Onchocerca volvulus: The Road from Basic Biology to a Vaccine.

Human onchocerciasis - commonly known as river blindness - is one of the most devastating yet neglected tropical diseases, leaving many millions in sub-Saharan Africa blind and/or with chronic disabilities. Attempts to eliminate onchocerciasis, primarily through the mass drug administration of ivermectin, remains challenging and has been heightened by the recent news that drug-resistant parasites are developing in some populations after years of drug treatment. Needed, and needed now, in the fight to eliminate onchocerciasis are new tools, such as preventive and therapeutic vaccines. This review summarizes the progress made to advance the onchocerciasis vaccine from the research laboratory into the clinic.

Where Is the Breakthrough Innovation for Parasite Control?

The need to improve parasite control to overcome drug-resistant parasite populations, and to improve compliance by more convenient drug application methods, is evident. While a number of incremental stepwise improvements are visible, the big disruptive innovation, an iPhone-equivalent breakthrough, has been hard to find. Why?

Surface Glycans: A Therapeutic Opportunity for Kinetoplastid Diseases.

Trypanosomal diseases are in need of innovative therapies that exploit novel mechanisms of action. The cell surface of trypanosomatid parasites is characterized by a dense coat of glycoconjugates with important functions in host cell recognition, immune evasion, infectivity, and cell function. The nature of parasite surface glycans is highly dynamic and changes during differentiation and in response to different stimuli through the action of glycosyltransferases and glycosidases. Here we propose a new approach to antiparasitic drug discovery that involves the use of carbohydrate-binding agents that bind specifically to cell-surface glycans, giving rise to cytotoxic events and parasite death. The potential and limitations of this strategy are addressed with a specific focus on the treatment of sleeping sickness.

A systematic review of factors that shape implementation of mass drug administration for lymphatic filariasis in sub-Saharan Africa.

BACKGROUND: Understanding factors surrounding the implementation process of mass drug administration for lymphatic filariasis (MDA for LF) elimination programmes is critical for successful implementation of similar interventions. The sub-Saharan Africa (SSA) region records the second highest prevalence of the disease and subsequently several countries have initiated and implemented MDA for LF. Systematic reviews have largely focused on factors that affect coverage and compliance, with less attention on the implementation of MDA for LF activities. This review therefore seeks to document facilitators and barriers to implementation of MDA for LF in sub-Saharan Africa. METHODS: A systematic search of databases PubMed, Science Direct and Google Scholar was conducted. English peer-reviewed publications focusing on implementation of MDA for LF from 2000 to 2016 were considered for analysis. Using thematic analysis, we synthesized the final 18 articles to identify key facilitators and barriers to MDA for LF programme implementation. RESULTS: The main factors facilitating implementation of MDA for LF programmes were awareness creation through innovative community health education programmes, creation of partnerships and collaborations, integration with existing programmes, creation of morbidity management programmes, motivation of community drug distributors (CDDs) through incentives and training, and management of adverse effects. Barriers to implementation included the lack of geographical demarcations and unregistered migrations into rapidly urbanizing areas, major disease outbreaks like the Ebola virus disease in West Africa, delayed drug deliveries at both country and community levels, inappropriate drug delivery strategies, limited number of drug distributors and the large number of households allocated for drug distribution. CONCLUSION: Mass drug administration for lymphatic filariasis elimination programmes should design their implementation strategies differently based on specific contextual factors to improve implementation outcomes. Successfully achieving this requires undertaking formative research on the possible constraining and inhibiting factors, and incorporating the findings in the design and implementation of MDA for LF.

Effect of uncertainty in total parasite infestation on accuracy and precision of estimates of ectoparasiticide efficacy.

In animal studies of ectoparasiticide efficacy the total number of parasites with which experimental animals are infested is not always equal to the intended number of parasites (usually n=50 per experimental animal in the case of ticks, and n=50 or n=100 in the case of fleas). That is, in the practical implementation of a study protocol, the infestation of experimental animals may be subject to variability so that total infestation is not known precisely. The purpose of the present study is to assess the impact of this variability on the accuracy and precision of efficacy estimates. The results of a thorough simulation study show clearly that uncertainty in total parasite infestation - of the magnitude encountered in well-controlled animal studies - has virtually no effect on the accuracy and precision of estimators of ectoparasiticide efficacy.

Natural products; pharmacological importance of family Cucurbitaceae: a brief review.

Compounds derived from nature have played a major role in drug discovery. They became the basis for the development of new pharmaceuticals. In this scope, family Cucurbitaceae is a prominent source of secondary metabolites, mainly triterpenoids. In this paper, we provide a brief review of cucurbitane metabolites that exhibit an extensive range of biological actions specifically antidiabetic, anti-inflammatory, cytotoxic, hepatoprotective, and antiparasitic effects.

