The protective effect of African IgG antibodies against Plasmodium falciparum malaria was investigated by passive transfer in Thai patients. Sera from 333 African adults were collected in the Cote d'Ivoire and subjected to extensive screening. One hundred fifty-three samples were discarded for safety reasons, and IgG was extracted from those remaining under conditions allowing their use by the intravenous (iv) route.Eight Thai patients with P. falciparum parasitemia were treated by iv inoculation of the IgG: six with a 100 mg/kg dose given over three days, one with a single 20 mg/kg dose, and one with a single 200 mg/kg dose. To ensure a safety margin of at least 48 hours, subjects were chosen among patients having a recrudescent parasitemia following quinine treatment failure at the RI level. At that stage, symptoms were mild or absent and parasitemia was low but increasing (range 4, 200–9,000/µl).The IgG pool exerted a profound, stage-specific, but non-sterilizing effect on each of the strains tested, and proved to be safe. Asexual parasitemia decreased by a mean 728-fold (range 46–1,086), while gametocytes were unaffected. Clearance of parasites and symptoms was as fast or faster than with drugs, and was consistent in the eight patients treated, suggesting that target antigens were equally expressed in geographically remote isolates. In peripheral blood smears, no mature forms were seen at any time during the followup, which does not support the hypothesis that reversal of cytoadherence occurred.After the disappearance of the transferred antibodies, recrudescent parasites from three patients were found to be susceptible to the same extent (mean decrease of 1,310-fold) to the same IgG preparation, indicating that selection of parasites able to escape the effect of antibodies had not occurred. No adverse side-effects were detected during the followup, which lasted one year.
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.
Dengue fever, caused by four serotypes of a mosquito-borne virus, is a growing problem in tropical countries. Currently, there is no treatment or vaccine. We evaluated safety and immunogenicity of two doses, given six months apart, of seven formulations of dengue tetravalent live-attenuated vaccine (containing different concentrations of the component viruses) versus placebo in 59 flavivirus-seronegative Thai adults. The first dose was the more reactogenic. Most volunteers experienced clinically moderate fever, headache, myalgia, eye pain or rash 7-11 days after injection, generally lasting three days or less. Modest decreases in platelets and neutrophils were observed. After one dose, 58% of dengue recipients seroconverted (neutralizing antibody level > or = 1:10) against > or = 3 serotypes; 35% seroconverted against all four. After the second dose, seroconversion was 76% and 71%, respectively. All subjects seroconverted to serotype 3 after one dose. Serotype 4 elicited the lowest primary response but the highest increase in seroconversion after the second dose.
A total of 66 Thai children with uncomplicated falciparum malaria were treated orally with regimens of either quinine or quinidine. Radical cures were observed in 85% (28 of 33) of the children who received quinine and in 88% (29 out of 33) of those who received quinidine. Treatment failures in both groups were RI responses.The mean trough level of quinidine (10 mumol/l) was about 2.5-times less than that of quinine (25 mumol/l). The electrocardiograms of the two treatment groups differed significantly in that there was an acute prolongation of the QT(c) interval in 56% of those who received quinidine compared with 21.0% of those given quinine. In vitro assays of the pretreatment drug susceptibilities of the isolates of Plasmodium falciparum indicated that the mean minimum inhibitory concentration (MIC) for quinidine (1.44 mumol/l) was about half that for quinine (3.02 mumol/l). Although both drugs are equally effective, quinine is recommended for treatment of multidrug-resistant malaria in paediatric patients, primarily because of the cardiac effects produced by quinidine.
A study was carried out to assess the efficacy of a modified 7 day course of quinine in children with falciparum malaria, in comparison with those of a 7 day course of quinine at standard dosage and a combination of a 7 day course of quinine and sulfadoxine-pyrimethamine, and in relation to the MIC, and to the serum levels of quinine during the course of treatment. Seventy seven children aged 2 years to 12 years with falciparum malaria were randomly treated with one of the 3 regimens. Group I, quinine 10 mg base per kg body wt. 8 hourly for 7 days, 21 of 28 cases (75%) were cured, while 6 cases (21%) showed RI and 1 case (4%) RII failure. Group II, quinine 10 mg base per kg body wt. 8 hourly for the first 4 days then 15 mg base per kg body wt. 8 hourly for the next 3 days, 20 of 23 cases (87%) were cured, while 3 cases (13%) showed RI failure. Group III, quinine 10 mg base per kg body wt. 8 hourly for 7 days and then sulfadoxine 30 mg per kg body wt. and pyrimethamine 1.5 mg per kg body wt., 16 of 26 cases (62%) were cured and 10 cases (38%) showed RI failure. The cure rates in the 3 groups were not statistically different. The three groups had similar serum quinine concentration profiles. Treatment with quinine was successful in cases in which serum quinine levels could be maintained above MIC for 7 days. There was no additional effect of sulfadoxine-pyrimethamine on quinine.
