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Objective: To estimate the influence of oxytocin infusion on operative blood loss and glycine deficit during hysteroscopic transcervical endometrial resection (TCRE) for abnormal uterine bleeding (AUB).Design: Prospective, randomized, placebo-controlled study (Canadian Task Force classification I).Setting: Tertiary Care University Hospital.Patients: Forty-eight women with abnormal uterine bleeding that was unresponsive to conservative medical management were randomly assigned to undergo hysteroscopic TCRE with either oxytocin infusion (group A) or saline (group B). Intravenous Ringer's lactate solution was used during surgery.Interventions: TCRE was carried out with glycine 1.5% mixed with 2% ethanol as a distension medium. For group A: one ampoule of oxytocin (10 U/mL/amp) was added to 500 mL Ringer's lactate solution running at a rate of 400 mU/min during surgery. In group B, one ampoule of saline solution was added to the Ringer's solution and run at a similar rate. The amount of distension medium used, fluid deficit, blood levels of albumin and ethanol, hematocrit, hemoglobin, changes in serum sodium levels (Na+), and central venous pressure were compared between the groups.Measurements and Main Results: The mean volume of distension fluid used and operating time were not significantly different in both groups (4.18 ± 0.2 vs 4.5 ± 0.5 L, and 28.3 ± 4.2 vs 27.5 ± 5.4 min, respectively). Although operating time, volume of distension fluid used, decrease in albumin level and hematocrit were less in the oxytocin than in the saline group, the differences were not statistically significant. The ethanol levels in blood, decrease in serum Na+, and glycine deficit were significantly lower in the oxytocin than in the saline group (17.4 ± 3.8 vs 25.3 ± 4.2 mg/ml, 6.7 ± 1.2 vs 9.1 ± 0.9 mEq/L, and 0.49 ± 0.08 vs 0.66 ± 0.05 L, respectively; p <.05). There was no significant difference in mean total uterine size, endometrial thickness, weight of resected tissue, and other demographic data between the study groups.Conclusions: Oxytocin infusion combined with skillful surgical techniques may prevent fluid overload and glycine deficit during hysteroscopic TCRE for abnormal uterine bleeding. Although there is a trend toward a decrease in operative blood loss, further randomized trials are required to confirm this finding. [ABSTRACT FROM AUTHOR]

Abstract Background Praziquantel (PZQ) is an isoquinoline derivative (2-cyclohexylcarbonyl-1, 2, 3, 6, 7, 11b-hexahydro-4H-pyrazino{2,1-a}-isoquinoline-4-one), and is currently the drug of choice for all forms of schistosomiasis. Silymarin, a standardized milk thistle extract, of which silibinin is the main component, is known for its hepatoprotective, anti-inflammatory, antioxidant activities, and hepatocyte regeneration. This study investigates the anti-inflammatory/anti-fibrotic effects of silymarin and/or PZQ on schistosomal hepatic fibrosis. Methods Schistosoma mansoni-infected mice were divided into two large groups (I & II), each with four subgroups and were run in parallel. (i) Infected untreated; (ii) treated with silymarin, starting from the 4th (3 weeks before PZQ therapy) or 12th (5 weeks after PZQ therapy) weeks post infection (PI); (iii) treated with PZQ in the 7th week PI; and (iv) treated with silymarin, as group (ii) plus PZQ as group (iii). Comparable groups of uninfected mice run in parallel with the infected groups. Mice of groups I and II were killed 10 and 18 weeks PI, respectively. Hepatic content of hydroxyproline (HYP), serum levels and tissue expression of matrix metalloproteinase-2 (MMP-2), transforming growth factor-β1 (TGF-β1) and number of mast cells were determined. In addition, parasitological, biochemical and histological parameters that reflect disease severity and morbidity were examined. Results Silymarin caused a partial decrease in worm burden; hepatic tissue egg load, with an increase in percentage of dead eggs; modulation of granuloma size, with significant reduction of hepatic HYP content; tissue expression of MMP-2, TGF-β1; number of mast cells, with conservation of hepatic reduced glutathione (GSH). PZQ produced complete eradication of worms, eggs and alleviated liver inflammation and fibrosis. The best results were obtained, in most parameters studied, in groups of mice treated with silymarin in addition to PZQ. Conclusions Our results point to silymarin as a promising anti-inflammatory and anti-fibrotic agent; it could be introduced as a therapeutic tool with PZQ in the treatment of schistosomal liver fibrosis, but further studies on mechanisms of silymarin and PZQ in chronic liver diseases may shed light on developing therapeutic methods in clinical practice.

