RESUMEN
BACKGROUND: Schistosomiasis is a chronic parasitic disease that affects millions of people's health worldwide. Because of the increasing drug resistance to praziquantel (PZQ), which is the primary drug for schistosomiasis, developing new drugs to treat schistosomiasis is crucial. Oxadiazole-2-oxides have been identified as potential anti-schistosomiasis reagents targeting thioredoxin glutathione reductase (TGR). METHODS: In this work, one of the oxadiazole-2-oxides derivatives furoxan was used as the lead compound to exploit a series of novel furoxan derivatives for studying inhibitory activity against both recombinant Schistosoma japonicum TGR containing selenium (rSjTGR-Sec) and soluble worm antigen protein (SWAP) containing wild-type Schistosoma japonicum TGR (wtSjTGR), in order to develop a new leading compound for schistosomiasis. Thirty-nine novel derivatives were prepared to test their activity toward both enzymes. The docking method was used to detect the binding site between the active molecule and SjTGR. The structure-activity relationship (SAR) of these novel furoxan derivatives was preliminarily analyzed. RESULTS: It was found that several new derivatives, including compounds 6a-6d, 9ab, 9bd and 9be, demonstrated greater activity toward rSjTGR-Sec or SWAP containing wtSjTGR than did furoxan. Interestingly, all intermediates bearing hydroxy (6a-6d) showed excellent inhibitory activity against both enzymes. In particular, compound 6d with trifluoromethyl on a pyridine ring was found to have much higher inhibition toward both rSjTGR-Sec (half-maximal inhibitory concentration, IC50,7.5nM) and SWAP containing wtSjTGR (IC50 55.8nM) than furoxan. Additionally, the docking method identified the possible matching sites between 6d and Schistosoma japonicum TGR (SjTGR), which theoretically lends support to the inhibitory activity of 6d. CONCLUSION: The data obtained herein showed that 6d with trifluoromethyl on a pyridine ring could be a valuable leading compound for further study.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Complejos Multienzimáticos/antagonistas & inhibidores , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , Oxadiazoles/farmacología , Schistosoma japonicum/efectos de los fármacos , Esquistosomiasis Japónica/tratamiento farmacológico , Animales , Antígenos Helmínticos/efectos de los fármacos , Cristalografía por Rayos X , Sistemas de Liberación de Medicamentos , Inhibidores Enzimáticos/uso terapéutico , Estructura Molecular , Oxadiazoles/química , Oxadiazoles/uso terapéutico , Schistosoma japonicum/enzimología , Selenio/químicaRESUMEN
Annual mass drug administration (MDA) is the recommended strategy for lymphatic filariasis (LF) elimination. We assessed the effect of six rounds of mass administration of diethylcarbamazine (DEC) and albendazole (ALB) on microfilaria (Mf) prevalence and intensity and vector infection and infectivity rates and circulating filarial antigenaemia (CFA) in a group of five villages in south India, endemic for Culex-transmitted bancroftian filariasis. During different rounds of MDA, 60-70% of the eligible population (>15 kg body weight) was treated. The MDA reduced the Mf prevalence from 8.10% (CI 6.18-10.01) to 1.01% (CI 0.31-1.71) (P<0.05) and geometric mean intensity of Mf from 0.31 (CI 0.22-0.40) to 0.02 (CI 0.00-0.04) (P<0.05), equivalent to a fall of 86% and 94% respectively. The vector infection and infectivity rates declined from 13.11% (CI 11.52-14.70) to 0.78% (CI 0.16-1.40) (P<0.05) and 1.04% (CI 0.56-1.52) to 0.13% (CI 0.00-0.39) (P<0.05), respectively. Four out of the five villages recorded <0.5% Mf prevalence and 0% vector infection rate. Circulating filarial antigenaemia (CFA) fell by 86% in the total population and 100% in 1-10 year old children. One of the five villages, which showed the highest baseline vector infection rate, showed >1.0% Mf rate. The results suggest that six rounds of mass administration of DEC and ALB, with 60-70% treatment coverage, is likely to achieve total interruption of transmission and elimination of LF in the majority of villages.
