Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 11 de 11
Filter
Add more filters










Publication year range
1.
Int J Mol Sci ; 24(7)2023 Apr 06.
Article in English | MEDLINE | ID: mdl-37047792

ABSTRACT

Schistosomiasis is a neglected tropical disease with high morbidity. Recently, the Schistosoma mansoni phosphodiesterase SmPDE4A was suggested as a putative new drug target. To support SmPDE4A targeted drug discovery, we cloned, isolated, and biochemically characterized the full-length and catalytic domains of SmPDE4A. The enzymatically active catalytic domain was crystallized in the apo-form (PDB code: 6FG5) and in the cAMP- and AMP-bound states (PDB code: 6EZU). The SmPDE4A catalytic domain resembles human PDE4 more than parasite PDEs because it lacks the parasite PDE-specific P-pocket. Purified SmPDE4A proteins (full-length and catalytic domain) were used to profile an in-house library of PDE inhibitors (PDE4NPD toolbox). This screening identified tetrahydrophthalazinones and benzamides as potential hits. The PDE inhibitor NPD-0001 was the most active tetrahydrophthalazinone, whereas the approved human PDE4 inhibitors roflumilast and piclamilast were the most potent benzamides. As a follow-up, 83 benzamide analogs were prepared, but the inhibitory potency of the initial hits was not improved. Finally, NPD-0001 and roflumilast were evaluated in an in vitro anti-S. mansoni assay. Unfortunately, both SmPDE4A inhibitors were not effective in worm killing and only weakly affected the egg-laying at high micromolar concentrations. Consequently, the results with these SmPDE4A inhibitors strongly suggest that SmPDE4A is not a suitable target for anti-schistosomiasis therapy.


Subject(s)
Phosphodiesterase 4 Inhibitors , Schistosomiasis , Animals , Humans , Cyclic Nucleotide Phosphodiesterases, Type 4/genetics , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Schistosoma mansoni , Benzamides/pharmacology , Phosphodiesterase 4 Inhibitors/pharmacology , Schistosomiasis/drug therapy , Nucleotides, Cyclic
2.
Exp Parasitol ; 239: 108293, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35667394

ABSTRACT

Treatment of schistosomiasis is heavily reliant on the single antischistosomal drug praziquantel (PZQ). The use of synergistic drug-drug interactions is one possible solution, which could be used to mitigate PZQ's poor and variable bioavailability. Itraconazole (ITZ), a triazole antifungal agent, is a potent CYP3A inhibitor that can cause significant drug-drug interactions when used with CYP3A substrates. This study investigates the effect of ITZ as adjuvant therapy with PZQ on worm load, egg deposition and maturation, and the consequent histopathology and biochemical abnormalities in the liver during the immature and mature stages of Schistosoma mansoni (S. mansoni) infection. S. mansoni-infected mice were divided into five groups of eight-ten mice each: (I) infected untreated, (II) infected and treated with PZQ 3 weeks PI, (III) infected and treated with both ITZ and PZQ 3 weeks PI, (IV) infected and treated with PZQ 7 weeks PI, and (V) infected and treated with both ITZ and PZQ 7 weeks PI. All mice were killed by rapid decapitation 9 weeks PI. Data revealed that ITZ in combination with PZQ at both immature and mature stages improved the parasitological criteria of cure, and greatly reduced inflammation, granuloma and fibrotic tissue formation, and apoptosis versus PZQ alone. Furthermore, it showed the greatest impact on improving liver injury and oxidative stress markers. Notably, the effect was considerably stronger at the mature stage of S. mansoni infection. These findings support the notion that ITZ increased PZQ's antischistosomal activity by inhibiting CYP450 expression, potentially reducing PZQ metabolism and increasing systemic exposure.


Subject(s)
Anthelmintics , Schistosomiasis mansoni , Animals , Anthelmintics/pharmacology , Anthelmintics/therapeutic use , Itraconazole/pharmacology , Itraconazole/therapeutic use , Liver/pathology , Mice , Praziquantel/pharmacology , Praziquantel/therapeutic use , Schistosoma mansoni , Schistosomiasis mansoni/drug therapy , Schistosomiasis mansoni/pathology
3.
J Enzyme Inhib Med Chem ; 35(1): 511-523, 2020 Dec.
Article in English | MEDLINE | ID: mdl-31939312