[Vigilance for veterinary medicinal products: declarations of adverse reactions in the year 2009]. / Vigilance der Tierarzneimittel: Gemeldete unerwünschte Wirkungen im Jahr 2009.

During the year 2009, 134 reports of suspected adverse drug reactions (ADRs) to veterinary medicinal products (VMPs) were received (106 in the year 2008). The distribution according to species and drug classes remained in line with previous years. Companion animals were involved in most of the reports (46 % dogs, 19 % cats), followed by cattle or calves (22 %). Antiparasitic drugs made the biggest part with 30 % of the reports, followed by antiinfectives (19 %) and hormones (13 %). Some reactions following their use are specifically discussed. 95 additional enquiries about ADRs of VMPs were received by the Swiss Toxicological Information Centre in Zürich. Most of them concerned dogs or cats and antiparasitics or anti-inflammatory drugs. In the vaccinovigilance program, a total of 1020 reports were received, of which 1000 were related to the vaccination against blue tongue disease. The most frequently reported adverse reactions were aborts, mastitis or alterations of milk quality and they are specifically discussed.

Parascaris equorum in foals and in their environment on a Swedish stud farm, with notes on treatment failure of ivermectin.

Environmental contamination and the egg excretion pattern of the ascarid Parascaris equorum (Nematoda) was investigated in relation to anthelmintic treatment on a Swedish stud farm. Faecal samples from 15 foals, dewormed every 8th-week with a paste formulation of ivermectin at the standard dose rate of 0.2 mg/kg bodyweight, were collected at five sampling occasions between August and November 2006. In addition, soil samples were obtained from four paddocks used by these foals in November 2006. The number of eggs per gram (epg) was counted in both faeces and soil. Egg excretion started when the foals were 3-4 months, and reached the highest levels when they were approximately 5-month-old, and was then followed by a decline. Egg excretion seemed to be unaffected by ivermectin despite these foals were dewormed at regular intervals. In four out of five foals examined 10 days after treatment, epg actually increased. In contrast, when either fenbendazol or pyrantel embonate were used instead of ivermectin, treatments were effective. The number of eggs in soil was significantly higher in the permanent paddock compared to in the temporarily used soil paddock and in the summer paddocks.

Efficacy of a novel formulation of metaflumizone plus amitraz for the treatment of sarcoptic mange in dogs.

A novel spot-on formulation containing metaflumizone plus amitraz (ProMeris/ProMeris Duo for Dogs, Fort Dodge Animal Health, Overland Park, KS) was evaluated for efficacy against sarcoptic mange mites in naturally infested dogs. Sixteen dogs were allocated to two equal groups and were housed individually. Eight of the dogs were treated topically with metaflumizone plus amitraz at the proposed minimum dose rate (20mg/kg of each of metaflumizone and amitraz, at a dose volume of 0.133ml/kg) on Days 0 and 28. The other eight were treated with metaflumizone plus amitraz at the proposed minimum dose rate on Days 0, 14, 28 and 42. To enumerate Sarcoptes scabiei mites, skin scrapings were taken on each of Days 2, 14, 28, 42 and 56. Clinical signs of mange and the extent of sarcoptic lesions were evaluated on each dog when scrapings were made. Evaluation of the efficacy of the treatment was based on the absence of mites supported by the absence of clinical signs associated with canine sarcoptic mange. Treatment with metaflumizone plus amitraz at the minimum proposed dose rate at monthly (two treatments) or two-weekly (four treatments) intervals resulted in a rapid reduction of mites and improved clinical signs. The overall cure rates at Day 56, based on zero mite counts and/or resolution of clinical signs were 75% and 83% of dogs for the monthly and two-weekly regimens, respectively.

Efficacy of a novel formulation of metaflumizone plus amitraz for the treatment of demodectic mange in dogs.

A novel spot-on formulation containing metaflumizone plus amitraz (ProMeris/ProMeris Duo for Dogs, Fort Dodge Animal Health, Overland Park, KS) was evaluated for efficacy against demodectic mange mites in naturally infested dogs. Sixteen dogs were allocated to two equal groups and individually housed. Eight of the dogs were treated topically with metaflumizone plus amitraz at the proposed minimum dose rate (20mg/kg of each of metaflumizone and amitraz, 0.133ml/kg) on Days 0, 28, and 56. The other eight were treated with metaflumizone plus amitraz at the proposed minimum dose rate on Days 0, 14, 28, 42, 56, and 70. Mite numbers were estimated from skin scrapings taken on Days -3 to -1, 28, 56, and 84. Clinical signs of mange and the extent of demodectic lesions on each dog were evaluated when skin scrapings were conducted. Efficacy of the treatment was based on a reduction in mite numbers and an assessment of the clinical signs associated with canine demodectic mange. Treatment at monthly or two-weekly intervals for 3 months resulted in a rapid reduction in mite numbers (>94 and >99% for the monthly and two-weekly treatments, respectively) and an improvement in clinical signs. Success rates, based on zero mite counts in skin scrapings at Day 84 were 42.9 and 62.5% of dogs for the monthly and two-weekly regimens, respectively.

