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1.
Indian J Med Res ; 149(6): 706-714, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31496523

RESUMO

Onchocerciasis and lymphatic filariasis (LF) are human filarial diseases belonging to the group of neglected tropical diseases, leading to permanent and long-term disability in infected individuals in the endemic countries such as Africa and India. Microfilaricidal drugs such as ivermectin and albendazole have been used as the standard therapy in filariasis, although their efficacy in eliminating the diseases is not fully established. Anti-Wolbachia therapy employs antibiotics and is a promising approach showing potent macrofilaricidal activity and also prevents embryogenesis. This has translated to clinical benefits resulting in successful eradication of microfilarial burden, thus averting the risk of adverse events from target species as well as those due to co-infection with loiasis. Doxycycline shows potential as an anti-Wolbachia treatment, leading to the death of adult parasitic worms. It is readily available, cheap and safe to use in adult non-pregnant patients. Besides doxycycline, several other potential antibiotics are also being investigated for the treatment of LF and onchocerciasis. This review aims to discuss and summarise recent developments in the use of anti-Wolbachia drugs to treat onchocerciasis and LF.


Assuntos
Filariose Linfática/tratamento farmacológico , Doenças Negligenciadas/tratamento farmacológico , Oncocercose/tratamento farmacológico , Wolbachia/patogenicidade , Adulto , Albendazol/uso terapêutico , Animais , Antibacterianos/uso terapêutico , Doxiciclina/uso terapêutico , Quimioterapia Combinada , Filariose Linfática/epidemiologia , Filariose Linfática/microbiologia , Humanos , Índia/epidemiologia , Doenças Negligenciadas/epidemiologia , Doenças Negligenciadas/microbiologia , Oncocercose/epidemiologia , Oncocercose/microbiologia , Medicina Tropical , Wolbachia/efeitos dos fármacos
2.
BMC Pharmacol Toxicol ; 20(1): 49, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31420005

RESUMO

BACKGROUND: The progress of mass, community-directed, treatment with ivermectin (CDTI) for onchocerciasis control was disrupted by severe adverse effects (SAE) in the Democratic Republic of Congo (DRC). The study aimed at determining the frequency of post-CDTI SAE as well as factors associated with the occurrence of SAE. METHODS: Our retrospective study relied on SAE collection cards, as archived by the DRC Ministry of Health, and compiled for people who benefited from ivermectin treatment then further developed SAE. The study included 945 post-CDTI SAE recorded in DRC between 2003 and 2017. These cases occurred in 15 projects out of 22 projects implemented in the country. All cards were reviewed and analysed. RESULTS: Between the years 2003 and 2017, the total average population treated was around 15,552,588 among which 945 cases of SAE were registered in DR Congo, i.e. 6 cases of SAE for 100,000 persons treated per year. 55 deaths related to post-CDTI SAE were recorded, which represents 5.8% of all cases of SAE. Non-neurological SAE were dominated by severe headaches (74.8%), myalgia (64.0%) and arthralgia (62.7%). Neurological SAE were mainly coma (94.1%), motor deficit (75.4%) and palpebral subconjunctival haemorrhages (38.8%). Factors associated with the occurrence of SAE were: male, age over 18 years old, alcohol consumption, hemp intake and the presence of loiasis. The study also highlighted weaknesses of the National Program for Onchocerciasis Control (NPOC)  in terms of awareness campaigns among the population. CONCLUSION: Co-endemicity of loiasis and onchocerciasis is one of the key factors responsible for the occurrence of SAE following ivermectin treatment. Mobilization of resources necessary to the appropriate management of SAE and awareness of populations are essential to achieve onchocerciasis control in DRC.


Assuntos
Filaricidas/efeitos adversos , Ivermectina/efeitos adversos , Adulto , Medicina Comunitária , República Democrática do Congo , Feminino , Filaricidas/uso terapêutico , Humanos , Ivermectina/uso terapêutico , Masculino , Oncocercose/tratamento farmacológico , Estudos Retrospectivos
4.
PLoS Negl Trop Dis ; 13(7): e0007300, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31314757

