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1.
PLoS Negl Trop Dis ; 14(3): e0008106, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32176703

RESUMO

Lymphatic filariasis has remained endemic in Fiji despite repeated mass drug administration using the well-established and safe combination of diethylcarbamazine and albendazole (DA) since 2002. In certain settings the addition of ivermectin to this combination (IDA) remains a safe strategy and is more efficacious. However, the safety has yet to be described in scabies and soil-transmitted helminth endemic settings like Fiji. Villages of Rotuma and Gau islands were randomised to either DA or IDA. Residents received weight-based treatment unblinded with standard exclusions. Participants were actively found and asked by a nurse about their health daily for the first two days and then asked to seek review for the next five days if unwell. Anyone with severe symptoms were reviewed by a doctor and any serious adverse event was reported to the Medical Monitor and Data Safety Monitoring Board. Of 3612 enrolled and eligible participants, 1216 were randomised to DA and 2396 to IDA. Age and sex in both groups were representative of the population. Over 99% (3598) of participants completed 7 days follow-up. Adverse events were reported by 600 participants (16.7%), distributed equally between treatment groups, with most graded as mild (93.2%). There were three serious adverse events, all judged not attributable to treatment by an independent medical monitor. Fatigue was the most common symptom reported by 8.5%, with headache, dizziness, nausea and arthralgia being the next four most common symptoms. Adverse events were more likely in participants with microfilaremia (43.2% versus 15.7%), but adverse event frequency was not related to the presence of scabies or soil-transmitted helminth infection. IDA has comparable safety to DA with the same frequency of adverse events experienced following community mass drug administration. The presence of co-endemic infections did not increase adverse events. IDA can be used in community programs where preventative chemotherapy is needed for control of lymphatic filariasis and other neglected tropical diseases.


Assuntos
Albendazol/efeitos adversos , Antiparasitários/efeitos adversos , Dietilcarbamazina/efeitos adversos , Inseticidas/efeitos adversos , Ivermectina/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Albendazol/administração & dosagem , Antiparasitários/administração & dosagem , Criança , Pré-Escolar , Infecções Comunitárias Adquiridas/tratamento farmacológico , Dietilcarbamazina/administração & dosagem , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Filariose Linfática/tratamento farmacológico , Feminino , Fiji , Helmintíase/tratamento farmacológico , Humanos , Lactente , Inseticidas/administração & dosagem , Ivermectina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Doenças Negligenciadas/tratamento farmacológico , População Rural , Escabiose/tratamento farmacológico , Resultado do Tratamento , Adulto Jovem
2.
Infect Dis Poverty ; 9(1): 22, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32114985

RESUMO

BACKGROUND: Lymphatic filariasis (LF), a neglected tropical disease (NTD) and leading cause of global disability, is endemic in 32 countries in Africa with almost 350 million people requiring regular drug administration, and only 16 countries achieving target coverage. Community Drug Distributors (CDDs) are critical for the success of NTD programs, and the distribution of medicines during mass drug administration (MDA) in Africa; however they could also be a weak link. The primary aim of this study is to explore and describe perceptions of CDDs during MDA for LF in Mvita sub-county in Mombasa county and Kaloleni sub-county in Kilifi county, Kenya; and provide recommendations for the effective engagement of communities and CDDs in low-resource settings. METHODS: In September 2018, we conducted six focus group discussions with community members in each sub-county, three with men aged 18-30, 31-50, and 51 years and above and three with women stratified into the same age groups. In each sub-county, we also conducted semi-structured interviews with nine community health extension workers (CHEWs), the national LF focal point, the county NTD focal points, and seven community leaders. Content analysis of the data was conducted, involving a process of reading, coding, and displaying data in order to develop a codebook. RESULTS: We found that several barriers and facilitators impact the engagement between CDDs and community members during MDA. These barriers include poor communication and trust between CDDs and communities; community distrust of the federal government; low community knowledge and perceived risk of LF, poor timing of MDA, fragmented supervision of CDDs during MDA; and CDD bias when distributing medicines. We also found that CDD motivation was a critical factor in their ability to successfully meet MDA targets. It was acknowledged that directly observed treatment and adequate health education were often not executed by CDDs. The involvement of community leaders as informal supervisors of CDDs and community members improves MDA. CONCLUSIONS: In order to achieve global targets around the elimination of LF, CDDs and communities must be effectively engaged by improving planning and implementation of MDA.


Assuntos
Agentes Comunitários de Saúde , Filariose Linfática/tratamento farmacológico , Filariose Linfática/epidemiologia , Filaricidas/uso terapêutico , Adulto , Agentes Comunitários de Saúde/organização & administração , Agentes Comunitários de Saúde/psicologia , Feminino , Grupos Focais , Humanos , Quênia/epidemiologia , Masculino , Administração Massiva de Medicamentos , Pessoa de Meia-Idade , Adulto Jovem
3.
PLoS Negl Trop Dis ; 13(11): e0007861, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31774820

RESUMO

BACKGROUND: The success of the global strategy to eliminate lymphatic filariasis (LF) through mass drug administration (MDA) campaigns is dependent on meeting high coverage levels over long periods of time. Community engagement plays a critical role in driving coverage and involvement of local communities in MDA for LF. This study explored how community engagement approaches used in MDA for LF shape participation in the programme, with a view of proposing effective engagement strategies. METHODS: The study was conducted in Luangwa, a rural District of Lusaka province, Zambia. An exploratory qualitative case study approach was employed. A total of nine focus group discussions, six in-depth and seven key informant interviews were conducted with various participants that included; community members, traditional leaders and programme managers, respectively. Data were analysed using a thematic approach, aided by NVivo 10 software. RESULTS: Three core thematic areas emerged from the data as priority focus areas for programme planners and implementers in designing effective community engagement strategies that facilitate participation. Firstly, employing of partnership approaches through adequate and timely engagement of traditional, government and non-governmental organisation structures. Secondly, use of appropriate and innovative health education initiatives to disseminate information about the programme. Thirdly, addressing context specific programme implementation barriers affecting community engagement in MDA for LF. CONCLUSION: Facilitating participation in MDA for LF will require designing and implementing effective community engagement strategies that take into account local context, but also seek to explore all avenues of maximizing participation for improved coverage levels. MDA for LF implementation teams should systematically consider the identified factors and seek to incorporate them in their implementation plans.


