RESUMEN
Onchocerciasis in Sudan exists in three distinct foci which exhibit differing clinical presentations. Previous studies have demonstrated that a tandemly repeated Onchocerca sequence family with a unit repeat length of 150 bp (the O-150 family) is a useful marker for deducing relationships among different O. volvulus populations. In the current study, the O-150 repeat families of O. volvulus from Sudan were analyzed and compared to each other and to those of parasites from West Africa. Similar to West African and American O. volvulus, the O-150 families of the Sudanese parasites could be divided into clusters within which little or no intracluster variation was evident, suggesting that the O-150 family in these parasites was subject to the forces of concerted evolution. Statistical analysis of the O-150 families from the different Sudanese parasite isolates, employing a nested algorithm based on an analysis of variance, revealed that O. volvulus endemic to the northern focus at Abu Hamed were significantly different from all other O. volvulus populations examined to date. In contrast, parasites from the southern and eastern foci of Sudan were indistinguishable from those endemic to the West African savanna. The significance of these data are discussed in light of knowledge of the biogeography and biology of transmission of O. volvulus in Africa.
Asunto(s)
Variación Genética , Onchocerca volvulus/genética , Oncocercosis/parasitología , África Occidental , Análisis de Varianza , Animales , Secuencia de Bases , Clonación Molecular , Análisis por Conglomerados , Secuencia de Consenso , ADN de Helmintos/química , Humanos , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Alineación de Secuencia , Sudán , Secuencias Repetidas en Tándem , YemenRESUMEN
The northernmost focus for Onchocerca volvulus Leuckhart (Nematoda: Onchocercidae), the causative agent of human onchocerciasis, is found along the Nile near the town of Abu Hamed in Sudan. The vector for O. volvulus at this focus is a single monomorphic population of Simulium (Edwardsellum) damnosum Theobald. This black fly population is limited to a small area between the fourth and fifth cataracts of the Nile River that is isolated geographically from all other populations of S. damnosum sensu lato. Phylogenies produced from cytological analyses and sequence data derived from the NADH dehydrogenase subunit 4 and 16S rRNA genes indicate that Abu Hamed black flies are similar to, but distinct from, the savanna-dwelling sibling species of S. damnosum s.l., Simulium (Edwardsellum) damnosum sensu strictu Theobald, and S. (Edwardsellum) sirbanum Vajime & Dunbar. The DNA sequence and the cytological data support the hypothesis that the black fly population present in Abu Hamed may represent a new sibling species of S. damnosum s.l. We propose that this population be informally designated as the hamedense form of the Simulium damnosum complex.
Asunto(s)
Simuliidae/clasificación , Animales , Clasificación , Femenino , Genes de Insecto , Humanos , NADH Deshidrogenasa/genética , ARN Ribosómico 16S/análisis , Simuliidae/enzimología , Simuliidae/genética , SudánRESUMEN
Beta-Tubulin is the target for the benzimidazole anthelmintics. Unfortunately, none of these drugs is clinically useful against adult filariae. However, beta-tubulin has been shown to be a target for antibody-based toxicity to Brugia pahangi. We cloned and characterized cDNAs encoding beta-tubulin from 2 filariae, Dirofilaria immitis and Onchocerca volvulus, to explore possible explanations for benzimidazole insensitivity among adult filariae and the likelihood that epitopes of beta-tubulin could be used as antigens for a broad-spectrum filarial vaccine. The proteins predicted by these cDNAs were almost identical to the beta-tubulin previously reported from B. pahangi but were less similar to a beta-tubulin cDNA from Onchocerca gibsoni. We cloned the genomic locus for the O. volvulus beta-tubulin cDNA and compared its organization to the reported genomic loci for beta-tubulin in B. pahangi and O. gibsoni. The comparison reinforces the conclusion that the published O. gibsoni gene is in a different family, possibly the beta2 family previously described in B. pahangi. The substitution of tyr for phe at position 200 of beta-tubulin is associated with benzimidazole resistance. All 4 filarial beta-tubulins are predicted to encode phe at this position, suggesting that filarial beta-tubulin is not inherently insensitive to the benzimidazoles. A monoclonal antibody that recognizes the COOH terminus of B. pahangi beta-tubulin is lethal to this parasite in culture. The COOH terminal region is the most variable among the different isotypes of beta-tubulin and distinguishes mammalian from nematode tubulins. This region is highly conserved in 3 of the filarial beta-tubulins.