Asunto(s)
Albendazol/administración & dosificación , Antígenos Helmínticos/efectos de los fármacos , Dietilcarbamazina/administración & dosificación , Filariasis Linfática/tratamiento farmacológico , Filaricidas/administración & dosificación , Microfilarias/efectos de los fármacos , Wuchereria bancrofti/efectos de los fármacos , Animales , Antígenos Helmínticos/inmunología , Culex , Esquema de Medicación , Filariasis Linfática/epidemiología , Filariasis Linfática/inmunología , Femenino , Humanos , India/epidemiología , Masculino , Microfilarias/inmunología , Prevalencia , Salud Rural , Wuchereria bancrofti/inmunologíaRESUMEN
OBJECTIVES: To evaluate the effect of multiple rounds of annual single dose of DEC (6 mg/kg) or albendazole (400mg) given alone or in combination on Wuchereria bancrofti microfilaraemia, anti-filarial IgG1 and IgG4 and antigenaemia. METHODS: A total of 170 participants were randomly assigned to albendazole (n = 62), DEC (n = 54), and DEC plus albendazole (DEC/ALB) combination (n = 54). Blood samples were collected at pre-treatment in 1998, at 1 week and 6 months after the first treatment and thereafter before subsequent treatments in 1999 and 2000. Effects of treatment on W. bancrofti infection were determined by changes in levels of microfilaraemia, antifilarial antibodies and circulating filarial antigen. RESULTS: Comparison of geometric mean microfilariae intensities between DEC/ALB combination and DEC or albendazole single therapy groups after two rounds of annual treatment and 24 months follow-up showed that combination therapy resulted in a greater reduction of microfilaraemia than single therapy with either albendazole (p < 0.001) or DEC alone (p = 0.146). The overall levels of anti-filarial antibodies decreased significantly (p = 0.028 for IgG1 and p < 0.043 for IgG4) in all treatment groups at 24 months follow-up. Additionally, overall reduction in geometric mean circulating filarial antigen levels at 24 months was 44%, 60% and 85% for albendazole, DEC and DEC/ALB groups, respectively. CONCLUSIONS: These study findings suggest that albendazole improved efficacy of DEC and mass administration of a combination of the two drugs would therefore enhance the interruption of transmission of W. bancrofti in endemic areas. This information has important implications for the ongoing Global Program for Elimination of Lymphatic Filariasis.
Asunto(s)
Albendazol/administración & dosificación , Antihelmínticos/administración & dosificación , Dietilcarbamazina/administración & dosificación , Filariasis Linfática/tratamiento farmacológico , Filariasis Linfática/inmunología , Filaricidas/administración & dosificación , Wuchereria bancrofti/efectos de los fármacos , Adolescente , Adulto , Albendazol/uso terapéutico , Animales , Antihelmínticos/uso terapéutico , Anticuerpos Antihelmínticos/sangre , Antígenos Helmínticos/sangre , Antígenos Helmínticos/efectos de los fármacos , Antígenos Helmínticos/inmunología , Niño , Dietilcarbamazina/uso terapéutico , Sinergismo Farmacológico , Quimioterapia Combinada , Filariasis Linfática/parasitología , Femenino , Filaricidas/uso terapéutico , Humanos , Inmunoglobulina G/sangre , Kenia , Masculino , Microfilarias/efectos de los fármacos , Microfilarias/inmunología , Persona de Mediana Edad , Resultado del Tratamiento , Wuchereria bancrofti/inmunología , Adulto JovenRESUMEN
Some immigrants from Myanmar to Thailand have brought Wuchereria bancrofti infections with them, causing a community health problem for Thai citizens. The seroprevalence of bancroftian filariasis was detected in 438 and 512 Myanmar immigrants residing in Bangkok and Ranong Provinces, respectively, along with 81 Thai citizens living in Bangkok. The immunochromatograpy card test was positive in 5 Myanmar immigrants living in Bangkok and 1 living in Ranong for a prevalence of 0.63%. Antifilarial IgG4 antibodies were found in 21 Myanmar immigrants living in Bangkok and 14 living in Ranong for a prevalence of 3.68%. None of the samples from Thai citizens were positive with either test. These prevalence rates are lower than those observed between 2001 and 2005. The Thai mass drug administration program to eliminate lymphatic filariasis among Myanmar immigrants appears to be a successful public health strategy.
