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PubMed1997

Atovaquone and proguanil for the treatment of malaria in Brazil.

The purpose of this study was to compare an experimental regimen of atovaquone plus proguanil with the standard regimen of quinine plus tetracycline for the treatment of uncomplicated falciparum malaria. The study was designed as an open, randomized study of men presenting with symptoms of uncomplicated malaria and thick-smear slide confirmation of parasitemia (1000-100,000 ring forms/microL). Subjects were hospitalized for 28 days to insure medication compliance and to rule out the possibility of reinfections. With 77 patients in each group, the cure rates were 98.7% and 100% for atovaquone plus proguanil and quinine plus tetracycline, respectively. The parasite clearance times (mean, 56 h) and fever clearance times (mean, 19 h) were significantly shorter in the atovaquone plus proguanil group, and there were significantly fewer side effects in the atovaquone plus proguanil group. Atovaquone plus proguanil is an efficacious, easily administered, safe regimen for the treatment of uncomplicated, multidrug-resistant falciparum malaria in Brazil.

Adolescent↗
PubMed1996

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.

Acute Disease↗
PubMed1989

Excretion of proguanil in human saliva.

After a single oral administration of a 300 mg dose of proguanil to six volunteers, the presence of the drug in saliva was established by chromatographic and spectrophotometric methods. The tmax and elimination half-life of proguanil derived from salivary levels were 4.0 +/- 1.26 h and 15.1 +/- 1.8 h, respectively. These results are in agreement with values previously reported for the drug using plasma level data. The mean saliva: plasma proguanil concentration ratio was 0.41 +/- 0.17 and this was not time dependent. There was a correlation (r = 0.82) between the saliva and simultaneous plasma proguanil concentration. The results suggest that proguanil is passively secreted into saliva and that saliva levels may be useful in the determination of pharmacokinetic parameters and the therapeutic monitoring of the drug.

Adult↗
PubMed1988

Malaria chemoprophylaxis in travellers to east Africa: a comparative prospective study of chloroquine plus proguanil with chloroquine plus sulfadoxine-pyrimethamine.

As malaria caused by Plasmodium falciparum has become resistant to chloroquine alternative drug regimens need to be developed. The prophylactic efficacy against malaria and the side effects of chloroquine phosphate 500 mg weekly with proguanil hydrochloride 200 mg daily was compared with the efficacy of chloroquine 500 mg weekly with sulfadoxine 500 mg-pyrimethamine 25 mg weekly in a randomised study of Scandinavian travellers to Kenya and Tanzania during 1984-5. A total of 767 subjects (416 male and 351 female; 384 taking chloroquine phosphate with proguanil hydrochloride and 383 taking chloroquine with sulfadoxine-pyrimethamine) completed a diary on the breakthrough of malaria and the side effects of treatment while taking the drugs. They were also asked to make thick blood films when symptoms like those of malaria occurred, which were sent to and analysed in Denmark. Four subjects taking chloroquine with proguanil hydrochloride and three taking chloroquine with sulfadoxine-pyrimethamine developed falciparum malaria, which was verified microscopically. Side effects were reported by 36 subjects taking chloroquine phosphate with proguanil hydrochloride and 55 taking the other regimen (p = 0.043). The side effects of both regimens were generally mild, but the combination of chloroquine phosphate with proguanil hydrochloride is recommended because it results in fewer side effects. As breakthroughs of malaria occurred at the earliest after seven weeks self treatment should not be recommended for travellers staying only a short time. Thick blood films are useful for diagnosis of suspected cases of malaria, can be prepared by non-specialists in Africa, and can be analysed successfully after long delays.

Adult↗
PubMed1988

Malaria prophylaxis with proguanil in children living in a malaria-endemic area.

We studied the effects of daily proguanil compared to weekly chloroquine as malaria prophylaxis in 170 children living in a malaria-endemic area along the Thai-Burmese border. Children aged 5-10 years were matched for age, weight, and presence of splenomegaly then randomly assigned to receive either proguanil (equivalent of 200 mg daily adult dose) or chloroquine (equivalent of 300 mg base weekly). All medications were administered by the investigators and malaria smears were performed on a weekly basis. Among 85 children taking proguanil for 524 human-weeks, there were 17 cases of falciparum malaria and 11 cases of vivax. Of 85 children on chloroquine for 537 human-weeks, there were 24 cases of falciparum and 1 case of vivax. There were no statistically significant differences between the two regimens when analyzed either as suppressive or as causal Plasmodium falciparum prophylactics. The data were suggestive that proguanil may have some causal prophylactic effect against falciparum malaria. There were significantly more vivax prophylactic failures (P less than 0.01) in the proguanil group. Side effects were infrequent, mild, and comparable in both groups.

Animals↗
PubMed1999

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.