Non-alcoholic fatty liver disease (NAFLD) constitutes a major health problem worldwide and intimately links with obesity and diabetes. This study aimed to explore the therapeutic impact of early treatment with metformin (MTF) alone or in combination with Lactobacillus reuteri DSM 17938 ( L. reuteri ) + metronidazole (MTZ) in male Sprague Dawley rats with high-fat diet (HFD)-induced NAFLD. Hepatic steatosis was induced by feeding rats HFD for 6 weeks. MTF (150 mg/kg/day) or L. reuteri (2 × 10 9 colony forming unit/day) were given orally for 4 weeks; meanwhile, MTZ (15 mg/kg/day, p.o.) was administered for 1 week. Administration of L. reuteri + MTZ in combination with MTF produced a superior effect concerning insulin resistance (IR), lipid profile, liver function, oxidative stress, inflammatory and autophagic markers than using each treatment alone. Besides, this combination resulted in disappearance of steatosis, inflammation and vacuolation within hepatic architecture. Moreover, it normalized short chain fatty acids (SCFAs) as well as Firmicutes and Bacteroidetes faecal contents. In conclusion, early treatment with L. reuteri + MTZ in combination with MTF could prevent NAFLD progression and liver injury through targeting gut dysbiosis, inflammation and autophagic pathways.

Autophagy and apoptosis are important players in the progression of hepatic fibrosis via activation of hepatic stellate cells (HSCs). Despite the recently depicted antifibrotic effects of alpha-lipoic acid (ALA), however, its modulatory effects on HSCs autophagy remain unverified. Our study aimed to elucidate the underlying antifibrotic mechanisms through which ALA mediates HSC autophagy and apoptosis. Liver fibrosis was induced via thioacetamide (TAA) intoxication in rats; TAA-intoxicated rats were treated with either silymarin or ALA. Effect of ALA on biochemical parameters and immunohistopathological examinations was measured and compared to silymarin. ALA restored normal hepatic architecture (S1 vs. S4), liver functions, hepatic glutathione, and transforming growth factor-β1 levels. ALA ameliorated hepatic levels of malondialdehyde, platelet-derived growth factor, tissue inhibitor metalloproteinases-1, hydroxyproline, and expression of alpha-smooth muscle actin. Moreover, ALA significantly reduced messenger RNA expression of LC3-II genes and triggered caspase-3 expression. Interestingly, ALA exhibited superior activities over silymarin regarding suppression of proliferation, activation and autophagy of HSCs, collagen deposition, and induction of HSCs apoptosis. In conclusion, treatment of TAA-intoxicated rats with ALA inhibited autophagy and induced apoptotic clearance of activated HSCs. Accordingly, this study provides mechanistic insights into the possible applicability of ALA in the treatment of hepatic fibrosis.

One of the problems of praziquantel (PZQ) is its very low aqueous solubility. Moreover, its dissolution rate is considered the limiting factor for its bioavailability. This work correlates the physical properties and the dissolution behavior of PZQ-polyvinylpyrrolidone (PVP) solid dispersion (SD) at the ratios of 1:1 and 3:7 with its oral bioavailability and its in vivo efficacy against Schistosoma mansoni (S. mansoni). The PZQ and PZQ-PVP SD were characterized by infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy (SEM) and solubility test. Results showed a decrease in crystallinity, possible interaction between PZQ and PVP, greater increase in dissolution rate and appreciable reduction in particle size. S. mansoni-infected mice treated orally with either pure PZQ or PZQ-PVP at a single dose of 500 mg/kg showed a higher increase in AUC((0-8h)), C (max), K(a) and t (1/2e) with a significant decrease in k (el) versus the corresponding uninfected mice. Moreover, uninfected and infected mice treated with PZQ-PVP SD showed 2.3-, 1.6- and 1.3-, 1.25-fold increase, respectively, in AUC((0-8h)) and C(max), with a decrease in k(el) and increase in t (1/2e) by twofold versus the corresponding pure PZQ-treated groups. Percentage worm reduction at all administered doses (62.5, 125, 250, 500 and 1,000 mg/kg) was significantly higher (1- to 1.5-fold) in mice treated with PZQ-PVP SD (ED₅₀ = 40.92) versus those treated with pure PZQ (ED₅₀ = 99.29). In addition, a significant reduction in total tissue egg load concomitant with a significant decrease in total immature and mature eggs and an increase in dead eggs in PZQ-PVP SD-treated groups versus their corresponding pure PZQ-treated groups was recorded. Solid dispersion of PZQ with PVP could lead to a further improvement in the effectiveness of PZQ therapy especially with the appearance of some PZQ-tolerant S. mansoni isolates.