Asunto(s)
ADN de Helmintos/química , Dirofilaria immitis/genética , Onchocerca volvulus/genética , Tubulina (Proteína)/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular , ADN de Helmintos/genética , Dirofilaria immitis/química , Femenino , Datos de Secuencia Molecular , Onchocerca volvulus/química , Reacción en Cadena de la Polimerasa , ARN de Helminto/genética , Homología de Secuencia de Ácido Nucleico , Tubulina (Proteína)/químicaRESUMEN
OBJECTIVE: To determine the distribution of ivermectin in plasma and tissues of onchocerciasis patients following a single oral dose of 150 micrograms kg-1. SETTING: Medical Department at Soba University Hospital, Khartoum. PATIENTS: Twenty five patients and fourteen healthy volunteers. METHODS: Serial blood samples were obtained from both groups. Tissue samples were removed from various patients as full thickness skin punch biopsies or during nodulectomy. Ivermectin concentration was determined by radioimmunoassay. RESULTS: The plasma pharmacokinetic variables for patients were; maximum plasma concentration 52.0 ng ml-1; time to achieve maximum concentration, 5.2 h.; elimination half life, 35.0 h; and the area under the plasma concentration curve versus time, 2852 ng.h.ml-1. In healthy volunteers, the plasma ivermectin distribution was similar to that in patients, and both groups showed a tendency for a second rise in plasma concentration of the drug suggestive of enterohepatic recirculation. Ivermectin was detected in tissues obtained from patients. Fat showed the highest and most persistent levels, whilst values for skin, nodular tissues, and worms were comparable. Subcutaneous fascia contained the lowest concentrations. CONCLUSIONS: Infection with O. volvulus does not affect the pharmacokinetics of ivermectin, and filarial infected tissues and parasites themselves do take up the drug. There may be prolonged retention of ivermectin because of depot formation in fat tissue.
Asunto(s)
Filaricidas/farmacocinética , Ivermectina/farmacocinética , Onchocerca volvulus , Oncocercosis/metabolismo , Tejido Adiposo/metabolismo , Animales , Área Bajo la Curva , Fascia/metabolismo , Femenino , Filaricidas/sangre , Humanos , Ivermectina/sangre , Masculino , Onchocerca volvulus/metabolismo , Oncocercosis/sangre , Radioinmunoensayo , Piel/metabolismoRESUMEN
A study to monitor ivermectin acceptability and post-treatment reactions during mass community distribution was carried out in eastern Sudan, where severe reactive onchodermatitis is prevalent. Of 1081 individuals eligible for treatment, 1076 (99.5%) accepted the ivermectin. Post-treatment reactions were monitored by self reporting, 5 d after a single dose of about 150 micrograms/kg (range 103-200 micrograms/kg); 230 persons reported adverse events (21.4%). No reaction was rated as severe. The most common problem was itching with cutaneous papular eruptions (16.2%). Local oedematous swelling was the second most common and the most slowly resolving complaint (5.4%), followed by musculoskeletal pain. There was a high acceptance rate of the treatment and remarkable tolerance of the post-treatment effects, probably due to efforts made to prepare the community to expect reactions to ivermectin, widespread awareness of the beneficial effects of treatment by villagers who had participated in clinical trials previously, and the encouragement we gave to the population to become involved in improvement of their health care services. Single doses of ivermectin resulted in good clinical responses and created much goodwill among villagers. Improvements in physical fitness, ability to work, and freedom from musculoskeletal pain were reported at the 3 months' follow-up. We recommend that, during mass distribution of ivermectin, community involvement in planning overall health improvement should be included, since the treatment initiates the process well. In areas where sowda syndrome is prevalent, medical surveillance for 3 d or more should be considered.