RESUMO

BACKGROUND: High epilepsy prevalence and incidence were observed in onchocerciasis-endemic villages in the Democratic Republic of Congo (DRC). We investigated the clinical characteristics of onchocerciasis-associated epilepsy (OAE), and the relationship between seizure severity and microfilarial density. METHODS: In October 2017, ivermectin-naive persons with epilepsy (PWE) were recruited from onchocerciasis-endemic areas in the Logo health zone in the DRC. Additional PWE were enrolled in the Aketi health zone, where ivermectin had been distributed annually for 14 years. Past medical history, clinical characteristics and skin snips for Onchocerca volvulus detection were obtained from participants. Bivariate and multivariable analyses were used to investigate associations with microfilarial density. RESULTS: Of the 420 PWE in the Logo health zone, 392 were skin snipped (36.5% positive). Generalized motor seizures were most frequent (392 PWE, 93.3%), and nodding seizures were reported in 32 (7.6%) participants. Twelve PWE (3.1%) presented Nakalanga features. Sixty-three (44.1%) skin snip-positive PWE had a family history of epilepsy, compared to only 82 (32.9%) skin snip-negative PWE (p = 0.027). Eighty-one onchocerciasis-infected PWE were recruited in the Aketi health zone. Positive correlations between seizure frequency and microfilarial density were observed in Logo (Spearman-rho = 0.175; p<0.001) and Aketi (Spearman-rho = 0.249; p = 0.029). In the multivariable model adjusted for age, gender, and previous treatment, high seizure frequency was associated with increasing microfilarial density in Aketi (p = 0.025) but not in Logo (p = 0.148). CONCLUSION: In onchocerciasis-endemic regions in the DRC, a wide spectrum of seizures was observed. The occurrence of Nodding seizures and Nakalanga features, as well as an association between seizure severity and O. volvulus microfilarial density suggest a high OAE prevalence in the study villages. TRIAL REGISTRATION: ClinicalTrials.gov NCT03052998.


Assuntos
Epilepsia/parasitologia , Microfilárias/isolamento & purificação , Oncocercose/complicações , Oncocercose/epidemiologia , Convulsões/epidemiologia , Adolescente , Adulto , Idoso , Animais , Antiparasitários/uso terapêutico , Criança , Pré-Escolar , Estudos Transversais , República Democrática do Congo/epidemiologia , Doenças Endêmicas , Feminino , Humanos , Lactente , Ivermectina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Onchocerca volvulus/efeitos dos fármacos , Oncocercose/diagnóstico , Oncocercose/tratamento farmacológico , Prevalência , Pesquisa Qualitativa , Ensaios Clínicos Controlados Aleatórios como Assunto , Convulsões/classificação , Convulsões/diagnóstico , Convulsões/parasitologia , Índice de Gravidade de Doença , Adulto Jovem
5.
Artigo em Inglês | MEDLINE | ID: mdl-31229910

RESUMO

Macrocyclic lactone (ML) anthelmintics are the most important class of anthelmintics because of our high dependence on them for the control of nematode parasites and some ectoparasites in livestock, companion animals and in humans. However, resistance to MLs is of increasing concern. Resistance is commonplace throughout the world in nematode parasites of small ruminants and is of increasing concern in horses, cattle, dogs and other animals. It is suspected in Onchocerca volvulus in humans. In most animals, resistance first arose to the avermectins, such as ivermectin (IVM), and subsequently to moxidectin (MOX). Usually when parasite populations are ML-resistant, MOX is more effective than avermectins. MOX may have higher intrinsic potency against some parasites, especially filarial nematodes, than the avermectins. However, it clearly has a significantly different pharmacokinetic profile. It is highly distributed to lipid tissues, less likely to be removed by ABC efflux transporters, is poorly metabolized and has a long half-life. This results in effective concentrations persisting for longer in target hosts. It also has a high safety index. Limited data suggest that anthelmintic resistance may be overcome, at least temporarily, if a high concentration can be maintained at the site of the parasites for a prolonged period of time. Because of the properties of MOX, there are reasonable prospects that strains of parasites that are resistant to avermectins at currently recommended doses will be controlled by MOX if it can be administered at sufficiently high doses and in formulations that enhance its persistence in the host. This review examines the properties of MOX that support this contention and compares them with the properties of other MLs. The case for using MOX to better control ML-resistant parasites is summarised and some outstanding research questions are presented.


Assuntos
Anti-Helmínticos/farmacologia , Resistência a Medicamentos , Macrolídeos/farmacologia , Onchocerca volvulus/efeitos dos fármacos , Oncocercose/parasitologia , Oncocercose/veterinária , Animais , Humanos , Onchocerca volvulus/crescimento & desenvolvimento , Oncocercose/tratamento farmacológico
6.
BMC Infect Dis ; 19(1): 431, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101085

RESUMO

BACKGROUND: Onchocerciasis is a neglected tropical disease which is still of immense major public health concern in several areas of Africa and the Americas. The disease manifests either as ocular or as dermal onchocerciasis with several symptoms including itching, nodules, skin thickening, visual impairment and blindness. Ivermectin has been an efficient microfilaricide against the causative agent of the disease (Onchocerca volvulus) but reports from some areas in Africa suggest the development of resistance to this drug. The aim of this study was to determine the prevalence of onchocerciasis and associated clinical conditions frequently associated with the disease in three endemic communities in Ghana which have been subjected to 18 to 20 rounds of mass drug administration of ivermectin. This was to help determine whether or not onchocerciasis persists in these communities. METHODS: A cross-sectional study design was adopted. Three communities (Tanfiano, Senya and Kokompe) in the Nkoranza North District of Ghana where mass drug administration of ivermectin had been ongoing for more than two decades were selected for the study. The population was randomly sampled and 114 participants recruited for the study based on the eligibility criteria. The study participants were examined for the presence of parasites and clinical manifestations of onchocerciasis following established protocols. RESULTS: The study showed that the prevalence of microfilaria in the Tanfiano, Senya, Kokompe communities were 13.2, 2.4, and 2.9%, with nodule prevalence being 5.3, 4.9 and 14.3% respectively. Females in the study communities had a higher prevalence of microfilaria carriers (5.17%) relative to males (2.44%), but this difference was not statistically significant (p = 0.2800, unpaired t test). The most frequent clinical manifestation observed in this study among all participants was dermatitis (25.4%), followed by visual impairment & nodules (7.9% each) and then by blindness (4.4%). CONCLUSION: The study showed that despite several years of mass drug administration with ivermectin, infection with onchocerciasis and the commonly associated clinical manifestations of the disease still persist in the study communities. This calls for a greater urgency for research and development aimed at discovering new or repurposed anti-filarial agents which will augment ivermectin if global onchocerciasis eradication targets are to be achieved.


