Debrah AY et al. (2006) Filaria J "Assessment of microfilarial loads in the skin of onchocerciasis patients after treatment with different regimens of doxycycline plus ivermectin."

Debrah AY, Marfo-Debrekyei Y, Mand S, Larbi J, Adjei O, Hoerauf A

[Filaria J, 2006]

BACKGROUND: Infection with the filarial nematode Onchocerca volvulus can lead to severe dermatitis, visual impairment, and ultimately blindness. Since the currently used drug, ivermectin does not have macrofilaricidal or strong permanent sterilising effects on the adult worm, more effective drugs are needed to complement the use of ivermectin alone. Wolbachia endosymbiotic bacteria in filariae have emerged as a new target for treatment with antibiotics which can lead to long -term sterilization of the adult female filariae. METHODS: In the Central Region of Ghana, 60 patients were recruited, allocated into four groups and treated with 200 mg doxycycline per day for 2 weeks, 4 weeks, 6 weeks respectively. Untreated patients served as controls. Some of the treated patients and the untreated controls were given 150 microg/kg ivermectin 8 months after the start of doxycycline treatment. RESULTS: A follow up study 18 months post treatment showed that when using doxycycline alone there was a significant reduction of microfilarial (mf) loads in patients treated for either 4 or 6 weeks. However, there was no significant difference between the untreated controls and those given the 2 weeks regimen. Although no significant difference was demonstrated between the 4 and 6 weeks regimens, there was a trend observed, in that, microfilarial reduction appeared to have been greater following the 6 weeks regimen. Twelve months after ivermectin (i.e. 20 months after doxycycline) treatment, 8 out of 11 ivermectin-alone treated patients were mf-positive. In contrast, 1 out of the 7 patients treated for 4 weeks with doxycycline and none of the 4 patients treated for 6 weeks doxycycline (who were available for re-examination) were mf-positive after the combined treatment of doxycycline plus ivermectin treatment. CONCLUSION: Treatment of onchocerciasis with doxycycline for 4 weeks is effective. Nonetheless, mf reduction appeared to be greater in the 6 weeks regimen. It is recommended that until further studies are carried out i.e. 4 weeks treatment with doxycycline is proven equivalent to the 6 weeks, selected groups of onchocerciasis patients should be treated for 6 weeks with doxycycline. As discussed earlier, this treatment should be accompanied by two doses of ivermectin.

Abe T et al. (1993) J Helminthol "Strongyloides ratti: dissociation of immunological memory of the protection against tissue migrating larvae and intestinal adult worms in mice."

Nawa Y, Yoshimura K, Abe T

[J Helminthol, 1993]

Immunological memory generated by infection with S. ratti was studied separately in the migratory and intestinal phases in mice. Protection against reinfection in the migratory phase was 96-98% at 2 weeks but significantly decreased to 60% at 12 weeks after the primary infection. However, protection in the intestinal phase was 96% even 12 weeks after the primary infection. Recall of immunity against the intestinal phase persists for longer than that against the migratory phase in mice.

Duke BO et al. (1991) Trop Med Parasitol "The embryogenesis of Onchocerca volvulus over the first year after a single dose of ivermectin."

Duke BO, Zea-Flores G, Munoz B

[Trop Med Parasitol, 1991]

Adult Onchocerca volvulus, extracted from nodules before, and at intervals of two weeks to 12 months after, a single 150 micrograms/kg dose of ivermectin, were examined longitudinally and by sequential transverse sections. The mean number of male worms per nodule fell, and the proportion of nodules with no male worm rose, within two weeks of ivermectin and remained so for 12 months. In female worms, at intervals after ivermectin, the percentages of the length of the lower genital tracts occupied by embryos at each stage of development, or by degenerating ova, embryos and microfilariae (mfs), were recorded: (a) in un(re-)inseminated worms whose original embryogenesis was continuing and in those in which it was completed; and (b) in worms, reinseminated post-ivermectin, in which a new embryogenesis had begun. The results indicated that: (a) the time needed for the zygotes of O. volvulus to develop to mfs is 8-12 weeks; (b) nearly 40 percent of females had not resumed mf production by 12 months after treatment; (c) many intrauterine mfs had not degenerated within the first two weeks of ivermectin; (d) some of the last embryos to mature to mfs did not degenerate but accumulated temporarily in the anterior uteri 8-16 weeks after ivermectin.