Assuntos
Participação da Comunidade , Transmissão de Doença Infecciosa/prevenção & controle , Filariose Linfática/tratamento farmacológico , Filariose Linfática/prevenção & controle , Filaricidas/uso terapêutico , Administração Massiva de Medicamentos/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Educação em Saúde , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Zâmbia
4.
PLoS Negl Trop Dis ; 13(9): e0007697, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31557154

RESUMO

BACKGROUND: Lymphatic filariasis (LF) is a neglected tropical disease, and the Global Program to Eliminate LF delivers mass drug administration (MDA) to 500 million people every year. Adverse events (AEs) are common after LF treatment. METHODOLOGY/PRINCIPAL FINDINGS: To better understand the pathogenesis of AEs, we studied LF-patients from a treatment trial. Plasma levels of many filarial antigens increased post-treatment in individuals with AEs, and this is consistent with parasite death. Circulating immune complexes were not elevated in these participants, and the classical complement cascade was not activated. Multiple cytokines increased after treatment in persons with AEs. A transcriptomic analysis was performed for nine individuals with moderate systemic AEs and nine matched controls. Differential gene expression analysis identified a significant transcriptional signature associated with post-treatment AEs; 744 genes were upregulated. The transcriptional signature was enriched for TLR and NF-κB signaling. Increased expression of seven out of the top eight genes upregulated in persons with AEs were validated by qRT-PCR, including TLR2. CONCLUSIONS/SIGNIFICANCE: This is the first global study of changes in gene expression associated with AEs after treatment of lymphatic filariasis. Changes in cytokines were consistent with prior studies and with the RNAseq data. These results suggest that Wolbachia lipoprotein is involved in AE development, because it activates TLR2-TLR6 and downstream NF-κB. Additionally, LPS Binding Protein (LBP, which shuttles lipoproteins to TLR2) increased post-treatment in individuals with AEs. Improved understanding of the pathogenesis of AEs may lead to improved management, increased MDA compliance, and accelerated LF elimination.


Assuntos
Filariose Linfática/tratamento farmacológico , Filaricidas/uso terapêutico , Adolescente , Adulto , Idoso , Albendazol/administração & dosagem , Albendazol/efeitos adversos , Antígenos de Helmintos/sangue , Citocinas/sangue , Citocinas/imunologia , Dietilcarbamazina/efeitos adversos , Dietilcarbamazina/uso terapêutico , Filariose Linfática/genética , Filariose Linfática/imunologia , Feminino , Filaricidas/efeitos adversos , Humanos , Ivermectina/administração & dosagem , Ivermectina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
5.
PLoS Negl Trop Dis ; 13(9): e0007685, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31483784

RESUMO

BACKGROUND: Despite decades of community-based mass drug administration (MDA) for neglected tropical diseases, it remains an open question as to what constitutes the best combination of community medicine distributors (CMDs) for achieving high (>65%/75%) treatment rates within a village. METHODS: Routine community-based MDA was evaluated in Mayuge District, Uganda. For one month, we tracked 6,148 individuals aged 1+ years in 1,118 households from 28 villages. Praziquantel, albendazole, and ivermectin were distributed to treat Schistosoma mansoni, lymphatic filariasis, and soil-transmitted helminths. The similarity/diversity between CMDs was observed and used to predict the division of labour and overall village treatment rates. The division of labour was calculated by dividing the lowest treatment rate by the highest treatment rate achieved by two CMDs within a village. CMD similarity was measured for 16 characteristics including friendship network overlap, demographic and socioeconomic factors, methods of CMD selection, and years as CMD. Relevant variables for MDA outcomes were selected through least absolute shrinkage and selection operators with leave-one-out cross validation. Final models were run with ordinary least squares regression and robust standard errors. RESULTS: The percentage of individuals treated with at least one drug varied across villages from 2.79-89.74%. The only significant predictor (p-value<0.05) of village treatment rates was the division of labour. The estimated difference between a perfectly equal (a 50-50 split of individuals treated) and unequal (one CMD treating no one) division of labour was 39.69%. A direct tie (close friendship) between CMDs was associated with a nearly twofold more equitable distribution of labour when compared to CMDs without a direct tie. CONCLUSIONS: An equitable distribution of labour between CMDs may be essential for achieving treatment targets of 65%/75% within community-based MDA. To improve the effectiveness of CMDs, national programmes should explore interventions that seek to facilitate communication, friendship, and equal partnership between CMDs.


