scholarly journals Antischistosomal Activities of Mefloquine-Related Arylmethanols

2012 ◽  
Vol 56 (6) ◽  
pp. 3207-3215 ◽  
Author(s):  
Katrin Ingram ◽  
William Ellis ◽  
Jennifer Keiser
Keyword(s):  
Body Weight ◽  
Worm Burden ◽  
Structural Features ◽  
Content Type ◽  
Antischistosomal Activity ◽  
Oral Doses ◽  
Related Compounds ◽  
Insight Into

ABSTRACTInteresting antischistosomal properties have been documented for the antimalarial mefloquine, a 4-quinolinemethanol. We evaluated the antischistosomal activities of nine mefloquine-related compounds belonging to the 4-pyridinemethanols, 9-phenanthrenmethanols, and 4-quinolinemethanols. Eight compounds revealed high activities againstSchistosoma mansoni in vitro, with two drugs (the 4-quinolinemethanols WR7573 and WR7930) characterized by significantly lower half-maximal inhibitory concentrations (IC50s) (2.7 and 3.5 μM, respectively) compared to mefloquine (11.4 μM). Mefloquine and WR7930 showed significantly decreased IC50s when incubated in the presence of hemoglobin. High worm burden reductions (WBR) were obtained with enpiroline (WBR, 82.7%; dosage, 200 mg/kg of body weight) and itsthreoisomers (+)-threo(WBR, 100%) and (−)-threo(WBR, 89%) and with WR7930 (WBR, 87%; dosage, 100 mg/kg) against adultS. mansoniin mice. Furthermore, excellentin vitroandin vivoantischistosomal activity was observed for two WR7930-related structures (WR29252 and WR7524). In addition, mefloquine (WBR, 81%), enpiroline (WBR, 77%), and WR7930 (WBR, 100%) showed high activities againstS. haematobiumharbored in mice following single oral doses of 200 mg/kg. These results provide a deeper insight into the structural features of the arylmethanols that rule antischistosomal activity. Further studies should be launched with enpiroline and WR7930.

scholarly journals Trematocidal Activity of Praziquantel and Artemisinin Derivatives: In Vitro and In Vivo Investigations with Adult Echinostoma caproni

2006 ◽  
Vol 50 (2) ◽  
pp. 803-805 ◽  
Author(s):  
Jennifer Keiser ◽  
Reto Brun ◽  
Bernard Fried ◽  
Jürg Utzinger
Keyword(s):  
Body Weight ◽  
Worm Burden ◽  
Echinostoma Caproni ◽  
Artemisinin Derivatives ◽  
Exposure Response ◽  
Oral Doses

ABSTRACT We examined the effects of praziquantel and the artemisinins on adult Echinostoma caproni. In vitro, both praziquantel and the artemisinins exhibited exposure-response relationships. In vivo, worm burden reductions of 100% were achieved with single oral doses of praziquantel, artesunate, and artemether at 50, 700, and 1,100 mg/kg of body weight, respectively.

scholarly journals Activity of Praziquantel Enantiomers and Main Metabolites against Schistosoma mansoni

2014 ◽  
Vol 58 (9) ◽  
pp. 5466-5472 ◽  
Author(s):  
Isabel Meister ◽  
Katrin Ingram-Sieber ◽  
Noemi Cowan ◽  
Matthew Todd ◽  
Murray N. Robertson ◽  
...  
Keyword(s):  
Schistosoma Mansoni ◽  
Significant Role ◽  
Worm Burden ◽  
Racemic Mixture ◽  
Content Type ◽  
Effector Molecule ◽  
Oral Doses ◽  
Newly Transformed Schistosomula

ABSTRACTA racemic mixture ofRandSenantiomers of praziquantel (PZQ) is currently the treatment of choice for schistosomiasis. Though theSenantiomer and the metabolites are presumed to contribute only a little to the activity of the drug, in-depth side-by-side studies are lacking. The aim of this study was to investigate thein vitroactivities of PZQ and its main metabolites, namely,R- andS-cis- andR- andS-trans-4′-hydroxypraziquantel, against adult worms and newly transformed schistosomula (NTS). Additionally, we explored thein vivoactivity and hepatic shift (i.e., the migration of the worms to the liver) produced by each PZQ enantiomer in mice. Fifty percent inhibitory concentrations ofR-PZQ,S-PZQ, andR-trans- andR-cis-4′-hydroxypraziquantel of 0.02, 5.85, 4.08, and 2.42 μg/ml, respectively, for adultS. mansoniwere determinedin vitro. S-trans- andS-cis-4′-hydroxypraziquantel were not active at 100 μg/ml. These results are consistent with microcalorimetry data and studies with NTS.In vivo, single 400-mg/kg oral doses ofR-PZQ andS-PZQ achieved worm burden reductions of 100 and 19%, respectively. Moreover, worms treatedin vivowithS-PZQ displayed an only transient hepatic shift and returned to the mesenteric veins within 24 h. Our data confirm thatR-PZQ is the main effector molecule, whileS-PZQ and the metabolites do not play a significant role in the antischistosomal properties of PZQ.

