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Metronidazole hydrazone conjugates (2-13) were synthesized and screened in vitro for antiamoebic activity against HM1: IMSS strain of Entamoeba histolytica. Six compounds were found to be better inhibitors of E. histolytica than the reference drug metronidazole. These compounds showed greater than 50-60% viability against HeLa cervical cancer cell line after 72 h treatment. Also, molecular docking study was undertaken on E. histolytica thioredoxin reductase (EhTHRase) protein which showed significant binding affinity in the active site. Out of the six actives, some of the compounds showed lipophilic characteristics., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Although amoebic liver abscess due to Entamoeba histolytica is one of the most common parasitic infections worldwide, invasive disease remains uncommon in industrialized countries. Metronidazole is the standard of care for complicated and uncomplicated invasive amoebiasis. Puncture of amebic liver abscesses is a treatment option primarily for complicated abscesses (localized in left lobe, multiple, and/or pyogenic abscesses). The role of image-guided percutaneous puncture in initially uncomplicated liver abscess formations still remains unanswered. A subset of patients with uncomplicated amoebic liver abscesses, however, fails to respond to conservative treatment alone. We report two cases of amoebic liver abscess formations in Austrian travelers. Two males, aged 67 and 43, presented with fever, chills and fatigue. Four months prior to admission both patients travelled together to Goa, India, for 4 weeks. Computed tomography showed uncomplicated liver abscess formations and serology for E. histolytica was positive in both patients. Therapy with metronidazole 500 mg four times daily was initiated. Computed tomography then showed an increase in size of liver abscess formations in both patients after 13 and 10 days of intravenous metronidazole therapy, respectively. Patient 1 developed pleural effusion and patient 2 additional liver abscess formations. Therefore CT-guided percutaneous therapeutic catheter drainage of liver abscess formations was performed in both patients without complications. Real time PCR of abscess drainage was positive for E. histolytica in both patients. After completion of metronidazole, paromomycin 500 mg three times daily was initiated for seven days for elimination of cysts and both patients were discharged without further complaints. This report highlights that conservative monotherapeutic treatment alone may not be sufficient in some patients with initially uncomplicated E. histolytica liver abscess. Implementation of additional image guided percutaneous puncture may reduce mortality and disease related costs.

Metronidazole thiosalicylate conjugates were synthesized and crystallised in order to discover new molecules having better efficacy than therapeutically administered drug metronidazole, used against Entamoeba histolytica. The three compounds (4-6) showed lower IC(50) values than metronidazole on HM1:IMSS strain of E. histolytica and displayed low cytotoxicity on MCF-7 cell line. In order to get an insight into the mechanisms of action of these compounds, a homology model of E. histolytica thioredoxin reductase (EhTHRase) was constructed and molecular docking was performed into the binding pocket to identify the nature of interactions. The docking studies suggest that the improved inhibitory activity of the newly synthesised metronidazole analogues could be due to involvement of the additional hydrophobic interactions in the binding mode. The result of the present study indicates the molecular fragments that play an essential role in improving the antiamoebic activity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Amoebiasis is a common cause of non-specific colitis in the Philippines. The prevalence of Clostridium difficile infection with colitis is unknown. Empiric use of metronidazole for colitis treatment is widely practiced. We investigated the association of C. difficile or Entamoeba histolytica infection with endoscopically/histopathologically proven colitis among adults in the Philippines. Two hundred and ten patients undergoing colonoscopy were enrolled. Demographic and clinical data were reviewed. Stool specimens were assayed for C. difficile and E. histolytica by ELISA. Microscopy was performed. The mean age of the patients was 53 y (range: 19-88 y) and 53% were male. Colitis was diagnosed in 39 of 205 patients. Clostridium difficile, E. histolytica and parasites were seen in 17 (43.6%), 10 (25.6%) and 11 (28.2%), respectively, of patients with colitis compared with 36 (21.7%; p=0.005), 13 (7.8%; p=0.001) and 56 (33.7%; p=0.51), respectively, of those without colitis. Diarrhoea and antibiotic intake history were significantly more common among patients with colitis than those without (43.6% and 20.5% vs 18.1% and 5.4%; p=0.001 and p=0.006, respectively). The mean duration of diarrhoea was 2.53 d shorter among patients with colitis. The most frequent antibiotics taken were fluoroquinolones and metronidazole (50% and 40% of antibiotic courses, respectively, in patients with colitis). This study suggests that C. difficile infection is common and might be overlooked in settings where amoebiasis and intestinal parasitism are endemic., (Copyright © 2012 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.)

Metronidazole, a 5-nitroimidazole drug, has been the gold standard for several decades in the treatment of infections with microaerophilic protist parasites, including Entamoeba histolytica. For activation, the drug must be chemically reduced, but little is known about the targets of the active metabolites. Applying two-dimensional gel electrophoresis and mass spectrometry, we searched for protein targets in E. histolytica. Of all proteins visualized, only five were found to form adducts with metronidazole metabolites: thioredoxin, thioredoxin reductase, superoxide dismutase, purine nucleoside phosphorylase, and a previously unknown protein. Recombinant thioredoxin reductase carrying the modification displayed reduced enzymatic activity. In treated cells, essential non-protein thiols such as free cysteine were also affected by covalent adduct formation, their levels being drastically reduced. Accordingly, addition of cysteine allowed E. histolytica to survive in the presence of otherwise lethal metronidazole concentrations and reduced protein adduct formation. Finally, we discovered that thioredoxin reductase reduces metronidazole and other nitro compounds, suggesting a new model of metronidazole activation in E. histolytica with a central role for thioredoxin reductase. By reducing metronidazole, the enzyme renders itself and associated thiol-containing proteins vulnerable to adduct formation. Because thioredoxin reductase is a ubiquitous enzyme, similar processes could occur in other eukaryotic or prokaryotic organisms.

