The mechanisms of action of antiprotozoal and anthelmintic drugs in man

Frayha, George J.; Smyth, J.D.; Gobert, J.G.; Savel, J

doi:10.1016/s0306-3623(96)00149-8

Cited by 98 publications

(68 citation statements)

References 67 publications

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“…This limited screen of small molecules, plus recent screens by Gareiss and colleagues and Pushechnikov and colleagues with short peptides and peptoids (34,35), clearly demonstrate that CUG repeats can be targeted and that high throughput screens with large libraries of small molecules will almost certainly produce many additional lead compounds other than pentamidine for further studies. (36,37). Although pentamidine has been shown to bind to both DNA and RNA, the mechanism of its antifungal activity is unknown.…”

Section: Discussionmentioning

confidence: 99%

Pentamidine reverses the splicing defects associated with myotonic dystrophy

Warf

Nakamori²,

Matthys³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

230

306

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Myotonic dystrophy (DM) is a genetic disorder caused by the expression (as RNA) of expanded CTG or CCTG repeats. The alternative splicing factor MBNL1 is sequestered to the expanded RNA repeats, resulting in missplicing of a subset of pre-mRNAs linked to symptoms found in DM patients. Current data suggest that if MBNL1 is released from sequestration, disease symptoms may be alleviated. We identified the small molecules pentamidine and neomycin B as compounds that disrupt MBNL1 binding to CUG repeats in vitro. We show in cell culture that pentamidine was able to reverse the missplicing of 2 pre-mRNAs affected in DM, whereas neomycin B had no effect. Pentamidine also significantly reduced the formation of ribonuclear foci in tissue culture cells, releasing MBNL1 from the foci in the treated cells. Furthermore, pentamidine partially rescued splicing defects of 2 pre-mRNAs in mice expressing expanded CUG repeats.alternative splicing ͉ triplet repeats ͉ MBNL1 ͉ muscleblind-like 1 ͉ RNA repeats M yotonic dystrophy (DM) is an autosomal dominant genetic disorder that is characterized by a variety of symptoms. There are 2 types of myotonic dystrophy, type 1 (DM1) and type 2 (DM2). DM1 is linked to a (CTG) n repeat expansion in the 3Ј untranslated region of the DMPK gene, whereas DM2 is linked to a (CCTG) n repeat expansion in intron 1 of the ZNF9 gene. The current model is that the expanded repeats are toxic on the RNA level, where either repeat can form a stable structured RNA that aberrantly interacts with proteins in the nucleus (for review see refs. 1, 2).One proposed molecular mechanism that may account for the disease symptoms is that, upon transcription of the expansions, either the CUG or CCUG repeats sequester RNA binding proteins from their normal cellular functions. The protein MBNL1 (Muscleblind-like 1) has been shown to bind both expanded CUG and CCUG repeats in vitro (3-5), and colocalize with these expanded repeats in vivo (6-10). MBNL1 is an alternative splicing factor and its sequestration leads to the missplicing of multiple pre-mRNAs in DM, which is thought to give rise to many of the symptoms of the disease. In support of this model, it has been shown that the disruption of the MBNL1 gene or expression of CUG repeats in mice causes symptoms and missplicing similar to those seen in DM patients (11)(12)(13)(14). Furthermore, disease symptoms can be rescued and missplicing of many pre-mRNAs can be reversed in mice expressing CUG repeats by overexpression of MBNL1 (15).Aside from the overexpression of MBNL1, another possible approach to overcoming the sequestration of MBNL1 is to identify small molecules that specifically bind the CUG repeats and competitively release the sequestered MBNL1. As a step toward identifying a small molecule therapeutic for DM, a small library of molecules known to bind structured nucleic acid were screened for their ability to disrupt an MBNL1-CUG repeat interaction in vitro. Two molecules were identified that strongly disrupted the complex in vitro. Further testing showed tha...