Assuntos
Anti-Helmínticos/administração & dosagem , Agentes Comunitários de Saúde/estatística & dados numéricos , Filariose Linfática/tratamento farmacológico , Doenças Negligenciadas/tratamento farmacológico , Esquistossomose mansoni/tratamento farmacológico , Adolescente , Adulto , Idoso , Albendazol/administração & dosagem , Animais , Criança , Pré-Escolar , Medicina Comunitária/estatística & dados numéricos , Estudos Transversais , Feminino , Humanos , Lactente , Ivermectina/administração & dosagem , Masculino , Administração Massiva de Medicamentos , Pessoa de Meia-Idade , Praziquantel/administração & dosagem , População Rural , Uganda , Adulto Jovem
6.
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
7.
PLoS Negl Trop Dis ; 13(9): e0007687, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31513587

RESUMO

Lymphatic filariasis (LF), a morbid disease caused by the tissue-invasive nematodes Wuchereria bancrofti, Brugia malayi, and Brugia timori, affects millions of people worldwide. Global eradication efforts have significantly reduced worldwide prevalence, but complete elimination has been hampered by limitations of current anti-filarial drugs and the lack of a vaccine. The goal of this study was to evaluate B. malayi intestinal UDP-glucuronosyltransferase (Bm-UGT) as a potential therapeutic target. To evaluate whether Bm-UGT is essential for adult filarial worms, we inhibited its expression using siRNA. This resulted in a 75% knockdown of Bm-ugt mRNA for 6 days and almost complete suppression of detectable Bm-UGT by immunoblot. Reduction in Bm-UGT expression resulted in decreased worm motility for 6 days, 70% reduction in microfilaria release from adult worms, and significant reduction in adult worm metabolism as detected by MTT assays. Because prior allergic-sensitization to a filarial antigen would be a contraindication for its use as a vaccine candidate, we tested plasma from infected and endemic normal populations for Bm-UGT-specific IgE using a luciferase immunoprecipitation assay. All samples (n = 35) tested negative. We then tested two commercially available medicines known to be broad inhibitors of UGTs, sulfinpyrazone and probenecid, for in vitro activity against B. malayi. There were marked macrofilaricidal effects at concentrations achievable in humans and very little effect on microfilariae. In addition, we observed that probenecid and sulfinpyrazone exhibit a synergistic macrofilaricidal effect when used in combination with albendazole. The results of this study demonstrate that Bm-UGT is an essential protein for adult worm survival. Lack of prior IgE sensitization in infected and endemic populations suggest it may be a feasible vaccine candidate. The finding that sulfinpyrazone and probenecid have in vitro effects against adult B. malayi worms suggests that these medications have promise as potential macrofilaricides in humans.


Assuntos
Brugia Malayi/efeitos dos fármacos , Brugia Malayi/enzimologia , Glucuronosiltransferase/metabolismo , Albendazol/farmacologia , Animais , Antígenos de Helmintos/sangue , Brugia Malayi/imunologia , Brugia Malayi/metabolismo , Quimioterapia Combinada , Filariose Linfática/tratamento farmacológico , Filariose Linfática/prevenção & controle , Feminino , Filaricidas/farmacologia , Glucuronosiltransferase/antagonistas & inibidores , Glucuronosiltransferase/genética , Humanos , Imunoglobulina E/sangue , Intestinos/enzimologia , Microfilárias/efeitos dos fármacos , Movimento , Probenecid/farmacologia , RNA Interferente Pequeno , Sulfimpirazona/farmacologia
8.
PLoS Negl Trop Dis ; 13(8): e0007115, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398203

RESUMO

BACKGROUND: Ghana started its national programme to eliminate lymphatic filariasis (LF) in 2000, with mass drug administration (MDA) with ivermectin and albendazole as main strategy. We review the progress towards elimination that was made by 2016 for all endemic districts of Ghana and analyze microfilaria (mf) prevalence from sentinel and spot-check sites in endemic districts. METHODS: We reviewed district level data on the history of MDA and outcomes of transmission assessment surveys (TAS). We further collated and analyzed mf prevalence data from sentinel and spot-check sites. RESULTS: MDA was initiated in 2001-2006 in all 98 endemic districts; by the end of 2016, 81 had stopped MDA after passing TAS and after an average of 11 rounds of treatment (range 8-14 rounds). The median reported coverage for the communities was 77-80%. Mf prevalence survey data were available for 430 communities from 78/98 endemic districts. Baseline mf prevalence data were available for 53 communities, with an average mf prevalence of 8.7% (0-45.7%). Repeated measurements were available for 78 communities, showing a steep decrease in mean mf prevalence in the first few years of MDA, followed by a gradual further decline. In the 2013 and 2014 surveys, 7 and 10 communities respectively were identified with mf prevalence still above 1% (maximum 5.6%). Fifteen of the communities above threshold are all within districts where MDA was still ongoing by 2016. CONCLUSIONS: The MDA programme of the Ghana Health Services has reduced mf prevalence in sentinel sites below the 1% threshold in 81/98 endemic districts in Ghana, yet 15 communities within 13 districts (MDA ongoing by 2016) had higher prevalence than this threshold during the surveys in 2013 and 2014. These districts may need to intensify interventions to achieve the WHO 2020 target.


Assuntos
Erradicação de Doenças/métodos , Filariose Linfática/tratamento farmacológico , Filariose Linfática/epidemiologia , Albendazol/uso terapêutico , Animais , Criança , Pré-Escolar , Filariose Linfática/diagnóstico , Filariose Linfática/prevenção & controle , Doenças Endêmicas , Feminino , Gana/epidemiologia , Pesquisa sobre Serviços de Saúde , Humanos , Ivermectina/uso terapêutico , Masculino , Administração Massiva de Medicamentos/métodos , Microfilárias/patogenicidade , Prevalência , Inquéritos e Questionários , Organização Mundial da Saúde
9.
PLoS Negl Trop Dis ; 13(7): e0007094, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31260444

