Antibodies that protect humans against Plasmodium falciparum blood stages do not on their own inhibit parasite growth and invasion in vitro, but act in cooperation with monocytes.

IgG extracted from the sera of African adults immune to malaria were injected intravenously into eight Plasmodium falciparum-infected nonimmune Thai patients. Clinical and parasitological improvement was reproducibly obtained in each case. After the disappearance of the transferred Ig, recrudescent parasites were equally susceptible to the same Ig preparation. High levels of antibodies to most parasite proteins were detected by Western blots in the receivers' sera (taken before transfer) as in the donors' Ig, thus indicating that the difference was qualitative rather than quantitative between donors and receivers. In vitro, the clinically effective Ig had no detectable inhibitory effect on either penetration or intra-erythrocytic development of the parasite. On the contrary, they sometimes increased parasite growth. In contrast, these IgG, as the receivers' Ig collected 4 d after transfer, but not those collected before transfer, proved able to exert an antibody-dependent cellular inhibitory (ADCI) effect in cooperation with normal blood monocytes. Results were consistent among the seven isolates studied in vitro, as with the recrudescent parasites. Thus, the results obtained in the ADCI assay correlate closely with clinical and parasitological observations.

Persistence of antibodies in children after intradermal or intramuscular administration of preexposure primary and booster immunizations with purified Vero cell rabies vaccine.

BACKGROUND: The use of intradermal (i.d.) injections of purified Vero cell rabies vaccine (PVRV) for preexposure prophylaxis has not been well-established. We studied the safety and immunogenicity of i.d. and intramuscular (i.m.) PVRV injections for primary and booster preexposure immunizations. METHODS: One of two rabies preexposure PVRV regimens comprising three doses of either 0.1 ml i.d. or 0.5 ml i.m. administered during 28 days was assigned at random to 190 school children. One booster dose was given 1 year later either i.d. or i.m., according to their initial randomization group. Serologic results were available from 155 (82%) children at 1 year after primary immunization and 118 (62%) children at 2 years after booster. RESULTS: Although children vaccinated i.d. had significantly lower rabies-neutralizing antibody titers after primary immunization as well as after booster than children vaccinated i.m. (P< 0.001 for all time points), there were no significant differences in the percentages of children with adequate titers (> or =0.15 IU/ml) between the i.d. and i.m. groups after both primary and booster immunizations. Mild local reactions were more frequent after i.d. vaccination. Mild or moderate systemic reactions were infrequent and similar after i.d. and i.m. vaccinations. Fever and headache were reported by < or =6%. The reactions after booster were not different from those of post-primary immunization. CONCLUSIONS: Purified Vero cell rabies vaccine appears to be safe and immunogenic for primary and booster preexposure immunizations. An i.d. PVRV preexposure regimen should be useful especially for rabies-endemic countries with low per capita income.

Parasitologic and clinical human response to immunoglobulin administration in falciparum malaria.

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/microliters). 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.

Comparative clinical trial of artesunate suppositories and oral artesunate in combination with mefloquine in the treatment of children with acute falciparum malaria.

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.

Efficacy and pharmacokinetics of atovaquone and proguanil in children with multidrug-resistant Plasmodium falciparum malaria.

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 micrograms/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 micrograms/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.

Evaluation of the safety, immunogenicity, and pharmacokinetic profile of a new, highly purified, heat-treated equine rabies immunoglobulin, administered either alone or in association with a purified, Vero-cell rabies vaccine.