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Section: Discussionmentioning

confidence: 99%

Pentamidine reverses the splicing defects associated with myotonic dystrophy

Warf

Nakamori²,

Matthys³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

230

306

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“…Ivermectin is a member of the family of compounds produced by the soil microorganism Streptomyces avermitilis and known generically as avermectins (Campbell & Benz, 1984). Ivermectin acts as an γ -aminobutyric acid (GABA) antagonist in nematodes to cause paralysis (Frayha et al, 1997). Ivermectin is effective against two major phyla of animal parasites-the Nematoda (roundworms) and the Arthropoda (insects, ticks, and mites).…”

Section: Introductionmentioning

confidence: 99%

“…Studies on its mode of action suggest that ivermectin is unlikely to be effective against species of the phylum Platyhelminthes (flukes and tapeworms); indeed, those platyhelminths that have been exposed to ivermectin have proved insusceptible (Campbell et al, 1983). It seems that cestodes and trematodes have nervous systems different from those of nematodes (Frayha et al, 1997). Due to the fact that pinworm eggs have been found on equipment, in dust and in ventilation air-intake ducts, drug therapy should be backed by routine hygienic measures (Habermann & Williams, 1958;Taffs, 1976).…”

Section: Introductionmentioning

confidence: 99%

Drinking water ivermectin treatment for eradication of pinworm infections from laboratory rat colonies

Lytvynets¹,

Langrová

Lachout

et al. 2010

Helminthologia

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233 SummaryThe effects of ivermectin were studied in laboratory rats naturally infected with the pinworm Syphacia muris. Ivermectin was administered over four 5-days periods in drinking water; the ivermectin dose was 2.5 mg/kg of body weight per day. All the rats were weighed every five days and their ova production was monitored by a cellophanetape test. Every fifth day six males and six females from the experimental group were euthanized and examined for adult pinworms and larvae. The rats' health condition, behaviour and consumption of food and water were monitored every day. The aim of this study was to investigate the effectiveness of orally administered ivermectin as a treatment against adult pinworms and their larvae in laboratory rat colonies.

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“…Στην ομάδα αυτή περιλαμβάνονται ανθελμινθικές ουσίες που αναστέλλουν το σχηματισμό των μικροσω-ληναριων και τη λειτουργία των μιτοχονδρίων, με απο τέλεσμα την αναστολή της μεταβολικής δραστηριότητας και της μιτωτικής διεργασίας των κυττάρων των παρά σιτων (Frayha et al 1997, Lynn 2003. Επειδή η δράση των ουσιών αυτών είναι ανάλογη με το χρόνο επαφής τους με τα παράσιτα, θα πρέπει να χορηγούνται για τρεις τουλάχιστον συνεχόμενες ημέρες και κάθε 12 ώρες (Zajac 1993, Elliott 2001, Lynn 2003.…”

Section: βενζιμιδαζολες/προβενζιμιδαζολεςunclassified

“…Οι ισοκινολόνες δρουν στις νευρομυικές συνάψεις και στον καλυπτήριο υμένα των παρασίτων, προκαλώντας παράλυση και κενοτοπίωση του υμένα, αντίστοιχα (Andrews et al 1983, Zajac 1993, Frayha et al 1997). …”

Section: ισοκινολονεςunclassified

Current aspects ση the anthelmintic management of gastrointestinal tapeworms and nematodes in the dog and cat

Tapes

Mylonakis

Papadopoulos

et al. 2017

J Hellenic Vet Med Soc

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Gastrointestinal parasitic infections in dogs and cats are a common problem in the clinical setting. Ascarids, hookworms, whipworms and tapeworms should be eliminated on a regular basis, not only to avoid possible health implications on the host itself, but also for the zoonotic potential of certain helminthes (ascarids, hookworms, Echinococcus spp.). Of the highly efficacious and safe medications that eliminate gastrointestinal helminths, commercially available in Greece are benzimidazoles, macrocyclic lactones, tetrahydropyrimidines and isokinolones. Since puppies, kittens, pregnant and nursing animals have a greater risk to acquire gastrointestinal parasites, more intensive anthelmintic schedules are usually instituted. In the less than 6-month old domestic carnivores, deworming should begin at the age of 2-3 weeks and proceed at biweekly intervals through the 12th week, followed thereafter by monthly administrations of the anthelmintics up to the age of 6 months. Nursing bitches and queens should be treated along with their offspring, since they often develop patent infections at that period of time. In animals older than 6 months, faecal examinations should be performed two to four times yearly, followed by the appropriate parasiticidal medication. In dogs which regularly receive heartworm preventatives, deworming schedules have to be modified according to their anthelmintic spectrum.

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The mechanisms of action of antiprotozoal and anthelmintic drugs in man

Cited by 98 publications

References 67 publications

Pentamidine reverses the splicing defects associated with myotonic dystrophy

Pentamidine reverses the splicing defects associated with myotonic dystrophy

Drinking water ivermectin treatment for eradication of pinworm infections from laboratory rat colonies

Current aspects ση the anthelmintic management of gastrointestinal tapeworms and nematodes in the dog and cat

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