scholarly journals Spiroindolone That Inhibits PfATPase4 Is a Potent, Cidal Inhibitor of Toxoplasma gondii TachyzoitesIn VitroandIn Vivo

2013 ◽  
Vol 58 (3) ◽  
pp. 1789-1792 ◽  
Author(s):  
Ying Zhou ◽  
Alina Fomovska ◽  
Stephen Muench ◽  
Bo-Shiun Lai ◽  
Ernest Mui ◽  
...  
Keyword(s):  
Body Weight ◽  
Toxoplasma Gondii ◽  
Inhibitory Concentration ◽  
Parasite Burden ◽  
Content Type ◽  
Medicine Development ◽  
Lead Candidate ◽  
Oral Doses

ABSTRACTHere, we show that spiroindolone, an effective treatment for plasmodia, is also active againstToxoplasma gondiitachyzoites.In vitro, spiroindolone NITD609 is cidal for tachyzoites (50% inhibitory concentration [IC50], 1μM) and not toxic to human cells at ≥10μM. Two daily oral doses of 100 mg/kg of body weight reduced the parasite burden in mice by 90% (P= 0.002), measured 3 days after the last dose. This inhibition ofT. gondiitachyzoitesin vitroandin vivoindicates that spiroindolone is a promising lead candidate for further medicine development.

scholarly journals The Investigational Agent E1210 Is Effective in Treatment of Experimental Invasive Candidiasis Caused by Resistant Candida albicans

2014 ◽  
Vol 59 (1) ◽  
pp. 690-692 ◽  
Author(s):  
Nathan P. Wiederhold ◽  
Laura K. Najvar ◽  
Annette W. Fothergill ◽  
Dora I. McCarthy ◽  
Rosie Bocanegra ◽  
...  
Keyword(s):  
Body Weight ◽  
Candida Albicans ◽  
Invasive Candidiasis ◽  
Content Type ◽  
Fungal Burden ◽  
Investigational Agent ◽  
Oral Doses ◽  
Potential Use

ABSTRACTThein vitroandin vivoactivity of the inositol acyltransferase inhibitor E1210 was evaluated against echinocandin-resistantCandida albicans. E1210 demonstrated potentin vitroactivity, and in mice with invasive candidiasis caused by echinocandin-resistantC. albicans, oral doses of 10 and 40 mg E1210/kg of body weight twice daily significantly improved survival and reduced fungal burden compared to those of controls and mice treated with caspofungin (10 mg/kg/day). These results demonstrate the potential use of E1210 against resistantC. albicansinfections.

scholarly journals The Novel Arylamidine T-2307 MaintainsIn VitroandIn VivoActivity against Echinocandin-Resistant Candida albicans

2014 ◽  
Vol 59 (2) ◽  
pp. 1341-1343 ◽  
Author(s):  
Nathan P. Wiederhold ◽  
Laura K. Najvar ◽  
Annette W. Fothergill ◽  
Rosie Bocanegra ◽  
Marcos Olivo ◽  
...  
Keyword(s):  
Body Weight ◽  
Candida Albicans ◽  
Invasive Candidiasis ◽  
Placebo Control ◽  
The Novel ◽  
Content Type ◽  
Fungal Burden ◽  
Potential Use

ABSTRACTWe evaluated thein vitroandin vivoactivities of the investigational arylamidine T-2307 against echinocandin-resistantCandida albicans. T-2307 demonstrated potentin vitroactivity, and daily subcutaneous doses between 0.75 and 6 mg/kg of body weight significantly improved survival and reduced fungal burden compared to placebo control and caspofungin (10 mg/kg/day) in mice with invasive candidiasis caused by an echinocandin-resistant strain. Thus, T-2307 may have potential use in the treatment of echinocandin-resistantC. albicansinfections.