Asunto(s)
Filariasis Linfática/prevención & control , Emigrantes e Inmigrantes/estadística & datos numéricos , Vacunación Masiva/normas , Wuchereria bancrofti/aislamiento & purificación , Adolescente , Adulto , Anciano , Animales , Antígenos Helmínticos/sangre , Antígenos Helmínticos/efectos de los fármacos , Antígenos Helmínticos/inmunología , Niño , Preescolar , Filariasis Linfática/etnología , Filariasis Linfática/inmunología , Femenino , Humanos , Lactante , Masculino , Vacunación Masiva/estadística & datos numéricos , Persona de Mediana Edad , Mianmar/etnología , Evaluación de Programas y Proyectos de Salud , Estudios Seroepidemiológicos , Tailandia/epidemiología , Wuchereria bancrofti/efectos de los fármacos , Wuchereria bancrofti/inmunología , Adulto JovenRESUMEN
Based on the beneficial influence of melatonin administration on the course of schistosomiasis and on its possible action on the immune system, we aimed in this study to establish an immunization program using Schistosoma mansoni adult worm antigen (SWAP) and cercarial antigen (CAP) alone or concurrently with melatonin treatment, for 30 successive days, in an attempt to enhance their efficacy against the infection in hamsters. Results showed that the worm reduction percentages were 53.8%, 67.01%, 56.4% and 99.3% for CAP, CAP+melatonin, SWAP, SWAP+melatonin, respectively, indicating that melatonin enhanced efficacy of SWAP but only produced a slight increase in efficacy of CAP. Highly significant reductions in egg load in the liver and alteration in the oogram pattern with a high percentage of immature eggs and few dead eggs were recorded in the groups that received melatonin treatment suggesting a possible role for melatonin in the regulation of egg production and development. On the other hand, melatonin clearly improved the oxidative status in the immunized groups. No antibody (Ab) response was recorded in the groups immunized with SWAP+melatonin while low Ab level was seen in the other melatonin-treated group. In addition to the antioxidant properties of melatonin, our results suggested that the early and continuous melatonin administration may result in immunomodulatory actions which in turn enhanced the efficacy of SWAP and CAP in different ways. This indicates the importance of further investigation of the mechanisms of melatonin action and the possible application in a vaccination program.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Antígenos Helmínticos/inmunología , Melatonina/farmacología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/prevención & control , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/uso terapéutico , Animales , Antígenos Helmínticos/efectos de los fármacos , Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Cricetinae , Inmunización/métodos , Inmunización/normas , Masculino , Melatonina/administración & dosificación , Melatonina/uso terapéutico , MesocricetusRESUMEN
BACKGROUND: There seems to be a large magnitude of parasitic worm loads caused by nocturnally periodic Wuchereria bancrofti and geohelminths, in cross-border Myanmar migrant workers in Thailand. We are therefore considering an effective Mass Drug Administration (MDA) with Diethylcarbamazine (DEC) and Albendazole (ABZ). Due to short periods of their residency and current situation of W. bancrofti antigenemics and concomitant geohelminths, treatment effects on the containment of the infections need to be analyzed. OBJECTIVES: Analyze short-term effects on reduction of W. bancrofti antigen (WbAg) and geohelminths' egg (GhE) loads. The efficacy of a single-dose combined treatment with 300 mg DEC (for filariasis) and 400 mg ABZ (for helminthiasis) was evaluated and compared with a single-dose treatment arm with 300 mg DEC alone. MATERIAL AND METHOD: A randomized clinical trial of two treatment choices in 28 Myanmar male workers (DEC/ABZ or group I = 15, DEC or group II = 13) was conducted in Phang Nga province, Southern Thailand. Because of the withdrawal of three subjects of the DEC group, all the 10 DEC subjects were follow-up monitored at post treatment 2, 4, 8 and 12 weeks. Their mean age was 26.4 years; worm loads (mean +/- SD x 10(3)) of W. bancrofti, Ascaris and Trichuris was 103.9 +/- 44.1 antigen units (AU)/ml, 47.3 +/- 38.7 eggs per gram (EPG) and 16.6 +/- 22.2 EPG respectively. The data on the 15 DEC/ABZ subjects showed a mean age of 25.7 years; corresponding worm loads = 96.1 +/- 54.6 AU/ml, 397.0 +/- 117.3 EPG and 54.5 +/- 42.8 EPG respectively. The Antigen Reduction Rates (ARR) and Egg Reduction Rates (ERR) were presented. RESULTS: At the 12-week post treatment, WbAg loads (mean +/- SD x 10(3) AU/ml) were 61.5 +/- 58.4 for group I and 76.8 +/- 40.7 for group II. A significant WbAg reduction was noted for both groups at weeks 8 and 12 (p < 0.05). Also, the significant reduction of GhE loads was more pronounced for both groups after week 2 (p < 0.05). When comparing efficacy of the treatment choices by the treatment retention time, it was more likely to show both groups had similar adulticidal effects on either WbAg, denoted as the ARR (F = 0. 064, p = 0.806) or GhE, denoted as the ERR (F = 0.196, p = 0.669). CONCLUSION: The single-dose 300 mg DEC plus 400 mg ABZ, or 300 mg DEC alone, can be effectively used for treating infections with W. bancrofti and concomitant geohelminths commonly observed in the area. But treatment rounds are required to clear the infections. The reduction of the parasitic worm loads in the legal Myanmar migrants provide values in monitoring and evaluating an effective MDA program with the DEC/ABZ at the provincial level.
