Atovaquone and proguani hydrochloride compared with chloroquine or pyrimethamine/sulfodaxine for treatment of acute Plasmodium falciparum malaria in Peru.

The efficacy and safety of a fixed-dose combination of atovaquone and proguanil hydrochloride (Malarone) were compared with chloroquine or pyrimethamine/sulfadoxine in patients with acute falciparum malaria in northern Peru. Patients were initially randomized to receive 1,000 mg atovaquone and 400 mg proguanil hydrochloride daily for 3 days (n=15) or 1,500 mg chloroquine (base) over a 3 day period (n=14) (phase 1). The cure rate with chloroquine was lower than expected and patients were subsequently randomized to receive a single dose of 75 mg pyrimethamine and 1,500 mg sulfadoxine (n=9) or atovaquone/proguanil as before (n=5) (phase 2). In phase 1, atovaquone/proguanil was significantly more effective than chloroquine (cure rate 100% [14/14] vs. 8% [1/13], P<0.0001). In phase 2, atovaquone/proguanil and pyrimethamine/sulfadoxine were both highly effective (cure rates 100% [5/5] and 100% [7/7]). There were no significant differences between treatment groups in parasite or fever clearance times. Adverse events were typical of malarial symptoms and did not differ significantly between groups. Overall efficacy of atovaquone/proguanil was 100% for treatment of acute falciparum malaria in a region with a high prevalence of chloroquine resistance.

Atovaquone and proguanil hydrochloride compared with choroquine or pyrimethamine/sulfadoxine for treatment of acute Plasmodium falciparum malaria in Peru

The efficacy and safety of a fixed-dose combination of atovaquone and proguanil hydrochloride (Malarone TM) were compared with chloroquine or pyrimethamine/sulfadoxine in patients with acute falciparum malaria in northern Peru. Patients were initially randomized to receive, 1,000 mg atovaquone and 400 mg mg proguanil hydrochloride daily for 3 days (n=15) or 1,500 mg chloroquine (base) over a 3 day period (n=14) (phase 1). The cure rate with chloroquine was lower than expected and patients were subsequently randomized to receive a single dose of 75 mg pyrimethamine and 1,500 mg sulfadoxine (n=9) or atovaquone/proguanil as before (n=5) (phase 2). In phase 1, atovaquone/proguanil was significantly more effective than chloriquine (cure rate 100 percent [14/14] versus 8 percent [1/13], P<0.0001). In phase 2, atovaquone/proguanil and pyrimethamine/sulfadoxine were both highly effective (cure rates 100 percent [5/5] and 100 percent [7/7]). There were no significant differences between treatment groups in parasite or fever clearance times. Adverse events were typical of malarium symptoms and did not differ significantly between groups. Overall efficacy of atovaquone/proguanil was 100 percent for treatment of acute falciparum malaria in a region with a high prevalence of chloroquine resistance.

Head injury monitoring using cerebral microdialysis and Paratrend multiparameter sensors.

INTRODUCTION: Following head injury complex pathophysiological changes occur in brain metabolism. The objective of the study was to monitor brain metabolism using the Paratrend multiparameter sensor and microdialysis catheters. PATIENTS, MATERIAL AND METHODS: Following approval by the Local Ethics Committee and consent from the relatives, patients with severe head injury were studied using a triple bolt inserted into the frontal region, transmitting an intracranial pressure monitor, microdialysis (10 mm or 30 mm membrane; glucose, lactate, pyruvate, glutamate) catheter and Paratrend multiparameter (oxygen, carbon dioxide, pH and temperature) sensor. A Paratrend sensor was also inserted into the femoral artery for continuous blood gas analysis. RESULTS: 21 patients were studied with cerebral microdialysis for a total of 91 monitoring days (range 19 hours to 12 days). Of these, 14 patients were also studied with cerebral and arterial Paratrend sensors. The mean (+/- 95% confidence intervals) arterial and cerebral oxygen levels were 123 +/- 10.9 mmHg and 27.9 +/- 5.71 mmHg respectively. The arterial and cerebral carbon dioxide levels were 34.3 +/- 2.35 mmHg and 45.3 +/- 3.07 mmHg respectively. Episodes of systemic hypoxia and hypotension resulting in falls in cerebral oxygen and rises in cerebral carbon dioxide were rapidly detected by the arterial and cerebral Paratrend sensors. Systemic pyrexia was reflected in the brain with the cerebral Paratrend sensor reading 0.17 degree C (mean) higher than the arterial sensor. Elevations of cerebral glucose were detected, but the overall cerebral glucose was low (mean 1.57 +/- 0.53 mM 10 mm membrane; mean 1.95 +/- 0.68 mM 30 mm membrane) with periods of undetectable glucose in 6 patients. Lactate concentrations (mean 5.08 +/- 0.73 mM 10 mm membrane; mean 8.27 +/- 1.31 mM 30 mm membrane) were higher than glucose concentrations in all patients. The lactate/pyruvate ratio was 32.1 +/- 5.16 for the 10 mm membrane and 30.6 +/- 2.17 for the 30 mm membrane. Glutamate concentrations varied between patients (mean 15.0 +/- 10.5 microM 10 mm membrane; mean 28.8 +/- 17.8 microM 30 mm membrane). CONCLUSION: The combination of microdialysis catheters and Paratrend sensors enabling the monitoring of substrate delivery and brain metabolism, and the detection of secondary metabolic insults has the potential to assist in the management of head-injured patients.