A clinical evaluation of a new, purified, heat-treated equine rabies immunoglobulin (PHT-Erig), F(ab')2 preparation, was carried out in Thailand and in the Philippines-two countries where rabies is endemic. An initial prospective, randomised, controlled trial (Study 1), compared the safety and pharmacokinetics (serum concentrations of rabies antibodies) after administration either of PHT-Erig or of a commercially-available, equine rabies immune globulin (Erig PMC). A second trial (Study 2) simulated post-exposure rabies prophylaxis by using a reference cell culture vaccine, the purified Vero-cell rabies vaccine (PVRV), administered in association with either Erig PMC or PHT-Erig. In Study 1, 27 healthy, Thai adults received a 40 IU kg(-1) dose of either Erig PMC (n = 12) or PHT-Erig (n = 15) via the intramuscular (i.m.) route; half of the dose was injected into the deltoid area and the other half into the buttocks. Serum for rabies antibody determination and F(ab')2 concentration was collected at hours (H) 0, 6 and 12, and on day (D) 2, 3, 4, 6, 8, 10, 12 and 15. Both products were safe, with no serious adverse events, and in particular, no anaphylactic reactions or serum sickness was reported. A statistical comparison of the pharmacokinetic parameters did not demonstrate bioequivalence of the two products. Nonetheless, the relative bioavailability of 93% and the similar absorption rates suggest the pharmacokinetic profiles of Erig and PHT-Erig are similar. The antibody level in either group were low throughout the 15-day study period. The geometric mean titer (GMT) values ranged from group 0.027-0.117 IU ml(-1) in the Erig group and from 0.029 to 0.072 IU ml(-1) in the PHT-Erig. There was no significant difference between the evolution of GMT values for the two groups. In Study 2, 71 healthy volunteers received 40 IU kg(-1) via the intramuscular route of either Erig PMC (n = 36) or PHT-Erig (n = 35) on D0, in association with five doses of PVRV on D0, D3, D7, D14 and D28. The safety evaluation was performed during the 28-day follow-up and serum samples for anti-rabies antibody titration were collected on D0 (before injection) D3, D7, D14 and D28. No serious reactions were reported in either group. In particular, no immediate (anaphylactic type) or delayed (serum sickness) allergic reactions were observed. Over the 28-day follow-up period, GMT profiles of the two groups were statistically equivalent. On D14, 100% of the subjects had protective antibody titers (anti-rabies antibodies > or = 0.5 IU ml(-1), which is the WHO-recommended level of seroconversion), and Erig PMC and PHT-Erig were indistinguishable according to the clinical definition chosen. On D28, the GMT values were 33.2 IU ml(-1) (95% CI, 23.8-46.1 IU ml(-1)) in the Erig PMC/PVRV group and 31.4 IU ml(-1) (95% confidence interval, CI, 23.4-42.2 IU ml(-1)) in the PHT-Erig/PVRV group, showing evidence of adequate vaccine-induced antibody responses in both groups. The increased purity, the heat-treatment step introduced in the manufacturing process of PHT-Erig, and the good clinical results substantiate the use of this new generation, purified equine F(ab')2 preparation in the post-exposure prophylaxis of rabies.

Treatment of quinine resistant falciparum malaria in Thai children.

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.

Treatment of giardiasis in children with quinacrine, metronidazole, tinidazole and ornidazole.

One hundred and twenty four children with symptomatic and parasitologically confirmed giardiasis were treated in a comparative trial. The dosage of antigiardia drug was adjusted to the body surface area of the patients from the adult basic dosage as 100 mg of quinacrine t.i.d. for 5 days, 200 mg of metronidazole t.i.d. for 7 days, 2 gm of metronidazole once, 2 gm of tinidazole once or 2 gm of ornidazole once. They were hospitalized for follow-up for 30 days. The parasitological follow-up consisted of daily examination of stool specimens. Reinfections were unlikely. The rates of success were: a 5-day course of quinacrine, cured all of them, 20 patients; a 7-day course of metronidazole, 12 of 20; metronidazole, single dose, 11 of 21; tinidazole, single dose, 18 of 21; ornidazole, single dose, 21 of 22; placebo, none of 20. After a single dose, 5 patients had transient elevation of transaminases, one patient in each of metronidazole and tinidazole group 3 patients in ornidazole group. A 5-day course of quinacrine gave excellent result but the drug is not widely marketed. Ornidazole or tinidazole were more effective, both of them were recommended as a drug of choice as single dose therapy, however transient increase of transaminases may occur in some cases.

Serum quinine concentrations following the initial dose in children with falciparum malaria.

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.

Red cell acetylcholinesterase activity in Plasmodium falciparum malaria.

Red cell ACHE activity was determined in 19 patients with P. falciparum malaria, 13 patients during convalescence as well as in 6 normal subjects. There was no significant difference between the mean values of ACHE in red cells of these 3 groups. After separation these blood samples into 2 portions by centrifugation in 5% Ficoll solution, the parasitized red cells in the lower portion which are mostly ring forms contained the same amount of ACHE activity as those of the normal subjects and the non-parasitized red cells. However, the parasitized red cells in the upper portion which contained predominantly mature asexual forms revealed a significantly higher ACHE activity than those of the normal red cells. There was also a reverse relationship between red cell ACHE activity and the parasitaemia from this portion of blood sample. These findings indicated that although malarial parasite invaded and caused the red cell membrane damage, it did not inactivate ACHE. It may be concluded that ACHE was not responsible for the anaemia and excessive erythrocyte destruction in patients with P. falciparum malaria.

Pharmacokinetics of primaquine in healthy volunteers.

