Browsing by Author "Batsa, Linda"

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    Anti-Wolbachia Treatment of Lymphatic Filariasis and Genetic Analysis of the Pathology of Lymphedema as a Clinical Manifestation of the Disease
    (2012) Batsa, Linda
    Lymphatic filariasis (LF) caused by Wuchereria bancrofti is a disease of considerable public health and socio-economic burden in the tropics. The recommended drugs (ivermectin and albendazole) for the control of lymphatic filariasis are only microfilaricidal. The regimen of the standard treatment with doxycycline which has proven macrofilaricidal is 200mg/d for 4 weeks. This is considered a long period and dissuades complaince by patients receiving treatment. Therefore reducing the duration or the dosage from the current 200mg/d to 100mg/d would be a better option and will also increase compliance. In search of a more effective drug to complement the existing ones, in an area endemic for bancroftian filariasis in Ghana, 261 adult worm positive men were recruited for a double blind placebo-controlled study in the Ahanta West District of Ghana. Six groups of patients were treated with the gold standard (4 weeks 200mg/d doxycycline), 5 weeks and 4 weeks 100mg/d doxycycline, 3 and 2 weeks combination of 200mg/d doxycycline and 10mg/kg rifampicin and 5 weeks placebo. The effect of the treatment on Wolbachia depletion was assessed at 4 months after treatment; adult worm vitality assessed at pre-treatment, 12, 18 and 24 months, and microfilarial depletion assessed at pre-treatment, 4, 12, 18 and 24 months follow up time points. In accordance with the national mass drug administration programme, all the study participants were given 150mg/kg ivermectin and 400mg albendazole four months after treatment. The treatment drugs were well tolerated with no serious adverse effects in both the treated and the placebo groups. There was significant Wolbachia depletion at 4 months time point in the standard group (p=0.001), 5 weeks 100mg doxycycline (p=0.019), 4 weeks 100mg doxycycline (p=0.03) and 3 weeks combination treatment (p=0.028). However there was no significant Wolbachia depletion in the 2 weeks combination group as well as the placebo group (p>0.05). Microfilarial assessment at 12, 18 and 24 months follow up time points showed a significant depletion in the standard group, 5 weeks and 4 weeks 100mg doxycycline groups as well as the 3 weeks combination of 200mg plus rifampicin group but not in the 2 weeks and placebo groups (p>0.05). The macrofilaricidal activity was significant at 12, 18 and 24 months in the standard and the 5 weeks groups. In the 4 weeks group, it was significant at 18 and 24 months time point and in the 3 weeks group it was significant at 18 months follow up time point, but no significant difference was observed for the 2 weeks and the placebo groups. On the other hand, there is the need to know the genetic markers associated with LF. Such knowledge will be beneficial in terms of diagnosis and possible therapy of various forms of the pathology. For this reason, a cross-sectional study of unrelated Ghanaian volunteers were designed to genotype single nucleotide polymorphisms (SNPs) in 266 lymphedema patients as cases and 691 infected patients without pathology as well as 346 endemic controls. Out of the 147 chosen SNPs that were genotyped, 11 SNPs in eight genes were found to be associated with lymphedema. The associated SNPs were in the vascular endothelial growth factor receptor 3 (VEGFR3), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (NFKB- inhibition alpha), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1), tissue inhibitor of metallopeptidase 2 (TIMP) genes, interleukin 10 and two SNPs in insulin like growth factor-1 (IGF-1) and matrix metallopeptidase 2 (MMP-2). A SNP in the interleukin 17 gene revealed a trend but there was significant haplotype association. In conclusion 5 weeks, 4 weeks and 3 weeks combination regimens of doxycycline were effective in treating LF infections, and SNPs in the angiogenic pathway were found to be associated with the pathology of lymphatic filariasis.