A new cranial access device for cerebral monitoring.

We report the design and clinical application of a new cranial access device (triple bolt) designed to transmit intracranial pressure monitors, multiparameter sensors, microdialysis catheters and laser doppler probes into the cerebral parenchyma. The objective was to achieve insertion on the Neuro-Critical Care Unit, imaging compatibility, angled trajectories and versatility of monitor application. The bolt has been successfully applied to 100 patients with severe head injury and subarachnoid haemorrhage.

Clinical cerebral microdialysis: a methodological study.

OBJECT: Clinical microdialysis enables monitoring of the cerebral extracellular chemistry of neurosurgical patients. Introduction of the technique into different hospitals' neurosurgical units has resulted in variations in the method of application. There are several variables to be considered, including length of the catheter membrane, type of perfusion fluid, flow rate of perfusion fluid, and on-line compared with delayed analysis of samples. The objects of this study were as follows: 1) to determine the effects of varying catheter characteristics on substance concentration; 2) to determine the relative recovery and true extracellular concentration by varying the flow rate and extrapolating to zero flow; and 3) to compare substance concentration obtained using a bedside enzyme analyzer with that of off-line high-performance liquid chromatography (HPLC). METHODS: A specially designed bolt was used to conduct two adjacent microdialysis catheters into the frontal cortex of patients with head injury or poor-grade subarachnoid hemorrhage who were receiving ventilation. One reference catheter (10-mm membrane, perfused with Ringer's solution at 0.3 microl/minute) was constant for all studies. The other catheter was varied in terms of membrane length (10 mm or 30 mm), perfusion fluid (Ringer's solution or normal saline), and flow rate (0.1-1.5 microl/minute). The effect of freezing the samples on substance concentration was established by on-line analysis and then repeated analysis after storage at -70 degrees C for 3 months. Samples assayed with the bedside enzyme analyzer were reassessed using HPLC for the determination of glutamate concentrations. CONCLUSIONS: Two adjacent microdialysis catheters that were identical in membrane length, perfusion fluid, and flow rate showed equivalent results. Variations in perfusion fluid and freezing and thawing of samples did not result in differences in substance concentration. Catheter length had a significant impact on substance recovery. Variations in flow rate enabled the relative recovery to be calculated using a modification of the extrapolation-to-zero-flow method. The recovery was approximately 70% at 0.3 microl/minute and 30% at 1 microl/minute (10-mm membrane) for all analytes. Glutamate results obtained with the enzyme analyzer showed good correlation with those from HPLC.

On-line monitoring of substrate delivery and brain metabolism in head injury.