Assuntos
Antiparasitários/uso terapêutico , Ivermectina/uso terapêutico , Oncocercose/tratamento farmacológico , Oncocercose/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Cegueira/parasitologia , Estudos Transversais , Doenças Endêmicas/prevenção & controle , Feminino , Gana/epidemiologia , Humanos , Masculino , Administração Massiva de Medicamentos , Microfilárias , Pessoa de Meia-Idade , Oncocercose/etiologia , Prevalência
7.
Parasit Vectors ; 12(1): 246, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31109348

RESUMO

BACKGROUND: The global burden of onchocerciasis is the heaviest in sub-Saharan Africa. Studies have shown the importance of the role of Community-Directed Distributors (CDDs) and nurses in onchocerciasis control, but little is known about their experience in implementing onchocerciasis control programmes. Our aim was to document the barriers that CDDs and local health administrators face in implementing onchocerciasis control activities. METHODS: We conducted a qualitative survey consisting of 16 in-depth interviews and 8 focus group discussions (FGDs) across three health districts of Cameroon. We interviewed a total of 9 local health officials at the district and Health Area levels, and 7 CDDs. Eight FGDs were conducted with CDDs and Health Committee members. RESULTS: The major barriers to the implementation of Community Directed Treatment with Ivermectin that we identified were linked and interrelated. Examples of these barriers included: contextual factors (geographical and cultural background), top-to-bottom planning, insufficient human and material resources, and lack of transparency in the management of the programme's funds. CONCLUSIONS: The CDTI at operational level still faces many obstacles which negatively affect therapeutic coverages. This can lead to the non-adhesion of the communities to the programme, consequently jeopardizing the sustainability of the onchocerciasis elimination programme. We recommend that the national programme planners put in place a transparent management and planning system for onchocerciasis elimination activities, with better communication with local programme stakeholders.


Assuntos
Implementação de Plano de Saúde/organização & administração , Controle de Infecções/organização & administração , Oncocercose/prevenção & controle , Avaliação de Programas e Projetos de Saúde , Participação dos Interessados , África ao Sul do Saara/epidemiologia , Animais , Antiparasitários/uso terapêutico , Camarões/epidemiologia , Serviços de Saúde Comunitária , Agentes Comunitários de Saúde , Efeitos Psicossociais da Doença , Estudos de Avaliação como Assunto , Feminino , Filaricidas/uso terapêutico , Grupos Focais , Implementação de Plano de Saúde/estatística & dados numéricos , Humanos , Controle de Infecções/estatística & dados numéricos , Ivermectina/uso terapêutico , Masculino , Oncocercose/tratamento farmacológico , Inquéritos e Questionários
8.
Sci Transl Med ; 11(483)2019 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-30867321

RESUMO

There is an urgent global need for a safe macrofilaricide drug to accelerate elimination of the neglected tropical diseases onchocerciasis and lymphatic filariasis. From an anti-infective compound library, the macrolide veterinary antibiotic, tylosin A, was identified as a hit against Wolbachia This bacterial endosymbiont is required for filarial worm viability and fertility and is a validated target for macrofilaricidal drugs. Medicinal chemistry was undertaken to develop tylosin A analogs with improved oral bioavailability. Two analogs, A-1535469 and A-1574083, were selected. Their efficacy was tested against the gold-standard second-generation tetracycline antibiotics, doxycycline and minocycline, in mouse and gerbil infection models of lymphatic filariasis (Brugia malayi and Litomosoides sigmodontis) and onchocerciasis (Onchocerca ochengi). A 1- or 2-week course of oral A-1535469 or A-1574083 provided >90% Wolbachia depletion from nematodes in infected animals, resulting in a block in embryogenesis and depletion of microfilarial worm loads. The two analogs delivered comparative or superior efficacy compared to a 3- to 4-week course of doxycycline or minocycline. A-1574083 (now called ABBV-4083) was selected for further preclinical testing. Cardiovascular studies in dogs and toxicology studies in rats and dogs revealed no adverse effects at doses (50 mg/kg) that achieved plasma concentrations >10-fold above the efficacious concentration. A-1574083 (ABBV-4083) shows potential as an anti-Wolbachia macrolide with an efficacy, pharmacology, and safety profile that is compatible with a short-term oral drug course for treating lymphatic filariasis and onchocerciasis.