scholarly journals Enterococcus faecalis 6-Phosphogluconolactonase Is Required for Both Commensal and Pathogenic Interactions with Manduca sexta

2014 ◽  
Vol 83 (1) ◽  
pp. 396-404 ◽  
Author(s):  
Jonathan F. Holt ◽  
Megan R. Kiedrowski ◽  
Kristi L. Frank ◽  
Jing Du ◽  
Changhui Guan ◽  
...  
Keyword(s):  
Enterococcus Faecalis ◽  
Manduca Sexta ◽  
Wild Type ◽  
Genetic Determinants ◽  
Content Type ◽  
Polystyrene Plate ◽  
Insect Gut ◽  
Insight Into

Enterococcus faecalisis a commensal and pathogen of humans and insects. InManduca sexta,E. faecalisis an infrequent member of the commensal gut community, but its translocation to the hemocoel results in a commensal-to-pathogen switch. To investigateE. faecalisfactors required for commensalism, we identifiedE. faecalisgenes that are upregulated in the gut ofM. sextausing recombinase-basedin vivoexpression technology (RIVET). The RIVET screen produced 113 clones, from which we identified 50 genes that are more highly expressed in the insect gut than in culture. The most frequently recovered gene was locus OG1RF_11582, which encodes a 6-phosphogluconolactonase that we designatedpglA. ApglAdeletion mutant was impaired in both pathogenesis and gut persistence inM. sextaand produced enhanced biofilms compared with the wild type in anin vitropolystyrene plate assay. Mutation of four other genes identified by RIVET did not affect persistence in caterpillar guts but led to impaired pathogenesis. This is the first identification of genetic determinants forE. faecaliscommensal and pathogenic interactions withM. sexta. Bacterial factors identified in this model system may provide insight into colonization or persistence in other host-associated microbial communities and represent potential targets for interventions to preventE. faecalisinfections.

scholarly journals New Insight into the Cleavage Reaction of Nostoc sp. Strain PCC 7120 Carotenoid Cleavage Dioxygenase in Natural and Nonnatural Carotenoids

2013 ◽  
Vol 79 (11) ◽  
pp. 3336-3345 ◽  
Author(s):  
Jinsol Heo ◽  
Se Hyeuk Kim ◽  
Pyung Cheon Lee
Keyword(s):  
Carotenoid Cleavage Dioxygenase ◽  
Cleavage Reaction ◽  
Natural Structure ◽  
Content Type ◽  
Substrate Preferences ◽  
Cleavage Reactions ◽  
Pcc 7120 ◽  
Insight Into

ABSTRACTCarotenoid cleavage dioxygenases (CCDs) are enzymes that catalyze the oxidative cleavage of carotenoids at a specific double bond to generate apocarotenoids. In this study, we investigated the activity and substrate preferences of NSC3, a CCD ofNostocsp. strain PCC 7120,in vivoandin vitrousing natural and nonnatural carotenoid structures. NSC3 cleaved β-apo-8′-carotenal at 3 positions, C-13C-14, C-15C-15′, and C-13′C-14′, revealing a unique cleavage pattern. NSC3 cleaves the natural structure of carotenoids 4,4′-diaponeurosporene, 4,4′-diaponeurosporen-4′-al, 4,4′-diaponeurosporen-4′-oic acid, 4,4′-diapotorulene, and 4,4′-diapotorulen-4′-al to generate novel cleavage products (apo-14′-diaponeurosporenal, apo-13′-diaponeurosporenal, apo-10′-diaponeurosporenal, apo-14′-diapotorulenal, and apo-10′-diapotorulenal, respectively). The study of carotenoids with natural or nonnatural structures produced by using synthetic modules could provide information valuable for understanding the cleavage reactions or substrate preferences of other CCDsin vivoandin vitro.

scholarly journals In VivoAntimalarial Activity and Mechanisms of Action of 4-Nerolidylcatechol Derivatives

2015 ◽  
Vol 59 (6) ◽  
pp. 3271-3280 ◽  
Author(s):  
Luiz Francisco Rocha e Silva ◽  
Karla Lagos Nogueira ◽  
Ana Cristina da Silva Pinto ◽  
Alejandro Miguel Katzin ◽  
Rodrigo A. C. Sussmann ◽  
...  
Keyword(s):  
Blood Plasma ◽  
Antimalarial Activity ◽  
Isoprenoid Biosynthesis ◽  
Metabolic Labeling ◽  
Mouse Blood ◽  
Content Type ◽  
Improved Stability ◽  
Oral Doses

