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2.
Parasitol Res ; 119(5): 1467-1483, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32219550

RESUMO

Feasibility of implementing a DEC-fortified (DEC at 0.2% w/w and iodine) salt strategy to hasten elimination of diurnally sub-periodic Wuchereria bancrofti (DspWB) from the lone foci in Nancowry islands, Nicobar district, India, was assessed. This is a two-arm community-based study: one arm (12 villages, population 2936) received double fortified salt along with annual mass drug administration (MDA) of DEC plus albendazole (DEC-salt+MDA-arm), and another (14 villages; population 4840) received MDA under the National Filaria Elimination Programme. DEC salt was distributed on camp mode supplemented by door delivery. Monthly survey was carried out in fixed and random households to assess the coverage, usage of DEC salt and DEC content. The impact on prevalence of mf at community level and antigenaemia among children was assessed. A total of 21 metric tonnes of free-flow DEC salt manufactured by Tamil Nadu Salt Corporation, India, was distributed for 1 year. In the DEC-salt+MDA-arm, > 90% of the households received and used the DEC salt. DEC was within therapeutic range (0.2-0.32% w/w) in the samples collected from kitchens. Community mf prevalence reduced from 2.27 to 0.14% in the DEC-salt-arm (< 1% in all the villages) and 1.26 to 0.74% (> 1% in 4 out of 14 villages) in the MDA-arm. Ag prevalence reduced to zero from 1.0 (DEC-salt+MDA-arm) and 6.3% (MDA-arm) in 2-3 years old, 1.2 and 3.6% from 2.9 in the DEC-salt-arm and 4.5% in the MDA-arm among 6-7 years old. It was feasible to deliver DEC-fortified salt covering > 90% of the households with compliance reaching the elimination target in the islands.


Assuntos
Suplementos Nutricionais , Dietilcarbamazina/administração & dosagem , Filariose Linfática/prevenção & controle , Administração Massiva de Medicamentos/métodos , Cloreto de Sódio na Dieta/administração & dosagem , Wuchereria bancrofti/efeitos dos fármacos , Albendazol/uso terapêutico , Animais , Antígenos de Helmintos/sangue , Criança , Pré-Escolar , Filariose Linfática/epidemiologia , Características da Família , Feminino , Filaricidas/administração & dosagem , Humanos , Índia/epidemiologia , Iodo/administração & dosagem , Ilhas/epidemiologia , Masculino , Prevalência , Resultado do Tratamento , Wuchereria bancrofti/imunologia
3.
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
4.
BMC Infect Dis ; 20(1): 63, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959110

RESUMO

BACKGROUND: Imported loiasis is a rare cause of consultation at the return of stay in central Africa, which often poses difficult diagnostic and therapeutic questions to practitioners especially those who are unaccustomed to tropical medicine. These difficulties can lead to risks for the patients especially if inappropriate treatment is given. Large series of imported loiasis are scarce. METHODS: We retrospectively studied the data including outcome in patients diagnosed with imported loiasis between 1993 and 2013 in the Paris area on the basis of a parasitological diagnosis (microfilaremia > 1/ml and/or serologic tests). We compared sub-Saharan and non sub-Saharan African patients. RESULTS: Of the 177 identified cases, 167 could be analysed. Sex ratio was 1, mean age 41 years and 83% were sub-Saharan Africans. Cameroon was the main country of exposure (62%). Incubation time may be long (up to 18 months). Of the 167 cases, 57% presented with characteristic symptoms (Calabar swellings, creeping dermatitis, eyeworm) whereas 43% were diagnosed fortuitously. Microfilaremia was evidenced in 105 patients (63%), and specific antibodies in 53%. Compared to sub-Saharan Africans, other patients were presenting less frequently with eyeworm migration and microfilaremia whereas they had higher eosinophilia and positive serology. Prevalence of Calabar swellings was not significantly different between the two groups. Cure rates were 52% with ivermectin alone, and 77% with ivermectin followed by diethylcarbamazine. No severe adverse event was reported. CONCLUSIONS: Presentation of imported loiasis varies according to ethnicity. A systematic screening should be recommended in patients with potential exposure in endemic country. Treatment with ivermectin followed by diethylcarbamazine could be a valuable option.


