Effect of D-propanolol on growth and motility of flagellate protozoa

Farthing, M. J. G.; Inge, P. M. G.; Pearson, Richard M.

doi:10.1093/jac/20.4.519

Cited by 17 publications

(7 citation statements)

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“…Because antineoplastic agents (group 1) can have serious side effects, these compounds will probably not be developed for treating giardiasis. The antigiardial activity of different adrenergic antagonists (group 2) extends a prior report of such activity for the ␤-adrenergic antagonist propranolol (17), but the ultimate utility of these agents in the treatment of giardiasis is also questionable due to their intended effects in the cardiovascular system and/or central nervous system. The known antimicrobials (group 3) were not further evaluated in this study.…”

Section: Screening Of Chemical Library Against Giardiasupporting

confidence: 55%

A Reprofiled Drug, Auranofin, Is Effective against Metronidazole-Resistant Giardia lamblia

Tejman-Yarden

Miyamoto

Leitsch

et al. 2013

Antimicrob Agents Chemother

136

117

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Giardiasis is one of the most common causes of diarrheal disease worldwide. Treatment is primarily with 5-nitro antimicrobials, particularly metronidazole. Resistance to metronidazole has been described, and treatment failures can occur in up to 20% of cases, making development of alternative antigiardials an important goal. To this end, we have screened a chemical library of 746 approved human drugs and 164 additional bioactive compounds for activity against Giardia lamblia. We identified 56 compounds that caused significant inhibition of G. lamblia growth and attachment. Of these, 15 were previously reported to have antigiardial activity, 20 were bioactive but not approved for human use, and 21 were drugs approved for human use for other indications. One notable compound of the last group was the antirheumatic drug auranofin. Further testing revealed that auranofin was active in the low (4 to 6)-micromolar range against a range of divergent G. lamblia isolates representing both humanpathogenic assemblages A and B. Most importantly, auranofin was active against multiple metronidazole-resistant strains. Mechanistically, auranofin blocked the activity of giardial thioredoxin oxidoreductase, a critical enzyme involved in maintaining normal protein function and combating oxidative damage, suggesting that this inhibition contributes to the antigiardial activity. Furthermore, auranofin was efficacious in vivo, as it eradicated infection with different G. lamblia isolates in different rodent models. These results indicate that the approved human drug auranofin could be developed as a novel agent in the armamentarium of antigiardial drugs, particularly against metronidazole-resistant strains. Giardiasis is one of the most common human parasitic infections of the intestinal tract worldwide, affecting hundreds of millions of people, mostly in developing countries. It has been included in the Neglected Diseases Initiative of the WHO (1). Giardia exists in two forms, the infectious cyst and the diseasecausing trophozoite that colonizes the small intestinal lumen. Cysts are spread through drinking water, food, and person-toperson contact. The clinical symptoms of giardiasis include diarrhea, abdominal pain, malabsorption, and weight loss. A recent cohort study following a major giardiasis outbreak in Norway showed that infection with Giardia lamblia was associated with a high prevalence of irritable bowel syndrome and chronic fatigue 3 years after acute illness (2), highlighting the major health impact of giardiasis even in areas where it is not endemic. Treatment of giardiasis relies on antimicrobial drug therapy, most commonly with 5-nitroheterocyclic drugs, particularly metronidazole and, more recently, nitazoxanide (3). However, cross-resistance among 5-nitro antimicrobials exists, and treatment failures occur in up to 20% of cases (4-6). Alternative antimicrobials exist, but these are generally less effective than 5-nitro drugs (3, 7).One important strategy in the development of new antimicrobials is the screening of e...