RESUMO

BACKGROUND: Salt fortified with the drug, diethylcarbamazine (DEC), and introduced into a competitive market has the potential to overcome the obstacles associated with tablet-based Lymphatic Filariasis (LF) elimination programs. Questions remain, however, regarding the economic viability, production capacity, and effectiveness of this strategy as a sustainable means to bring about LF elimination in resource poor settings. METHODOLOGY AND PRINCIPAL FINDINGS: We evaluated the performance and effectiveness of a novel social enterprise-based approach developed and tested in Léogâne, Haiti, as a strategy to sustainably and cost-efficiently distribute DEC-medicated salt into a competitive market at quantities sufficient to bring about the elimination of LF. We undertook a cost-revenue analysis to evaluate the production capability and financial feasibility of the developed DEC salt social enterprise, and a modeling study centered on applying a dynamic mathematical model localized to reflect local LF transmission dynamics to evaluate the cost-effectiveness of using this intervention versus standard annual Mass Drug Administration (MDA) for eliminating LF in Léogâne. We show that the salt enterprise because of its mixed product business strategy may have already reached the production capacity for delivering sufficient quantities of edible DEC-medicated salt to bring about LF transmission in the Léogâne study setting. Due to increasing revenues obtained from the sale of DEC salt over time, expansion of its delivery in the population, and greater cumulative impact on the survival of worms leading to shorter timelines to extinction, this strategy could also represent a significantly more cost-effective option than annual DEC tablet-based MDA for accomplishing LF elimination. SIGNIFICANCE: A social enterprise approach can offer an innovative market-based strategy by which edible salt fortified with DEC could be distributed to communities both on a financially sustainable basis and at sufficient quantity to eliminate LF. Deployment of similarly fashioned intervention strategies would improve current efforts to successfully accomplish the goal of LF elimination, particularly in difficult-to-control settings.


Assuntos
Dietilcarbamazina/economia , Erradicação de Doenças/economia , Filariose Linfática/tratamento farmacológico , Filaricidas/economia , Medicina Social/economia , Cloreto de Sódio na Dieta/administração & dosagem , Administração Oral , Análise Custo-Benefício , Dietilcarbamazina/administração & dosagem , Erradicação de Doenças/métodos , Filariose Linfática/prevenção & controle , Filaricidas/administração & dosagem , Haiti , Recursos em Saúde/economia , Humanos , Administração Massiva de Medicamentos , Modelos Teóricos , Doenças Negligenciadas/tratamento farmacológico , Medicina Social/métodos , Cloreto de Sódio na Dieta/economia
10.
Parasit Vectors ; 12(1): 276, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31146779

RESUMO

BACKGROUND: Lymphatic filariasis (LF) is still a public health burden in many developing countries. In Benin, a West African country, at least 6.6 million people are at risk for LF. With the goal of eliminating LF by 2020, mass drug administration (MDA) has been scaled-up during the last decade. Currently, 23 districts are believed to have eliminated LF as a public health problem, and 25 other districts are still under treatment. In this study we report the results of the first transmission assessment survey of LF (TAS1) in 13 districts from the second group, which have received at least six rounds of MDA with albendazole and ivermectin. METHODS: The 13 districts were grouped into six evaluation units (EU). In each EU, 30 schools randomly selected by survey sample builder (SSB) software were surveyed. Children aged six and seven were sampled in schools and for each child the Alere™ Filariasis Test Strip test was carried out using finger-prick blood to detect the circulating filarial antigen from Wuchereria bancrofti. RESULTS: Overall, 9381 children were sampled in 191 schools from the six EU with 47.6% of the children aged six years and 52.4% aged seven years. Five EU passed the assessment, with no positive cases identified. The EU of Ouinhi which grouped the districts of Ouinhi, Cove, Za-Kpota and Zagnanado failed, with 47 positive cases. These cases were clustered in the districts of Ouinhi (n = 20), Za-Kpota (n = 11) and Zagnanado (n = 16). No cases were found in the district of Cove. CONCLUSIONS: The findings of our study indicate that Benin has made important progress towards elimination in most districts evaluated. However, this study also shows that transmission of LF is ongoing in the EU of Ouinhi, part of the Zou department. The MDA strategy needs to be strengthened in order to control the human reservoir of infection in these districts.


Assuntos
Filariose Linfática/tratamento farmacológico , Filariose Linfática/transmissão , Filaricidas/uso terapêutico , Wuchereria bancrofti/efeitos dos fármacos , Albendazol/uso terapêutico , Animais , Antígenos de Helmintos/sangue , Benin/epidemiologia , Criança , Erradicação de Doenças , Feminino , Humanos , Ivermectina/uso terapêutico , Masculino , Administração Massiva de Medicamentos , Saúde Pública , Inquéritos e Questionários , Resultado do Tratamento
11.
Curr Top Med Chem ; 19(14): 1252-1262, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31218959

RESUMO

BACKGROUND: Lymphatic filariasis (LF) is a parasitic disease that causes permanent disability (elephantiasis). Currently used antifilarial drugs are failing to control LF and there is resurgence in some areas. Looking for new antifilarial leads, we found that Calotropis procera plant parts have been used in traditional medicine for alleviating elephantiasis but the antifilarial activity is not known. OBJECTIVE: In the present study, the antifilarial activity of ethanolic extract (A001) and its hexane fraction (F001) of C. procera flowers was investigated using the human filarial parasite Brugia malayi. METHODS: A001 and F001 were tested for antifilarial activity using motility and 3-(4,5-dimethylthiazol-2- yl)-2,5 diphenyltetrazolium bromide (MTT) assays (in vitro) and in the rodent models B. malayi- Meriones unguiculatus and B. malayi-Mastomys coucha. In the rodent models, A001 and F001 were administered orally for 5 consecutive days, and the adult worm burden and course of microfilaraemia were determined. RESULTS: Both A001 and F001 showed microfilaricidal and macrofilaricidal activity in vitro. In animal models, A001 killed ~49-54% adult worms. In M. coucha model, F001 killed 12-60% adult worms in a dose (125-500 mg/kg) dependent manner; A001 and F001 suppressed microfilaraemia till days 91 and 35 post initiation of treatment, respectively. HPTLC revealed 0.61% lupeol, 0.50% ß-sitosterol and 1.50% triacontanol in F001. CONCLUSION: Flowers of C. procera have definite microfilaricidal and macrofilaricidal activities. Whether this activity is due to lupeol, ß-sitosterol and triacontanol found in the hexane fraction remains to be investigated. This is the first report on the antifilarial efficacy of flowers of the plant C. procera.