ABSTRACT

A previous phenotypic screening campaign led to the identification of a quinazoline derivative with promising in vitro activity against Schistosoma mansoni. Follow-up studies of the antischistosomal potential of this candidate are presented here. The in vivo studies in a S. mansoni mouse model show a significant reduction of total worms and a complete disappearance of immature eggs when administered concomitantly with praziquantel in comparison with the administration of praziquantel alone. This fact is of utmost importance because eggs are responsible for the pathology and transmission of the disease. Subsequently, the chemical optimisation of the structure in order to improve the metabolic stability of the parent compound was carried out leading to derivatives with improved drug-like properties. Additionally, the putative target of this new class of antischistosomal compounds was envisaged by using computational tools and the binding mode to the target enzyme, aldose reductase, was proposed.


Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Schistosoma mansoni/drug effects , Aldehyde Reductase/metabolism , Animals , Anthelmintics , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Male , Mice , Models, Molecular , Molecular Structure , Quinazolines/chemical synthesis , Schistosoma mansoni/enzymology , Structure-Activity Relationship
4.
Article in English | MEDLINE | ID: mdl-30669086

ABSTRACT

We report the evaluation of 265 compounds from a PDE-focused library for their antischistosomal activity, assessed in vitro using Schistosoma mansoni. Of the tested compounds, 171 (64%) displayed selective in vitro activity, with 16 causing worm hypermotility/spastic contractions and 41 inducing various degrees of worm killing at 100 µM, with the surviving worms displaying sluggish movement, worm unpairing and complete absence of eggs. The compounds that did not affect worm viability (n = 72) induced a complete cessation of ovipositing. 82% of the compounds had an impact on male worms whereas female worms were barely affected. In vivo evaluation in S. mansoni-infected mice with the in vitro 'hit' NPD-0274 at 20 mg/kg/day orally for 5 days resulted in worm burden reductions of 29% and intestinal tissue egg load reduction of 35% at 10 days post-treatment. Combination of praziquantel (PZQ) at 10 mg/kg/day for 5 days with NPD-0274 or NPD-0298 resulted in significantly higher worm killing than PZQ alone, as well as a reduction in intestinal tissue egg load, disappearance of immature eggs and an increase in the number of dead eggs.


Subject(s)
Anthelmintics/pharmacology , Imidazoles/pharmacology , Schistosoma mansoni/drug effects , Small Molecule Libraries , 3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Animals , Anthelmintics/chemistry , Drug Discovery , Fibroblasts/drug effects , High-Throughput Screening Assays , Humans , Imidazoles/chemistry , Male , Mice , Parasite Egg Count , Praziquantel/pharmacology
5.
Pharm Biol ; 52(12): 1581-90, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25243881

ABSTRACT

CONTEXT: Liver disease is a serious problem. Polyphenolic compounds have marked antioxidant effect and can prevent the liver damage caused by free radicals. In vitro studies have revealed the strong antioxidant activity of an ellagitannin-rich plant, namely, Melaleuca styphelioides Sm. (Myrtaceae). OBJECTIVE: In view of the limited therapeutic options available for the treatment of liver diseases, the hepatoprotective potential of the methanol extract of M. styphelioides leaves (MSE) was investigated against CCl4-induced liver injury in mice. MATERIALS AND METHODS: MSE was administered (500 and 1000 mg/kg/d p.o.) along with CCl4 for 6 weeks. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were determined in the serum. Glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione transferase (GST), and malondialdehyde (MDA) were estimated in the liver homogenate. The bioactive components of MSE were identified by NMR, UV and HRESI-MS/MS data. RESULTS: MSE treatment (500 and 1000 mg/kg/d) markedly inhibited the CCl4-induced increase in the levels of AST (31 and 38%), ALT (29 and 32%), ALP (13 and 19%), and MDA (22 and 37%) at the tested doses, respectively. MSE treatment markedly increased the levels of GSH (29 and 57%) and antioxidant enzymes compared with the CCl4-treated group. MSE was more effective than silymarin in restoring the liver architecture and reducing the fatty changes, central vein congestion, Kupffer cell hyperplasia, inflammatory infiltration, and necrosis induced by CCl4. The LD50 of MSE was more than 5000 mg/kg. CONCLUSION: MSE confers potent antioxidant and hepatoprotective effects against CCl4-induced toxicity.