Adult↗
PubMed1999

[Variability of in vitro activity of proguanil and cycloguanil on erythrocyte stages of Plasmodium falciparum as a function of culture conditions].

The in vitro activity of proguanil, cycloguanil (active metabolite of proguanil), pyrimethamine, and chloroquine was determined for 14 isolates of Plasmodium falciparum and the chloroquine-resistant W2 clone. In vitro assays were performed by using different types of RPMI 1640 culture medium and incubation period. The use of the standard RPMI medium or RPMI medium containing low concentrations of folate and para-aminobenzoic acid increases the 50% inhibitory concentrations of cycloguanil and pyrimethamine, as compared with the use of folate- and para-aminobenzoic acid-free RPMI medium. The concentrations of folate and para-aminobenzoic acid did not affect the in vitro activity of proguanil and chloroquine. However, prolongation of the incubation period from 42 to 66 hours decreased the 50% inhibitory concentrations of all test compounds. The weak antagonism in vitro between chloroquine and proguanil or cycloguanil does not seem to have any repercussion on the in vivo efficacy of chloroquine-proguanil combination.

Animals↗
PubMedDate not supplied

Daily chlorproguanil is an effective alternative to daily proguanil in the prevention of Plasmodium falciparum malaria in Kenya.

To test the efficacy of chlorproguanil prophylaxis, 156 malaria-free schoolchildren in the coastal region of Kenya were allocated at random to receive either 7.5 mg chlorproguanil daily, 50 mg chlorproguanil weekly, 100 mg proguanil daily, or 100 mg calcium lactate weekly (placebo). The children were followed up daily for 169 d, by which time Plasmodium falciparum parasitaemia had occurred in 92% of the placebo group, 31% of the daily proguanil group, 38% of the daily chlorproguanil group and 55% of the weekly chlorproguanil group. There was significant reduction (P < 0.001) in the risk of parasitaemia in all the groups receiving chemoprophylaxis. Daily chlorproguanil and daily proguanil were equally effective, and significantly more effective than weekly high dose chlorproguanil. No significant toxicity was reported or observed. Thus daily chlorproguanil 20 mg/60 kg is a cheap and effective alternative to proguanil for chemoprophylaxis.

Child↗
PubMed2006

Simultaneous determination of monodesethylchloroquine, chloroquine, cycloguanil and proguanil on dried blood spots by reverse-phase liquid chromatography.

A method for simultaneous analysis of chloroquine, proguanil and their metabolites from a whole blood sample (80 microL) dried on a filter paper was developed. Sample preparation included a liquid extraction from the filter paper, followed by a solid-phase extraction (C18 Bond Elut cartridge). Separation was obtained by reverse-phase liquid chromatography (HPLC) using a gradient elution on an X-Terra column; UV detection was made at 254 nm. This assay was linear between 150 and 2500 ng mL(-1) for chloroquine (and metabolite) and 300 and 2500 ng mL(-1) for proguanil and cycloguanil. The lower limit of quantification was close to 50 ng mL(-1) for chloroquine (and its metabolite) and 100 ng mL(-1) for proguanil (and its metabolite). No chromatographic interference from endogenous compounds or other tested anti-malarial drugs was evidenced. Chromatographic separation takes about 40 min with a coefficient of variation below 10.3% for within- and between-batch precision. The paper sampling method was validated in 10 healthy subjects treated by Savarine. The stability of compounds and metabolites on the filter paper was evaluated at four temperatures (-20, +4, 20 and 50 degrees C) and for 1, 5 and 20 days. Cycloguanil concentrations were not influenced by storage conditions, whereas, high temperatures and prolonged storage decreased chloroquine and proguanil levels. The proposed HPLC assay is accurate, precise and cost-effective; it can be used for pharmacokinetic and epidemiological studies on anti-malarial treatments.

Antimalarials↗
PubMed2005

Efficacy of chloroquine-proguanil malaria prophylaxis in a non-immune population in Bangui, Central African Republic: a case-control study.

A case-control study was conducted to evaluate the efficacy of the combination of chloroquine plus proguanil as malaria prophylaxis in a non-immune population living in the Central African Republic. Cases were patients presenting with a malaria attack confirmed by a positive blood film and/or an HRP2 positive antigen test at the Pasteur Institute of Bangui. Two control subjects were included per case: one was a relative or close friend and the other was matched to the patient with respect to the length of stay. A questionnaire assessing malaria prophylaxis habits and malarial risk factors over the 2-month period prior to inclusion in the study was given to 48 cases and 96 controls. A conditional logistic regression was used to identify risk factors. The efficacy of the chloroquine plus proguanil regimen was found to be high (95.5%, 95% CI 74.0-99.2%) in this country known for high chloroquine resistance. Our data lend some support to the use of chloroquine plus proguanil in Bangui, and the protective efficacy of chloroquine plus proguanil should now be studied prospectively as part of a randomised controlled trial of various prophylactic drugs.