Assuntos
Brugia Malayi/efeitos dos fármacos , Calotropis/química , Filaricidas/farmacologia , Flores/química , Extratos Vegetais/farmacologia , Animais , Filariose Linfática/tratamento farmacológico , Filaricidas/química , Filaricidas/isolamento & purificação , Testes de Sensibilidade Parasitária , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação
12.
PLoS Med ; 16(6): e1002839, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31233507

RESUMO

BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) provides antifilarial medications to hundreds of millions of people annually to treat filarial infections and prevent elephantiasis. Recent trials have shown that a single-dose, triple-drug treatment (ivermectin with diethylcarbamazine and albendazole [IDA]) is superior to a two-drug combination (diethylcarbamazine plus albendazole [DA]) that is widely used in LF elimination programs. This study was performed to assess the safety of IDA and DA in a variety of endemic settings. METHODS AND FINDINGS: Large community studies were conducted in five countries between October 2016 and November 2017. Two studies were performed in areas with no prior mass drug administration (MDA) for filariasis (Papua New Guinea and Indonesia), and three studies were performed in areas with persistent LF despite extensive prior MDA (India, Haiti, and Fiji). Participants were treated with a single oral dose of IDA (ivermectin, 200 µg/kg; diethylcarbamazine, 6 mg/kg; plus albendazole, a fixed dose of 400 mg) or with DA alone. Treatment assignment in each study site was randomized by locality of residence. Treatment was offered to residents who were ≥5 years of age and not pregnant. Adverse events (AEs) were assessed by medical teams with active follow-up for 2 days and passive follow-up for an additional 5 days. A total of 26,836 persons were enrolled (13,535 females and 13,300 males). A total of 12,280 participants were treated with DA, and 14,556 were treated with IDA. On day 1 or 2 after treatment, 97.4% of participants were assessed for AEs. The frequency of all AEs was similar after IDA and DA treatment (12% versus 12.1%, adjusted odds ratio for IDA versus DA 1.15, 95% CI 0.87-1.52, P = 0.316); 10.9% of participants experienced mild (grade 1) AEs, 1% experienced moderate (grade 2) AEs, and 0.1% experienced severe (grade 3) AEs. Rates of serious AEs after DA and IDA treatment were 0.04% (95% CI 0.01%-0.1%) and 0.01% (95% CI 0.00%-0.04%), respectively. Severity of AEs was not significantly different after IDA or DA. Five of six serious AEs reported occurred after DA treatment. The most common AEs reported were headache, dizziness, abdominal pain, fever, nausea, and fatigue. AE frequencies varied by country and were higher in adults and in females. AEs were more common in study participants with microfilaremia (33.4% versus 11.1%, P < 0.001) and more common in microfilaremic participants after IDA than after DA (39.4% versus 25.6%, P < 0.001). However, there was no excess of severe or serious AEs after IDA in this subgroup. The main limitation of the study was that it was open-label. Also, aggregation of AE data from multiple study sites tends to obscure variability among study sites. CONCLUSIONS: In this study, we observed that IDA was well tolerated in LF-endemic populations. Posttreatment AE rates and severity did not differ significantly after IDA or DA treatment. Thus, results of this study suggest that IDA should be as safe as DA for use as a MDA regimen for LF elimination in areas that currently receive DA. TRIAL REGISTRATION: Clinicaltrials.gov registration number: NCT02899936.


Assuntos
Antiparasitários/administração & dosagem , Antiparasitários/efeitos adversos , Filariose Linfática/tratamento farmacológico , Administração Massiva de Medicamentos/efeitos adversos , Administração Massiva de Medicamentos/métodos , Adulto , Análise por Conglomerados , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Filariose Linfática/diagnóstico , Filariose Linfática/epidemiologia , Fadiga/induzido quimicamente , Fadiga/epidemiologia , Feminino , Seguimentos , Cefaleia/induzido quimicamente , Cefaleia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
Curr Top Med Chem ; 19(14): 1226-1240, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31244425

RESUMO

Human lymphatic filariasis (LF), a parasitic infection caused by the nematodes Wuchereria bancrofti, Brugia malayi and B. timori, and transmitted by mosquito, results in a debilitating disease commonly identified as 'elephantiasis'. LF affects millions of people in India and several other tropical and sub-tropical countries imposing a huge economic burden on governments due to disability associated loss of man-hours and for disease management. Efforts to control the infection by WHO's mass drug administration (MDA) strategy using three antifilarials diethylcarbamazine, albendazole and ivermectin are only partly successful and therefore, there is an immediate need for alternative strategies. Some of the alternative strategies being explored in laboratories are: enhancing the immune competence of host by immunomodulation, combining immunomodulation with antifilarials, identifying immunoprophylactic parasite molecules (vaccine candidates) and identifying parasite molecules that can be potential drug targets. This review focuses on the advances made in this direction.