Specht S et al. (2008) Parasitol Res "Efficacy of 2- and 4-week rifampicin treatment on the Wolbachia of Onchocerca volvulus."

Marfo-Debrekyei Y, Hoerauf A, Adjei O, Specht S, Konadu P, Buttner DW, Debrah AY, Mand S

[Parasitol Res, 2008]

The microfilaricidal and temporarily sterilizing drug ivermectin is used for mass treatment of filarial infections. Filariae containing Wolbachia endobacteria can also be treated by the antibiotic doxycycline. The loss of Wolbachia results in sterilization of Onchocerca volvulus and macrofilaricidal effects. Besides doxycycline, other antibiotics may be effective in depleting Wolbachia. A preliminary study on the effects of rifampicin on the endobacteria, embryogenesis and microfilariae production of O. volvulus was carried out in the year 2000 in Ghana. Twenty-six onchocerciasis patients were treated for 2 or 4 weeks with 10 mg/kg/day rifampicin. From 17 treated and nine untreated patients, all palpable nodules were extirpated 1 or 18 months after the start of the study and examined for Wolbachia and embryogenesis using immunohistology. One and 18 months after rifampicin treatment, the proportion of Wolbachia-positive worms was significantly reduced compared to the untreated group. In patients treated 4 weeks with rifampicin, only 21% and 18% of living female filariae contained Wolbachia after 1 and 18 months, respectively, compared to 92% in the untreated patients. The reduction of Wolbachia after 2 weeks rifampicin was less but also significant. Embryogenesis and microfilariae production were reduced after 4 weeks rifampicin treatment, rendering rifampicin an antibiotic with anti-wolbachial efficacy in human onchocerciasis. This treatment is less efficient than treatment with 6 weeks doxycycline, but might be an alternative for cases that cannot be treated with doxycycline, e.g. children, or might be further developed for combination therapy.

Weiss N et al. (1986) Trans R Soc Trop Med Hyg "Detection of serum antibodies and circulating antigens in a chimpanzee experimentally infected with Onchocerca volvulus."

Barbiero VK, Prince AM, Albiez EJ, Forsyth K, Weiss N, van den Ende MC

[Trans R Soc Trop Med Hyg, 1986]

The course of the humoral immune response was followed in a chimpanzee experimentally infected over 27 weeks with a total of 168 Onchocerca volvulus 3rd-stage larvae obtained from naturally infected wild-caught blackflies. Antibodies against an adult worm extract could be detected by ELISA from week 16 onwards (after the inoculation of 44 larvae). Peak antibody levels were observed between weeks 66 and 74 (about one year after the last larval injection). Thereafter, antibody levels markedly decreased but rose again after week 120. First microfilariae could be detected from week 124 onwards. Microfilarial counts remained low (not more than two microfilariae per skin snip) until the end of the observation period. High levels of IgM antibodies against adult O. volvulus antigens were detectable between weeks 26 and 80 by ELISA. Total IgE levels were found to be only marginally elevated during the course of the infection. Circulating parasite antigens were only detectable for a short time (weeks 34 to 44) of the prepatent period by immuno-radiometric assays (IRMAs) using monoclonal antibodies which were raised against O. gibsoni eggs. Competitive radio-immuno-assays detected host antibodies inhibiting binding of 125I-labelled monoclonal antibodies to parasite antigens from week 28 onwards. Host antibodies clearly interfere later in infection with the detection of circulating antigens.

Jackson-Thompson BM et al. (2018) PLoS Negl Trop Dis "Brugia malayi infection in ferrets - A small mammal model of lymphatic filariasis."

