A Randomized, Single-Ascending-Dose, Ivermectin-Controlled, Double-Blind Study of Moxidectin in Onchocerca volvulus Infection

Awadzi, K.; Opoku, Nicholas; Attah, Simon K.; Lazdins-Helds, Janis K.; Kuesel, Annette C.

doi:10.1371/journal.pntd.0002953

Cited by 94 publications

(133 citation statements)

References 52 publications

(64 reference statements)

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“…Apart from ivermectin, other microfilaricides include moxidectin, which has a longer-lasting effect than ivermectin and with little re-population [85] but it has yet to be licensed. Doxycycline, a macrofilaricide (see below) also has a deleterious effect on microfilariae as it inhibits their rate of development in vectors and so influences transmission rates [86].…”

Section: Microfilaricidesmentioning

confidence: 99%

Factors affecting onchocerciasis transmission: lessons for infection control

Cheke

2017

Expert Review of Anti-infective Therapy

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Introduction: Onchocerca volvulus infects in excess of 15 million people. The vectors are Simulium blackflies, varieties of which differ in their ecologies, behaviour and vectorial abilities. Control of the vectors and mass administrations of ivermectin have succeeded in reducing prevalences with elimination achieved in some foci, particularly in Central and southern America. In Africa, progress towards elimination has been less successful.Areas covered: Even with community directed treatment with ivermectin (CDTI), control has been difficult in African areas with initial prevalences in excess of 55%, especially if only annual treatments are dispensed. This is partly attributable to insufficient coverage, but the appearance of incipiently resistant non-responding parasites and lack of attention to vector biology in modelling and planning outcomes of intervention programmes have also played their parts, with recrudescence now appearing in some treated areas. Expert commentary:The biology of onchocerciasis is complex involving different vectors with differing abilities to transmit parasites, diverse pathologies related to geographical and parasite variations and endosymbionts in both parasite and vector. Modelling to predict epidemiological and control outcomes is addressing this complexity but more attention needs to be given to the vectors' roles to further understanding of where and when control measures will succeed.

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Section: Microfilaricidesmentioning

confidence: 99%

Factors affecting onchocerciasis transmission: lessons for infection control

Cheke

2017

Expert Review of Anti-infective Therapy

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“…Ivermectin (IVM) was the first ML approved for use in animals and remains today the sole ML registered for use in humans, mainly to treat onchocerciasis through mass chemotherapy. Another ML, moxidectin (MOX), was subsequently commercialized for the veterinary market and is currently being evaluated for possible use against human onchocerciasis (3). Inevitably, the intensive use of these compounds has led to the emergence of resistance in small ruminant, cattle, and some human nematode parasites (4)(5)(6)(7).…”

mentioning

confidence: 99%

“…To visualize the amphid dendrites of the C. elegans wild-type Bristol N2, IVM-selected, and MOX-selected strains, worms were synchronized at late L4. The larvae were then incubated in a dye solution containing 10 ng/ml of DilC 12 (3) in M9 broth with gentle shaking for 2 h at 21°C. After a recovery period of 2 h on NGM plates, worms were paralyzed by using levamisole (40 mM), and dye-filled L4 larvae were observed by using a Nikon Eclipse 50i microscope equipped with a Luca S camera and analyzed by using Nikon ACT-1 software.…”

