SciCombinator

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Concept: Anthelmintics

173

The currently used anthelmintic drugs, in single oral application, have low efficacy against Trichuris trichiura infection, and hence novel anthelmintic drugs are needed. Nitazoxanide has been suggested as potential drug candidate.

Concepts: Pharmacology, Randomized controlled trial, Drug, Pharmaceutical industry, Clinical research, Whipworm, Anthelmintics, Anthelmintic

168

BACKGROUND: Soil-transmitted helminth (STH) infections are responsible for a huge public health burden, however treatment options are limited. The discovery and development of novel efficacious drugs or drug combinations for the treatment of STH infections therefore has a high research priority. METHODS: We studied drug combination effects using the main standard anthelmintics, albendazole, mebendazole, levamisole, pyrantel pamoate and ivermectin in the Trichuris muris model. Drug combinations were first tested in vitro and additive and synergistic combinations investigated further in vivo in female mice using ratios based on the ED50 of the respective drugs. RESULTS: In vitro all 10 combinations of the standard anthelmintics tested against T. muris revealed synergistic behaviour. We identified three drug combinations in vivo as strongly synergistic, namely mebendazole-ivermectin (Combination index (CI)=0.16), mebendazole-levamisole (CI=0.17) and albendazole-mebendazole (CI=0.23). For albendazole-ivermectin, moderate synergism was observed (CI=0.81) and for albendazole-levamisole a nearly additive effect was documented (CI=0.93) in vivo. Five combinations (albendazole-pyrantel pamoate, mebendazole-pyrantel pamoate, levamisole-pyrantel pamoate, levamisole-ivermectin and pyrantel pamoate-ivermectin) were antagonistic in vivo. CONCLUSION: Our results strengthen the evidence that combination chemotherapy might play a role in the treatment of Trichuris infections. Albendazole-mebendazole should be studied in greater detail in preclinical studies.

Concepts: In vivo, Praziquantel, In vitro, Anthelmintics, Anthelmintic, Pinworm, Emodepside, Pyrantel pamoate

28

Albendazole is an anthelmintic drug widely used in the treatment of neurocysticercosis (NCC), an infection of the brain with Taenia solium cysts. However, drug levels of its active metabolite, albendazole sulfoxide (ABZSO), are erratic, likely resulting in decreased efficacy and suboptimal cure rates in NCC. Racemic albendazole sulfoxide is composed of (ABZSO (+)-®- and (-)-(S)- enantiomers that have been shown to differ in pharmacokinetics and activity against other helminths. The antiparasitic activities of racemic ABZSO and its (+)-®- and (-)-(S)- enantiomers were evaluated in vitro against T. solium cysts. Parasites were collected from naturally infected pigs, cultured and exposed to the racemic mixture or to each enantiomer (range 10 to 500 ng/ml) or to praziquantel as a reference drug. The activity of each compound on cysts was assayed by measuring ability to evaginate and inhibition of alkaline phosphatase (AP) and parasite antigen release. (+)-®-ABZSO was significantly more active than (-)-(S)-ABZSO in suppressing the release of AP and antigen into the supernatant in a dose- and time- dependent manner, indicating that most of the activity of ABZSO resides in the (+)-®-enantiomer. Use of this enantiomer alone may lead increased efficacy and/or less toxicity compared to albendazole.

Concepts: Pharmacology, Intestinal parasite, Stereochemistry, Enantiomer, Anthelmintics, Racemic mixture, Taenia solium, Albendazole

27

Numerous bipolar plugged capillarid eggs were detected on a routine centrifugal fecal flotation examination of a 2 yr old castrated male boxer-Chinese shar pei mixed-breed. The eggs were identified as Eucoleus boehmi (E. boehmi), the nasal capillarid, based on size and shell wall surface morphology. The dog had a history of chronic sneezing (> 5 times/day) and intermittent postexercise nasal discharge. Currently, there are no anthelmintics approved for use in dogs for the treatment of E. boehmi. Treatment of the dog with 0.5-1 mg/kg milbemycin oxime was ineffective, but treatment with 2 mg/kg milbemycin oxime resulted in negative fecal examinations 7-28 days and 5 mo posttreatment. The dog’s postexertion nasal discharge greatly lessened, and the sneezing behavior improved (it was only noted 2-3 times/wk), but neither the discharge nor sneezing completely resolved following the anthelmintic treatments. Use of milbemycin oxime at an increased dose (2 mg/kg) appeared to be an effective treatment against E. boehmi infection in this dog based on clinical response and the cessation of fecal egg shedding.

Concepts: Egg, Dog, Examination, Dog breed, Anthelmintics, Anthelmintic, Shar Pei, Milbemycin oxime

26

Mebendazole (MBZ) is an extremely insoluble and therefore poorly absorbed drug and the variable clinical results may correlate with blood concentrations. The necessity of a prolonged high dose treatment of this drug increases the risk of adverse effects.