Counterfeit or substandard antimicrobial drugs: a review of the scientific evidence.

There is growing universal concern regarding counterfeit medications. In particular, counterfeit antimicrobial drugs are a threat to public health with many devastating consequences for patients; increased mortality and morbidity and emergence of drug resistance. In addition, physicians treating these patients lose their confidence in the medications used and report high levels of bacterial resistance. The problem with fake and suboptimal medications got worse with the advent of the World Wide Web; a significant proportion of medications that are sold through Internet pharmacies is counterfeit. Various initiatives of the WHO (the International Medical Products Anti-Counterfeiting Taskforce) are hopefully going to tackle this very important public health issue. In this article, we review the available evidence in peer-reviewed articles and World Wide Web information resources regarding the issue of counterfeit antimicrobials.

Improved method for determination of abamectin and ivermectin in cattle plasma.

A liquid chromatographic (LC) method was developed for determination of abamectin (ABM) and ivermectin (IVM) in cattle plasma. The sample was extracted with acetonitrile and cleaned up on an alumina column. After conversion to stable fluorescent derivative with trifluoroacetic anhydride and N-methylimidazole, the sample was analyzed by LC with fluorescence detection (Ex 365 nm and Em 475 nm). Doramectin was used as an internal standard. Recoveries ranged from 91.2 to 100.7% for IVM and from 87.0 to 98.7% for ABM, with 1-50 ng/mL fortified samples. The coefficients of variation were <10.1%. The limit of detection was 0.02 ng/mL for ABM and IVM in 1.0 mL samples.

Demonstrating the validity of natural products as anti-infective drugs.

This presentation reviews the synthetic or classical development pathway of drug development and contrasts it with developing natural products as drugs. Also presented is an example of a traditional medicine that has been developed from a natural product and has become a "new/old" antiparasitic drug used in the treatment of malaria. The classic paradigm of synthetic drug development breaks down into drug discovery, drug design, preclinical studies, and clinical studies. This paradigm, constructed to weed out failures, results in a drug-development process that is high risk, time consuming, and expensive. The process requires screening an average of 10,000 active compounds to find a single compound that successfully makes its way through validation to drug approval and the marketplace. Following this paradigm, researchers progress from identifying a chemical lead to testing the compound in humans. The World Health Organization (WHO) Guidelines for the Assessment of Herbal Medicines are based on the classical guidelines and follow the classical approach to validating quality, safety, and efficacy--with one major difference. The starting point is to look at the natural product in humans. By taking into account the traditional experience with the product, the validation standard for safety and efficacy of natural products allows for the prolonged and apparently uneventful use of a substance to offer testimony of its safety. The reliance, then, is on experience--or what Western regulatory agencies would call "anecdotal information." Since most phytomedicines are a combination of several active ingredients, the WHO guidelines cover two kinds of combination products: Combinations that are already used in traditional medicine are considered "old" combination products. "New" combination products are well-known substances that are now being used in combination. Artemisia annua, a pervasive weed, has been referred to in Chinese medicine for thousands of years as a treatment for fever. In 1971, an extraction of artemisia yielded activity against Plasmodium berghei, a mouse model for malaria. The isolated compound, artemisinin, is an example of a traditional medicine that started out in humans, but which then provided a lead structure for a standard drug-development paradigm. Today, artemisinin derivatives are being used widely in combination therapy, especially in areas of the world where there is multidrug-resistant malaria.

Evaluation of efficacy of selamectin and fipronil against Ctenocephalides felis in cats.

OBJECTIVE: To evaluate efficacy of monthly administration of selamectin and fipronil against Ctenocephalides felis in cats. DESIGN: Randomized controlled trial. ANIMALS: 36 healthy cats. PROCEDURE: Cats known to be free of fleas were infested with 100 unfed adult fleas on days -28 and -21. On days 0, 30, 60, 90, and 120, sixteen cats (8 pairs/treatment group) were treated by topical administration of selamectin (6 mg/kg [2.7 mg/lb] of body weight) or fipronil (7.5 mg/kg [3.4 mg/lb]). Four control cats (2 pairs) were not treated. On day -6 and every 2 weeks after initial treatment, comb counts were performed to detect fleas. Flea counts were recorded, and fleas (< or =50) that had been removed were replaced onto the cat. On day 89, fleas were not replaced. On day 91 and every 7 days until the end of the study (day 150), cats were challenged with 20 adult fleas. Flea counts were compared between and within treatments. RESULTS: 14 days after treatment, geometric mean flea counts were reduced by 71.2% by fipronil treatment and 35.3% by selamectin treatment. Both treatments resulted in 97 to 98% reduction in flea counts on day 29 and 99.8 to 100% reduction from day 44 to the end of the study. CONCLUSIONS AND CLINICAL RELEVANCE: Selamectin is as effective as fipronil in treating infestation in cats housed for 3 months in a flea-infested environment under conditions known to support the flea life cycle and in protecting against subsequent weekly challenges with C felis for an additional 2 months.