Assuntos
Filariose Linfática/tratamento farmacológico , Filariose Linfática/microbiologia , Macrolídeos/administração & dosagem , Macrolídeos/uso terapêutico , Oncocercose/tratamento farmacológico , Oncocercose/microbiologia , Wolbachia/fisiologia , Administração Oral , Animais , Modelos Animais de Doenças , Filariose Linfática/sangue , Feminino , Macrolídeos/efeitos adversos , Masculino , Camundongos Endogâmicos BALB C , Camundongos SCID , Oncocercose/sangue , Resultado do Tratamento , Tilosina/sangue , Tilosina/síntese química , Tilosina/química , Tilosina/uso terapêutico
9.
Parasit Vectors ; 12(1): 114, 2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30890155

RESUMO

BACKGROUND: Surveys conducted in 1991-1992 in the Mbam Valley (Cameroon) revealed that onchocerciasis was highly endemic, with community microfilarial loads (CMFL) > 100 microfilariae/snip in some villages. Also in 1991-1992, a survey of suspected cases of epilepsy (SCE) found 746 SCE using a questionnaire administered to individuals identified by key informants, with prevalences reaching 13.6% in some communities. From 1998, annual community-directed treatment with ivermectin (CDTI) was implemented to control onchocerciasis. In 2017, a door-to-door household survey was conducted in three of the villages visited in 1991-1992, using a standardized 5-item epilepsy screening questionnaire. RESULTS: In 2017, a total of 2286 individuals living in 324 households were screened (582 in Bayomen, 553 in Ngongol and 1151 in Nyamongo) and 112 SCE were identified (4.9%). Neurologists examined 92 of these SCE and confirmed the diagnosis of epilepsy for 81 of them (3.5%). Between the surveys in 1991-1992 and 2017, the prevalence of SCE decreased from 13.6% to 2.5% in Bayomen (P = 0.001), from 8.7% to 6.6% in Ngongol (P = 0.205) and from 6.4% to 5.4% in Nyamongo (P = 0.282). The median age of SCE shifted from 20 (IQR: 12-23) to 29 years (IQR: 18-33; P = 0.018) in Bayomen, from 16 (IQR: 12-21) to 26 years (IQR: 21-39; P < 0.001) in Ngongol and from 16 (IQR: 13-19) to 24 years (IQR: 19-32; P < 0.001) in Nyamongo. The proportions of SCE aged < 10, 10-19, 20-29 and ≥ 30 years shifted from 9.5, 58.3, 25.0 and 7.1% in 1991-1992 to 2.7, 20.5, 39.3 and 37.5% in 2017, respectively. CONCLUSIONS: SCE prevalence decreased overall between 1991-1992 and 2017. The age shift observed is probably due to a decrease in the number of new cases of epilepsy resulting from the dramatic reduction of Onchocerca volvulus transmission after 19 years of CDTI.


Assuntos
Antinematódeos/uso terapêutico , Epilepsia/epidemiologia , Ivermectina/uso terapêutico , Oncocercose/tratamento farmacológico , Adolescente , Adulto , Camarões/epidemiologia , Criança , Epilepsia/etiologia , Epilepsia/prevenção & controle , Feminino , Humanos , Incidência , Ivermectina/administração & dosagem , Masculino , Administração Massiva de Medicamentos , Oncocercose/complicações , Prevalência , Adulto Jovem
10.
Am J Trop Med Hyg ; 100(5): 1208-1215, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30915956

RESUMO

Mass drug administration (MDA) with ivermectin must reach a high treatment coverage (90% of the eligible population) if onchocerciasis is to be eliminated. Questions have been raised as to whether reported treatment figures reaching such high coverage are reliable. Sample surveys are proposed as the method of choice for "validating" reported coverage figures. The purpose of this study was to compare the district-level MDA coverage reported by programs with contemporaneous surveys of randomly selected respondents living in those same districts. Over an 8-year period, 19,219 households were selected using multistage random sampling; 38,433 adult male and female heads of those households were asked about their recent ivermectin MDA treatment experience. District coverage reports were considered "accurate" if they fell within the 95% CIs determined by the corresponding district's survey. Ninety-eight treatment rounds were evaluated over an 8-year period. Overall, the reported coverage of 96.5% (range: 68-100%) was significantly higher than the 92.5% surveyed coverage (range: 62.1-99.6%, 95% CI: 91.9-93.2%). However, only 20% of districts reported significantly higher coverage than surveys, 68% of district program reports were judged as accurate, and 12% of districts reported significantly lower coverage figures than their corresponding surveys. Eighty-eight percent of districts reported coverage ≥ 90% threshold for success, compared with 97% of surveys that included 90% in their 95% CIs. We conclude that when analyzed statistically at the district level, most surveys verified the reported coverage.