Unlabelled: This study investigates the possible use of pentoxifylline (PTX), with antifibrotic and anti-inflammatory properties, as adjuvant in treatment of schistosomal liver fibrosis through determination of some profibrogenic cytokines, oxidative stress and collagen deposition. Animals were classified into seven groups: normal control (i), Schistosoma mansoni-infected untreated (ii), infected treated with praziquantel (PZQ) curative, 1000mg/kg (iii) or sub curative, 200mg/kg dose (iv), infected treated with PTX alone (10mg/kg/day; 5days/wk) for 8weeks starting from the 2nd to the 10th week post infection (v), or in addition to curative (vi) or sub curative dose of PZQ (vii). Serum transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), matrix metalloproteinases-2 (MMP-2) and hepatic hydroxyproline (Hyp) content, glutathione related antioxidant enzymes and malondialdehyde (MDA) were determined. Results showed that S. mansoni infection produced remarkable elevations in the serum levels of TGF-β1, TNF-α, MMP-2 and the hepatic contents of Hyp, glutathione reductase (GR), MDA with significant reduction in reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and superoxide dismutase (SOD) when compared with their corresponding normal controls. Treatment of infected mice with PTX in addition to PZQ curative rather than its sub curative dose produced the best results evidenced by complete normalization in the previously mentioned serum and hepatic parameters., Conclusion: PTX could attenuate liver fibrosis in early stages of S. mansoni infection through downregulation of profibrogenic cytokines, oxidative stress and collagen deposition., (Copyright © 2011 Elsevier Inc. All rights reserved.)

This study investigates the efficacy, bioavailability and drug metabolizing enzymes mainly involved in the metabolism of the commercial brands of praziquantel (PZQ) in Egypt in comparison with the original pure powder. Mice infected with PZQ-susceptible (CD) or PZQ-insusceptible (EE2) Schistosoma mansoni isolates were divided each into seven groups, six of them received PZQ brands (Distocide, Epiquantel, Biltricide, Bilharzid, Praziquantel, and pure PZQ), while the seventh one was left as infected untreated. Seven weeks post-infection, worms were quantified and hepatic CYP450 and CYT b5 were examined. For PZQ pharmacokinetics, groups of normal mice were given the different PZQ brands and divided into subgroups, killed at 2, 5, 15, 30, 60, 90, 120,150, 180, 240 and 360 min post-dosing. Physicochemical examination revealed better dissolution rates for Biltricide, Distocide and PZQ T3A rather than Epiquantel and Bilharzid. Significant decrease in worm burden was recorded in all groups of mice regardless of the brand of PZQ used, but with better results obtained with CD isolate rather than the EE2 isolate. Biltricide and Distocide showed higher C(max) and AUC(0-6h) in normal mice, in addition to higher worm reduction with least inhibition of CYP450 and CYT b5 in EE2-infected mice. PZQ T3A, Bilharzid and Epiquantel showed, in addition to lower efficacy, higher K(el), lower t(1/2e), C(max) and AUC(0-6h). The 32-46% reduction of their bioavailability reflected on their antischistosomal efficacy and recovery of drug metabolizing enzymes. Quality of generic PZQ should include, in addition to examining the physicochemical characteristics of the brands, biological testing including efficacy and bioavailability studies., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Pentoxifylline (PTX) was proved to exert both anti-inflammatory and anti-fibrotic effects, and was used therapeutically in this experimental model to investigate its role alone or with praziquantel (PZQ) in Schistosoma mansoni-infected mice, and to explore its impact on the tissue expression of transforming growth factor-beta1 (TGF-beta1). S. mansoni-infected mice were divided into seven groups: Control untreated (I), treated with curative dose of PZQ, 500 mg/kg/day for 2 consecutive days (II), or subcurative dose, 100 mg/kg/day for 2 consecutive days (III), treated with PTX (10 mg/kg/day for 5 days/wk) alone for 4 weeks (IV) or in addition to subcurative dose of PZQ (V), and treated with PTX alone for 8 weeks (VI) or in addition to subcurative dose of PZQ (VII). All animals were killed 10 weeks post infection. Parasitological assessment of worm burden, tissue egg load and oogram pattern was carried out. The degree of granulomatous fibrosis and eosinophilic cell population was quantified in Sirius-red-stained sections and tissue transforming growth factor beta-1 expression was estimated immunohistochemically. Serum ALAT and GGT, as well as hepatic content of reduced GSH, were measured. The results revealed the highest percent of worm reduction and dead ova in groups (II) and (VII) accompanied by significant diminution in granulomatous parameters, collagen content and TGF-beta1 tissue expression. Moreover, treatments with PTX and/or PZQ ameliorated the liver functions. In conclusion, prolonged treatment with PTX has a potent anti-fibrogenic role especially when used in the early stages of infection, with limited toxic effects on schistosome worms and eggs. Thus, PTX can be used as an adjuvant therapeutic tool with anti-helminthic drugs in the treatment of human schistosomiasis.