Adolescent↗
PubMedDate not supplied

The mosquito transmission of malaria: the effects of atovaquone-proguanil (Malarone) and chloroquine.

Despite its recognized importance, the prevention of patients with malaria from continuing to infect mosquitoes after treatment is not always achieved in practice. An inevitable consequence of the prolonged life-span and relative metabolic stasis of the mature gametocytes of Plasmodium falciparum is that they are not cleared by most antimalarials, and few antimalarials block infection in the mosquito vector. Previous research on the constituents of Malarone, a new 'combined antimalarial', suggested that the active components, atovaquone and proguanil, might inhibit infectivity of gametocytes to mosquitoes. We contrast here the impact of atovaquone-proguanil and chloroquine on the transmission of P. falciparum and P. berghei. While chloroquine enhanced infectivity of P. falciparum, atovaquone-proguanil caused a significant reduction. Surprisingly, sporontocidal activity against the rodent parasite persisted long after the levels of the constituent drugs would have been expected to have fallen below effective plasma concentrations on the basis of the established pharmacokinetics of atovaquone and proguanil. The P. berghei model may thus have provided a sensitive bioassay, detecting drug(s) at levels below that normally found with the usual chemical assays.

Animals↗
PubMed1999

Safety and efficacy of atovaquone and proguanil hydrochloride for the prophylaxis of Plasmodium falciparum malaria in South Africa.

The objective of this study was to determine the safety and efficacy of atovaquone and proguanil hydrochloride combination therapy for the prophylaxis of Plasmodium falciparum malaria in at-risk nonimmune subjects in South Africa. This open-label trial was conducted at research sites in South Africa during the main malaria transmission season, February through July. The study volunteers were temporarily living in, or traveling to, a malaria-endemic area. They received I tablet of 250 mg atovaquone and 100 mg proguanil hydrochloride once daily for up to 10 weeks. Subjects were monitored using sequential clinical and laboratory assessments. Thick blood smears were stained and evaluated by a central laboratory. An immunochromatographic test for P. falciparum was also used for on-site patient management. Prophylactic success was summarized using a 95% confidence interval for the proportion of subjects who did not develop parasitemia or who withdrew due to a treatment-related adverse event. A total of 175 subjects (15% women) were enrolled in the trial. The mean duration of drug exposure was 8.9 weeks. The combination of atovaquone and proguanil hydrochloride was well tolerated. The most frequently reported adverse events considered possibly related to study treatment were headache (7%), abdominal pain (2%), increased cough (2%), and skin disorder (2%). No serious adverse events were reported, and no treatment-emergent effects were noted for any laboratory variables. One subject who was noncompliant with therapy developed parasitemia, and 3 subjects withdrew due to a treatment-related adverse event (2 subjects with headache and 1 with nausea and dizziness). The prophylaxis success rate was 97%. In this study, atovaquone and proguanil hydrochloride combination therapy had an excellent safety and efficacy profile for prophylaxis of P. falciparum malaria in nonimmune subjects.

Adult↗
PubMed1997

Modified high-performance liquid chromatographic method to measure both dextromethorphan and proguanil for oxidative phenotyping.

The activities of the polymorphic enzymes cytochromes P450 2D6 and 2C19 can be assessed by administering the probe drugs, dextromethorphan and proguanil, respectively. An existing high-performance liquid chromatographic technique, which measures dextromethorphan and its metabolites, has been modified to also measure proguanil and its polymorphic metabolite, cycloguanil in urine. Proguanil and cycloguanil are assayed in separate aliquots of urine to that used for dextromethorphan/dextrorphan as pretreatment with beta-glucuronidase is required for the analysis of dextrorphan. To assay all four compounds a common extraction procedure is used and a single reversed-phase column and isocratic mobile phase with UV and fluorescence detectors connected in series are required. This technique is specific and sensitive for each analyte (limits of detection, dextrorphan/dextromethorphan/proguanil: 0.1 microgram/ml, cycloguanil: 0.2 microgram/ml). All assays are linear over the concentration ranges investigated (dextromethorphan/dextrorphan: 0.5-10 micrograms/ml, proguanil/cycloguanil: 1-20 micrograms/ml). The method described therefore uses laboratory resources very efficiently for all the assays required for hydroxylation phenotyping using proguanil and dextromethorphan.

Antimalarials↗
PubMed1984

The activity of proguanil and its metabolites, cycloguanil and p-chlorophenylbiguanide, against Plasmodium falciparum in vitro.

