Browsing by Author "Folb, Peter"

Now showing 1 - 3 of 3
  • No Thumbnail Available
    Item
    Open Access
    A study of the immune response in murine experimental malaria, with special reference to the effects of South African medicinal plants, artesunate and chloroquine
    (2003) Gumede, Bonginkosi; Folb, Peter; Ryffel, Bernhard
    The role of pro-inflarrnnatory cytokines (TNF and IFN-y) in a murine experimental malaria model for cerebral malaria is reported in this thesis. Wild type and receptor knockout mice (IFN-y deficient mice (IFN-l") and TNF-a/fr1- double deficient) were infected with Plasmodium berghei ANKA {PbA). PbA induced fatal cerebral malaria in wild type mice, which died within 5 to 8 days. In contrast, IFN-f1- and TNF-a/[r1-were completely resistant to PbA-induced cerebral malaria. Both wild type and mutant mice developed a similar degree of parasitaemia in the initial phase, and anaemia and leukocytosis were not different, showing that both anaemia and mobilisation of leukocytes occur in the absence of TNF and IFN-y. The results show that TNF'- and IFN,f'- mice are resistant to PbA-induced cerebral malaria, and confirm the role played by Thl cytokines in its pathogenesis. Plasmodium chabaudi chabaudi AS infection results in splenomegaly, and activation of the immune system. Resistant C57BL/6 mice, which eliminate the parasites and survive the infection, developed marked splenomegaly. Susceptible A/J mice develop minimal splenomegaly. In this work it has been shown that there is a rapid deterioration in splenic architecture, although immunohistochemistry confirmed preservation of a high level of structure and organisation. CD 11 c {dendritic) cells moved from the marginal zone into the CD4+ T cell area (where their antigen presenting function would be maximal). The juxtaposition of CDllc and T cells might be associated with immune complex formation in the spleen during the infection. The findings were similar for C57BL/6 and A/J mice. A 14-day course of artesunate 100 mg/kg prevented completely the development of parasitaemia and cerebral malaria in Plasmodium berghei ANKA infected mice, with survival of more than 60d. Chloroquine enhanced production of IL-10. Artesunate displayed enhanced IL-1 0 activity but no effect on production of pro-inflammatory cytokines. Extracts of W. salutaris, a South African medicinal plant, reduced parasitaemia by >50% at doses of 100 and 500mg/kg, and of A. annua reduced parasitaemia by 64% at a dose of 200 mg/kg. These extracts, and extracts of H. procumbens, had immunomodulatory activity on TNF-a., IFN-y, IL-12 and IL-10 production by Con A- and LPS-induced splenocytes.
  • Thumbnail Image
    Item
    Open Access
    Combination of tunicamycin with anticancer drugs synergistically enhances their toxicity in multidrug-resistant human ovarian cystadenocarcinoma cells
    (BioMed Central Ltd, 2007) Hiss, Donavon; Gabriels, Gary; Folb, Peter
    BACKGROUND:The pharmacologic modulatory effects of the antibiotic, tunicamycin (TM), on multidrug-resistant human UWOV2 ovarian cancer cells are reported. The UWOV2 cell line was derived from a cystadenocarcinoma in a patient refractory to combination chemotherapy with actinomycin D, vincristine (VCR), cis-diaminedichloroplatinum (II) (CDDP) and doxorubicin (DXR). In an attempt to explain drug resistance in this cell line, we examined the effects of TM on their sensitivity to various anticancer drugs, the uptake, efflux and retention of [3H]VCR, and their ability to bind [14C]DXR and [3H]azidopine (AZD), a photoaffinity label of the multidrug transporter, P-glycoprotein (Pgp). RESULTS: TM effectively decreased the EC50 for DXR, EXR, VCR and CDDP, thus enhancing their cytotoxicity. The antibiotic also prolonged the intracellular retention time of [3H]VCR and increased the binding of both [14C]DXR and [3H]AZD to the cells. CONCLUSION: It is concluded that the pharmacomodulatory effects of TM in these cells are mediated by global inhibition of protein and glycoprotein synthesis and synergistic interaction with antineoplastic drugs. The ability of TM to enhance the sensitivity of drug resistant tumour cells may have impact on the design and optimization of novel resistance modifiers to improve the efficacy of combination treatment of intractable neoplasms.
  • Thumbnail Image
    Item
    Open Access
    Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients
    (Public Library of Science, 2006) Simpson, Julie A; Agbenyega, Tsiri; Barnes, Karen I; Perri, Gianni Di; Folb, Peter; Gomes, Melba; Krishna, Sanjeev; Krudsood, Srivicha; Looareesuwan, Sornchai; Mansor, Sharif
    A study of the population pharmacokinetics of intra-rectal artesunate in patients with moderately severe falciparum malaria found the pharmacokinetic properties of dihydroartemisinin were affected only by gender and body weight.