Jaiswal S, Jackson-Thompson BM, Dardzinski BJ, Scott JR, Fite JJ, Laurie K, Kim SY, Jones SR, Mitre E, Morris CP, Hoy AR

[PLoS Negl Trop Dis, 2018]

BACKGROUND: The lack of effective short-course therapies for treatment of the adult stage of filarial worms is a major limitation in the global effort to eliminate lymphatic filariasis. Studies using current small mammal models of lymphatic filariasis are limited by difficulties in quantifying adult worm numbers and in assessing lymphatic anatomy and function. METHODOLOGY/PRINCIPAL FINDINGS: Here, we re-established Brugia malayi infection of ferrets as a model for lymphatic filariasis and demonstrated parasitological, immunological, and histological parallels with human infection. Subcutaneous injection of L3 larvae into a hind-footpad resulted in a mean of 18 adult worms recovered 16 weeks post-infection, primarily from the draining inguinal and femoral lymphatics of the injected limb. Infected ferrets developed microfilaremia, with patency lasting from 12-26 weeks post-infection. Quantitative PCR assessing cytokine transcription by antigen-stimulated lymph node cells demonstrated a mixed Th1/Th2 response occurring during early infection. Immunoregulation with production of down-regulatory cytokine IL-10 occurred just prior to peak microfilaremia. Histological analysis revealed progressive inflammation of the lymphatic vessel walls, with intimal thickening and disorganization of collagen fibers. Inflammation was observed as early as 8 weeks post-infection and extended into the perivascular and subcutaneous tissues by 16 weeks post-infection. Finally, we developed a novel ferret PET/CT lymphoscintigraphy method demonstrating substantial changes in lymphatic anatomy and function as early as 3 weeks post-infection, with progression over the course of infection. CONCLUSIONS/SIGNIFICANCE: B. malayi infection of ferrets is a robust model of human lymphatic filariasis that can be utilized to study efficacy of novel antifilarial agents against adult worms residing within lymphatic vessels. In conjunction with PET/CT lymphoscintigraphy, this model can also be used to investigate pathogenesis of lymphatic dysfunction in lymphatic filariasis and efficacy of medications aimed at reversing lymphatic dysfunction after clearance of adult worms.

Mak JW et al. (1988) Parasitol Res "Effect of ivermectin against subperiodic Brugia malayi infection in the leaf monkey, Presbytis cristata."

Mak JW, Lam PL, Suresh K, Rain AN

[Parasitol Res, 1988]

Ivermectin at single doses of 0.2-1.0 mg/kg body weight reduced the microfilarial counts of subperiodic Brugia malayi in Presbytis cristata by 59.9%-89.6% of initial counts, 4 weeks after treatment. Adult filaricidal activity was poor, live adult worms being recovered from all animals at autopsy. There was no serious side effect at these doses.

Walter RD (1988) Trop Med Parasitol "In vitro maintenance of Onchocerca volvulus for harvest of excretory and secretory products."

Walter RD

[Trop Med Parasitol, 1988]

Recommendations are given for maintenance of female Onchocerca volvulus; conditions as standardized here for drug screening and harvest of secreted-excreted products resulted in survival of worms in culture medium for up to four and six weeks in absence and presence of serum, respectively. As parameter for viability of worms lactate excretion was determined beside control of motility.

Strote G (1985) Trop Med Parasitol "Development of infective larvae of Onchocerca volvulus in diffusion chambers implanted into Mastomys natalensis."

Strote G

[Trop Med Parasitol, 1985]

Diffusion chambers containing vector-derived infective larvae of O. volvulus were implanted into male Mastomys natalensis and removed after periods up to 100 days. Nearly all chambers contained motile living parasites. After two weeks lengths and diameters of the larvae had increased significantly and after 100 days one juvenile worm showed well developed papillae at the posterior end.

Mojon M et al. (1987) J Antimicrob Chemother "Albendazole and thiabendazole in murine strongyloidiasis."

Roojee N, Saura C, Mojon M, Tran Manh Sung R

[J Antimicrob Chemother, 1987]

The activity of albendazole and thiabendazole, two derivatives of benzimidazole, were tested in an experimental model of Strongyloides ratti infestation in the rat. Two series of seven consecutive daily negative parasitic plate cultures, separated by four weeks of steroid therapy, confirmed cure of the infestation. Both drugs were inactive against larvae in the tissue phase, but completely effective in the intestinal phase.