Assuntos
Grupo com Ancestrais do Continente Africano , Doenças Transmissíveis Importadas/etnologia , Doenças Transmissíveis Importadas/epidemiologia , Loa/imunologia , Loíase/etnologia , Loíase/epidemiologia , Adolescente , Adulto , África do Norte/etnologia , Animais , Criança , Pré-Escolar , Doenças Transmissíveis Importadas/diagnóstico , Doenças Transmissíveis Importadas/tratamento farmacológico , Dietilcarbamazina/uso terapêutico , Feminino , Humanos , Lactente , Recém-Nascido , Ivermectina/uso terapêutico , Loíase/diagnóstico , Loíase/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Paris/epidemiologia , Prevalência , Estudos Retrospectivos , Resultado do Tratamento , Medicina Tropical , Adulto Jovem
5.
Am J Trop Med Hyg ; 102(1): 96-99, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31769393

RESUMO

Fear of adverse events (AEs) negatively affects compliance to mass drug administration (MDA) for lymphatic filariasis (LF) elimination program. Systemic AEs are believed to occur because of killing of microfilariae, whereas localized soft tissue reactions might be due to the death of adult worms following therapy. Most AEs are mild and self-limited. However, localized AEs are sometimes more significant and of concern to participants. Here, we describe localized AEs that were noted during a large community study that evaluated the safety of a triple-drug regimen (ivermectin, diethylcarbamazine, and albendazole) for the treatment of LF in India. We have also discussed the importance of timely detection and careful management of AEs for preserving community confidence in MDA.


Assuntos
Albendazol/efeitos adversos , Anti-Helmínticos/efeitos adversos , Dietilcarbamazina/efeitos adversos , Filariose Linfática/prevenção & controle , Ivermectina/efeitos adversos , Administração Massiva de Medicamentos , Adolescente , Adulto , Albendazol/administração & dosagem , Albendazol/uso terapêutico , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/uso terapêutico , Dietilcarbamazina/administração & dosagem , Dietilcarbamazina/uso terapêutico , Quimioterapia Combinada/efeitos adversos , Feminino , Humanos , Índia/epidemiologia , Ivermectina/administração & dosagem , Ivermectina/uso terapêutico , Masculino
6.
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
7.
Infect Dis Poverty ; 8(1): 66, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31387644

RESUMO

BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) was launched in response to the call proposed at the 50th World Health Assembly. The goal of the GPELF is to ensure that all the countries where the disease is endemic would have been transmission-free or would have entered post-intervention mass drug administration (MDA) surveillance by 2020. However, several countries are still not on track to discontinue MDA as planned. Thus, issues remain regarding the achievement of stated goals and how to effectively monitor the disease in the post-control and post-elimination phases. MAIN TEXT: China was once a lymphatic filariasis (LF) endemic country with heavy disease burden. There were three milestones in the LF control phase of China, including: the proposal that the major focus of the control strategy should be on infectious sources; the three regimens of diethylcarbamazine (DEC) administration according to LF endemic extent; and the establishment of the threshold for LF transmission interruption. It has been ten years since China entered the post-elimination stage (declaration of LF elimination in China was in 2007). Two schemes and a diagnostic criterion were issued to guide all levels of disease control and prevention workers that conduct LF surveillance, as well as those caring for chronic filariasis patients. Regular training courses are held to maintain LF control skills in grass-root institutions. The Notifiable Diseases Reporting System, which included LF in 2004, plays an important role in LF post-elimination surveillance. Until now, no resurgence of LF cases has been detected, except for LF residue foci being found in Fuchuan County of the Guangxi Zhuang Autonomous Region. To confirm that transmission is no longer achievable after a decade since the declaration of LF elimination in China, it is expected within the next two years a transmission assessment survey, conducted in previous LF-endemic areas. CONCLUSIONS: DEC-fortified salt can help accelerate the progress of GPELF before the sprite phase. Sophisticated diagnostic criteria, systematic surveillance regimes, the Direct Network Report system, and regular trainings can effectively prevent the recrudescence of LF during surveillance phases.