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    Doxycycline targeting of wolbachia endosymbiotic bacteria in the treatment of wuchereria bancrofti infections in the Western Region of Ghana
    (2005-11-03) Batsa, Linda
    Chemotherapeutic approaches to the control and treatment of filarial disease have normally been a difficult topic because radical curative agents are not available. Present control strategies rely on drugs (ivermectin and albendazole) thai have only microfilaricidal activities (Ismail, 2001). As such, there is the need for a macrofilaricide or long term sterilising agent to complement ivermectin. The effect of tetracycline on the symbiotic endobacteria Wolbachia, in filarial worms has led to a novel chemotherapeutic approach in Wuchereria hancrofti infection and disease. In the Nzema East district in the Western Region of Ghana, 135 microfilarial positive patients were recruited for a double blind and an open group study. 110 patients were recruited for the double blind study which consisted of four groups. Two groups received 200mg/day doxycycline for either 3 weeks or 6 weeks. The other two groups were given placebo for 3 weeks and 6weeks. The open group study was undertaken with 25 patients. Eighteen patients were treated for 4 weeks with doxycycline and the rest served as controls without treatment. The effect of the doxycycline on Woihachia depletion was assessed at four months after treatment. All the doxycycline and placebo/control treated patients were given ivermectin (150mg/kg) and albendazole (400mg) four months after treatment and re-examined at 12 and 24 months after treatment. Parameters examined included pre-treatment microfilarial analysis, post-treatment microfilarial loads at 4, 12 and 24 months after doxycycline treatment, adverse reactions due to doxycycline (during doxycycline treatment) and also adverse effect due to ivermectin and albendazole (48 hours after ivermectin and albenda.zole treatment). Doxycycline was well tolerated with few incidents of adverse effects (18.1%) in contrast to the placebo groups (23.8%). Microfilarial assessment at 4 months did not yield significant results in both the 3 weeks and the 6 weeks regimen when compared with their placebo counterparts. Significant difference in the rnicrofilarial loads was observed in the four weeks group when compared with its control (p 0.0144). 12 months after treatment significant difference was observed in all the treatment groups when compared with their controls (3weeks p = 0.0004, 4weeks p = <0.0001 and 6weeks p = <0.0001). The significant difference was sustained up to 24 months after treatment in all (he treatment groups. The qualitative PCR revealed a total depletion of Wolbachia at 2 months in the 4 weeks and the 6weeks groups. For the 3 weeks treatment group, two patients remained positive even at 12 months after treatment, However 31 out of a total of 46 placebo patients examined at 12 months were positive. 4weeks and 6weeks treatment with doxycycline has proved effective in the depletion of Wolbachia in Wuchereria hancrofti infection thereby exhibiting a long term sterilizing effect. Though 3 weeks treatment could also deplete Woihachia, the depletion was not as complete as the 4 and 6 weeks regimen. The combination of doxycycline with ivermectin /albendazole reduced the microfliarial loads and the Wolbachia depletion sustained the amicrofilaraemia of the various treatment groups up to 24 months after treatment. Since 3 weeks doxycycline treatment was effective in causing sterility in the Wuchereria bancrofti but not as effective as the 4 and 6 weeks, combination of 4 weeks doxycycline with a single dose of ivermectin/albendazole will be enough to treat selected populations of bancroftian filariasis infection. A longer duration to achieve macrofilaricidal activity is worth considering. In addition vector control should also be incorporated especially in endemic areas.
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    Elevated adaptive immune responses are associated with latent infections of wuchereria bancrofti
    (PLOS, 2012-04) Arndts, Kathrin; Deininger, Susanne; Specht, Sabine; Klarmann, Ute; Mand, Sabine; Adjobimey, Tomabu; Debrah, Alexander Y.; Batsa, Linda; Kwarteng, Alexander; Epp, Christian; Taylor, Mark; Adjei, Ohene; Layland, Laura E.; Hoerauf, Achim
    In order to guarantee the fulfillment of their complex lifecycle, adult filarial nematodes release millions of microfilariae (MF), which are taken up by mosquito vectors. The current strategy to eliminate lymphatic filariasis as a public health problem focuses upon interrupting this transmission through annual mass drug administration (MDA). It remains unclear however, how many rounds of MDA are required to achieve low enough levels of MF to cease transmission. Interestingly, with the development of further diagnostic tools a relatively neglected cohort of asymptomatic (non-lymphedema) amicrofilaremic (latent) individuals has become apparent. Indeed, epidemiological studies have suggested that there are equal numbers of patent (MF+) and latent individuals. Since the latter represent a roadblock for transmission, we studied differences in immune responses of infected asymptomatic male individuals (n = 159) presenting either patent (n = 92 MF+) or latent (n = 67 MF2) manifestations of Wuchereria bancrofti. These individuals were selected on the basis of MF, circulating filarial antigen in plasma and detectable worm nests. Immunological profiles of either Th1/Th17, Th2, regulatory or innate responses were determined after stimulation of freshly isolated PBMCs with either filarial-specific extract or bystander stimuli. In addition, levels of total and filarial-specific antibodies, both IgG subclasses and IgE, were ascertained from plasma. Results from these individuals were compared with those from 22 healthy volunteers from the same endemic area. Interestingly, we observed that in contrast to MF+ patients, latent infected individuals had lower numbers of worm nests and increased adaptive immune responses including antigen-specific IL-5. These data highlight the immunosuppressive status of MF+ individuals, regardless of age or clinical hydrocele and reveal immunological profiles associated with latency and immune-mediated suppression of parasite transmission.