Asunto(s)
Albendazol/administración & dosificación , Antígenos Helmínticos/efectos de los fármacos , Dietilcarbamazina/farmacología , Filariasis/tratamiento farmacológico , Filaricidas/farmacología , Wuchereria bancrofti , Adulto , Albendazol/farmacología , Análisis de Varianza , Animales , Dietilcarbamazina/administración & dosificación , Filariasis/epidemiología , Filariasis/prevención & control , Filaricidas/administración & dosificación , Humanos , Masculino , Mianmar/etnología , Estudios Seroepidemiológicos , Tailandia/epidemiología , MigrantesRESUMEN
Seven microfilaremic Myanmar patients were treated with a single 300 mg dose of diethylcarbamazine (DEC) orally, as part of a case-finding survey in Ranong Province, Southern Thailand. This was conducted in order to evaluate the short-term effects of single-dose DEC on Wuchereria bancrofti microfilaremia and antigenemia during a 12-week course of treatment. Analysis of microfilarial periodicity on initial treatment revealed the microfilarial peak density (k) was at 52 minutes after midnight (0052). The periodicity index was then 103.26%. Single-dose DEC treatment did not affect the k values. A linear model of W. bancrofti microfilarial density reduction predicts a sharp decrease in the mean microfilarial density 2 weeks after DEC intake (Z = -2.197, p = 0.028). Over a longer period, a non-linear model predicts an increase in the mean microfilarial density to pre-treatment levels, having little or no macrofilaricidal effects. We reconfirmed the existence of nocturnally periodic W. bancrofti infection in Myanmar migrants in Ranong Province, and the short-term microfilaricidal activity of 300 mg single-dose DEC treatment used for biannual mass treatment and the DEC provocative test. Without an adequate DEC treatment dose, recrudescence can occur. A rational approach to the management of introduced nocturnally periodic W. bancrofti in Myanmar migrants, who came for short periods of stay in transmission-prone areas, is needed.
Asunto(s)
Antígenos Helmínticos/efectos de los fármacos , Dietilcarbamazina/administración & dosificación , Filariasis/tratamiento farmacológico , Filaricidas/administración & dosificación , Microfilarias/efectos de los fármacos , Periodicidad , Wuchereria bancrofti/efectos de los fármacos , Adolescente , Adulto , Animales , Antígenos Helmínticos/sangre , Dietilcarbamazina/uso terapéutico , Esquema de Medicación , Femenino , Filariasis/sangre , Filariasis/prevención & control , Filaricidas/uso terapéutico , Humanos , Masculino , Microfilarias/aislamiento & purificación , Mianmar/etnología , Prevención Secundaria , Tailandia/epidemiología , Migrantes , Wuchereria bancrofti/aislamiento & purificaciónRESUMEN
Inhibitor sensitivity assays using azocaesin and FTC-caesin as substrates showed that the excretory/secretory (E/S) products of the infective-stage larvae of Trichinella spiralis contained serine, metallo-, cysteine and aspartic proteinases. The activity of the metallo-proteinase was zinc ion dependent (within a range of ZnSO(4) concentrations). Gelatin-substrate gel electrophoresis revealed two bands of molecular mass 48 and 58 kDa which were sensitive to the metallo-proteinase inhibitor EDTA. The former peptide was probably a cleavage product of the latter. The authenticity of the 58 kDa metallo-proteinase as an E/S product was confirmed by immunoprecipitation. Using PCR and RACE reactions, a complete nucleotide sequence of the metallo-proteinase gene was obtained. It comprised 2,223 bp with an open reading frame encoding 604 amino acid residues. The 3' untranslated region consisted of 352 bp, including a polyadenylation signal AATAA. A consensus catalytic zinc-binding motif was present. The conserved domains suggest that the cloned metallo-proteinase belongs to the astacin family and occurs as a single copy gene with 11 introns and 10 exons. Cluster analysis showed that the sequence of the metallo-proteinase gene of T. spiralis resembles those of Caenorhabdites elegans and Strongyloides stercoralis.
