro against sensitive and multidrug-resistant P. falciparum strains and P. vivax field isolates in the nanomolar range, as well as being effective against an in vivo murine model of Plasmodium yoelii. Transmission-blocking activity was observed for epirubicin in vitro and in vivo. Finally, using yeast-based haploinsufficiency chemical genomic profiling, we aimed to get insights into the mechanism of action of epirubicin. Beyond the target predicted in silico (a DNA gyrase in the apicoplast), functional assays suggested a GlcNac-1-P-transferase (GPT) enzyme as a potential target. Docking calculations predicted the binding mode of epirubicin with DNA gyrase and GPT proteins. Epirubicin is originally an antitumoral agent and presents associated toxicity. However, its antiplasmodial activity against not only P. falciparum but also P. vivax in different stages of the parasite life cycle supports the use of this drug as a scaffold for hit-to-lead optimization in malaria drug discovery.

scholarly journals Sontochin as a Guide to the Development of Drugs against Chloroquine-Resistant Malaria

2012 ◽  
Vol 56 (7) ◽  
pp. 3475-3480 ◽  
Author(s):  
Sovitj Pou ◽  
Rolf W. Winter ◽  
Aaron Nilsen ◽  
Jane Xu Kelly ◽  
Yuexin Li ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Plasmodium Yoelii ◽  
Significant Activity ◽  
Drug Resistant ◽  
Content Type ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Derivatives Of

ABSTRACTSontochin was the original chloroquine replacement drug, arising from research by Hans Andersag 2 years after chloroquine (known as “resochin” at the time) had been shelved due to the mistaken perception that it was too toxic for human use. We were surprised to find that sontochin, i.e., 3-methyl-chloroquine, retains significant activity against chloroquine-resistant strains ofPlasmodium falciparum in vitro. We prepared derivatives of sontochin, “pharmachins,” with alkyl or aryl substituents at the 3 position and with alterations to the 4-position side chain to enhance activity against drug-resistant strains. Modified with an aryl substituent in the 3 position of the 7-chloro-quinoline ring, Pharmachin 203 (PH-203) exhibits low-nanomolar 50% inhibitory concentrations (IC50s) against drug-sensitive and multidrug-resistant strains andin vivoefficacy against patent infections ofPlasmodium yoeliiin mice that is superior to chloroquine. Our findings suggest that novel 3-position aryl pharmachin derivatives have the potential for use in treating drug resistant malaria.

scholarly journals Evaluation of in vitro and in vivo Antiplasmodial Activity of the Leaf Latex of Aloe Weloensis (Aloaceae)

2020 ◽  
Author(s):  
Gedefaw Getnet Amare ◽  
Tadesse Awgichew ◽  
Solomon Ahmed ◽  
Zemene Demelash Kifle
Keyword(s):  
Antioxidant Activity ◽  
Antioxidant Activities ◽  
Antimalarial Activity ◽  
Potential Effect ◽  
Pack Cell Volume ◽  
Curative Effect ◽  
Parasitemia Level ◽  
Dose Dependent

Abstract Background: Nature has gifted a variety of plants having potential effect against plasmodium parasites. The present study was aimed to determine in vitro and in vivo antimalarial activity of the leaf latex of Aloe weloensis.Methods: In vitro antimalarial activity of the leaf latex of A. weloensis was determined against 3D7 strain of P. falciparum. Antimalarial activity of the three doses the latex was evaluated in 4 day-suppressive and curative models against P. berghei infected mice. Antioxidant activity of the leaf latex of A. weloensis was assessed in 2,2- diphenyl 1- picrylhydrazine assay model. Results: Antioxidant activity of the latex was concentration dependent; the strongest inhibition was measured at 400 μg/mL (73.54%). The leaf latex of A. weloensis was demonstrated inhibitory activity against 3D7 malarial strain (IC50 = 9.14 μg/ml). Suppressive and curative effect of the latex was found to be dose dependent. Parasitemia reduction was significant (200 mg/kg, p<0.01, 400 and ,600 mg/kg, p<0.001) in 4-day suppressive test compared to vehicle control. Parasitemia level of the mice treated with 200, 400 and 600 mg/kg doses of the latex significantly (p<0.001) reduced with suppression of 36%, 58% and 64% respectively in curative test. Administration of the leaf latex of A. weloensis significantly (p<0.01) improved mean survival time, pack cell volume, rectal temperature and body weight of P. berghei infected mice. Conclusion: The finding showed that the leaf latex of Aloe weloensis endowed prominent antimalarial and antioxidant activities. The result can serve as a step towards the development of safe and effective herbal therapy against plasmodium parasites.

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

2019 ◽  
Vol 40 (3) ◽  
pp. 931-971 ◽  
Author(s):  
Lian‐Shun Feng ◽  
Zhi Xu ◽  
Le Chang ◽  
Chuan Li ◽  
Xiao‐Fei Yan ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Drug Resistant ◽  
Hybrid Molecules

Endemic Emergence of Cephalosporin-Resistant Enterobacter: Relation to Prior Therapy

1986 ◽  
Vol 7 (S2) ◽  
pp. 120-123 ◽  
Author(s):  
Robert A. Weinstein
Keyword(s):  
Cardiac Surgery ◽  
Wide Spectrum ◽  
Clinical Settings ◽  
Third Generation ◽  
Prior Therapy ◽  
Cephalosporin Resistance ◽  
Resistant Strains ◽  
High Doses ◽  
Third Generation Cephalosporins