Head injury is associated with complex pathophysiological changes in metabolism. The objective of the study was to investigate these changes by applying on-line bedside monitoring of cerebral metabolism using microdialysis. Following approval by the Local Ethics Committee and consent from the next of kin, a microdialysis catheter was inserted into the frontal cortex of patients with severe head injury. Twenty-one patients were studied for 102.3 +/- 26.9 hours (mean +/- 95% confidence interval; total 89.4 patient monitoring days). The overall cerebral glucose (mean of means) was 1.63 +/- 0.31 mM with periods of undetectable glucose recorded. The cerebral lactate and lactate/pyruvate ratio were 4.69 +/- 0.61 mM and 29.9 +/- 3.73 respectively. Patients who died (n = 4) or who were severely disabled (not proceeding to rehabilitation, n = 5) had a tendency towards lower glucose (1.39 +/- 0.35 mM), higher lactate (5.10 +/- 1.02 mM) and higher lactate/pyruvate ratios (35.5 +/- 7.67) compared to patients with good outcome (home or proceeding to rehabilitation, n = 12, glucose 1.80 +/- 0.49 mM, lactate 4.38 +/- 0.85 mM, lactate/pyruvate ratio 27.9 +/- 4.33). Trends in these metabolic parameters relating to outcome were identifiable. In the majority of patients, cerebral glutamate levels (overall mean of means 9.47 +/- 4.59 microM) were initially high and then declined to stable levels. Patients in whom the glutamate level remained elevated or in whom secondary rises in glutamate were seen had a poor outcome. The application of bedside analysis of microdialysis enables the progress of the patient to be monitored on-line. In addition to establishing trends of improving and deteriorating metabolism, the technique has the potential to monitor the effects of therapeutic manoeuvres on the biochemistry.

Atovaquone and proguanil versus pyrimethamine/sulfadoxine for the treatment of acute falciparum malaria in Zambia.

Atovaquone and proguanil hydrochloride are blood schizonticides that demonstrate in vitro synergy against drug-resistant strains of Plasmodium falciparum. When coadministered, they may therefore be effective for the treatment of malaria in regions where there is known or suspected drug resistance. In an open-label, randomized, parallel-group, clinical trial conducted in Zambia, 163 patients (age range, 14 to 54 years) with acute P falciparum malaria were randomly assigned to receive treatment with atovaquone and proguanil hydrochloride (1000 and 400 mg, respectively, administered orally at 24-hour intervals for 3 doses; n = 82) or pyrimethamine/sulfadoxine (75/1500 mg administered orally as a single dose; n = 81). Efficacy was assessed by cure rate (the percentage of patients in whom parasitemia was eliminated and did not recur during 28 days of follow-up), parasite clearance time (PCT), and fever clearance time (FCT). Safety was determined by sequential clinical and laboratory assessments over 28 days. Cure rates did not differ significantly between patients treated with atovaquone and proguanil (100%) and those treated with pyrimethamine/sulfadoxine (98.8%). Patients in the atovaquone and proguanil group had a significantly shorter FCT than patients in the pyrimethamine/sulfadoxine group (mean, 30.4 vs 44.9 hours; P < 0.05) but a longer PCT (mean, 64.0 vs 51.4 hours; P < 0.05). Both treatments were well tolerated; adverse events and laboratory abnormalities were typical of those normally observed in patients with malaria. In this study, the combination of atovaquone and proguanil was equally effective and as well tolerated as pyrimethamine/sulfadoxine for the treatment of acute, uncomplicated, drug-resistant falciparum malaria in Zambia.

Monitoring of brain metabolism during aneurysm surgery using microdialysis and brain multiparameter sensors.

The aim of the study was to monitor brain metabolism during aneurysm clipping using microdialysis and multiparameter sensors, particularly to investigate the effects of temporary clipping of vessels. Microdialysis catheters (n = 10) and Paratrend brain multiparameter (O2, CO2, pH and temperature) sensors (n = 15) were inserted into the cerebral cortex via a specially designed triple bolt prior to craniotomy. Baseline brain O2 levels ranging from 15-45 mmHg (2.0-6.0 kPa) and glucose levels from 0.5-3 mmol l-1 were stable during uneventful periods. The mean lactate/pyruvate (L/P) ratio ranged from 32 to 65 (normal < 30), indicating a tendency towards anerobic metabolism in all patients. Overall, short periods of temporary clipping (< 3 min; n = 6) were well tolerated producing no significant reduction in brain O2 (pre-clip mean 23 mmHg (3.0 kPa) vs. post-clip mean 20 mmHg (2.6 kPa)) or elevation of the L/P ratio (pre-clip mean 42 vs. post-clip mean 43). Two patients with prolonged temporary clipping showed derangements in the Paratrend parameters associated with increases in the L/P ratio. The results demonstrated that the monitored variables remained stable during uneventful procedures, including transient temporary clipping, but adverse events such as prolonged temporary clipping resulted in pronounced changes in brain metabolism. Monitoring of metabolism during aneurysm surgery may be of benefit in selected patients.