mentioning

confidence: 99%

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Ménez

Alberich

Kansoh

et al. 2016

Antimicrob Agents Chemother

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cIvermectin and moxidectin are the most widely administered anthelmintic macrocyclic lactones (MLs) to treat human and animal nematode infections. Their widespread and frequent use has led to a high level of resistance to these drugs. Although they have the same mode of action, differences in terms of selection for drug resistance have been reported. Our objective was to study and compare changes occurring upon ivermectin or moxidectin selection in the model nematode Caenorhabditis elegans. C. elegans worms were submitted to stepwise exposure to increasing doses of moxidectin. The sensitivity of moxidectin-selected worms to MLs was determined in a larval development assay and compared with those of wild-type and ivermectin-selected strains. Selection with either ivermectin or moxidectin led to acquired tolerance to ivermectin, moxidectin, and eprinomectin. Importantly, moxidectin was the most potent ML in both ivermectin-and moxidectin-selected strains. Interestingly, this order of potency was also observed in a resistant Haemonchus contortus isolate. In addition, ivermectin-and moxidectin-selected strains displayed constitutive overexpression of several genes involved in xenobiotic metabolism and transport. Moreover, verapamil potentiated sensitivity to ivermectin and moxidectin, demonstrating that ABC transporters play a role in ML sensitivity in ML-selected C. elegans strains. Finally, both ivermectin-and moxidectin-selected strains displayed a dye-filling-defective phenotype. Overall, this work demonstrated that selection with ivermectin or moxidectin led to cross-resistance to several MLs in nematodes and that the induction of detoxification systems and defects in the integrity of amphidial neurons are two mechanisms that appear to affect the responsiveness of worms to both ivermectin and moxidectin.T he broad-spectrum anthelmintic macrocyclic lactones (MLs) are most commonly used in veterinary medicine to treat diseases caused by gastrointestinal nematodes and external parasites in livestock (1, 2). Ivermectin (IVM) was the first ML approved for use in animals and remains today the sole ML registered for use in humans, mainly to treat onchocerciasis through mass chemotherapy. Another ML, moxidectin (MOX), was subsequently commercialized for the veterinary market and is currently being evaluated for possible use against human onchocerciasis (3). Inevitably, the intensive use of these compounds has led to the emergence of resistance in small ruminant, cattle, and some human nematode parasites (4-7). Discovering the mechanisms by which resistance to MLs occurs remains an important challenge today.There is consistent evidence that ATP-binding-cassette (ABC) transporters such as P-glycoproteins (Pgps) play an important role in multidrug resistance (MDR) in many organisms, including several nematode species. Gene expression levels of ABC transporters or allele frequencies were modified after ML selection (8-13), and they are involved in the tolerance of Caenorhabditis elegans (9, 14-16) and parasitic nematodes s...

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“…Es un antiparasitario usado en animales, con mecanismo de acción similar al de la ivermectina, no obstante, se ha encontrado que tiene acción tanto microfilaricida como macrofilaricida, por lo que se ha buscado usar en humanos 58 . Recientemente ha entrado en estudios fase III, con resultados prometedores 67 .…”

Section: Moxidectinaunclassified

Oncocercosis: de lo básico a lo clínico

Fernández

Saldarriaga

Suárez-Escudero

et al. 2016

MedUPB

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RESUMENLa oncocercosis es una de las enfermedades tropicales desatendidas, producida por el nemátodo filárico Onchocerca volvulus y transmitida por la picadura de la mosca negra del género Simulium. Es considerada la segunda causa mundial de ceguera prevenible y está presente en 35 naciones de tres continentes: África, América y Asia. Existen tres países declarados libres de oncocercosis: Colombia, Ecuador y México. Las principales manifestaciones clínicas son dermatológicas y oculares; sin embargo, también se han descrito alteraciones linfáticas y neurológicas. El diagnóstico se realiza por identificación de microfilarias en biopsia de piel o esclerocorneal, nodulectomía para buscar gusanos adultos o con lámpara de hendidura y observar el parásito en el ojo. Existe tratamiento farmacológico con ivermectina o quirúrgico con extracción directa de los nemátodos adultos de los oncocercomas. Los programas mundiales se basan en control vectorial y farmacoterapia. Con los conocimientos actuales y esfuerzos mundiales, la oncocercosis continúa siendo un grave problema de salud pública y causa de discapacidad. Por estas razones, se hace necesario una actualización en el tema. Palabras clave: oncocercosis; Simuliidae; ivermectina. ABSTRACTOnchocerciasis is one of the neglected tropical diseases; it is produced by the filarial nematode Onchocerca volvulus and is transmitted through the bites of infected black flies of the Simulium genus. It is considered the second leading cause of preventable blindness and is present in 35 countries on three continents: Africa, America, and Asia. The following three countries have been declared free from onchocerciasis: Colombia, Ecuador, and Mexico. The main clinical manifestations are dermatological and ocular; however, lymphatic and neurological alterations have also been described. Diagnosis is made by identification of microfilariae in skin or sclerocorneal biopsy, by nodulectomy in search of adult worms, or by using a slit lamp to observe the parasite in the eye. There is pharmacological treatment through the use of ivermectin or surgical treatment by direct removal of adult nematodes from the onchocercomas. World programs are based on vector control and drug therapy. Despite current knowledge and global efforts, onchocerciasis remains a serious public health issue and an important cause of disability. Thus, an update on the topic is warranted.

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A Randomized, Single-Ascending-Dose, Ivermectin-Controlled, Double-Blind Study of Moxidectin in Onchocerca volvulus Infection

Cited by 94 publications

References 52 publications

Factors affecting onchocerciasis transmission: lessons for infection control

Factors affecting onchocerciasis transmission: lessons for infection control

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Oncocercosis: de lo básico a lo clínico

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