Evaluation of efficacy of selamectin, fipronil, and imidacloprid against Ctenocephalides felis in dogs.

OBJECTIVE: To evaluate efficacy of monthly administration of selamectin, fipronil, and imidacloprid against Ctenocephalides felis in dogs. DESIGN: Randomized controlled trial. ANIMALS: 44 healthy dogs. PROCEDURE: Dogs known to be free of fleas were infested with 100 unfed adult fleas on days -28 and -21. On days 0, 30, 60, 90, and 120, dogs (12/group) were treated by topical administration of selamectin (6 mg/kg [2.7 mg/lb] of body weight), fipronil (7.5 mg/kg [3.4 mg/lb]), or imidacloprid (10 mg/kg [4.5 mg/lb]); 8 untreated dogs were used as controls. On day -6 and every 2 weeks after initial treatment, comb counts of viable adult fleas were made, and fleas (< or =50/dog) were replaced onto the dog from which they were removed. On day 89, fleas were not replaced. On day 91 and every 7 days until the end of the study, dogs were challenged with 20 adult fleas. RESULTS: 14 days after initial treatment, geometric mean flea counts were reduced by 97.5 to 99.1 % for all treatments, compared with pretreatment counts on day -6. Selamectin, fipronil, and imidacloprid reduced geometric mean flea counts by 99.7 to 100% from day 29 to the end of the study. CONCLUSIONS AND CLINICAL RELEVANCE: Selamectin is as effective as fipronil and imidacloprid in reducing C felis infestation in dogs housed for 3 months in a flea-infested environment under conditions known to support the flea life cycle, and in protecting against subsequent weekly challenges with C felis for an additional 2 months.

Efficacy of an ivermectin and pyrantel pamoate combination against adult hookworm, Ancylostoma braziliense, in dogs.

A chewable tablet incorporating ivermectin and pyrantel was tested in 12 Beagle dogs for efficacy against the adult hookworm, Ancylostoma braziliense. The dogs were administered infective larvae of A braziliense orally. Twenty-one days after infection the dogs were weighed and allocated randomly to receive either an oral treatment with ivermectin and pyrantel in a beef-based chewable tablet or no treatment. The chewable tablet was a commercially available product, which was made to deliver ivermectin at 6 micrograms/kg and pyrantel at 5.0 mg/kg to each dog. Seven days after treatment the dogs were euthanased, necropsied, and examined for adult hookworms. At necropsy, no adult A braziliense was observed in any of the 6 treated dogs and all 6 dogs that had been left untreated were infected with adult A braziliense (range, 48 to 161). It was concluded that this combination product is 100% efficacious against adult A braziliense.

Effectiveness of the ivermectin sustained-release bolus in the control of bovine nematodosis.

OBJECTIVE: To evaluate the nematocidal effectiveness of the ivermectin sustained-release bolus throughout its 135-day delivery period. DESIGN: Twenty-four naturally infected calves were randomly allocated to 1 of 3 equivalent experimental groups: group-T1 calves were untreated controls, group-T2 calves each received a sustained-release bolus on trial day 0, and group-T3 calves were rendered nematode-free and used at 35-day intervals during the study as tracers. One contaminated pasture was used for all principal calves for the 135-day grazing interval of the study. Calves of groups T1 and T2 were also artificially administered mixed infective nematode larvae at intervals during the grazing period, after which, all calves were confined to concrete for 21 days prior to necropsy. ANIMALS: All calves were approximately 6 months old on trial day 0, weighed from 136 to 216 kg, and were of mixed breeding and sex. PROCEDURE: At intervals during the study, feces from all calves were analyzed for nematode egg counts, and all calves were weighed and examined for bolus retention (T2 calves only). For nematode recovery, all calves were necropsied 21 to 22 days after removal from the contaminated pasture. RESULTS: Parasitic populations of Haemonchus, Ostertagia, Trichostrongylus, Cooperia, Bunostomum, and Oesophagostomum spp were significantly reduced in cattle treated with the ivermectin sustained-release bolus. CONCLUSION: The nematocidal activity of the ivermectin sustained-release bolus proved highly effective, with > 98% efficacy for all nematode species present.