The antiprotozoan activity of secnidazole was studied in Cercocebus t. torquatus, Cercopithecus campbelli, Erythrocebus patas (Cercopithecidae), and Gorilla gorilla (Pongidae) compared with that of paromomycin in Cercocebus t. lunulatus (Cercopithecidae), E. patas, and G. gorilla (Pongidae) by coprological analysis. The antiprotozoan activity of both drugs depended on the parasite species and the host species. The drugs acted in a similar way on Entamoeba coli parasitising C. t. torquatus, and E. patas. This activity was different from that observed on I. buestchlii from the same host species. Nevertheless, E. coli parasitising cercopithecids and pongids responded to drugs differently.

Background: Metronidazole is often administered to patients with irritable bowel syndrome with an erroneous diagnosis of 'chronic amebiasis'., Aims: To assess how patients with irritable bowel syndrome respond to metronidazole in the absence of amebae in their stools., Methods: We randomly allocated 45 patients (35 men; aged 15-59 years) with irritable bowel syndrome to receive isapghul (10 g bid x 60 days), metronidazole (400 mg tid X 10 days, followed by placebo x 50 days), or placebo (1 capsule bid x 60 days). Symptoms were evaluated and scored on days 0, 15, 30, 45 and 60. Rectosigmoid manometry was performed in 5 of 15 patients in each group on days 0 and 60., Results: There was a significant time effect and treatment effect on the symptom scores in all groups (isapghul > metronidazole > placebo); total score decreased from mean 25.8, 24.0 and 24.6 on day 0 to 7.2, 10.9 and 18.1 on day 60, respectively. Severity, duration and frequency of pain; and mucus in stool were all significantly reduced in all treatment groups (p < 0.001 for each). Treatment with isapghul increased the mean amplitude of propagated activity from 26.2 mmHg to 30.1 mmHg at 20 cm (p < 0.025) and from 23.1 mmHg to 27.4 mmHg at 10 cm (p < 0.05) from the anal verge, as well as the total duration of propagated activity at both sites (p < 0.05), with decrease in number of propagated contractions per 10 min (p < 0.025). Metronidazole and placebo had no effect on manometric findings., Conclusions: Metronidazole provides symptom relief in irritable bowel syndrome, without affecting rectosigmoid motility. This symptom response may be misinterpreted as supporting a diagnosis of 'chronic amebiasis'.

Platelets are part of body defence system, especially the anti-parasite immunologic response. Platelets manifest their functions only after their activation. Thrombine activates platelets inducing change of their shape and causing secretion of certain substances. This study was designed to estimate platelet morphology as an indicator of their activation and effectiveness of anti-parasite therapy. The study was conducted in group of 30 patients infested with E. histolytica before treatment (A) and group of 23 patients after 2-week treatment course (B). The diagnosis of amoebiasis was based on detection of cyst forms in faeces. During the course of amoebiasis increase of platelets count and platelet crit (PCT) was observed. Mean platelet volume (MPV) in both groups (A and B) was decreased as compared with control group. We suggest that E. histolytica activates platelets, and the degree of their activation determines their morphologic parameters, and these changes come back to normal values during anti-parasite treatment.

The authors have treated: a) 48 cases of E. histolytica histolytica intestinal amoebiasis by a single dose of 35 mg/kg of secnidazole with 98 p. 100 of parasitological success; b) 122 cases of E. histolytica minuta with several procedures: a unique dose of 25 mg/kg gives no success in 16.6 p. 100 of the cases, but the same single dose during three days gets only 2 p. 100 of failure; c) 22 cases of hepatic amoebiasis by a daily dose of 25 to 33 mg/kg during 5 days with success in every cases. Tolerance has been excellent. These short cures, facilitated by the long half-life of secnidazole are particularly easy to apply in developing countries.

Metronidazole, in a dose of 40 mg/kg body weight in 3 divided doses for 10 days was used to treat 194 patients infected with Entamoeba histolytica. When 166 subjects were checked 1 month after treatment, with 3 stool samples taken on different days, 20 failures were found giving a parasitic cure rate of 88%. A lower-than-expected failure rate was noted in children, immigrants and asymptomatic subjects. No more failures were found in 78 patients who went through an extended follow-up, with examinations after 4 and 10-12 months.

One hundred and fifteen persons with asymptomatic Entamoeba histolytica or E. hartmanni infection, or both, were given metronidazole (750 mg three times daily for 5 days), tinidazole (1 g twice daily on 2 consecutive days), or a starch placebo. Three post-treatment stools were examined in the 2 weeks following initiation of treatment. Cysts of E. histolytica reappeared in the stools of 37% of 30 given metronidazole, 62% of 34 given tinidazole, and 70% of 31 given placebo. Cysts of E. hartmanni reappeared in the stools of 46% of 24 given metronidazole, 69% of 16 given tinidazole, and 90% of 10 given placebo. Rapid absorption and short duration of treatment make both drugs ineffective for the treatment of ameba carriers.

The present report concerns a patient with ulceration around an artificial anus. The condition had been treated for some time as pyoderma gangrenosum but finally proved to be cutaneous amoebiasis; the presence of Entamoeba histolytica was demonstrated. A cure was achieved with metronidazol (Flagy) and diloxanide furoate (Furamide) given orally.