Asunto(s)
Metaloendopeptidasas , Trichinella spiralis/enzimología , Secuencia de Aminoácidos , Animales , Anticuerpos Antihelmínticos/inmunología , Antígenos Helmínticos/efectos de los fármacos , Antígenos Helmínticos/inmunología , Secuencia de Bases , Clonación Molecular , Ácido Edético/farmacología , Proteínas del Helminto/efectos de los fármacos , Proteínas del Helminto/inmunología , Proteínas del Helminto/metabolismo , Larva/enzimología , Metaloendopeptidasas/química , Metaloendopeptidasas/genética , Metaloendopeptidasas/metabolismo , Ratones , Ratones Endogámicos ICR , Datos de Secuencia Molecular , Filogenia , Conejos , Ratas , Ratas Wistar , Alineación de Secuencia , Trichinella spiralis/crecimiento & desarrollo , Trichinella spiralis/metabolismo , Triquinelosis/parasitología , Zinc/farmacologíaRESUMEN
SDS-PAGE separation of soluble worm antigen preparation (SWAP), cercarial antigen preparation (CAP), and soluble egg antigen (SEA) of Schistosoma mansoni showed obvious qualitative and quantitative differences. The shared polypeptides of the three stages of S. mansoni were 116, 72.768 and 32.367 kDa under reducing conditions. The different anti-sera raised in rabbits against the different stages of antigens were recognized by electroimmune transfer blotting (EITB). Each of the 3 groups separated eight bands. Carnosine treatment of rabbits immunized with SWAP, CAP or SEA resulted in the disappearance of two bands in SWAP group and one band in CAP group in comparison with the non-treated immunized groups. This indicated that the carnosine modulated immune response of rabbits against S. mansoni antigens.
Asunto(s)
Anticuerpos Antihelmínticos/biosíntesis , Antígenos Helmínticos/inmunología , Carnosina/farmacología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/prevención & control , Animales , Anticuerpos Antihelmínticos/efectos de los fármacos , Antígenos Helmínticos/química , Antígenos Helmínticos/efectos de los fármacos , Electroforesis en Gel de Poliacrilamida/métodos , Humanos , Sueros Inmunes/biosíntesis , Sueros Inmunes/efectos de los fármacos , Sueros Inmunes/inmunología , Inmunización , Masculino , Peso Molecular , Conejos , Schistosoma mansoni/efectos de los fármacos , Esquistosomiasis mansoni/inmunologíaRESUMEN
Using qualitative ICT Filariasis and quantitative Og4C3 ELISA, we assessed a long-term macrofilaricidal effect of two-year biannual mass treatments with a 300 mg oral-dose FILADEC tablet, a reformulation of 6 mg/kg diethylcarbamazine (DEC), on clearance of the Wuchereria bancrofti adult worm circulating filarial antigens (CFA) in Myanmar migrants, at risk of emergence of imported bancroftian filariasis in Southern Thailand. Of the 34 antigenemic Myanmar index cases of varying initial CFA levels, who were initially screened out with the ICT Filariasis, 13 index cases were follow-up treated and monitored at the DEC post treatments, 6, 12, and 18 months. At the 18-month post treatment, residual antigenemias (%) in 4 of 5 index cases (group 1) with high antigen titers (99.7-181.6 x 10(3) AU/ml) were 54.44%, 33.58%, 27.43%, and 9.97%. Significant decreases of the CFA levels in only 3 out of 5 index cases were affected by the response to DEC treatments (p < 0.007). The treatment effects on clearance of the CFA in 8 index cases (group II) with low antigen titers (15.4-37.2 x 10(3) AU/ml) were shown for at least 6 months post DEC treatment and hence had 100% efficacy in the first 6 months of the first year of year round treatment. Group I, was more likely to show an increase of the DEC efficacy after the first 6 months of the second year round treatment, but there was no statistically significant difference (p = 0.063). We reemphasized that, for use in the national program to eliminate lymphatic filariasis (PELF) in Thailand, such a DEC regimen had a macrofilaricidal effect on antigenemia clearance, and confirmed its value in evaluating response to the treatment and monitoring the long-term efficacy of the DEC regimen in W. bancrofti adult worm burden reductions in Myanmar migrants on a wide scale.