Subject(s)
Antioxidants/pharmacology , Liver Diseases/prevention & control , Melaleuca/chemistry , Plant Extracts/pharmacology , Animals , Antioxidants/administration & dosage , Antioxidants/toxicity , Carbon Tetrachloride/toxicity , Disease Models, Animal , Dose-Response Relationship, Drug , Lethal Dose 50 , Magnetic Resonance Spectroscopy , Male , Mice , Plant Extracts/administration & dosage , Plant Extracts/toxicity , Plant Leaves , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, Ultraviolet , Tandem Mass Spectrometry
6.
Biomed Res Int ; 2014: 245171, 2014.
Article in English | MEDLINE | ID: mdl-24955350

ABSTRACT

The hepatoprotective and antioxidant activity of Bauhinia hookeri ethanol extract (BHE) against CCl4-induced liver injury was investigated in mice. BHE was administered (500 and 1000 mg/kg/day) along with CCl4 for 6 weeks. The hepatic marker enzymes: alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were determined in the serum. The antioxidant parameters: glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione transferase (GST), and malondialdehyde (MDA) were estimated in the liver homogenate. BHE treatment significantly inhibited the CCl4-induced increase in ALT (44 and 64%), AST (36 and 46%), ALP (28 and 42%), and MDA (39 and 51%) levels at the tested doses, respectively. Moreover, BHE treatment markedly increased the activity of antioxidant parameters GSH, GPx, GR, GST, and SOD. Histological observations confirmed the strong hepatoprotective activity. These results suggest that a dietary supplement of BHE could exert a beneficial effect against oxidative stress and various liver diseases by enhancing the antioxidant defense status, reducing lipid peroxidation, and protecting against the pathological changes of the liver. The hepatoprotective activity of BHE is mediated, at least in part, by the antioxidant effect of its constituents. The active constituents of BHE were identified by HPLC-PDA-ESI/MS/MS.


Subject(s)
Antioxidants/administration & dosage , Carbon Tetrachloride Poisoning/drug therapy , Chemical and Drug Induced Liver Injury/drug therapy , Plant Extracts/administration & dosage , Animals , Antioxidants/chemistry , Bauhinia/chemistry , Carbon Tetrachloride/toxicity , Carbon Tetrachloride Poisoning/metabolism , Carbon Tetrachloride Poisoning/pathology , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Chromatography, High Pressure Liquid , Lipid Peroxidation , Mice , Oxidative Stress , Phytotherapy , Plant Extracts/chemistry , Tandem Mass Spectrometry
7.
J Egypt Soc Parasitol ; 44(2): 295-308, 2014 Aug.
Article in English | MEDLINE | ID: mdl-25597144

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) includes a broad spectrum of fat-induced liver injury, ranging from mild steatosis to cirrhosis and liver failure. This study investigates the hepatoprotective properties of garlic and onion in NAFLD rat model. Ninety male Sprague-Dawley rats were randomly divided into 9 groups; normal (I), NAFLD induced with high fat diet (HFD; II), NAFLD switched to regular diet (RD; III), NAFLD-HFD or NAFLD-RD treated with garlic (IV, V), onion (VI, VII) or the combined garlic+onion (VIII, IX) respectively. A NAFLD rat model was established by feeding the animals with a high-fat diet for 12 wk. These animals were then treated with garlic or/and onion or vehicle for 8 wk (weeks 13-20) and then killed to obtain serum samples and liver tissues. Liver histology, lipids, parameters of oxidative stress, TNF-α and TGF-ß were measured. The liver in NAFLD-HFD showed typical steatosis, accompanied with mild to moderate lobular inflammatory cell infiltration. Serum levels of ALT, AST, ALP, leptin, cholesterol, triglycerides, TNF-α, TGF-ß and hepatic MDA' were significantly increased (P < 0.05) compared with normal group. This was accompanied with reduction of hepatic GSH, GR, GPx, GST, SOD and serum adiponectin. These changes were to a less degree in NAFLD-RD group. Combined administration of garlic+onion produced a better and significant decrease in liver steatosis, serum liver enzymes, oxidative markers and lipid peroxidation versus each one alone. In the same time, NAFLD-induced inflammation was also mitigated via reduction of TNF-α and TGF-ß. In addition, these results were better in the group IX versus group VIII.