Combination atovaquone and proguanil hydrochloride vs. halofantrine for treatment of acute Plasmodium falciparum malaria in children.

BACKGROUND: Malaria is a major cause of pediatric mortality in sub-Saharan Africa. Worldwide estimates of mortality among children with Plasmodium falciparum malaria range from 1 to 2 million deaths per year. Management of malaria is increasingly difficult because of the global spread of drug-resistant strains of P. falciparum. There is an urgent need for safe and effective new therapies to treat multidrug-resistant malaria. METHODS: This open label, randomized trial compared atovaquone and proguanil hydrochloride with halofantrine for treatment of acute, uncomplicated P. falciparum malaria in children age 3 to 12 years (84 patients per group). Study drug dosages were adjusted by weight (approximately 20 and 8 mg/kg daily for three doses for atovaquone and proguanil hydrochloride and 8 mg/kg every 6 h for three doses for halofantrine). Patients were monitored by serial clinical and laboratory assessments for 28 days after starting treatment. RESULTS: Both regimens were effective (cure rate, 93.8% for atovaquone and proguanil hydrochloride and 90.4% for halofantrine) and produced prompt defervescence. Mean parasite clearance times were 50.2 h for halofantrine and 64.9 h for atovaquone and proguanil hydrochloride. More adverse experiences were reported in children treated with halofantrine (119) than with atovaquone and proguanil hydrochloride (73). CONCLUSIONS: In Kenyan children the combination of atovaquone and proguanil hydrochloride has efficacy comparable with that of halofantrine for treatment of acute uncomplicated multidrug-resistant falciparum malaria and is associated with a lower rate of adverse events.

Atovaquone-proguanil compared with chloroquine and chloroquine-sulfadoxine-pyrimethamine for treatment of acute Plasmodium falciparum malaria in the Philippines.

This randomized, open-label clinical trial compared a fixed-dose combination of atovaquone and proguanil (n=55) with chloroquine (n=23) or a combination of chloroquine, sulfadoxine, and pyrimethamine (n=32) for treatment of acute falciparum malaria in the Philippines. Patients were hospitalized for 28 days to ensure medication compliance and prevent reinfection. Atovaquone-proguanil produced a significantly higher cure rate (100%) compared with that for chloroquine (30.4%; P<.0001) or chloroquine-sulfadoxine-pyrimethamine (87.5%; P<.05). Treatments did not differ significantly with respect to parasite clearance time (mean: 46.7 h for atovaquone-proguanil, 60.0 h for chloroquine, and 42.8 h for chloroquine-sulfadoxine-pyrimethamine) or fever clearance time (mean, 38.8, 46.8, and 34.5 h, respectively). Adverse events were typical of malaria symptoms; the most frequently reported events were vomiting (18% for atovaquone-proguanil, 17% for chloroquine, and 9% for chloroquine-sulfadoxine-pyrimethamine), abdominal pain (15%, 17%, and 3%, respectively), anorexia (11%, 13%, and 0%, respectively), and headache (6%, 17%, and 3%, respectively). Atovaquone-proguanil was well tolerated and more effective than chloroquine or chloroquine-sulfadoxine-pyrimethamine for treatment of multidrug-resistant falciparum malaria in the Philippines.

Efficacy and safety of atovaquone/proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand.