ABSTRACT4-Nerolidylcatechol (1) is an abundant antiplasmodial metabolite that is isolated fromPiper peltatumroots.O-Acylation orO-alkylation of compound1provides derivatives exhibiting improved stability and significantin vitroantiplasmodial activity. The aim of this work was to study thein vitroinhibition of hemozoin formation, inhibition of isoprenoid biosynthesis inPlasmodium falciparumcultures, andin vivoantimalarial activity of several 4-nerolidylcatechol derivatives. 1,2-O,O-Diacetyl-4-nerolidylcatechol (2) inhibitedin vitrohemozoin formation by up to 50%. In metabolic labeling studies using [1-(n)-3H]geranylgeranyl pyrophosphate, diester2significantly inhibited the biosynthesis of isoprenoid metabolites ubiquinone8, menaquinone4, and dolichol12in cultures ofP. falciparum3D7. Similarly, 2-O-benzyl-4-nerolidylcatechol (3) significantly inhibited the biosynthesis of dolichol12.P. falciparumin vitroprotein synthesis was not affected by compounds2or3. At oral doses of 50 mg per kg of body weight per day, compound2suppressedPlasmodium bergheiNK65 in infected BALB/c mice by 44%. Thisin vivoresult for derivative2represents marked improvement over that obtained previously for natural product1. Compound2was not detected in mouse blood 1 h after oral ingestion or in mixtures with mouse blood/blood plasmain vitro. However, it was detected afterin vitrocontact with human blood or blood plasma. Derivatives of 4-nerolidylcatechol exhibit parasite-specific modes of action, such as inhibition of isoprenoid biosynthesis and inhibition of hemozoin formation, and they therefore merit further investigation for their antimalarial potential.

scholarly journals Nitrotriazole-Based Compounds as Antichagasic Agents in a Long-Treatment In Vivo Assay

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Maria V. Papadopoulou ◽  
William D. Bloomer ◽  
Howard S. Rosenzweig ◽  
Ana Lia Mazzeti ◽  
Karolina Ribeiro Gonçalves ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Adverse Effects ◽  
Myocardial Inflammation ◽  
Reference Drug ◽  
Content Type ◽  
Number Of Treatment ◽  
Better Than

ABSTRACT 3-Nitrotriazole-based compounds belonging to various chemical subclasses were found to be very effective against Chagas disease both in vitro and in vivo after a short administration schedule. In this study, five compounds with specific characteristics were selected to be administered for longer periods of time to mice infected with the virulent Trypanosoma cruzi Y strain to further evaluate their effectiveness as antichagasic agents and whether or not potential adverse effects occur. Benznidazole was included for comparison purposes. Complete parasitemia depletion, weight gain, 100% survival, and a lack of myocardial inflammation were observed with four of the compounds and benznidazole administered intraperitoneally at 15 or 20 mg/kg of body weight/day for 40 days. There was a significant reduction in the number of treatment days (number of doses) necessary to induce parasitemia suppression with all four compounds compared to that required with benznidazole. Partial cures were obtained with only one compound tested at 15 mg/kg/day and on the schedule mentioned above but not with benznidazole. Taken together, our data suggest that these compounds demonstrate potent trypanocidal activity comparable to or better than that of the reference drug, benznidazole, when they are administered at the same dose and on the same schedule.

Gluten protein functionality in wheat flour processing: a review

2001 ◽  
Vol 52 (12) ◽  
pp. 1311 ◽  
Author(s):  
P. W. Gras ◽  
R. S. Anderssen ◽  
M. Keentok ◽  
F. Békés ◽  
R. Appels
Keyword(s):  
Structural Features ◽  
Protein Functionality ◽  
Gluten Protein ◽  
Physical Processes ◽  
Naturally Occurring ◽  
Wheat Flours ◽  
Insight Into

Gluten protein functionality remains the basis of any understanding of the end-product quality of wheat flours. Information about this functionality has been obtained by both in vivo and in vitro studies. Recent advances include structure/function studies of deletion mutants and transformed genotypes, where the genes incorporated were both naturally occurring genes and genes which have been desired to provide specific structural features. The contributions of these specific changes in structure to the rheology of the resulting doughs allow insight into the underlying physical processes that determine dough and end-product properties.

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