Assuntos
Administração Massiva de Medicamentos/estatística & dados numéricos , Oncocercose/prevenção & controle , Inquéritos e Questionários , Adulto , Camarões/epidemiologia , Doenças Endêmicas/estatística & dados numéricos , Feminino , Filaricidas/uso terapêutico , Geografia , Humanos , Ivermectina/uso terapêutico , Masculino , Oncocercose/tratamento farmacológico , Uganda/epidemiologia
11.
PLoS Negl Trop Dis ; 13(2): e0007159, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30818326

RESUMO

There is a significant need for improved treatments for onchocerciasis and lymphatic filariasis, diseases caused by filarial worm infection. In particular, an agent able to selectively kill adult worms (macrofilaricide) would be expected to substantially augment the benefits of mass drug administration (MDA) with current microfilaricides, and to provide a solution to treatment of onchocerciasis / loiasis co-infection, where MDA is restricted. We have identified a novel macrofilaricidal agent, Tylosin A (TylA), which acts by targeting the worm-symbiont Wolbachia bacterium. Chemical modification of TylA leads to improvements in anti-Wolbachia activity and oral pharmacokinetic properties; an optimized analog (ABBV-4083) has been selected for clinical evaluation.


Assuntos
Antibacterianos/farmacologia , Descoberta de Drogas , Filaricidas/farmacologia , Tilosina/análogos & derivados , Tilosina/farmacologia , Wolbachia/efeitos dos fármacos , Animais , Antibacterianos/farmacocinética , Filariose Linfática/tratamento farmacológico , Feminino , Filaricidas/farmacocinética , Filarioidea/efeitos dos fármacos , Filarioidea/microbiologia , Gerbillinae , Camundongos , Camundongos Endogâmicos BALB C , Oncocercose/tratamento farmacológico , Simbiose/efeitos dos fármacos
12.
Int J Infect Dis ; 79: 187-194, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30711145

RESUMO

OBJECTIVES: To investigate the reasons for the high prevalence of epilepsy (>6%) discovered in 2015 in the Aketi health zone in the north of the Democratic Republic of the Congo. METHODS: Persons with epilepsy (PWE) diagnosed in a door-to-door survey in 2015 were traced and re-examined in 2017 by a neurologist. Confirmed PWE were paired with matched controls. For onchocerciasis assessment, children 7-10 years old were tested for IgG4 Onchocerca volvulus (OV16) antibodies, a rapid epidemiological mapping of onchocerciasis (REMO) study was performed, and ivermectin coverage was investigated. RESULTS: Forty-three (61.4%) previously diagnosed PWE were traced; the neurologist confirmed the epilepsy diagnosis in all of them. The overall OV16 positivity rate was 64.5%. Poor ivermectin coverage (55.9%) and a high prevalence of onchocercal nodules (>70%) were observed. The prevalence of epilepsy was 5.7% in Aketi rural town, with nine PWE (13.8%) experiencing head nodding seizures. A case-control study showed that PWE had lower body weight and higher ivermectin coverage in 2017 than healthy controls. CONCLUSIONS: The high prevalence of epilepsy in the Aketi health zone, despite 14 years of community-directed treatment with ivermectin (CDTI), was found to be associated with high onchocerciasis transmission and low ivermectin use. An awareness programme to increase ivermectin coverage and the introduction of a bi-annual CDTI programme should be considered.


Assuntos
Epilepsia/epidemiologia , Ivermectina/uso terapêutico , Oncocercose/epidemiologia , Adolescente , Adulto , Animais , Anticorpos Anti-Helmínticos/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , República Democrática do Congo/epidemiologia , Feminino , Grupos Focais , Humanos , Imunoglobulina G/sangue , Masculino , Onchocerca volvulus/isolamento & purificação , Oncocercose/tratamento farmacológico , Prevalência , População Rural , Convulsões/epidemiologia , Adulto Jovem
13.
PLoS Negl Trop Dis ; 13(1): e0006356, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30650071

RESUMO

The Onchocerca ochengi adult implant and Brugia malayi microfilariemic Severe-Combined Immunodeficient (SCID) mouse models are validated screens to measure macrofilaricidal and microfilaricidal activities of candidate onchocerciasis drugs. The purpose of this study was to assess whether 5 daily sub-cutaneous (s.c.) injections of standard flubendazole (FBZ) suspension (10mg/kg), a single s.c. injection (10mg/kg) or 5 daily repeated oral doses of FBZ amorphous solid dispersion (ASD) formulation (0.2, 1.5 or 15mg/kg) mediated macrofilaricidal efficacy against O. ochengi male worms implanted into SCID mice. The direct microfilaricidal activity against circulating B. malayi microfilariae of single dose FBZ ASD formulation (2 or 40 mg/kg) was also evaluated and compared against the standard microfilaricide, ivermectin (IVM). Systemic exposures of FBZ/FBZ metabolites achieved following dosing were measured by pharmacokinetic (PK) bioanalysis. At necropsy, five weeks following start of FBZ SC injections, there were significant reductions in burdens of motile O. ochengi worms following multiple injections (93%) or single injection (82%). Further, significant proportions of mice dosed following multiple injections (5/6; 83%) or single injection (6/10; 60%) were infection negative (drug-cured). In comparison, no significant reduction in recovery of motile adult O. ochengi adult worms was obtained in any multiple-oral dosage group. Single oral-dosed FBZ did not mediate any significant microfilaricidal activity against circulating B. malayi mf at 2 or 7 days compared with >80% efficacy of single dose IVM. In conclusion, multiple oral FBZ formulation doses, whilst achieving substantial bioavailability, do not emulate the efficacy delivered by the parenteral route in vivo against adult O. ochengi. PK analysis determined FBZ efficacy was related to sustained systemic drug levels rather than achievable Cmax. PK modelling predicted that oral FBZ would have to be given at low dose for up to 5 weeks in the mouse model to achieve a matching efficacious exposure profile.