Concepts: Pharmacology, Effectiveness, Adverse drug reaction, Anthelmintics, Mebendazole

23

This study reports ivermectin and moxidectin egg reappearance periods (ERP) from UK horses with persistently positive faecal egg counts (FEC), defined as positive FEC within the ERP of an anthelmintic post-treatment, or with FECs that remained positive after the normal ERP post-anthelmintic treatment. A selected population of UK pleasure horses deemed at high risk of strongyle infection was studied. The earliest ERP recorded after ivermectin or moxidectin, using first positive FEC, was 5 weeks. From 16 premises where moxidectin was used, five had ERP ≥12 weeks using two further metrics. For premises where moxidectin was administered to only one animal (present or tested), and evaluated as one group (n = 61), ERP was ≥10 weeks. For premises where ivermectin was used, the ERP was ≥5 weeks. Premises with only one horse (present or tested), dosed with ivermectin (n = 31), analysed as one group, demonstrated egg reappearance ≥6 weeks. These field data suggest shortened ERPs following macrocyclic lactone treatment compared to previously published values (8-10 and >13 weeks respectively) when these drugs were first marketed.

Concepts: United Kingdom, Mammal, The Normal, Horse, Normal distribution, Anarchy in the U.K., Anthelmintics, Onchocerciasis

12

Soil-transmitted helminths (STHs) are the most prevalent intestinal helminths of humans, and a major cause of morbidity in tropical and subtropical countries. The benzimidazole (BZ) drugs albendazole (ABZ) and mebendazole (MBZ) are used for treatment of human STH infections and this use is increasing dramatically with massive drug donations. Frequent and prolonged use of these drugs could lead to the emergence of anthelmintic resistance as has occurred in nematodes of livestock. Previous molecular assays for putative resistance mutations have been based mainly on PCR amplification and sequencing. However, these techniques are complicated and time consuming and not suitable for resource-constrained situations. A simple, rapid and sensitive genotyping method is required to monitor for possible developing resistance to BZ drugs.

Concepts: DNA, Molecular biology, Single-nucleotide polymorphism, Nematodes, Genotyping, Anthelmintics, Hookworm, Pinworm

1

There is an urgent need to discover novel antimicrobial therapies. Drug repurposing can reduce the time and cost risk associated with drug development. We report the inhibitory effects of anthelmintic drugs (niclosamide, oxyclozanide, closantel, rafoxanide) against Helicobacter pylori strain 60190 and pursued further characterization of niclosamide against H. pylori. The MIC of niclosamide against H. pylori was 0.25 μg/mL. Niclosamide was stable in acidic pH and demonstrated partial synergy with metronidazole and proton pump inhibitors, such as omeprazole and pantoprazole. Niclosamide administration at 1 × MIC concentration, eliminated 3-log10CFU of H. pylori adhesion/invasion to AGS cells. Interestingly, no resistance developed even after exposure of H. pylori bacteria to niclosamide for 30 days. The cytotoxic assay demonstrated that niclosamide is not hemolytic and has an IC50of 4 μg/mL in hepatic and gastric cell lines. Niclosamide administration decreased transmembrane pH as determined by DiSC3(5) assay indicating that the mechanism of action of the anti-H. pylori activity of niclosamide was the disruption of H. pylori proton motive force. Niclosamide was effective in the Galleria mellonella-H. pylori infection model (p = 0.0001) and it can be develop further to combat H. pylori infection. However, results need to be confirmed with other H. pylori and clinical strains.

Concepts: Bacteria, Gastroenterology, Stomach, Helicobacter pylori, Helicobacter, Anthelmintics, Anthelmintic, Niclosamide

1

Despite increased international efforts to control schistosomiasis using preventive chemotherapy, several challenges still exist in reaching the target populations. Until recently, preschool-aged children had been excluded from the recommended target population for mass drug administration, i.e. primary school children aged 6-15 years. Our studies and those of others provided the evidence base for the need to treat preschool-aged children that led to recommendations by the World Health Organization to include preschool-aged children in treatment programmes in 2010. The major challenge now lies in the unavailability of a child-size formulation of the appropriate anthelmintic drug, praziquantel.The currently available formulation of praziquantel presents several problems. First, it is a large tablet, making it difficult for young children and infants to swallow it and thus requires its breaking/crushing to allow for safe uptake. Second, it is bitter so it is often mixed with a sweetener to make it palatable for young children. Third, the current formulation of 600 mg does not allow for flexible dose adjustments for this age group. Thus, there is a need to formulate a child-appropriate praziquantel tablet.This paper discusses the target product profile for paediatric praziquantel, as well as knowledge gaps pertinent to the successful control of schistosome infection and disease in preschool-aged children.

Concepts: Demography, Population, Schistosomiasis, Praziquantel, World Health Organization, Anthelmintics, Anthelmintic, Emodepside

1

The lack of new anthelmintic agents is of growing concern because it affects human health and our food supply, as both livestock and plants are affected. Two principal factors contribute to this problem. First, nematode resistance to anthelmintic drugs is increasing worldwide and second, many effective nematicides pose environmental hazards. In this paper we address this problem by deploying a high throughput screening platform for anthelmintic drug discovery using the nematode Caenorhabditis elegans as a surrogate for infectious nematodes. This method offers the possibility of identifying new anthelmintics in a cost-effective and timely manner.

Concepts: Caenorhabditis elegans, Caenorhabditis, Nematode, Model organism, Sydney Brenner, Anthelmintics, Anthelmintic