Asunto(s)
Antígenos Helmínticos/efectos de los fármacos , Dietilcarbamazina/farmacología , Filariasis/tratamiento farmacológico , Filaricidas/farmacología , Wuchereria bancrofti , Adolescente , Adulto , Análisis de Varianza , Animales , Estudios Transversales , Dietilcarbamazina/administración & dosificación , Femenino , Filariasis/epidemiología , Filariasis/prevención & control , Filaricidas/administración & dosificación , Humanos , Estudios Longitudinales , Masculino , Mianmar/etnología , Estudios Seroepidemiológicos , Tailandia/epidemiología , MigrantesRESUMEN
A number of different schistosome antigens are capable of partially protecting experimental animals from challenge infection. More than 100 such antigens have been identified, about 15% of which are strongly protective and deemed promising though they do not reach the level close to sterile immunity seen after vaccination with irradiated cercariae. Studies of human correlate reactions, i.e. serological reactions and cytokine responses to schistosomiasis antigens, in individuals living in areas endemic for schistosomiasis have shown associations between certain antigen-specific immune responses and lack of re-infection over time. This approach was applied in Brazil and Egypt where it was possible to epidemiologically follow cohorts of individuals in endemic areas for extended periods of time correlating infection status with immune responses against a panel of well-researched, highly purified vaccine candidates. The immune correlates found were unique to each antigen and could be either positive or negative, i.e. associated with resistance or with susceptibility to re-infection. However, few antigens were clear-cut in this respect, i.e. the majority of them induced ambiguous responses. For example, a single antigen might have a significant positive correlation when antigen-driven interferon (INF)-gamma production is measured but also show a significant negative correlation with respect to the IgG1 titre induced. These observations suggest that there are desirable, antigen-specific immune responses that would be valuable in a vaccine but they also indicate that there are responses that must be avoided. The insights gained should be useful not only for antigen selection but also for vaccine formulation prior to Phase I/II trials in humans. It would be of great value if similar independent, long-term human correlate studies could also be undertaken in areas endemic for Schistosoma japonicum.
Asunto(s)
Antígenos Helmínticos/efectos de los fármacos , Schistosoma/efectos de los fármacos , Esquistosomiasis/prevención & control , Vacunas , Animales , Antígenos Helmínticos/inmunología , Humanos , Ratones , Investigación , Schistosoma/inmunología , Esquistosomiasis/inmunologíaRESUMEN
We used a recently developed sandwich enzyme-linked immunosorbent assay to determine the kinetics of Schistosoma mansoni circulating soluble egg antigen (CSEA) after chemotherapy and compared these with previously determined levels of circulating cathodic antigen (CCA). Urine samples were collected from 35 Egyptian patients with S. mansoni infection before, and one, 3 and 6 weeks after treatment. Thirteen patients were treated with 60 mg praziquantel/kg body weight and 22 patients with 40 mg/kg. Following chemotherapy, the kinetics of CSEA in urine appeared to be clearly different from those of the worm-derived antigen CCA, levels of which decreased markedly within one week after chemotherapy; CSEA levels decreased at a much lower rate. Six weeks after successful chemotherapy, CSEA could still be detected in urine of 7 cases while CCA had already disappeared and no viable egg was found by faecal examination. There was no significant difference between the 2 dose regimens during follow-up in the percentage remaining positive or in the CSEA level. These results suggest that the egg antigens detected are primarily derived from viable eggs in the tissues and might be used as a marker for morbidity.