Assuntos
Erradicação de Doenças/estatística & dados numéricos , Filariose Linfática/prevenção & controle , Monitoramento Epidemiológico , Vigilância da População/métodos , China , Dietilcarbamazina/uso terapêutico , Filaricidas/uso terapêutico , Humanos
8.
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
9.
PLoS Negl Trop Dis ; 13(7): e0007541, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31314753

RESUMO

BACKGROUND: The World Health Organization (WHO) currently recommends height or age-based dosing as alternatives to weight-based dosing for mass drug administration lymphatic filariasis (LF) elimination programs. The goals of our study were to compare these alternative dosing strategies to weight-based dosing and to develop and evaluate new height-based dosing pole scenarios. METHODOLOGY/PRINCIPAL FINDINGS: Age, height and weight data were collected from >26,000 individuals in five countries during a cluster randomized LF clinical trial. Weight-based dosing for diethylcarbamazine (DEC; 6 mg/kg) and ivermectin (IVM; 200 ug/kg) with tablet numbers derived from a table of weight intervals was treated as the "gold standard" for this study. Following WHO recommended age-based dosing of DEC and height-based dosing of IVM would have resulted in 32% and 27% of individuals receiving treatment doses below those recommended by weight-based dosing for DEC and IVM, respectively. Underdosing would have been especially common in adult males, who tend to have the highest LF prevalence in many endemic areas. We used a 3-step modeling approach to develop and evaluate new dosing pole cutoffs. First, we analyzed the clinical trial data using quantile regression to predict weight from height. We then used weight predictions to develop new dosing pole cutoff values. Finally, we compared different dosing pole cutoffs and age and height-based WHO dosing recommendations to weight-based dosing. We considered hundreds of scenarios including country- and sex-specific dosing poles. A simple dosing pole with a 6-tablet maximum for both DEC and IVM reduced the underdosing rate by 30% and 21%, respectively, and was nearly as effective as more complex pole combinations for reducing underdosing. CONCLUSIONS/SIGNIFICANCE: Using a novel modeling approach, we developed a simple dosing pole that would markedly reduce underdosing for DEC and IVM in MDA programs compared to current WHO recommended height or age-based dosing.


Assuntos
Cálculos da Dosagem de Medicamento , Filariose Linfática/prevenção & controle , Filaricidas/administração & dosagem , Administração Massiva de Medicamentos/métodos , Razão Cintura-Estatura , Adolescente , Adulto , Estatura , Peso Corporal , Criança , Estudos de Coortes , Dietilcarbamazina/administração & dosagem , Feminino , Saúde Global , Humanos , Ivermectina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Prevalência , Análise de Regressão , Adulto Jovem
10.
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
11.
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
14.
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
15.
J Pharm Biomed Anal ; 170: 243-253, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30947125

RESUMO

A sensitive and relatively fast, cost-effective high-performance liquid chromatographic method coupled with mass spectrometer (HPLC-MS) is herein reported for the first time for a simultaneous quantification of plasma and organs concentration of three therapeutic agents that are widely used in treatment of lymphatic filariasis (LF), namely, doxycycline (DOX), diethylcarbamazine (DEC) and albendazole (ABZ) metabolites. The method was developed and validated as per ICH and FDA guidelines and successfully employed to quantify DOX, DEC and ABZ metabolites (albendazole sulfoxide (ABZ-OX) and albendazole sulfone (ABZ-ON)) in the plasma and organs of Sprague Dawley rats after oral concomitant administration of the above mentioned therapeutic agents. Importantly, a simple, one-step protein precipitation and extraction method was used to extract the four compounds efficiently with a recovery in the range of 79.88 ± 5.02%-90.71 ± 5.13%, 85.72 ± 7.22%-93.17 ± 5.55%, 94.38 ± 7.35%-101.00 ± 8.88% and 94.38 ± 7.35%-99.87 ± 10.22% in plasma and organs for DOX, DEC, ABZ-OZ and ABZ-ON, respectively. Separation of all analytes was performed on a Xselect CSH™ C18 HPLC column (Waters, 3.0 x 150 mm, 3.5 µm particle size) with gradient elution employing a mobile phase consisting of 0.1% v/v formic acid in water and methanol with a run time of 20 min. Quantification was carried out employing a single, quadruple MS detector operated with single ion monitoring (SIM) mode and the ion transitions at m/z of 445.4, 200.2, 282.3 and 298.3 for DOX, DEC, ABZ-OX and ABZ-ON respectively. The MS response for plasma samples was linear across the concentration range of 2.5-2500 ng/mL for DOX, 0.5-500 ng/mL for DEC, 1-1000 ng/mL for ABZ-OX and ABZ-ON with a correlation coefficient (r2) ≥ 0.998. The method was selective, precise and accurate. This method allowed us to get an insight into the pharmacokinetics and biodistribution of the three therapeutic agents after simultaneous oral administration to Sprague Dawley rats. This bioanalytical method could provide a reliable, reproducible and excellent tool for routine therapeutic drug monitoring of the above mentioned therapeutic agents and also support other clinical pharmacokinetic-based studies.