The pharmacokinetics of primaquine were investigated in 8 healthy subjects (4 males and 4 females). The volunteers received 15 mg base of primaquine daily for 14 days. The results showed that the concentration-time profiles in whole blood and in plasma were similar. The mean values (+/- SD) of area under the curve (AUC) of the last dose were significantly decreased when compared to the values of the first dose both in whole blood and in plasma (909.96 +/- 603.07, 1,147.05 +/- 684.8 ng.hr/ml respectively in whole blood with p = 0.007 and 1,255.11 +/- 531.59, 1,603.66 +/- 505.45 ng.hr/ml respectively in plasma with p = 0.023). The decrease in the concentration-time profile of the last dose was due to enhancement of drug elimination with significant increase in clearance after the last dose (4.871 +/- 1.741 and 6.443 +/- 2.514 ml/min/kg respectively in whole blood with p = 0.007, 3.199 +/- 1.197 and 4.422 +/- 2.068 ml/min/kg respectively in plasma with p = 0.016).

Plasma retinol and alpha-tocopherol level and growth indices of 7 months old healthy Thai infants in Bangkok.

A cross-sectional study was conducted to measure plasma retinol and alpha-tocopherol status and the growth indices of 66 healthy Thai infants aged about 7 months old. The mean (SD) plasma retinol and alpha-tocopherol level were 1.59(0.31) and 25.40(7.01) micromol/l respectively. For their weight, height, and body mass index, the mean (SD) values were 7.96(0.93) kg, 69.95(2.42) cm, and 16.25(1.43) respectively. There was a remarkable proportion of improper feeding. However there were no correlations between plasma retinol level, plasma alpha-tocopherol level, growth indices and duration of breast milk, formula milk, weaning food feeding except alpha-tocopherol level which positively correlated with duration of breastfeeding.

Pharmacokinetics of mefloquine in children aged 6 to 24 months.

The study was carried out in 12 children aged 6 months to 2 years, with uncomplicated falciparum malaria admitted to the Hospital for Tropical Diseases, Bangkok. They were treated with mefloquine in the form of MSP (mefloquine 250 mg+sulfadoxine 500 mg+pyrimethamine 25 mg) at a single dose of 25 mg mefloquine base/kg body weight. All of them were cured (28 days follow-up) with minimal side effects. Pharmacokinetic parameter determination was carried out in 9 cases. The results revealed that MRT, t1/2 and tmax in this study (children 6-24 months old) are comparable to the values in children aged 5-12 years, but shorter than in adult patients. Cmax and AUC in children 6-24 months old are comparable to those in children of 5-12 years, but much higher than in adult patients. Vz/f values in this study are comparable to those in children 5-12 years old, but lower than in adult patients.

Pharmacokinetic study of mefloquine in Thai children aged 5-12 years suffering from uncomplicated falciparum malaria treated with MSP or MSP plus primaquine.

A triple combination of mefloquine, sulfadoxine and pyrimethamine (MSP) was used with primaquine for the radical treatment of falciparum malaria in Thailand. Primaquine was reported to inhibit hepatic microsomal enzymes and drug metabolism in animal and man. 23 children hospitalized in the Hospital for Tropical Diseases, Faculty of Tropical Medicine, Bangkok, Thailand, were randomly allocated into two groups, group I received MSP equivalent to 20 mg base of mefloquine/kg body weight and group II received MSP plus primaquine (0.75 mg/kg). No statistical difference was noted for clinical response except the gametocyte clearance time was shorter in children given MSP plus primaquine (7 +/- 2.7 days) than the children given MSP alone (21.9 +/- 4.4 days) (P < 0.01). No serious side effects were recorded in this study. The plasma samples were obtained for kinetic calculations by HPLC in 18 children (11 in group I, 7 in group II). Mean Cmax was 7.4 +/- 5.2 h in group I and 6.6 +/- 7.0 h in group II. Mean t1/2, Cl/f and Vd/f were 9.8 +/- 1.6 days, 0.43 +/- 0.16 ml/min/kg and 8.84 +/- 4.21 l/kg in group I, 9.3 +/- 1.4 days, 0.41 +/- 0.12 ml/min/kg and 8.91 +/- 3.00 l/kg group II, respectively. The comparison of kinetic parameters in groups I and II revealed no significant difference (P > 0.05) suggesting no drug interaction. These kinetic values in children given MSP suspension were considerably different to those in adult patients with shorter tmax, t1/2 and MRT. The coadministration of MSP and primaquine in children would benefit by reducing the transmission of malaria in endemic areas.

In vivo and in vitro sensitivity of Falciparum malaria to quinine in Thai children.