Assuntos
Brugia Malayi/efeitos dos fármacos , Filaricidas/farmacologia , Mebendazol/análogos & derivados , Microfilárias/efeitos dos fármacos , Onchocerca/efeitos dos fármacos , Oncocercose/tratamento farmacológico , Administração Oral , Animais , Modelos Animais de Doenças , Filaricidas/administração & dosagem , Ivermectina/administração & dosagem , Ivermectina/farmacologia , Masculino , Mebendazol/administração & dosagem , Mebendazol/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Carga Parasitária
14.
PLoS Negl Trop Dis ; 13(1): e0006436, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30650160

RESUMO

Benzimidazole anthelmintics have long been employed for the control of soil-transmitted helminth infections. Flubendazole (FBZ) was approved in 1980 for the treatment of gastrointestinal nematode infections in both veterinary and human medicine. It has also long been known that parenteral administration of FBZ can lead to high macrofilaricidal efficacy in a variety of preclinical models and in humans. As part of an effort to stimulate the discovery and development of new macrofilaricides, particularly for onchocerciasis, research has recently been devoted to the development of new formulations that would afford high oral bioavailability of FBZ, paving the way for potential clinical development of this repurposed drug for the treatment of human filariases. This review summarizes the background information that led to this program and summarizes some of the lessons learned from it.


Assuntos
Filariose Linfática/tratamento farmacológico , Filaricidas/uso terapêutico , Mebendazol/análogos & derivados , Microfilárias/efeitos dos fármacos , Onchocerca volvulus/efeitos dos fármacos , Oncocercose/tratamento farmacológico , Wuchereria bancrofti/efeitos dos fármacos , Albendazol/uso terapêutico , Animais , Dietilcarbamazina/uso terapêutico , Filariose Linfática/parasitologia , Filariose Linfática/transmissão , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/parasitologia , Humanos , Ivermectina/uso terapêutico , Mebendazol/uso terapêutico , Oncocercose/parasitologia , Oncocercose/transmissão
15.
Proc Natl Acad Sci U S A ; 116(4): 1414-1419, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30617067

RESUMO

Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, Wolbachia, using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti-Wolbachia candidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis.


Assuntos
Antibacterianos/farmacologia , Wolbachia/efeitos dos fármacos , Animais , Filariose Linfática/tratamento farmacológico , Filariose Linfática/microbiologia , Feminino , Masculino , Camundongos , Camundongos SCID , Oncocercose/tratamento farmacológico , Oncocercose/microbiologia , Pirimidinas/farmacologia , Quinazolinas/farmacologia
16.
Enferm. infecc. microbiol. clín. (Ed. impr.) ; 36(10): 633-639, dic. 2018. tab, ilus, graf
Artigo em Espanhol | IBECS | ID: ibc-176928

RESUMO

Introduction: Onchocerciasis is caused by Onchocerca volvulus and mainly leads to pruritus and skin and visual disorders, including blindness. Seventeen million people are infected in 38 countries; 31 of these are in sub-Saharan Africa, six in Latin America and one on the Arabian Peninsula. More than 99% of cases occur in sub-Saharan Africa where 120 million people are at risk of infection. Eye disorders have been well-documented; however, skin disorders have not been described accurately. The objective of our study was to describe the epidemiology, main skin manifestations and treatment of imported onchocerciasis. Material and methods: A retrospective study was thus conducted by analysing the main demographic, clinical and treatment data regarding a cohort of 400 patients attending a reference clinical unit over a 17-year period. Results: Most patients were female (55%) with mean age 37.5 ± 16.7 years. All the migrants came from sub-Saharan countries. The most frequently occurring dermatological symptom was pruritus. Ivermectin had been used as first-line therapy and adverse reactions had been described in 11 patients (3.2%). Conclusions: The results indicate the fact that there should be a clinical suspicion of onchocerciasis regarding immigrants from endemic areas having skin lesions compatible with the disease's profile or asymptomatic patients having eosinophilia or unexplained high IgE. Moreover, skin snips from the buttocks region were very fruitful and treatment with ivermectin was seen to be safe. This is the largest case series regarding imported onchocerciasis described up to the present time