Assuntos
Albendazol/sangue , Cromatografia Líquida de Alta Pressão/métodos , Dietilcarbamazina/sangue , Doxiciclina/sangue , Plasma/química , Espectrometria de Massas em Tandem/métodos , Administração Oral , Albendazol/análogos & derivados , Animais , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
16.
Int J Biol Macromol ; 133: 202-213, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991069

RESUMO

Setaria equina heat shock protein (SeqHSP) 70 gene was characterized, cloned and expressed to recombinant protein (rSeqHSP70). The protein was tested for binding with an anti-filarial drug "diethylcarbamazine citrate (DEC)" by equilibrium dialysis method. Molecular docking was also used to determine the binding sites and residues of binding with DEC. The mice were immunized with the protein alone or bound to DEC. Serum IFN-γ levels in the immunized group with protein-drug complex were significantly higher (P < 0.05) than the protein-immunized group. Mouse anti-SeqHSP70 polyclonal IgG recognized 2 bands at 70 and 75 kDa in S. equina adult worm and human cancer cell lines (HepG2 and MCF-7) extracts. The proliferation assay for mice splenocytes revealed a potentiation and down-regulating effects in non-immunized and immunized groups, respectively with the drug-protein complex. The proliferation and IFN-γ assays for purified human NK cells indicated a potentiating effect of the drug-protein complex (DEC concentration is 50 µM) comparable to the protein. DEC at lower concentration (25 mM) could also show a significant increase (P < 0.05) in IFN-γ. From the results, DEC was postulated to induce conformational changes in the protein exposing more epitopes for NK cell binding and activation.


Assuntos
Dietilcarbamazina/metabolismo , Filarioidea/genética , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Helminto/genética , Proteínas de Helminto/metabolismo , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/metabolismo , Adjuvantes Imunológicos/farmacologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Proliferação de Células/efeitos dos fármacos , Clonagem Molecular , Reações Cruzadas , Expressão Gênica , Proteínas de Choque Térmico HSP70/química , Proteínas de Choque Térmico HSP70/farmacologia , Proteínas de Helminto/química , Proteínas de Helminto/farmacologia , Humanos , Interferon gama/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Conformação Proteica , Análise de Sequência , Baço/imunologia
18.
Respir Investig ; 57(2): 97-110, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30600174

RESUMO

The steps leading to the discovery of leukotrienes and the researchers that played a major part in this long process are presented. The pharmacology of these exquisitely potent compounds shows that they express bronchoconstrictor activity and numerous cellular effects via very specific receptors. Experimental evidence strongly suggests that these mediators play a significant role in asthma physiopathology. Numerous approaches were taken to block their effects on the lungs and this led to the discovery of selected drugs used for asthma treatment. The complexity of this disease and its treatment is emphasized.


Assuntos
Asma/etiologia , Leucotrienos , Terapia de Alvo Molecular , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Asma/tratamento farmacológico , Asma/metabolismo , Asma/patologia , Dietilcarbamazina/farmacologia , Cobaias , Humanos , Leucotrienos/metabolismo , Prostaglandinas/metabolismo , SRS-A/metabolismo
19.
Cochrane Database Syst Rev ; 1: CD003753, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30620051