Subject(s)
Dietary Fats/adverse effects , Garlic , Non-alcoholic Fatty Liver Disease/drug therapy , Onions , Animals , Antioxidants , Apoptosis , Cytokines/genetics , Cytokines/metabolism , Liver/metabolism , Liver/pathology , Male , Non-alcoholic Fatty Liver Disease/chemically induced , Oxidative Stress , Rats , Rats, Sprague-Dawley
8.
J Egypt Soc Parasitol ; 41(1): 77-88, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21634244

ABSTRACT

The potential role of hepatoprotective and antipathological effect of Ficus sycomorus and Azadirachta indica extracts was evaluated for scavenging the reactive oxygen species (ROS) and reduced the oxidative damage and pathological changes in the liver of S. mansoni infected mice. The levels of alanine aminotransferase (ALT), asparate aminotransferase (AST) and gamma glutamyl transferase (GGT) were evaluated in the infected mice and treated orally with each plant extract 12 weeks post infection (P.I.) in a dose of 500 mg/kg of each plant extract for five consecutive days and sacrificed two weeks P.I. The infection of mice showed an elevation of ALT, AST & GGT. Treatment of mice with 70% methanol extract of each plant extract reduced significantly ALT, AST & GGT elevation. The highest reduction was with the methanolic extract of F. sycomorus (42%, 35% &44% for ALT, AST & GGT respectively). Fractionation of the methanolic extract of each plant was carried out. The effect of ethyl acetate and butanolic fractions of each plant was also evaluated. The result showed that the two fractions lowered the levels of the tested enzymes and decreased the number and size of granuloma diameters with an increased in the percentage of degenerated ova.


Subject(s)
Azadirachta/chemistry , Ficus/chemistry , Liver/parasitology , Plant Extracts/chemistry , Plant Extracts/pharmacology , Schistosomiasis mansoni/drug therapy , Animals , Free Radical Scavengers/chemistry , Free Radical Scavengers/pharmacology , Liver/drug effects , Male , Mice , Plant Leaves , Reactive Oxygen Species , Schistosoma mansoni/drug effects
9.
J Parasitol ; 94(2): 537-41, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18564758

ABSTRACT

The stability of praziquantel (PZQ)-insusceptible S. mansoni isolates and the possible selection of PZQ-insusceptible parasites upon applying therapeutic pressure were examined over several life cycle passages (snails to mice). To test isolate stability, 3 PZQ-susceptible and 7 PZQ-insusceptible isolates were used to establish infection in mice, and they were passaged each for 2-5 life cycles. After each passage, 6 groups of mice were used to assess the PZQ dose at which the worm burden was decreased by 50% (ED50). Five of them were treated with doses of PZQ (12.5, 25, 50, 100, and 200 mg/kg for 5 days) 7 wk after infection; the last group represented infected, but untreated, controls. Possible selection of PZQ-insusceptible parasites under therapeutic pressure was examined by subjecting 1 PZQ-susceptible and 1 PZQ-insusceptible S. mansoni isolate to therapeutic pressure by PZQ for 8 passages. After the final passage, PZQ ED50 was estimated. All PZQ-susceptible S. mansoni isolates showed stable susceptibility to PZQ (mean PZQ ED50 = 85 mg/kg) over all passages. Two of the 7 PZQ-insusceptible S. mansoni isolates (847 and ER5) showed normal sensitivity to PZQ in 1-2 passages (although not the last passage, and without a declining ED50 profile), whereas the remaining passages kept a sustained insusceptibility to the drug (mean PZQ ED50 = 217 mg/kg). Worm maturity and sex were irrelevant to variability in drug ED50 within an individual isolate over different passages, revealing the heterogeneous nature of the parasite. Therapeutic pressure for limited life cycle passages did not result in a significant increase in drug ED50. The fact that reversion of some of the PZQ-insusceptible S. mansoni isolates to normal drug-sensitive state is not long lasting and that the therapeutic pressure by PZQ in the field is not comparable with that in the laboratory (unlimited), make monitoring the response of patients to the drug in the field an integral part of schistosomiasis control measures.