Some have claimed that triclabendazole, a safe and efficacious drug for the treatment of fascioliasis, also exhibits antischistosomal properties, but results are conflicting. We assessed the effect of triclabendazole and its two main metabolites against two different strains of Schistosoma mansoni harbored in mice. Low worm burden reductions (18.6-35.9%) were observed in mice infected with an Egyptian strain of S. mansoni and treated with a single dose of 120 mg/kg 3 days before infection or single/double doses of 120-200 mg/kg 7 weeks after infection. Triclabendazole failed to significantly reduce hepatic and intestinal tissue egg loads, and eggs of all developmental stages were observed. Administration of 400 mg/kg of either triclabendazole, triclabendazole sulphone, or triclabendazole sulfphoxide to mice infected with a Liberian strain of S. mansoni resulted in worm burden reductions < 10%. In comparison, high worm burden reductions (82-100%) were observed in S. mansoni-infected mice treated with single oral doses of 400, 500, or 500 mg/kg twice a day praziquantel, regardless of the S. mansoni strain. We conclude that triclabendazole and its main metabolites display weak and inconsistent schistosomicidal activities.

Artemether is an efficacious antimalarial drug that also displays antischistosomal properties. Grapefruit juice increases the oral availability of a variety of the CYP3A4 substrates. This study was designed to evaluate the effect of repeated administration of grapefruit juice with artemether on the hepatic activities of cytochrome P-450 (CYP450) and cytochrome b5 (cyt b5), on the serum levels of some biochemical enzymes and antischistosome efficacy. Results showed that administration of grapefruit juice alone induced more inhibition in the hepatic activities of CYP450 and cyt b5 than that produced by Schistosoma mansoni infection. Moreover, it enhanced degeneration of eggs and accelerated healing of the pathological granulomatous lesions. Treatment of S. mansoni-infected mice with artemether at a total dose of 300 mg/kg resulted in total and female worm burden reductions of 66.7 and 90.1%, respectively, hence protecting the host from damage induced by schistosome eggs. Treatment of S. mansoni-infected mice with artemether at 150 mg/kg reduced the total and female worm numbers by 43.3 and 54.4%, respectively, thus somewhat ameliorating hepatic granulomatous lesions compared with the infected untreated group. This was associated with no change in the hepatic activities of CYP450 and cyt b5 and in the serum levels of total protein, albumin, globulin and alanine aminotransferase compared with the uninfected control group. Coadministration of grapefruit juice with the lower dose (150 mg/kg) of artemether eliminated eggs and granulomatous reactions. In this group, the inhibitory effects of grapefruit juice on CYP450 and cyt b5 were apparent but serum liver enzymes were unchanged compared with the uninfected control group. Coadministration of grapefruit juice with artemether achieved complete protection of the host from damage induced by schistosomal infection.

After placement in mice of PZQ-sensitive and -insensitive S. mansoni isolates obtained from villagers responding and not responding to PZQ, parasitological criteria reflecting their biological development and also the host anti-immature worm immunoglobulin isotypes were examined 8 and 10 weeks post infection. Hepatic granuloma diameter, hepatic histopathological changes and immunolocalization of IgG and IgM on the surface of PZQ-sensitive and -resistant worms were also examined 10 weeks post infection. Data showed that parasitological criteria were not significantly different between mice infected with the PZQ-sensitive and -insensitive S. mansoni isolates. As regards serum immunoglobulins, in mice infected with the PZQ-insensitive S. mansoni isolate, IgG and IgG1 were significantly (p<0.05) lower 8 and 10 weeks post infection, respectively (1.41+/-0.07 and 1.08+/-0.10 and 1.35+/-0.06 and 1.09+/-0.07) than in mice infected with the PZQ-sensitive S. mansoni isolate (1.73+/-0.15 and 1.38+/-0.10 and 1.73+/-0.17 and 1.54+0.21) after the same observation periods. IgM level was nearly the same while IgE was lower than that recorded in mice infected with the PZQ-sensitive S. mansoni isolate. IgG immunofluorescence was also lower (60%+/-6.78) on the surface of resistant worms than that of sensitive worms (66.6%+/-5.27); meanwhile, hepatic granuloma diameter was significantly larger (296.5+/-3.0 vs 283.6+/-4.0) in mice infected with the PZQ-insensitive S. mansoni isolate with higher percentage of intact eggs. Differences in the immunogenic make up of PZQ-sensitive and -insensitive S. mansoni isolates qualitatively and/or quantitatively favoring a certain Th cell subpopulation response could be the underlying reason for such differences recorded in the host immunoglobulin isotype response and also the egg-induced hepatic histopathological changes.