Assuntos
Filariose Linfática/tratamento farmacológico , Filaricidas/farmacologia , Sistema Imunitário/efeitos dos fármacos , Doenças Negligenciadas/tratamento farmacológico , Filariose Linfática/imunologia , Humanos , Sistema Imunitário/imunologia , Doenças Negligenciadas/imunologia , Testes de Sensibilidade Parasitária
14.
PLoS Negl Trop Dis ; 13(5): e0007325, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31107869

RESUMO

BACKGROUND: A single co-administered dose of ivermectin (IVM) plus diethylcarbamazine (DEC) plus albendazole (ALB), or triple-drug therapy, was recently found to be more effective for clearing microfilariae (Mf) than standard DEC plus ALB currently used for mass drug administration programs for lymphatic filariasis (LF) outside of sub-Saharan Africa. Triple-drug therapy has not been previously tested in LF-uninfected individuals from Africa. This study evaluated the pharmacokinetics (PK), safety, and efficacy of triple-drug therapy in people with and without Wuchereria bancrofti infection in West Africa. METHODS: In this open-label cohort study, treatment-naïve microfilaremic (>50 mf/mL, n = 32) and uninfected (circulating filarial antigen negative, n = 24) adults residing in Agboville district, Côte d'Ivoire, were treated with a single dose of IVM plus DEC plus ALB, and evaluated for adverse events (AEs) until 7 days post treatment. Drug levels were assessed by liquid chromatography and mass spectrometry. Persons responsible for assessing AEs were blinded to participants' infection status. FINDINGS: There was no difference in AUC0-inf or Cmax between LF-infected and uninfected participants (P>0.05 for all comparisons). All subjects experienced mild AEs; 28% and 25% of infected and uninfected participants experienced grade 2 AEs, respectively. There were no severe or serious adverse events. Only fever (16 of 32 versus 4 of 24, P<0.001) and scrotal pain/swelling in males (6 of 20 versus 0 of 12, P = 0.025) were more frequent in infected than uninfected participants. All LF positive participants were amicrofilaremic at 7 days post-treatment and 27 of 31 (87%) remained amicrofilaremic 12 months after treatment. CONCLUSIONS: Moderate to heavy W. bancrofti infection did not affect PK parameters for IVM, DEC or ALB following a single co-administered dose of these drugs compared to uninfected individuals. The drugs were well tolerated. This study confirmed the efficacy of the triple-drug therapy for clearing W. bancrofti Mf and has added important information to support the use of this regimen in LF elimination programs in areas of Africa without co-endemic onchocerciasis or loiasis. TRIAL REGISTRATION: ClinicalTrials.gov NCT02845713.


Assuntos
Albendazol/administração & dosagem , Dietilcarbamazina/administração & dosagem , Filariose Linfática/tratamento farmacológico , Filaricidas/administração & dosagem , Ivermectina/administração & dosagem , Wuchereria bancrofti/efeitos dos fármacos , Adolescente , Adulto , Idoso , Albendazol/efeitos adversos , Albendazol/farmacocinética , Animais , Estudos de Coortes , Costa do Marfim , Dietilcarbamazina/efeitos adversos , Dietilcarbamazina/farmacocinética , Combinação de Medicamentos , Filariose Linfática/parasitologia , Feminino , Filaricidas/efeitos adversos , Filaricidas/farmacocinética , Humanos , Ivermectina/efeitos adversos , Ivermectina/farmacocinética , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Wuchereria bancrofti/fisiologia , Adulto Jovem
15.
Infect Dis Poverty ; 8(1): 38, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31130143

RESUMO

BACKGROUND: Lymphatic filariasis is endemic in nine of the eleven Member States of the World Health Organization South East Asia Region. This article describes the intensive interventions with the National Programme for Elimination of Lymphatic Filariasis in Thailand since its launch in 2001 till the validation of its elimination in 2017. METHODS: A baseline epidemiological survey was initiated in 2001 to identify both brugian and bancroftian filarial areas and delineate its endemicity. Mass drug administration (MDA) with diethylcarbamazine citrate (DEC) and albendazole (ALB) was implemented in a total of 357 implementation units (IUs) in 11 lymphatic filariasis (LF) endemic provinces. The implementing unit (IU) was a sub-village. Stop-MDA surveys were conducted in 2006 in the 11 LF endemic provinces among population over 6 years of age and children of ≤6 years using immunochromatographic test (ICT) for Wuchereria bancrofti antigen and microfilariae (mf) detection for Brugia malayi. In Narathiwat province, Stop-MDA surveys were done in 2011 using ELISA. Transmission assessment surveys (TAS) were conducted in 2012-2013, 2015 and 2016-2017 among school students in the 6-7-year age-group. Surveillance of migrant populations through the national migrant health checkup were intensified in seven provinces over 2002-2017 for LF antigenaemia using ICT test cards. In four B. malayi endemic provinces, annual surveys to detect LF reservoir in domestic cats commenced in 1994. A 2001 survey of the chronic disease burden for LF established a register of the cumulative number of people with lymphedema/elephantiasis. RESULTS: A total of five rounds of MDA annually were implemented over 2002-2006 in all IUs. Additional annual rounds of MDA were required in 87 IUs of Narathiwat province from 2007 to 2011 due to persistent infection. The annual national drug coverage with MDA over 2002-2012 was in the range of 68.0 to 95.4%. Stop-MDA surveys in 2006 in the 11 LF endemic provinces found nine mf positive cases in seven IUs in Narathiwat province with the highest prevalence of 0.8% (range: 0.1-0.8%). In Narathiwat TAS-1, TAS-2 and TAS-3 detected below transmission threshold rates for B. malayi mf among antibody positive children (0.3, 0.2 and 0.7% respectively). Contact tracing both all mf cases in all three TAS yielded no positive cases. Through the migrant health checkup, a total of 23 477 persons were tested, showing a positive rate of 0.7% (range: 0.1-2.7%) over years 2002-2017. In Narathiwat province, annual ivermectin treatment among cats commenced in 2003 resulting in a decline of mf prevalence among cats from 8.0% in 1995 to 0.8% in 2015. As of April 2017, a total of 99 lymphoedema/elephantiasis patients were registered and followed-up under 34 health facilities. CONCLUSIONS: Thailand over the years 2002 to 2011 conducted extensive MDA with high coverage rates. Through periodic and regular monitoring surveys it delineated LF transmission areas at sub-village level and demonstrated through its evaluation surveys - the Stop-MDA surveys and TAS, below transmission threshold rates that enabled its validation of LF elimination. In September 2017, World Health Organization acknowledged the Ministry of Health Thailand had eliminated lymphatic filariasis as a public health problem.