RESUMO

BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis recommends mass treatment of albendazole co-administered with the microfilaricidal (antifilarial) drugs diethylcarbamazine (DEC) or ivermectin; and recommends albendazole alone in areas where loiasis is endemic. OBJECTIVES: To assess the effects of albendazole alone, and the effects of adding albendazole to DEC or ivermectin, in people and communities with lymphatic filariasis. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials, MEDLINE (PubMed), Embase (OVID), LILACS (BIREME), and reference lists of included trials. We also searched the World Health Organization (WHO) International Clinical Trials Registry Platform and ClinicalTrials.gov to identify ongoing trials. We performed all searches up to 15 January 2018. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and cluster-RCTs that compared albendazole to placebo or no placebo, or compared albendazole combined with a microfilaricidal drug to a microfilaricidal drug alone, given to people known to have lymphatic filariasis or communities where lymphatic filariasis was known to be endemic. We sought data on measures of transmission potential (microfilariae (mf) prevalence and density); markers of adult worm infection (antigenaemia prevalence and density, and adult worm prevalence detected by ultrasound); and data on clinical disease and adverse events. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed the trials, evaluated the risks of bias, and extracted data. The main analysis examined albendazole overall, whether given alone or added to a microfilaricidal drug. We used data collected from all randomized individuals at time of longest follow-up (up to 12 months) for meta-analysis of outcomes. We evaluated mf density data up to six months and at 12 months follow-up to ensure that we did not miss any subtle temporal effects. We conducted additional analyses for different follow-up periods and whether trials reported on individuals known to be infected or both infected and uninfected. We analysed dichotomous data using the risk ratio (RR) with a 95% confidence interval (CI). We could not meta-analyse data on parasite density outcomes and we summarized them in tables. Where data were missing, we contacted trial authors. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included 13 trials (12 individually-randomized and one small cluster-randomized trial) with 8713 participants in total. No trials evaluated population-level effects of albendazole in mass drug administration programmes. Seven trials enrolled people with a variety of inclusion criteria related to filarial infection, and six trials enrolled individuals from endemic areas. Outcomes were reported as end or change values. Mf and antigen density data were reported using the geometric mean, log mean and arithmetic mean, and reductions in density were variously calculated. Two trials discounted any increases in mf density in individuals at follow-up by setting any density increase to zero.For mf prevalence over two weeks to 12 months, albendazole alone or added to another microfilaricidal drug makes little or no difference (RR 0.95, 95% CI 0.85 to 1.07; 5027 participants, 12 trials, high-certainty evidence). For mf density there is no trend, with some trials reporting a greater reduction in mf density with albendazole and others a greater reduction with the control group. For mf density up to six months and at 12 months, we do not know if albendazole has an effect (one to six months: 1216 participants, 10 trials, very low-certainty evidence; at 12 months: 1052 participants, 9 trials, very low-certainty evidence).For antigenaemia prevalence between six to 12 months, albendazole alone or added to another microfilaricidal drug makes little or no difference (RR 1.04, 95% CI 0.97 to 1.12; 3774 participants, 7 trials, high-certainty evidence). For antigen density over six to 12 months, the trend shows little or no effect of albendazole; but we do not know if albendazole has an effect on antigen density (1374 participants, 5 trials, very low-certainty evidence). For adult worm prevalence detected by ultrasound at 12 months, albendazole added to a microfilaricidal drug may make little or no difference (RR 1.16, 95% CI 0.72 to 1.86; 165 participants, 3 trials, low-certainty evidence).For people reporting adverse events, albendazole makes little or no difference (RR 0.97, 95% CI 0.84 to 1.13; 2894 participants, 6 trials, high-certainty evidence).We also provide meta-analyses and GRADE tables by drug, as operationally this may be of interest: for albendazole versus placebo (4 trials, 1870 participants); for albendazole with DEC compared to DEC alone (8 trials, 3405 participants); and albendazole with ivermectin compared to ivermectin alone (4 trials, 3438 participants). AUTHORS' CONCLUSIONS: There is good evidence that albendazole makes little difference to clearing microfilaraemia or adult filarial worms in the 12 months post-treatment. This finding is consistent in trials evaluating albendazole alone, or added to DEC or ivermectin. Trials reporting mf density included small numbers of participants, calculated density data variously, and gave inconsistent results.The review raises questions over whether albendazole has any important contribution to the elimination of lymphatic filariasis. To inform policy for areas with loiasis where only albendazole can be used, it may be worth conducting placebo-controlled trials of albendazole alone.


Assuntos
Albendazol/uso terapêutico , Filariose Linfática/tratamento farmacológico , Filaricidas/uso terapêutico , Antígenos de Helmintos/sangue , Dietilcarbamazina/uso terapêutico , Quimioterapia Combinada , Filariose Linfática/imunologia , Humanos , Ivermectina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
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
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