Introducción: La oncocercosis está causada por Onchocerca volvulus que produce fundamentalmente trastornos cutáneos, prurito y alteraciones visuales. Diecisiete millones de personas están infectadas en 38 países; 31 de ellos en África subsahariana, 6 en América Latina y uno en la península arábiga. Más del 99% de los casos se producen en el África subsahariana, donde 120 millones de personas están en riesgo de infección. Mientras los trastornos oculares han sido bien documentados, los trastornos cutáneos no se han descrito con precisión. El objetivo de nuestro estudio es describir la epidemiología, las principales manifestaciones cutáneas y el tratamiento de la oncocercosis importada. Material y métodos: Estudio retrospectivo de una cohorte de 400 pacientes atendidos en una unidad de referencia a lo largo de un período de 17 años con los principales datos demográficos, clínicos y de tratamiento. Resultados: La mayoría de pacientes eran mujeres (55%) con una edad media de 37,5 ± 16,7 años. Todos los migrantes procedían de países subsaharianos. El síntoma dermatológico más frecuente fue el prurito. La ivermectina fue el fármaco de elección, describiéndose reacciones adversas en 11 pacientes (3,2%). Conclusiones: Los resultados señalan de que se debe mantener una sospecha clínica de oncocercosis en inmigrantes procedentes de áreas endémicas y lesiones cutáneas sugerentes o en pacientes asintomáticos con eosinofilia o IgE inexplicada. Además, los pellizcos cutáneos de glúteos fueron altamente rentables. El tratamiento con ivermectina es seguro. Esta es la mayor serie de casos de oncocercosis importada descrita hasta la fecha


Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Onchocerca volvulus/isolamento & purificação , Oncocercose/diagnóstico , Oncocercose/tratamento farmacológico , Doenças Negligenciadas , Dermatopatias/parasitologia , Estudos Retrospectivos , Estudos de Coortes , Emigração e Imigração , Dermatopatias/diagnóstico , Dermatopatias/tratamento farmacológico
17.
Seizure ; 63: 93-101, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30468964

RESUMO

PURPOSE: To determine the prevalence and incidence of epilepsy in an onchocerciasis endemic region of South Sudan. METHODS: In May 2018, a door-to-door household survey was conducted in 8 study sites in an onchocerciasis endemic area in Maridi County. RESULTS: A total of 2511 households agreed to participate in the study, corresponding to 17,652 individuals. An epilepsy screening questionnaire identified 799 persons suspected to have epilepsy (4.5%); in 736 of the 766 persons (96.1%) seen by a clinical officer the diagnosis of epilepsy was confirmed. Adding 38 persons who were not seen but with a positive answer to a combination of screening questions, 774 persons (4.4%) had epilepsy. Epilepsy prevalence was highest in the 11-20 age group (10.5%); 66 persons with epilepsy (PWE) developed their first seizures in the year preceding the survey (annual incidence = 373.9/100.000). Neurocysticercosis cannot explain the high epilepsy prevalence since no pigs are kept in the area. Independent risk factors for epilepsy included male gender, belonging to a "permanent household" and a farming family, and living in a village bordering the Maridi River. Only 7209 (40.8%) of the population took ivermectin in 2017. CONCLUSION: A very high prevalence and incidence of epilepsy was observed in several villages in Maridi County located close to the Maridi River and the Maridi dam. Urgent action is needed to prevent children in Maridi County from developing OAE by strengthening the onchocerciasis elimination program.


Assuntos
Epilepsia/epidemiologia , Epilepsia/etiologia , Oncocercose/epidemiologia , Oncocercose/etiologia , Adolescente , Adulto , Antiparasitários/uso terapêutico , Criança , Pré-Escolar , Doenças Endêmicas , Feminino , Geografia Médica , Humanos , Incidência , Lactente , Recém-Nascido , Ivermectina/uso terapêutico , Masculino , Oncocercose/tratamento farmacológico , Prevalência , Fatores de Risco , Rios , Sudão do Sul/epidemiologia , Adulto Jovem
18.
Infect Dis Poverty ; 7(1): 112, 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30424817

RESUMO

BACKGROUND: Nodding syndrome (NS) is a devastating epileptic illness of unknown aetiology mainly affecting children 5-15 years of age. Head nodding distinguishes NS from other forms of epilepsy. Other manifestations of the illness include mental and physical growth retardation. Many children die as a result of falling in fires or drowning. Recently, it was shown that NS is only one of the phenotypic presentations of onchocerciasis associated epilepsy (OAE). Despite the strong epidemiological association between epilepsy and onchocerciasis, the causal mechanism is unknown. After implementation of bi-annual community directed treatment with ivermectin (CDTi) and larviciding of rivers in northern Uganda, new cases of NS have ceased, while new cases continue to emerge in South Sudanese onchocerciasis-endemic areas with an interrupted CDTi programme. This study is designed to evaluate the potential effects of bi-annual CDTi on reducing the incidence of NS/OAE in onchocerciasis-endemic areas in South Sudan. METHODS: A pre-intervention door-to-door population-based household survey will be conducted in selected onchocerciasis-endemic villages in Mundri and Maridi Counties, which have a high prevalence of epilepsy. Using a validated questionnaire, the entire village will be screened by community research assistants for suspected epilepsy cases. Suspected cases will be interviewed and examined by a trained clinical officer or medical doctor who will confirm or reject the diagnosis of epilepsy. Bi-annual CDTi will be implemented in the villages and a surveillance system for epilepsy set up. By implementing an epilepsy onchocerciasis awareness campaign we expect to obtain > 90% CDTi coverage of eligible individuals. The door-to-door survey will be repeated two years after the baseline survey. The incidence of NS/OAE will be compared before and after bi-annual CDTi. DISCUSSION: Our study is the first population-based study to evaluate the effect of bi-annual CDTi to reduce the incidence of NS/OAE. If the study demonstrates such a reduction, these findings are expected to motivate communities in onchocerciasis-endemic regions to participate in CDTi, and will encourage policy makers, funders and other stakeholders to increase their efforts to eliminate onchocerciasis.