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Section: Screening Of Chemical Library Against Giardiasupporting

confidence: 55%

A Reprofiled Drug, Auranofin, Is Effective against Metronidazole-Resistant Giardia lamblia

Tejman-Yarden

Miyamoto

Leitsch

et al. 2013

Antimicrob Agents Chemother

136

117

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“…Several studies mentioned briefly the toxic effect of deconjugated bile salts on Giardia (Farthing et al, 1983 , 1985 , 1987 ; Gillin, 1987 ). To our knowledge, our study is the first to demonstrate their dose-dependent anti-giardial activity.…”

Section: Discussionmentioning

confidence: 99%

Deconjugated Bile Salts Produced by Extracellular Bile-Salt Hydrolase-Like Activities from the Probiotic Lactobacillus johnsonii La1 Inhibit Giardia duodenalis In vitro Growth

et al. 2016

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Giardiasis, currently considered a neglected disease, is caused by the intestinal protozoan parasite Giardia duodenalis and is widely spread in human as well as domestic and wild animals. The lack of appropriate medications and the spread of resistant parasite strains urgently call for the development of novel therapeutic strategies. Host microbiota or certain probiotic strains have the capacity to provide some protection against giardiasis. By combining biological and biochemical approaches, we have been able to decipher a molecular mechanism used by the probiotic strain Lactobacillus johnsonii La1 to prevent Giardia growth in vitro. We provide evidence that the supernatant of this strain contains active principle(s) not directly toxic to Giardia but able to convert non-toxic components of bile into components highly toxic to Giardia. By using bile acid profiling, these components were identified as deconjugated bile-salts. A bacterial bile-salt-hydrolase of commercial origin was able to mimic the properties of the supernatant. Mass spectrometric analysis of the bacterial supernatant identified two of the three bile-salt-hydrolases encoded in the genome of this probiotic strain. These observations document a possible mechanism by which L. johnsonii La1, by secreting, or releasing BSH-like activity(ies) in the vicinity of replicating Giardia in an environment where bile is present and abundant, can fight this parasite. This discovery has both fundamental and applied outcomes to fight giardiasis, based on local delivery of deconjugated bile salts, enzyme deconjugation of bile components, or natural or recombinant probiotic strains that secrete or release such deconjugating activities in a compartment where both bile salts and Giardia are present.

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“…In a patient with metronidazole-resistant Giardia infection, the ␤-adrenergic antagonist DL-propranolol, given in a dose of 40 mg three times a day with 400 mg of metronidazole three times a day for 10 days, cleared infection, demonstrating clinical efficacy in humans (197). In vitro studies demonstrate that propranolol exerts its effect by inhibiting the motility and growth of the protozoan, most probably due to the membrane-stabilizing activity of the drug (85). However, further studies with DL-propranolol and the related compound D-propranolol are needed before they can be recommended as anti-Giardia agents.…”

Section: Classes Of Agents and Clinical Propertiesmentioning

confidence: 99%

Treatment of Giardiasis

2001

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Giardia lamblia is both the most common intestinal parasite in the United States and a frequent cause of diarrheal illness throughout the world. In spite of its recognition as an important human pathogen, there have been relatively few agents used in therapy. This paper discusses each class of drugs used in treatment, along with their mechanism of action, in vitro and clinical efficacy, and side effects and contraindications. Recommendations are made for the preferred treatment in different clinical situations. The greatest clinical experience is with the nitroimidazole drugs, i.e., metronidazole, tinidazole, and ornidazole, which are highly effective. A 5- to 7-day course of metronidazole can be expected to cure over 90% of individuals, and a single dose of tinidazole or ornidazole will cure a similar number. Quinacrine, which is no longer produced in the United States, has excellent efficacy but may be poorly tolerated, especially in children. Furazolidone is an effective alternative but must be administered four times a day for 7 to 10 days. Paromomycin may be used during early pregnancy, because it is not systematically absorbed, but it is not always effective. Patients who have resistant infection can usually be cured by a prolonged course of treatment with a combination of a nitroimidazole with quinacrine

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Effect of D-propanolol on growth and motility of flagellate protozoa

Cited by 17 publications

References 0 publications

A Reprofiled Drug, Auranofin, Is Effective against Metronidazole-Resistant Giardia lamblia

A Reprofiled Drug, Auranofin, Is Effective against Metronidazole-Resistant Giardia lamblia

Deconjugated Bile Salts Produced by Extracellular Bile-Salt Hydrolase-Like Activities from the Probiotic Lactobacillus johnsonii La1 Inhibit Giardia duodenalis In vitro Growth

Treatment of Giardiasis

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