A trial was conducted in 32 Thai children with uncomplicated multidrug-resistant falciparum malaria to assess the efficacy, safety and pharmacokinetics of atovaquone and proguanil; plasma concentrations of atovaquone, proguanil and its metabolite, cycloguanil, were measured in a subset of 9 children. The children received atovaquone (17 mg/kg/d for 3 d) plus proguanil (7 mg/kg/d for 3 d). Twenty-six children who had only Plasmodium falciparum infection and remained in hospital for 28 d were assessed for drug efficacy. The combination regimen produced a cure rate of 100%. Parasite and fever clearance times were 47 h (range 8–75) and 50 h (range 7–111), respectively. Atovaquone and proguanil were rapidly absorbed, with median time to peak concentrations of 6 h (range 6–24) and 6 h (range 6–12), respectively. Peak concentrations of cycloguanil were achieved between 6 and 12 h (median 6) after administration of proguanil. Mean peak plasma concentration of atovaquone on day 3 was 5·1 μg/mL (SD = 2·1). The day 3 mean peak plasma concentration of proguanil was 306 ng/mL (SD = 108) compared with 44·3 ng/mL (SD = 27.3) for cycloguanil. Mean values for the AUC (area under plasma concentration-time curve) were 161·8 μg/mL · h (SD = 126·9) for atovaquone, 4646 ng/mL · h (SD = 1226) for proguanil, and 787 ng/mL · h (SD = 397) for cycloguanil. Terminal elimination half-lives of atovaquone, proguanil and cycloguanil were estimated as 31·8 h (SD = 8.9), 14·9 h (SD = 3·3) and 14·6 h (SD = 2·6), respectively. No major adverse effect was attributable to the study drugs. Atovaquone/proguanil combination is safe and highly effective, and should be especially valuable for treatment of multidrug-resistant falciparum malaria.
Objective. The safety and immunogenicity of tetravalent live-attenuated dengue vaccines after a three dose vaccination series were evaluated in Thai children. Method. One hundred three healthy flavivirus-seronegative schoolchildren ages 5 to 12 years were randomized to receive either dengue vaccine containing 3, 2, 1 and 2 log10 of the 50% cell culture infective dose, respectively, of the live-attenuated dengue vaccine serotypes 1, 2, 3 and 4 per dose (F3212; n = 40) or 3, 3, 1 and 3 log10 of the 50% cell culture infective dose (F3313; n = 42) or purified Vero cell rabies vaccine (control group; n = 21) given in a two dose schedule (3 to 5 months apart). A third dose was administered 8 to 12 months after the second dose to 90 subjects. Safety and immunogenicity were evaluated within 28 days after each injection. Results. No serious adverse event related to the vaccines occurred. Most children experienced mild to moderate fever, rash, headache and myalgia occurring within 12 days after Dose 1 and generally lasting 3 days or less. One subject in Group F3212 had a 1-week dengue-like fever. Reactogenicity was minimal after Doses 2 and 3. Transient mild variations in liver enzymes and hematologic indices were noted mainly after Dose 1. After the third dose 89% of the subjects in Group F3212 seroconverted (neutralizing antibody response, ≥10) to all four serotypes, and all children in Group F3313 seroconverted. Conclusion. This study demonstrates a moderate although improvable reactogenicity and high seroconversion rates against the four serotypes of dengue after a three dose schedule of tetravalent live-attenuated dengue vaccine in children.
Seventy Plasmodium falciparum isolates, collected from two geographically separate areas of Thailand, were tested for their in vitro responses to pyrimethamine, sulfadoxine, and a combination of these two drugs. The effects of pyrimethamine and pyrimethamine-sulfadoxine combinations against P. falciparum isolates were found to be significantly greater in a northern area where the combined drug was an effective therapeutic agent than in a south-eastern area, near the Thai-Kampuchean border, where the combined drug was no longer effective. However, the actions of sulfadoxine against parasites obtained from the two areas were not significantly different. There was no significant difference between the mean values of plasma 4-aminobenzoic acid (PABA) in falciparum malaria patients and in healthy controls. The test for PABA determinations used in this study gave positive readings with both PABA and sulfadoxine.
Serum quinine concentrations were determined in 51 children with uncomplicated falciparum malaria and 22 controls. Quinine 10 mg salt/kg was given one-hour, two-hour, four-hour intravenously in group A (14 patients, 5 controls), group B (12 patients, 6 controls), Group C (10 patients, 6 controls) and given orally in group D (15 patients, 5 controls). In malaria patients, the highest serum quinine levels were observed at the end of intravenous infusion and by the 4th hour after oral medication. Mean of the peaks of the drug concentrations of the 4 schedules were not significantly different, ranging from 22 to 28 n mol/ml. Serum concentrations in the patients were significantly higher than those of the controls. The total clearance of quinine in the patients were approx. 1 ml/min/kg, which was significantly less than those of the controls. The total apparent volume of distribution of the drug was similarly reduced. In patients it was about 0.8 litre/kg. The elimination half times of quinine ranged from 9 to 11 hours, whereas the value in the controls ranged from 3 to 7 hours. Side effects of quinine were not observed.
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