Asunto(s)
Ivermectina/efectos adversos , Onchocerca volvulus , Oncocercosis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Animales , Niño , Preescolar , Femenino , Humanos , Ivermectina/uso terapéutico , Masculino , Persona de Mediana Edad , Aceptación de la Atención de Salud , SudánRESUMEN
Ivermectin efficacy and post-treatment reactions in asymmetric severe reactive ochodermatitis (sowda) were studied in 8 patients with sowda syndrome and 6 with mild generalized onchodermatitis in Sudan. Initial skin snips from 12 patients contained microfilariae (1-9 per mg skin). Patients were treated in hospital with a single oral dose of c. 150 micrograms/kg ivermectin (103-200 micrograms/kg) and monitored for frequency and severity of post-treatment reactions for 4 weeks. Serial samples of heparinized blood were collected over the first 24 h after treatment for determination of ivermectin pharmacokinetics. Skin snips from all patients on days 3 and 28 revealed no microfilariae. Post-treatment reactions were more common and severe in individuals with sowda; they consisted mainly of musculoskeletal pain, local swellings with pitting oedema, and lymph gland tenderness and enlargement. No relation was established between these reactions, the microfilarial infection intensity, or the plasma pharmacokinetic profiles. A single oral dose of ivermectin cleared the skin of microfilariae and led to improvement of symptoms and dermatological signs of sowda, but resulted in more marked reactions than in cases of generalized onchodermatitis.
Asunto(s)
Antiparasitarios , Ivermectina/uso terapéutico , Onchocerca volvulus , Oncocercosis/tratamiento farmacológico , Adolescente , Adulto , Animales , Femenino , Humanos , Ivermectina/efectos adversos , Ivermectina/farmacocinética , Masculino , Persona de Mediana Edad , Oncocercosis/patología , Enfermedades Cutáneas Parasitarias/parasitología , Enfermedades Cutáneas Parasitarias/patología , SudánRESUMEN
Chloroquine bioavailability in healthy males was examined following oral coadministration of 600 mg with three common Sudanese beverages, Aradaib (Tamarindus indica), Karkadi (Hibiscus sabdarifa) and Lemon (Citrus limetta) and drinking water. The tablets and beverages were taken on an empty stomach after an overnight fast. The plasma chloroquine concentrations were measured by HPLC. The extent and rate of chloroquine bioavailability were described by the area under the plasma concentrations versus time curve (AUC), the peak plasma concentration (Cmax) and with the time to reach Cmax (Tmax), respectively. The mean (+/- S.E.) AUC values after administration with water (control) and Aradaib, Karkadi and Lemon, respectively, were 7.52 +/- 0.87, 2.60 +/- 0.24, 2.16 +/- 0.30 and 2.41 +/- 0.29 mg.h/L. The corresponding mean Cmax values were 553 +/- 17.8, 184 +/- 21.3, 148 +/- 14.1 and 210 +/- 17.4 mg/L and the corresponding Tmax values were 3.0 +/- 1.0, 3.2 +/- 1.2, 2.6 +/- 0.8 and 2.5 +/- 1.0 h. The results indicate a statistically significant reduction in the AUC and Cmax of chloroquine as a result of a coadministration with each of the three beverages. A parallel reduction in the drugs antimalarial efficacy might be expected.
Asunto(s)
Bebidas , Cloroquina/farmacocinética , Adulto , Disponibilidad Biológica , Humanos , Masculino , SudánRESUMEN
Patients infected with Onchocerca volvulus in the Cayapa River focus in north-east Ecuador were given 500 mg chloroquine diphosphate (CQ) orally prior to nodulectomy. The concentrations of CQ were determined in parasite fragments and host tissue dissected from the nodules, in skin overlying the nodules, and in plasma at 3, 4, 7, and 24 hours after dosing. Onchocerca volvulus took up CQ rapidly, in some cases accumulating the drug to concentrations of over 600 pmol mg-1 worm tissue by three hours, and maintaining similar concentrations through 24 hours. These amounts were markedly higher than peak concentrations in plasma (3.16 pmol microliters-1) and in host tissues (78 pmol mgm-1) and skin (up to 93 pmol mg-1). In vitro uptake of CQ by females of O. volvulus was greater under alkaline conditions (pH 8.4) than at pH 6.8 and 7.4. Uptake reached equilibrium after one to two hours, with final concentrations being approximately 10 times lower than those reached in vivo. Inhibitory effects of chloroquine and its major metabolite desethylchloroquine on the motility of O. volvulus and other filariae have been observed previously in vitro; whether or not the drug had adverse effects on adult parasites in vivo was not determined in these experiments. However, the results illustrate the accessibility of O. volvulus to blood borne agents in vivo, and the potential importance of pharmacodynamic characteristics in the search for new macrofilaricidal agents.