Using an in vitro radioisotopic method, the activity was measured of proguanil, its metabolites cycloguanil and p-chlorophenylbiguanide (PBG), pyrimethamine, and chloroquine against seven Kenyan and three South East Asian strains of Plasmodium falciparum. Five Kenyan isolates were sensitive to both pyrimethamine and cycloguanil in vitro, while the Smith and two Kenyan strains were resistant to both these drugs. Cross-resistance was incomplete: the Camp strain was resistant to pyrimethamine but not cycloguanil, and the FVO strain was resistant to cycloguanil but not pyrimethamine. Both proguanil and PBG exhibited weak antimalarial activity in vitro, but inhibitory blood levels of either compound are unlikely to occur after a normal human dose of proguanil. The results indicate that the activity of proguanil against P. falciparum is due entirely to the action of its active metabolite cycloguanil.

Animals↗
PubMed1999

Intrinsic efficacy of proguanil against falciparum and vivax malaria independent of the metabolite cycloguanil.

Mutations in human CYP2C19 and parasite dihydrofolate reductase (dhfr) genes, related to poor metabolism of proguanil and resistance to cycloguanil, respectively, have both been assumed to be associated with poor antimalarial effect by proguanil. To study this, 95 subjects with uncomplicated Plasmodium falciparum or Plasmodium vivax infections in Vanuatu received proguanil treatment for 3 days (adult relative dose of 300-500 mg/day) and were followed up for 28 days. A similarly high antimalarial efficacy against both infections was observed in 62 patients with CYP2C19-related poor metabolizer genotype and in 33 with extensive metabolizer genotype, even though blood cycloguanil was significantly more often detected in those with extensive metabolizer genotype than in those with poor metabolizer genotype. All 28 P. falciparum isolates had two dhfr mutations (residues 59 and 108), suggesting moderate resistance to cycloguanil. The results suggest that the parent compound proguanil has significant intrinsic efficacy against falciparum and vivax malaria independent of the metabolite cycloguanil.

Adolescent↗
PubMed1998

Improved validated assay for the determination of proguanil and its metabolites in plasma, whole blood, and urine using solid-phase extraction and high-performance liquid chromatography.

An improved and validated method is presented for the determination of proguanil, cycloguanil, and 4-chlorophenylbiguanide in plasma, whole blood, and urine using solid-phase extraction (SPE) technique and reversed-phase high-performance liquid chromatography (HPLC). The HPLC method uses isocratic elution with acetonitrile:phosphate buffer 0.1 mol/l, pH 2.6 (21.5:78.5 vol/vol) at a flow rate of 1.0 ml/min for the separation. The recovery of proguanil and metabolites ranged from 82% to 104%. The limit of determination was 20 nmol/l for proguanil and its metabolites in plasma and approximately 50 nmol/l for proguanil and metabolites in whole blood. Different stationary phases for HPLC and SPE were tested and the best chromatographic separation from endogenous constituents and other antimalarial drugs was achieved with cyanopropyl stationary phases.

Antimalarials↗
PubMed1995

Evidence for the polymorphic oxidation of debrisoquine and proguanil in a New Zealand Maori population.

The genetic oxidation polymorphisms of debrisoquine and proguanil were studied in a New Zealand Maori population. A bimodal distribution was observed in the 0-4 h urinary debrisoquine/4-hydroxydebrisoquine metabolic ratio. Of 101 Maori subjects phenotyped, five subjects (5%) were identified as poor metabolizers of debrisoquine, according to criteria established in studies of Caucasian populations. The prevalence of the debrisoquine poor metabolizer phenotype in the Maori appears to be similar to that reported for the Caucasian populations, but higher than that found in Asian (non-Caucasian) populations. The distribution of proguanil:cycloguanil (PG:CG) ratios obtained from 43 Maori subjects was highly skewed. Using a PG:CG ratio of 10 as the cut-off point, three Maori subjects (7%) were classified as poor metabolizers of proguanil. The incidence of the poor metabolizer phenotype of proguanil oxidation of 7% seems to be higher in Maori compared with Caucasian populations, but this is lower than the usual ranges (15-35%) reported in Asian populations.

Adolescent↗
PubMed1995

Evidence for the polymorphic oxidation of debrisoquine and proguanil in a Khmer (Cambodian) population.

The frequency distributions of the urinary metabolic ratios of debrisoquine and proguanil were measured in a population of unrelated Khmers. Out of 98 Khmer subjects studied, two were identified as poor metabolisers of debrisoquine when a metabolic ratio of 12.6 was used as the cut off point. This represents a prevalence of debrisoquine poor metabolisers of 2.1% (95% confidence interval 0.25-7.3%) which is similar to other Asian populations. Based on the distribution of the ratio of proguanil to cycloguanil excreted in urine, and using an antimode value of 10, the prevalence of poor metabolisers of proguanil in a Khmer population was estimated to be 18.4% (95% confidence interval 10.9-28.1%). The frequency of poor metabolisers of proguanil in Khmers was higher than that described for Caucasian populations, but similar to most reported results in Asian populations.

Adrenergic Agents↗