Asunto(s)
Antihelmínticos/uso terapéutico , Antígenos Helmínticos/orina , Praziquantel/uso terapéutico , Schistosoma mansoni/inmunología , Esquistosomiasis/orina , Adolescente , Adulto , Animales , Antígenos Helmínticos/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática/métodos , Humanos , Masculino , Persona de Mediana Edad , Recuento de Huevos de Parásitos , Esquistosomiasis/tratamiento farmacológico , Esquistosomiasis/inmunologíaRESUMEN
As part of a systematic examination of the protective epitopes on H11, groups of sheep were vaccinated with preparations of purified H11 used untreated (group A), or progressively denatured (linearized) by incubation with sodium dodecyl sulphate (SDS) (group B) or by boiling with SDS in the presence of dithiothreitol (group C). All the sheep developed antibodies which bound to the untreated H11. When challenged with 10,000 infective larvae of Haemonchus contortus the mean levels of protection relative to the mean values for adjuvant controls were 99.8%, 85% and 79% for faecal egg counts and 95%, 79% and 54% for worm burden at post-mortem for groups A, B and C respectively. The H11-specific antibodies inhibited the microsomal aminopeptidase activity of H11 in vitro up to 80%. The levels of inhibition by sera from individual animals correlated with levels of protection with r2, of 0.69-0.87.
Asunto(s)
Antígenos Helmínticos/inmunología , Antígenos CD13 , Hemoncosis/prevención & control , Proteínas del Helminto/inmunología , Proteínas de la Membrana/inmunología , Vacunas/inmunología , Aminopeptidasas/metabolismo , Animales , Anticuerpos Antihelmínticos/sangre , Antígenos Helmínticos/efectos de los fármacos , Heces/parasitología , Femenino , Hemoncosis/sangre , Hemoncosis/inmunología , Hemoncosis/parasitología , Proteínas del Helminto/efectos de los fármacos , Masculino , Proteínas de la Membrana/efectos de los fármacos , Microsomas , Recuento de Huevos de Parásitos , Desnaturalización Proteica , Ovinos , Dodecil Sulfato de Sodio/farmacología , VacunaciónRESUMEN
Circulating filarial antigen (CFA), determined with Og4C3 ELISA, is a marker of Wuchereria bancrofti adult worm infection. The reduction of CFA over 2 years was determined in 185 microfilaremic and 111 amicrofilaremic but CFA+ adults given an annual dose of either diethylcarbamazine (DEC) or ivermectin or the two combined. Reduction of CFA level was good with DEC but weak with ivermectin and followed the same pattern in amicrofilaremic and microfilaremic groups. Combinations and DEC alone had a similar impact on CFA level. CFA clearance was observed in amicrofilaremic but not in microfilaremic persons in all DEC-containing treatments. However, the highest clearance rate was observed in persons treated with DEC at 6 mg/kg combined with ivermectin. Continuous reduction of CFA level after repeated treatments shows that elimination of W. bancrofti infection, monitored by CFA clearance, might be achieved within a few years with annual treatments of DEC combined with ivermectin.
Asunto(s)
Antígenos Helmínticos/efectos de los fármacos , Dietilcarbamazina/uso terapéutico , Filariasis/tratamiento farmacológico , Filaricidas/uso terapéutico , Ivermectina/uso terapéutico , Wuchereria bancrofti , Adulto , Animales , Antígenos Helmínticos/sangre , Antígenos Helmínticos/inmunología , Biomarcadores/sangre , Dietilcarbamazina/administración & dosificación , Quimioterapia Combinada , Filariasis/epidemiología , Filariasis/prevención & control , Filaricidas/administración & dosificación , Humanos , Ivermectina/administración & dosificación , Polinesia/epidemiología , Prevalencia , Estudios SeroepidemiológicosRESUMEN
Small doses of diethylcarbamazine (DEC) clear microfilariae (MF) from the blood of Wuchereria bancrofti-infected persons, but the dose and regimen required to kill adult worms is not clearly defined. A prospective study was undertaken to examine the macrofilaricidal effect of DEC and the ability of an assay for circulating filarial antigen (CFA) to define the effect. Twenty-five MF-positive subjects and 7 MF-negative but CFA-positive subjects were treated with DEC and followed for 18 months. Of the 25 MF-positive patients, 24 cleared MF, and 22 of 26 CFA-positive subjects cleared CFA. A significantly greater decrease in antifilarial IgG4 was seen in patients who cleared CFA than in those who did not. The complete clearance of CFA observed after therapy with DEC indicates that assessment of CFA clearance is a useful means for detecting macrofilaricidal effects of antifilarial chemotherapy.