The increasing frequency of therapeutic failures in falciparum malaria underscores the need for novel, rapidly effective antimalarial drugs or drug combinations. Atovaquone and proguanil are blood schizonticides that demonstrate synergistic activity against multi-drug-resistant Plasmodium falciparum in vitro. In an open-label, randomized, controlled clinical trial conducted in Thailand, adult patients with acute P. falciparum malaria were randomly assigned to treatment with atovaquone and proguanil/hydrochloride (1,000 mg and 400 mg, respectively, administered orally at 24-hr intervals for three doses) or mefloquine (750 mg administered orally, followed 6 hr later by an additional 500-mg dose). Efficacy was assessed by cure rate (the percentage of patients in whom parasitemia was eliminated and did not recur during 28 days of follow-up), parasite clearance time (PCT), and fever clearance time (FCT). Safety was assessed by sequential clinical and laboratory assessments for 28 days. Atovaquone/proguanil was significantly more effective than mefloquine (cure rate 100% [79 of 79] vs. 86% [68 of 79]; P < 0.002). The atovaquone/proguanil and mefloquine treatments did not differ with respect to PCT (mean = 65 hr versus 74 hr) or FCT (mean = 59 hr versus 51 hr). Adverse events were generally typical of malaria symptoms and each occurred in < 10% of the patients in either group, with the exception of increased vomiting found in the atovaquone/proguanil group. Transient elevations of liver enzyme levels occurred more frequently in patients treated with atovaquone/proguanil than with mefloquine, but the differences were not significant and values returned to normal by day 28 in most patients. The combination of atovaquone and proguanil was well tolerated and more effective than mefloquine in the treatment of acute uncomplicated multidrug-resistant falciparum malaria in Thailand.

Malarone (atovaquone and proguanil hydrochloride): a review of its clinical development for treatment of malaria. Malarone Clinical Trials Study Group.

The continuing spread of drug-resistant malaria emphasizes the need for new antimalarial drugs. Atovaquone is a broad-spectrum antiprotozoal drug with a novel mechanism of action, via inhibition of parasite mitochondrial electron transport, and a favorable safety profile. Early studies with atovaquone alone for treatment of malaria demonstrated good initial control of parasitemia but an unacceptable rate of recrudescent parasitemia. Parasites isolated during recrudescence after treatment with atovaquone alone were resistant to atovaquone in vitro. The combination of atovaquone and proguanil is synergistic in vitro, and clinical studies demonstrated enhanced efficacy of the combination compared to either drug alone for treatment of malaria. Malarone, a fixed-dose combination of 250 mg of atovaquone and 100 mg of proguanil hydrochloride, is available in many countries for treatment of acute, uncomplicated malaria caused by Plasmodium falciparum. At the recommended dose (in adults, four tablets once a day for three days), the overall cure rate was > 98% in more than 500 patients with falciparum malaria. In four randomized, controlled clinical trials, treatment with atovaquone and proguanil hydrochloride was significantly more effective than mefloquine (Thailand), amodiaquine (Gabon), chloroquine (Peru and the Philippines) or chloroquine plus pyrimethamine/sulfadoxine (Philippines). In clinical trials where the comparator drug was highly effective, treatment with atovaquone and proguanil hydrochloride was equally effective. Parasites isolated during recrudescence after treatment with the combination of atovaquone and proguanil were not resistant to atovaquone in vitro. The most commonly reported adverse events in clinical trials (abdominal pain, anorexia, nausea, vomiting, diarrhea and coughing) occurred with similar frequency in patients treated with a comparator drug. Malarone is a safe and effective new agent for treatment of 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.

Population pharmacokinetics of atovaquone in patients with acute malaria caused by Plasmodium falciparum.

The population pharmacokinetics of atovaquone were examined in 458 black, Oriental, and Malay patients with acute Plasmodium falciparum malaria receiving atovaquone alone or concomitantly with other drugs. Oral clearance (CL/F) showed a 0.674 power relationship with weight and is similar in Oriental and Malay subjects but 58.5% lower in black subjects. On the basis of mean body weight, the population estimate of CL/F is 3.28, 8.49, and 9.13 L/hr in black, Oriental, and Malay subjects, respectively. The relationship between apparent volume of distribution (V area/F) and weight was linear and similar in all three races at 7.98 L/kg. The population estimate of V area/F is 345, 383, and 428 L in black, Oriental, and Malay subjects, respectively. The bioavailability of the high and low doses of atovaquone was similar. Neither CL/F nor V area/F were significantly affected by age, gender, and the coadministration with chloroguanide (proguanil), pyrimethamine, and tetracycline. Half-life (t1/2) showed a 0.326 power relationship with weight; thus, the population estimate of t1/2 in black, Oriental, and Malay subjects is 72.9, 31.3, and 32.5 hours, respectively. The final magnitudes of interpatient variability in CL/F and V area/F were 68% and 49%, respectively.