The study was carried out to assess the efficacy of quinine in children with Falciparum malaria in relation to in vitro sensitivity (measured in terms of minimum inhibitory concentration: MIC) and to trough serum levels of quinine during the course of treatment. Fifty children aged ten months to 12 years with Falciparum malaria were randomly divided into two groups. Group I: 24 children were treated with quinine 10 mg base per body weight every eight hours for 14 days. Group II: 26 children were treated with quinine at the dosage adjusted to the body surface area based on an adult dose of 500 mg base eight hourly for 14 days. There were three treatment failures, one RI and one RII in group I, and one RI in group II. The serum concentrations of quinine reached a peak level on day two and levelled off by the end of the first week. Concentrations in group II were higher than in group I. The mean minimal inhibitory concentration (MIC) of quinine in the two groups was 14.89 nmol per ml ranging from 8-26 nmol per ml. In cases with treatment failure, the trough serum quinine levels became lower than the corresponding MIC after day six (RI) and after day two (RII). The rise of MIC suggests that sensitivity of Falciparum malaria parasites to quinine may be decreasing in Thailand. Failures of treatment in standard dosage may occur in cases infected by parasites with high MIC, in which trough serum quinine levels cannot be maintained above the MIC longer than six days during the course of treatment. However in one cured case, the trough serum quinine levels were below the MIC throughout treatment. More research is needed on the real relationship between serum quinine concentrations, the MIC, and clinical and parasitological response to quinine.

In vivo and in vitro responses to quinine and quinidine of Plasmodium falciparum.

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.

Evaluation of an in vitro test method for the assessment of sensitivity of Plasmodium falciparum to pyrimethamine and sulfadoxine.

Twenty three Plasmodium falciparum isolates collected from two highly pyrimethamine/sulfadoxine-resistant areas of Thailand were evaluated for their in vitro responses to pyrimethamine, sulfadoxine and combinations of these two drugs in various conditions. The test procedure was based on inhibition of parasite multiplication and of schizont formation, using the recommended modified RPMI medium 1640 with PABA 0.5 mug per litre and folic acid 10 mug per litre (LPLF). The optimum blood/medium ratios and inoculum sizes for parasite multiplication and for schizont formation were 1:19, 100 mul/well and 1:9, 50 mul/well, respectively. The appropriate incubation period was 48 hours. It was found that inhibition of either parasite multiplication or schizont formation could be used as the endpoint for evaluating the antiplasmodial action of pyrimethamine and combined pyrimethamine/sulfadoxine in vitro for field investigations; however, inhibition of only parasite multiplication should be used for determination of sulfadoxine activity. The actions of pyrimethamine in the combination pyrimethamine/sulfadoxine in ratios of 1:80 and 1:200 were similar. In vitro testing using combined pyrimethamine/sulfadoxine should be more precise than pyrimethamine alone for monitoring parasite susceptibility to the combined drug (Fansidar).

Treatment of soil-transmitted nematode infections in children with mebendazole.

Treatment of soil-transmitted nematodes with mebendazole was carried out in 137 children aged 6--15 years in Thailand. There were 100 cases of hookworm infection, 37 of ascariasis, 16 of trichuriasis and 32 of strongyloidiasis. Mebendazole was given at 100 mg twice daily for three consecutive days irrespective of age or weight. The reduction rates as seen by mean egg counts four weeks after treatment were 94.9% for hookworm infection, 100% for ascariasis and 93.9% for trichuriasis; the reduction rates of the mean larval count in 15 cases of strongyloidiasis was 82.1%. No side-effects were observed. Mebendazole was thus confirmed as effective and safe in the treatment of soil-transmitted nematode infections in children in Thailand.

In vitro susceptibility of Plasmodium falciparum collected from pyrimethamine-sulfadoxine sensitive and resistant areas in Thailand.

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.

Red cell and plasma concentrations of combined quinine-quinidine and quinine in falciparum malaria.

Red cell and plasma quinine-quinidine, and quinine concentrations in children with uncomplicated falciparum malaria who were treated with a combination of quinine/quinidine/cinchonine (combined drug) and quinine alone, respectively, were measured, using the extraction fluorescence method. The cure rates obtained with the high dose regimen of the combined drug (100%) were significantly higher than in the low dose regimen group (37.5%) (p less than 0.05), and the quinine regimen produced a 50% cure rate. Similar mild and transient ECG effects were noted in both the combined drug group and the quinine group. In patients treated with the combined drug, quinine-quinidine concentrations in both red cell and plasma of the high dose regimen group were significantly higher than those in the low dose regimen group (p less than 0.001, p less than 0.001). In quinine-treated patients, red cell quinine concentration in those with RII failure was significantly lower than that in patients with cure or RI failure (p less than 0.05). Both red cell and plasma levels of quinine-quinidine were higher than quinine levels. The red cell:plasma quinine-quinidine concentration ratios rose steadily to the high level from day 3 to day 6, while the ratio of quinine alone fluctuated around the low level and then gradually fell. The evidence suggests that red cell drug concentrations are more closely related to the outcome of treatment than to plasma concentrations and that the combined drug may be very useful for treatment of multi-drug-resistant P. falciparum infections. Further study is needed.