Assuntos
Albendazol/uso terapêutico , Anti-Helmínticos/uso terapêutico , Dietilcarbamazina/uso terapêutico , Filariose Linfática/tratamento farmacológico , Filariose Linfática/prevenção & controle , Administração Massiva de Medicamentos/métodos , Adolescente , Adulto , Animais , Anticorpos Anti-Helmínticos , Antígenos de Helmintos , Doenças do Gato/parasitologia , Gatos , Criança , Pré-Escolar , Erradicação de Doenças/métodos , Reservatórios de Doenças/parasitologia , Uso de Medicamentos , Doenças Endêmicas , Feminino , Filaricidas/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Prática de Saúde Pública , Inquéritos e Questionários , Tailândia , Migrantes , Wuchereria bancrofti/efeitos dos fármacos , Wuchereria bancrofti/imunologia , Adulto Jovem
16.
PLoS Negl Trop Dis ; 13(5): e0007436, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31120872

RESUMO

Despite worldwide mass drug administration, it is estimated that 68 million individuals are still infected with lymphatic filariasis with 19 million hydrocele and 17 million lymphedema reported cases. Despite the staggering number of pathology cases, the majority of LF-infected individuals do not develop clinical symptoms and present a tightly regulated immune system characterized by higher frequencies of regulatory T cells (Treg), suppressed proliferation and Th2 cytokine responses accompanied with increased secretion of IL-10, TGF-ß and infection-specific IgG4. Nevertheless, the filarial-induced modulation of the host`s immune system and especially the role of regulatory immune cells like regulatory B (Breg) and Treg during an ongoing LF infection remains unknown. Thus, we analysed Breg and Treg frequencies in peripheral blood from Ghanaian uninfected endemic normals (EN), lymphedema (LE), asymptomatic patent (CFA+MF+) and latent (CFA+MF-) W. bancrofti-infected individuals as well as individuals who were previously infected with W. bancrofti (PI) but had cleared the infection due to the administration of ivermectin (IVM) and albendazole (ALB). In summary, we observed that IL-10-producing CD19+CD24highCD38dhigh Breg were specifically increased in patently infected (CFA+MF+) individuals. In addition, CD19+CD24highCD5+CD1dhigh and CD19+CD5+CD1dhighIL-10+ Breg as well as CD4+CD127-FOXP3+ Treg frequencies were significantly increased in both W. bancrofti-infected cohorts (CFA+MF+ and CFA+MF-). Interestingly, the PI cohort presented frequency levels of all studied regulatory immune cell populations comparable with the EN group. In conclusion, the results from this study show that an ongoing W. bancrofti infection induces distinct Breg and Treg populations in peripheral blood from Ghanaian volunteers. Those regulatory immune cell populations might contribute to the regulated state of the host immune system and are probably important for the survival and fertility (microfilaria release) of the helminth.


Assuntos
Anti-Helmínticos/administração & dosagem , Linfócitos B Reguladores/imunologia , Filariose Linfática/tratamento farmacológico , Filariose Linfática/imunologia , Interleucina-10/imunologia , Linfócitos T Reguladores/imunologia , Wuchereria bancrofti/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Albendazol/administração & dosagem , Animais , Filariose Linfática/genética , Filariose Linfática/parasitologia , Feminino , Gana , Humanos , Interleucina-10/genética , Ivermectina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Células Th2/imunologia , Adulto Jovem
17.
Am J Trop Med Hyg ; 101(1): 271-278, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31115301

RESUMO

The transmission assessment survey (TAS) is recommended to determine whether cessation of mass drug administration (MDA) for lymphatic filariasis (LF) is warranted. Ministries of health typically implement TASs in evaluation units (EUs) that have had more than five rounds of annual MDA. Under TAS guidelines, sample size calculations determine a decision value: if the number of individuals testing positive exceeds this threshold, then MDA continues in the EU. The objective of this study was to determine whether fine scale geospatial covariates could be used to identify predictors of TAS failure. We geo-referenced 746 TAS EUs, of which 65 failed and extracted geospatial covariates using R to estimate odds of failure. We implemented stepwise backward elimination to select covariates for inclusion in a logistic regression to estimate the odds of TAS failure. Covariates included environmental predictors (aridity, distance to fresh water, elevation, and enhanced vegetation index), cumulative rounds of MDA, measures of urbanicity and access, LF species, and baseline prevalence. Presence of Brugia was significantly associated with TAS failure (odds ratio [OR]: 4.79, 95% CI: 2.52-9.07), as was population density (OR: 2.91, 95% CI: 1.06-7.98). The presence of nighttime lights was highly protective against failure (OR: 0.22, 95% CI: 0.10-0.50), as was an increase in elevation (OR: 0.36, 95% CI: 0.18-0.732). This work identifies predictors associated with TAS failure at the EU areal level, given the data presently available, and also identifies the need for more granular data to conduct a more robust assessment of these predictors.