Assuntos
Antiparasitários/uso terapêutico , Epilepsia/epidemiologia , Ivermectina/uso terapêutico , Oncocercose/tratamento farmacológico , Oncocercose/epidemiologia , Adolescente , Criança , Pré-Escolar , Doenças Endêmicas , Epilepsia/etiologia , Feminino , Humanos , Incidência , Masculino , Síndrome do Cabeceio/epidemiologia , Síndrome do Cabeceio/etiologia , Oncocercose/complicações , Prevalência , Saúde Pública , Sudão do Sul/epidemiologia
19.
PLoS Negl Trop Dis ; 12(11): e0006794, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30418968

RESUMO

Progress towards controlling and eliminating parasitic worms, including schistosomiasis, onchocerciasis, and lymphatic filariasis, is advancing rapidly as national governments, multinational NGOs, and pharmaceutical companies launch collaborative chemotherapeutic control campaigns. Critical questions remain regarding the potential for achieving elimination of these infections, and analytical methods can help to quickly estimate progress towards-and the probability of achieving-elimination over specific timeframes. Here, we propose the effective reproduction number, Reff, as a proxy of elimination potential for sexually reproducing worms that are subject to poor mating success at very low abundance (positive density dependence, or Allee effects). Reff is the number of parasites produced by a single reproductive parasite at a given stage in the transmission cycle, over the parasite's lifetime-it is the generalized form of the more familiar basic reproduction number, R0, which only applies at the beginning of an epidemic-and it can be estimated in a 'model-free' manner by an estimator ('ε'). We introduce ε, demonstrate its estimation using simulated data, and discuss how it may be used in planning and evaluation of ongoing elimination efforts for a range of parasitic diseases.


Assuntos
Erradicação de Doenças/métodos , Administração Massiva de Medicamentos/estatística & dados numéricos , Schistosoma/efeitos dos fármacos , Esquistossomose/epidemiologia , Esquistossomose/prevenção & controle , Animais , Número Básico de Reprodução , Coleta de Dados , Erradicação de Doenças/estatística & dados numéricos , Métodos Epidemiológicos , Humanos , Administração Massiva de Medicamentos/métodos , Modelos Teóricos , Oncocercose/tratamento farmacológico , Parasitos/fisiologia , Doenças Parasitárias/tratamento farmacológico , Doenças Parasitárias/epidemiologia , Doenças Parasitárias/parasitologia , Reprodução , Schistosoma/fisiologia , Esquistossomose/tratamento farmacológico , Esquistossomose/transmissão
20.
Math Biosci Eng ; 15(4): 841-862, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30380312

RESUMO

Onchocerciasis is an endemic disease in parts of sub-Saharan Africa. Complex mathematical models are being used to assess the likely efficacy of efforts to eradicate the disease; however, their predictions have not always been borne out in practice. In this paper, we represent the immunological aspects of the disease with a single empirical parameter in order to reduce the model complexity. Asymptotic approximation allows us to reduce the vector-borne epidemiological model to a model of an infectious disease with nonlinear incidence. We then consider two versions, one with continuous treatment and a more realistic one where treatment occurs only at intervals. Thorough mathematical analysis of these models yields equilibrium solutions for the continuous case, periodic solutions for the pulsed case, and conditions for the existence of endemic disease equilibria in both cases, thereby leading to simple model criteria for eradication. The analytical results and numerical experiments show that the continuous treatment version is an excellent approximation for the pulsed version and that the current onchocerciasis eradication strategy is inadequate for regions where the incidence is highest and unacceptably slow even when the long-term behavior is the disease-free state.


Assuntos
Doenças Endêmicas , Modelos Biológicos , Oncocercose/tratamento farmacológico , Oncocercose/epidemiologia , África ao Sul do Saara/epidemiologia , Animais , Simulação por Computador , Esquema de Medicação , Doenças Endêmicas/prevenção & controle , Filaricidas/administração & dosagem , Humanos , Insetos Vetores/parasitologia , Ivermectina/administração & dosagem , Conceitos Matemáticos , Microfilárias/efeitos dos fármacos , Dinâmica não Linear , Onchocerca/efeitos dos fármacos , Oncocercose/parasitologia , Simuliidae/parasitologia , Software
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