Browsing by Author "D. G. Heppner"

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    Comparative clinical trial of artesunate suppositories and oral artesunate in combination with mefloquine in the treatment of children with acute falciparum malaria
    (1998-01-01) A. Sabchareon; P. Attanath; P. Chanthavanich; P. Phanuaksook; V. Prarinyanupharb; Y. Poonpanich; D. Mookmanee; P. Teja-Isavadharm; D. G. Heppner; T. G. Brewer; T. Chongsuphajaisiddhi; Mahidol University; Thong Pha Phum Hospital; Armed Forces Research Institute of Medical Sciences, Thailand; U. States Army Med. Res. Inst. I.
    A randomized pilot study to compare the safety and efficacy of artesunate suppositories (15 mg/kg/day for three days) versus oral artesunate (6 mg/kg/day for three days), both in combination with mefloquine (25 mg/kg), was conducted in 52 Thai children with uncomplicated multidrug-resistant falciparum malaria. Forty-five patients (87%) had a full 28-day follow-up in the hospital to assess efficacy and exclude reinfection. Mean [range] times to fever clearance of the two groups were similar (42 hr [15-104] versus 42 hr [6-119]). Artesunate suppositories resulted in significantly longer times to achieve 50% and 90% reductions of the initial parasite counts (17 and 26 hr versus 9 and 15 hr; P < 0.05 and P < 0.001). Time [range] to parasite clearance was longer in the artesunate suppositories group (42 hr [14-93] versus 35 hr [16-69]), but the difference was not significant. The cure rates by days 28 were not significantly different, 92% for artesunate suppository- treated patients and 100% for oral artesunate-treated patients. Both drug regimens are safe and effective. Further studies are needed to characterize the pharmacokinetic properties and the optimum regimen of artesunate suppositories for the treatment of severe malaria.
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    CpG oligodeoxynucleotide enhances immunity against blood-stage malaria infection in mice parenterally immunized with a yeast-expressed 19 kDa carboxyl-terminal fragment of Plasmodium yoelii merozoite surface protein-1 (MSP119) formulated in oil-based Montanides
    (2003-06-20) C. Hirunpetcharat; J. Wipasa; S. Sakkhachornphop; T. Nitkumhan; Y. Z. Zheng; S. Pichyangkul; A. M. Krieg; D. S. Walsh; D. G. Heppner; M. F. Good; Mahidol University; Chiang Mai University; QIMR Berghofer Medical Research Institute; Armed Forces Research Institute of Medical Sciences, Thailand; University of Iowa Carver College of Medicine; VA Medical Center; Walter Reed Army Institute of Research
    The 19kDa carboxyl-terminal fragment of Plasmodium yoelii merozoite surface protein-1 (MSP119), an analog of the leading falciparum malaria vaccine candidate, induces protective immunity to challenge infection when formulated with complete/incomplete Freund's adjuvant (CFA/IFA), an adjuvant unsuitable for use in humans. In this study, we investigate Montanide ISA51 and Montanide ISA720 as well as CpG oligodeoxynucleotide (ODN) as adjuvants for induction of immunity to MSP119. Mice immunized with MSP119adjuvanted with Montanide ISA51 were protected even though some mice experienced low-grade parasitemia before resolving the infection. Mice immunized with MSP119adjuvanted with Montanide ISA720 showed delayed patent parasitemia with all mice ultimately succumbing to infection. Interestingly, when the synthetic CpG ODN 1826 was included in either Montanide formulation, mice were completely protected with no parasites detected in the blood. MSP119-specific antibodies in MSP119-immunized mice adjuvanted with Montanide ISA51 or Montanide ISA720 showed predominantly IgG1 antibody and low levels of IgG2a. CpG ODN 1826 significantly enhanced both IgG1 and IgG2a antibody responses in Montanide ISA51-adjuvanted mice but significantly enhanced only the IgG2a antibody response in Montanide ISA720-adjuvanted mice. To investigate the relative roles of antibody and CD4+T cells in protection, MSP119-immunized mice adjuvanted with Montanide ISA720 and CpG ODN 1826 were depleted of CD4+T cells just prior to challenge. Results showed that three of nine immunized/T cell depleted mice died following infection. These results suggest that antibody and CD4+T cells are critical for protection following immunization with MSP119adjuvanted with Montanide and CpG ODN and that the formulation of a human malaria vaccine candidate in Montanide ISA720 or ISA51 together with human compatible CpG ODN would be useful for improving efficacy. © 2003 Elsevier Science Ltd. All rights reserved.