Population pharmacokinetics of proguanil in patients with acute P. falciparum malaria after combined therapy with atovaquone.

1. The pharmacokinetics of proguanil were evaluated in patients with acute P. falciparum malaria receiving concomitantly proguanil hydrochloride and atovaquone. The population consisted of 203 Blacks, 112 Orientals and 55 Malays; 274 males and 96 females. Of the 370 patients, 114 and 256 patients were classified as 'poor' and 'extensive' metabolizers of proguanil, respectively. Body weight and age ranged between 11-110 kg and 3-65 years, respectively. 2. A one compartment model with first-order absorption and elimination was fitted to proguanil plasma concentration-time profiles, using non-linear mixed effect modelling (NONMEM). 3. Oral clearance (CLo) showed a 0.785 power relationship with body weight and was 13% higher in Orientals than Blacks and Malays and 17% lower in 'poor' than 'extensive' metabolizers. According to the mean weight of each population, the final population estimates of CLo in Blacks, Orientals and Malays who are 'extensive' metabolizers were 54.0, 61.5 and 64.3 l h-1, respectively. Age, gender and dose had no significant effects on CLo. 4. Apparent volume of distribution (V/F) showed a 0.88 power relationship with body weight. The final population estimates were 562 and 1629 l in children (< or = 15 years) and patients aged > 15 years, respectively, who had a mean body weight of 22.6 and 54.8 kg, respectively. The effect of other covariates on V/F was not examined. 5. The final magnitudes of interpatient variability in CLo and V/F were relatively low at 22.5 and 17.0%, respectively. 6. Population pharmacokinetic parameter estimates in Black, Oriental and Malay patients with acute P. falciparum malaria are in good agreement with results of pharmacokinetic studies in healthy Caucasian volunteers. In view of the 30-50% residual variability in proguanil plasma concentrations, the slight effects of Orientals and 'poor' metabolizers on CLo are unlikely to be clinically significant. Hence, dose recommendation will be solely based on body weight.

Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand.

The therapy of Plasmodium falciparum malaria continues to be a problem in many parts of Southeast Asia because of multidrug resistance to nearly all existing antimalarial drugs. Atovaquone is a novel hydroxynaphthoquinone with broad spectrum anti-protozoal activity. We recently evaluated the antimalarial activity of atovaquone in a series of dose-ranging studies in 317 patients with malaria at the Bangkok Hospital for Tropical Diseases. Originally, the drug was administered alone. Using atovaquone alone resulted in satisfactory, initial clinical responses in all patients; the mean parasite and fever clearance times were 62 and 53 hr, respectively. However, irrespective of the duration of therapy, overall cure rates were approximately 67%. In vitro sensitivity studies on parasites taken from patients prior to treatment and at the time of recrudescence showed a marked decrease in susceptibility to atovaquone in the recrudescent parasites. To improve cure rates, atovaquone was administered in combination with other drugs with antimalarial activity. Proguanil and tetracycline were chosen due to laboratory evidence of potentiation; doxycycline was selected because it has a longer half-life than tetracycline. Although pyrimethamine did not show laboratory evidence of potentiation with atovaquone, it was chosen as an alternative inhibitor of dihydrofolic acid reductase with a longer half-life than proguanil. The clinical studies with these drug combinations confirmed the laboratory results with marked improvement in cure rates for proguanil, tetracycline, and doxycycline; pyrimethamine showed only minimal improvement. Proguanil was subsequently selected as the preferred drug partner because of its long record of safety and the ability to use the drug in pregnant women and children. Of the 104 patients with falciparum malaria treated with atovaquone plus proguanil for 3-7 days, 101 were cured and had virtually no adverse side effects. The combination of atovaquone and proguanil also was effective in eliminating erythrocytic forms of P. vivax, but parasitemia recurred in most patients.

Evaluation of atovaquone in the treatment of patients with uncomplicated Plasmodium falciparum malaria.

The activity of atovaquone in patients with oligosymptomatic Plasmodium falciparum malaria was assessed in an open, non-comparative clinical study. The patients showed a good clinical response, but there was a high rate of recrudescence. The activity of atovaquone in combination with another antimalarial agent should be investigated.