Subject(s)
Anthelmintics/pharmacology , Praziquantel/pharmacology , Schistosoma mansoni/drug effects , Schistosomiasis mansoni/drug therapy , Animals , Anthelmintics/therapeutic use , Biomphalaria , Female , Humans , Inhibitory Concentration 50 , Male , Mice , Parasitic Sensitivity Tests , Praziquantel/therapeutic use , Schistosoma mansoni/growth & development , Serial Passage
10.
J Parasitol ; 92(6): 1344-9, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17304818

ABSTRACT

The level of drug-metabolizing enzymes (cytochrome P450 [CYP450] and cytochrome b5 [cyt b5]) and the bioavailability of praziquantel (PZQ) were investigated in batches of mice infected with Schistosoma mansoni displaying either a decreased susceptibility to PZQ ("EE2" and "BANL"-isolates), or a normal susceptibility to the drug ("CD" isolate). Each batch was divided into 2 groups. The first group was further subdivided into 5 subgroups. Subgroups 1 to 4 were treated 7 wk postinfection (PI) with oral PZQ at 25, 50, 100, and 200 mg/kg for 5 consecutive days, whereas the fifth subgroup was administered the vehicle only as control. Animals were perfused 9 wk PI, and worms were counted to estimate PZQ ED50. CYP450 and cyt b5 were examined in hepatic microsomes of infected untreated mice and of infected mice treated with 25 and 200 mg/ kg PZQ. The second group was given PZQ 7 wk PI and was further subdivided into 11 subgroups, killed at 2, 5, 15, 30, 60, 90, 120, 150, 180, 240, and 360 min postdosing to study pharmacokinetic parameters of PZQ. Mice harboring S. mansoni isolates having higher PZQ ED50 (170.3 mg/kg for EE2 and 249.9 mg/kg for BANL vs. 82.96 mg/kg for CD) had higher levels of CYP450 and cyt b5, a PZQ Cmax decreased by 19-30% and area under the serum concentration-time curve0-6 hr decreased by 57-74%. Data suggest that S. mansoni isolates that are less sensitive to PZQ induce a lower inhibition of hepatic drug-metabolizing enzymes, with a consequently higher metabolic transformation of PZQ.


Subject(s)
Anthelmintics/pharmacokinetics , Cytochrome P-450 Enzyme System/metabolism , Cytochromes b5/metabolism , Praziquantel/pharmacokinetics , Schistosoma mansoni/drug effects , Schistosomiasis mansoni/metabolism , Animals , Anthelmintics/metabolism , Anthelmintics/pharmacology , Biological Availability , Humans , Male , Mice , Microsomes, Liver/enzymology , Parasitic Sensitivity Tests , Praziquantel/metabolism , Praziquantel/pharmacology , Schistosomiasis mansoni/enzymology , Schistosomiasis mansoni/parasitology
11.
Int J Parasitol ; 34(8): 979-87, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15217737

ABSTRACT

The dose of praziquantel required to kill 50% of adult worms in vivo (i.e. the ED50) was estimated for nine different isolates of Schistosoma mansoni in infected mice. Four of the isolates were selected because they had not knowingly been in contact with the drug (i.e. they were putatively praziquantel-susceptible). Five putatively praziquantel-resistant isolates were chosen because they had been selectively bred for drug-resistance in the laboratory and/or had previously been shown to be relatively resistant to praziquantel in the field. The work was performed in three laboratories in different countries using pre-agreed and comparable experimental protocols. All four praziquantel-susceptible isolates had ED50s estimated to be <100 mg/kg (mean=70+/-7 SD; median=68), while all five putatively praziquantel-resistant isolates had estimated ED50s >100 mg/kg (mean=209+/-48 SD; median=192). Thus, the five praziquantel-resistant isolates, including two that had been subjected to drug pressure during more than 20 passages in mice, had drug ED50s that were approximately three times as great as those of the praziquantel-susceptible isolates. Two of the five isolates in the putatively resistant group had previously been passaged 15 or more times in mice without administration of drug-pressure, but had ED50s consistent with the other three isolates in the group, indicating that the trait of praziquantel-resistance did not necessarily impair biological fitness during laboratory passage. The protocols used here to estimate the praziquantel ED50s of S. mansoni isolates should be useful for establishing and monitoring the drug susceptibility/resistance profiles of parasite isolates freshly obtained from endemic areas, particularly those in which increased usage of the drug is likely to occur.


Subject(s)
Anthelmintics/administration & dosage , Praziquantel/administration & dosage , Schistosoma mansoni/drug effects , Schistosomiasis mansoni/drug therapy , Adolescent , Animals , Dose-Response Relationship, Drug , Drug Resistance , Female , Humans , Lethal Dose 50 , Mice , Parasite Egg Count/methods , Parasitic Sensitivity Tests/methods , Schistosoma mansoni/isolation & purification
SELECTION OF CITATIONS
SEARCH DETAIL
...