Assuntos
Transmissão de Doença Infecciosa/prevenção & controle , Filariose Linfática/prevenção & controle , Filariose Linfática/transmissão , Monitoramento Epidemiológico , Coleta de Dados , Ecossistema , Filariose Linfática/tratamento farmacológico , Filaricidas/administração & dosagem , Filaricidas/uso terapêutico , Humanos , Administração Massiva de Medicamentos/economia , Fatores Socioeconômicos , Organização Mundial da Saúde
18.
BMC Infect Dis ; 19(1): 332, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31014256

RESUMO

BACKGROUND: Lymphatic filariasis (LF) is a mosquito-borne parasitic disease and a major cause of disability worldwide. To effectively plan morbidity management programmes, it is important to estimate disease burden and evaluate the needs of patients. This study aimed to estimate patient numbers and characterise the physical, social and economic impact of LF in in rural Nigeria. METHODS: This is a matched cross-sectional study which identified lymphedema and hydrocele patients with the help of district health officers and community-directed distributors of mass drug administration programmes. A total of 52 cases were identified and matched to 52 apparently disease-free controls, selected from the same communities and matched by age and sex. Questionnaires and narrative interviews were used to characterise the physical, social and economic impact of lymphedema and hydrocele. RESULTS: Forty-eight cases with various stages of lower limb lymphedema, and 4 with hydrocele were identified. 40% of all cases reported feeling stigma and were 36 times (95% CI: 5.18-1564.69) more likely to avoid forms of social participation. Although most cases engaged in some form of income-generating activity, these were low paid employment, and on average cases spent significantly less time than controls working. The economic effects of lower income were exacerbated by increased healthcare spending, as cases were 86 times (95% CI: 17.48-874.90) more likely to spend over US $125 on their last healthcare payment. CONCLUSION: This study highlights the importance of patient-search as a means of estimating the burden of LF morbidity in rural settings. Findings from this work also confirm that LF causes considerable psychosocial and economic suffering, all of which adversely affect the mental health of patients. It is therefore important to incorporate mental health care as a major component of morbidity management programmes.


Assuntos
Filariose Linfática/patologia , Linfedema/patologia , Adulto , Estudos Transversais , Filariose Linfática/tratamento farmacológico , Filariose Linfática/economia , Feminino , Humanos , Renda , Entrevistas como Assunto , Linfedema/tratamento farmacológico , Linfedema/economia , Masculino , Saúde Mental , Pessoa de Meia-Idade , Nigéria , População Rural , Índice de Gravidade de Doença , Estigma Social , Inquéritos e Questionários , Adulto Jovem
19.
PLoS Negl Trop Dis ; 13(4): e0007365, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31009482

RESUMO

BACKGROUND: Sri Lanka's Anti-Filariasis Campaign conducted 5 annual rounds of mass drug administration (MDA) with diethylcarbamazine (DEC) plus albendazole to eliminate lymphatic filariasis (LF) in all endemic districts between 2002 and 2006. Post-MDA surveillance has consistently documented Wuchereria bancrofti microfilaremia (Mf) rates below 1% in all sentinel and spot check sites since that time, and all implementation units easily satisfied WHO's target for school-based transmission assessment surveys (school-TAS) in 2013. However, more detailed studies have identified foci of persistent infection in the large coastal evaluation unit (EU) (population about 0.6 million) in Galle district. Therefore, the purpose of this study was to assess the sensitivity and feasibility of community-based TAS in adults (adult-TAS) and to compare results obtained by adult-TAS with prior school-TAS and molecular xenomonitoring (MX, molecular detection of filarial DNA in systematically sampled mosquitoes) results in this known problem area. METHODOLOGY AND PRINCIPAL FINDINGS: Two cluster surveys were performed in independent samples of 30 evaluation areas (EAs) in the coastal Galle EU in 2015. Each survey tested approximately 1,800 adults for circulating filarial antigenemia (CFA) with the Alere Filariasis Test Strip. The CFA prevalence for all persons tested (N = 3,612) was 1.8% (CI 1.4-2.2), and this was significantly higher than the CFA rate of 0.4% obtained by school-TAS in 2013. CFA prevalences in the two samples were similar [1.5% (CI 1.0-2.2), and 2.0% (CI 1.4-2.7)]. Antigenemia prevalence in sampled EUs was highly variable (range 0-11%), and it exceeded 5% in 6 EAs. The 30 EAs sampled in one of our adult-TAS surveys had recently been assessed for persistent filariasis by molecular xenomonitoring (MX). CFA prevalence in adults and filarial DNA prevalence in mosquitoes in these EAs were significantly correlated (r = 0.43; P = 0.02). CONCLUSIONS: Community based adult-TAS provided a reproducible measure of persistent W. bancrofti infection in a large evaluation unit in Sri Lanka that has low-level persistence of LF following multiple rounds of MDA. In addition, adult-TAS and MX results illustrate the focality of persistent LF in this setting. Adult-TAS may be more sensitive than school-TAS for this purpose. Adult-TAS and MX are potential options for post-MDA and post-validation surveillance programs to identify problem areas that require mop-up activities. Adult-TAS should also be useful for remapping areas with uncertain LF endemicity for possible inclusion in national LF elimination programs.


Assuntos
Albendazol/administração & dosagem , Dietilcarbamazina/administração & dosagem , Filariose Linfática/tratamento farmacológico , Filariose Linfática/epidemiologia , Wuchereria bancrofti/isolamento & purificação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Masculino , Administração Massiva de Medicamentos , Pessoa de Meia-Idade , Prevalência , Sri Lanka/epidemiologia , Inquéritos e Questionários , Adulto Jovem
20.
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
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