Asunto(s)
Antígenos Helmínticos/efectos de los fármacos , Dietilcarbamazina/uso terapéutico , Filariasis/tratamiento farmacológico , Wuchereria bancrofti/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Anticuerpos Antihelmínticos/sangre , Antígenos Helmínticos/inmunología , Niño , Relación Dosis-Respuesta a Droga , Femenino , Filariasis/inmunología , Humanos , Inmunoglobulina G/sangre , Masculino , Microfilarias/efectos de los fármacos , Microfilarias/inmunología , Persona de Mediana Edad , Estudios Prospectivos , Pruebas Serológicas/métodos , Wuchereria bancrofti/efectos de los fármacosRESUMEN
An early treatment with artemether given in appropriate regimens was tested in mice, rabbits and dogs for prevention purposes. Artemether was administered intragastrically (ig) to the hosts on day 7 after infection with Schistosoma japonicum cercariae at a single dose, and the same dose of artemether was repeated every 1 or 2 weeks for 2-4 times. As a result, most of the female worms were killed before their oviposition with female worm reduction rates of 90-100%, resulting in protection of the host from damage induced by schistosome eggs. When rabbits were treated ig with artemether 10 mg kg-1 on day 7 after infection, followed by repeated dosing every week for 4 times, some parameters related to acute schistosomiasis, such as temperature, eosinophil count and eggs in the feces were negative, and low specific antigen and antibody levels in serum were seen. Further study showed that the appropriate regimens of Artemether were also effective in early treatment of reinfection with cercariae. When rabbits infected with 48-52 cercariae once every other day for 5 times were treated ig with artemether 15 mg kg-1, followed by repeated dosing every 1 or 2 week for 2- 3 times, the female worm reduction rates were 92.1-98.4%. Histopathological examination of the livers showed that the above-mentioned early treatment with Artemether exhibited a promising protective effect on dogs and rabbits. The major features included normal appearance of the liver resembling those of uninfected dogs and rabbits; few or no dispersed miliary egg tubercles appeared on the surface of the liver; the structure of the hepatic lobules was normal with normal arrangement of the liver bundles; few or no eggs appeared in the portal vein area and there was apparent diminution of total egg granuloma, comprising inflammatory, fibrous or scarred egg granuloma. On the basis of above-mentioned results, early treatment with Artemether could be recommended for field trial for controlling acute schistosomiasis, reducing infection rate and intensity of infection.
Asunto(s)
Artemisininas , Esquistosomiasis Japónica/tratamiento farmacológico , Esquistosomicidas/uso terapéutico , Sesquiterpenos/uso terapéutico , Animales , Anticuerpos Antihelmínticos/sangre , Anticuerpos Antihelmínticos/efectos de los fármacos , Antígenos Helmínticos/sangre , Antígenos Helmínticos/efectos de los fármacos , Arteméter , Temperatura Corporal , Perros , Relación Dosis-Respuesta a Droga , Eosinófilos/efectos de los fármacos , Eosinófilos/metabolismo , Femenino , Granuloma de Cuerpo Extraño/parasitología , Granuloma de Cuerpo Extraño/patología , Hígado/parasitología , Hígado/patología , Hepatopatías/parasitología , Hepatopatías/patología , Masculino , Ratones , Recuento de Huevos de Parásitos , Conejos , Esquistosomiasis Japónica/sangre , Esquistosomiasis Japónica/parasitología , Esquistosomicidas/farmacología , Sesquiterpenos/farmacología , Factores de TiempoRESUMEN
Host immune responses have been shown to enhance the efficacy of several schistosomicidal drugs. The evidence derives mainly from experiments on Schistosoma mansoni infections in the mouse with their immune status variously modulated; this review emphasises praziquantel (PZQ), which is now the main drug used for treatment of human schistosomiasis. Electron microscopy and indirect immunofluorescence indicate that PZQ disrupts the integrity of the surface membranes of S. mansoni, particularly those covering the dorsal tubercles of adult male worms, and this causes antigens which are the targets of antibody attack to be revealed. We review the evidence that two S. mansoni antigens in particular are implicated in the immune-dependent action of PZQ: a 200 kDa glycoprotein and a 27 kDa antigen with non-specific esterase activity. Consistent with the involvement of the latter antigen, increased non-specific esterase activity was demonstrated histochemically on the surface of intact PZQ-treated male worms, and we describe a chromogenic substrate assay for quantifying the amount of esterase activity that is exposed after drug treatment. The potential relevance of these observations for enhancing the efficacy of drugs currently used to treat human schistosomiasis, and for devising novel therapeutic strategies, is discussed.