The “second” and “third” generation cephalosporins offer striking antimicrobial activity against a wide spectrum of Enterobacteriaceae. Nevertheless, mutants resistant to these drugs have emerged in both laboratory and clinical settings. For example, before the commercial availability of the third-generation agents, we treated three cardiac surgery patients for Enterobacter mediastinitis with aminoglycosides and high doses of cefamandole. In two, initial treatment failed due to emergence of strains that were not only resistant to cefamandole, but also to then experimental third-generation drugs. Despite such reports and in vitro studies of the mechanisms of resistance, the frequency with which broad-spectrum cephalosporin resistance develops in clinical practice is not clear. To help delineate this problem, we have reviewed our hospital's experience with Enterobacter strains resistant to newer cephalosporins (using cefamandole and cefotaxime as prototypes) and the relation of resistant strains to cephalosporin use, with special attention to our cardiac surgery patients.

scholarly journals In VitroAntimalarial Activity of Novel Semisynthetic Nocathiacin I Antibiotics

2015 ◽  
Vol 59 (6) ◽  
pp. 3174-3179 ◽  
Author(s):  
Indu Sharma ◽  
Margery Sullivan ◽  
Thomas F. McCutchan
Keyword(s):  
Antimalarial Activity ◽  
Wide Spectrum ◽  
Multidrug Resistant ◽  
Water Soluble ◽  
Growth Inhibition Assay ◽  
Content Type ◽  
Drug Candidates ◽  
Gram Positive Bacteria ◽  
Multiple Drugs

ABSTRACTPresently, the arsenal of antimalarial drugs is limited and needs to be replenished. We evaluated the potential antimalarial activity of two water-soluble derivatives of nocathiacin (BMS461996 and BMS411886) against the asexual blood stages ofPlasmodium falciparum. Nocathiacins are a thiazolyl peptide group of antibiotics, are structurally related to thiostrepton, have potent activity against a wide spectrum of multidrug-resistant Gram-positive bacteria, and inhibit protein synthesis. Thein vitrogrowth inhibition assay was done using three laboratory strains ofP. falciparumdisplaying various levels of chloroquine (CQ) susceptibility. Our results indicate that BMS461996 has potent antimalarial activity and inhibits parasite growth with mean 50% inhibitory concentrations (IC50s) of 51.55 nM forP. falciparum3D7 (CQ susceptible), 85.67 nM forP. falciparumDd2 (accelerated resistance to multiple drugs [ARMD]), and 99.44 nM forP. falciparumK1 (resistant to CQ, pyrimethamine, and sulfadoxine). Similar results at approximately 7-fold higher IC50s were obtained with BMS411886 than with BMS461996. We also tested the effect of BMS491996 on gametocytes; our results show that at a 20-fold excess of the mean IC50, gametocytes were deformed with a pyknotic nucleus and growth of stage I to IV gametocytes was arrested. This preliminary study shows a significant potential for nocathiacin analogues to be developed as antimalarial drug candidates and to warrant further investigation.

scholarly journals New Active Drugs against Liver Stages of Plasmodium Predicted by Molecular Topology

2008 ◽  
Vol 52 (4) ◽  
pp. 1215-1220 ◽  
Author(s):  
Nassira Mahmoudi ◽  
Ramon Garcia-Domenech ◽  
Jorge Galvez ◽  
Khemais Farhati ◽  
Jean-François Franetich ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Plasmodium Yoelii ◽  
New Drugs ◽  
Topological Model ◽  
Parasite Development ◽  
Molecular Topology ◽  
Qsar Study ◽  
Vitro Assay ◽  
Linear Discriminant

ABSTRACT We conducted a quantitative structure-activity relationship (QSAR) study based on a database of 127 compounds previously tested against the liver stage of Plasmodium yoelii in order to develop a model capable of predicting the in vitro antimalarial activities of new compounds. Topological indices were used as structural descriptors, and their relation to antimalarial activity was determined by using linear discriminant analysis. A topological model consisting of two discriminant functions was created. The first function discriminated between active and inactive compounds, and the second identified the most active among the active compounds. The model was then applied sequentially to a large database of compounds with unknown activity against liver stages of Plasmodium. Seventeen drugs that were predicted to be active or inactive were selected for testing against the hepatic stage of P. yoelii in vitro. Antiretroviral, antifungal, and cardiotonic drugs were found to be highly active (nanomolar 50% inhibitory concentration values), and two ionophores completely inhibited parasite development. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed on hepatocyte cultures for all compounds, and none of these compounds were toxic in vitro. For both ionophores, the same in vitro assay as those for P. yoelii has confirmed their in vitro activities on Plasmodium falciparum. A similar topological model was used to estimate the octanol/water partition of each compound. These results demonstrate the utility of the QSAR and molecular topology approaches for identifying new drugs that are active against the hepatic stage of malaria parasites. We also show the remarkable efficacy of some drugs that were not previously reported to have antiparasitic activity.

Synthesis and antimalarial activity of new 4-aminoquinolines active against drug resistant strains

RSC Advances ◽  
2016 ◽  
Vol 6 (107) ◽  
pp. 105676-105689 ◽  
Author(s):  
Srinivasarao Kondaparla ◽  
Awakash Soni ◽  
Ashan Manhas ◽  
Kumkum Srivastava ◽  
Sunil K. Puri ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Drug Resistant ◽  
New Class ◽  
Resistant Strains ◽  
Drug Resistant Strains

In the present study we have synthesized a new class of 4-aminoquinoline derivatives and bioevaluated them for antimalarial activity against theP. falciparum in vitro(3D7 & K1) andP. yoelii in vivo(N-67 strain).

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