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    Plasmodium falciparum antimalarial drug susceptibility on the north-western border of Thailand during five years of extensive use of artesunate-mefloquine
    (2000-01-01) A. Brockman; R. N. Price; M. Van Vugt; D. G. Heppner; D. Walsh; P. Sookto; T. Wimonwattrawatee; S. Looareesuwan; N. J. White; F. Nosten; Shoklo Malaria Research Unit; Mahidol University; John Radcliffe Hospital; Armed Forces Research Institute of Medical Sciences, Thailand; Academic Medical Centre, University of Amsterdam
    Following a marked decline in the efficacy in vivo of mefloquine between 1990 and 1994, a combination of artesunate (4 mg/kg/d for 3 d) and mefloquine (25 mg/kg) has been used as first line treatment of uncomplicated falciparum malaria in camps for displaced persons located along the north-western border of Thailand. Antimalarial drug susceptibility of fresh isolates of Plasmodium falciparum from this population was evaluated using a radioisotope microdilution assay between 1995 and 1999. In total, 268 isolates were collected, of which 189 were from primary infections and 79 from recrudescent infections. The geometric mean 50% inhibitory concentration (IC50) values from primary infections were: dihydroartemisinin 1.2 ng/mL, artesunate 1.6 ng/mL, artemether 4.8 ng/mL, atovaquone 0.4 ng/mL, lumefantrine 32 ng/mL, chloroquine 149 ng/mL, quinine 354 ng/mL, mefloquine 27 ng/mL and halofantrine 4.1 ng/mL. A significant positive correlation was found between the susceptibility in vitro to artesunate and quinine (r = 0·43, P < 0·001), mefloquine (r = 0·46, P < 0·001), and halofantrine (r = 0·51, P < 0.001). These levels of resistance in vitro are among the highest reported and confirm continuing high level multidrug resistance in this area. Despite intensive use of the combination between 1995 and 1999 there has been a significant improvement in mefloquine sensitivity (P < 0.001) and artesunate sensitivity (P < 0·001). This supports observations in vivo that the combination of artesunate and mefloquine has reversed the previous decline in mefloquine sensitivity.
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    SPf66 malaria vaccine is safe and immunogenic in malaria naive adults in Thailand
    (1997-09-30) S. Migasena; D. G. Heppner; D. E. Kyle; T. Chongsuphajaisiddhi; D. M. Gordon; P. Suntharasamai; B. Permpanich; A. Brockman; P. Pitiuttutham; C. Wongsrichanalai; P. Srisuriya; B. Phonrat; K. Pavanand; C. Viravan; W. R. Ballou; Mahidol University; Armed Forces Research Institute of Medical Sciences, Thailand; Walter Reed Army Institute of Research; Shoklo Malaria Research Unit
    In preparation for an efficacy trial of malaria vaccine SPf66 in Thailand, a series of overlapping Phase I trials were conducted of US- manufactured SPf66. Here, two clinical lots were evaluated for safety and immunogenicity in a combined open-label trial. Eleven healthy, malaria naive, 18-44 year-old Thai men and women received three doses by subcutaneous injection in alternate arms at 0, 1 and 6 months. Safety was assessed by monitoring local and systemic reactogenicity and laboratory parameters. Common side effects were mild erythema, induration and tenderness at the site of injection which resolved within 24-48 h. At third immunization, two volunteers developed acute bilateral reactions with induration, erythema and pruritus limited to the sites of the second and third immunizations. Eight of 11 volunteers sero-converted by ELISA, six of whom would be classified as high responders by Colombian standards. Eight of 11 volunteers developed a lymphoproliferative response to the SPf66 antigen. Side effects were more common and antibody and lymphoproliferative responses greatest, among the four female volunteers. This initial study of SPf66 malaria vaccine in Asia constitutes an essential link between the initial Phase I study in the US and subsequent field studies in a semi-immune population in a malaria endemic area of Thailand. This study further establishes comparability of US- manufactured SPf66 with that of Colombian provenance and substantiates the validity of the subsequent negative efficacy results of SPf66 in a field trial in Thailand.