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At least 19 recordsLinked to original sources
PubMed1990

Multiple-dose pharmacokinetic study of proguanil and cycloguanil following 12-hourly administration of 100 mg proguanil hydrochloride.

A pharmacokinetic study with 12-hourly doses of 100 mg proguanil hydrochloride over 15 days has been conducted in six adult male Malaysian volunteers. Steady state for proguanil was established after the fourth dose on Day 2, for the active metabolite cycloguanil as from Day 3 inclusive. The steady state mean peak concentration of proguanil was 1201.6 +/- 132.4 nmol/l, the mean trough concentration 650.0 +/- 58.1 nmol/l. The corresponding values for cycloguanil were 317.0 +/- 44.4 nmol/l (mean peak) and 230.8 +/- 35.1 nmol/l (mean trough). The profiles and peak/trough ratios of proguanil and cycloguanil with 12-hourly dosing offer better prospects for protection against malaria than those obtained with 24-hourly doses of 200 mg proguanil hydrochloride, the current routine in malaria chemoprophylaxis.

Adult↗
PubMed1989

Inter-subject variability in the metabolism of proguanil to the active metabolite cycloguanil in man.

1. The metabolism of proguanil to the active metabolite cycloguanil has been evaluated in 135 British Troops and 26 Kenyan schoolchildren. 2. Large inter-subject variability was observed in both plasma and urinary concentrations of proguanil and cycloguanil after standard doses of drug. 3. Based on the ratio of proguanil to cycloguanil (P/C) in urine the British troops formed a non-normal distribution. 90% of the population formed a discrete distribution with P/C ranging from 0.5 to 9.0 while the remaining 10% were scattered throughout the distribution to an extreme value of 39. A similar pattern of variability was observed using P/C from a 6 h plasma sample. 4. This variability was due to differences in the ability of individuals to metabolise proguanil to cycloguanil. 5. Thirteen schoolchildren who had experienced malaria during prophylaxis with proguanil and thirteen matched controls each received proguanil (100 mg). We could not discriminate between the two groups based on P/C ratio in either a 6 h plasma or 0-6 h urine sample.

Adolescent↗
PubMedDate not supplied

Variability in the metabolism of proguanil to the active metabolite cycloguanil in healthy Kenyan adults.

Extensive metabolizers (EM) and poor metabolizers (PM) of the malaria chemoprophylactic drug proguanil have been identified by measuring the proguanil/cycloguanil ratio in urine following a single dose of the pro-drug. The pharmacokinetic characteristics of proguanil were similar in 8 EM and 8 PM subjects, but there were significant differences between the 2 groups with respect to cycloguanil pharmacokinetics. In none of the PM subjects could cycloguanil be detected in whole blood samples at any time after proguanil dosage. Plasma cycloguanil was measureable in only 2 of 8 PM subjects, despite an analytical sensitivity in the high-performance liquid chromatographic assay of 1 ng/ml cycloguanil. A comparatively high proportion of Black Kenyan adults appear to metabolize proguanil poorly, possibly because they lack the specific mixed function oxidase which will accept proguanil as substrate.

Adult↗
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↗
PubMed1989

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

The effects of three separate antimalarial prophylactic regimens (proguanil, sulfisoxazole, and proguanil plus sulfisoxazole) and of vitamins in a control group were compared in a study population of 380 children living in a malaria endemic area along the Thai-Burmese border. The subjects, aged 5-16 years, were matched for age, weight, and presence of splenomegaly, then randomly assigned to one of the four groups. All medications were administered daily by the investigators and malaria smears were performed on a weekly basis. Among 99 subjects taking proguanil plus sulfisoxazole for a total of 1464 man-weeks, there was only one case of falciparum and no vivax malaria. Statistically, this regimen proved superior to each of the other groups against both Plasmodium falciparum and P. vivax. The data show that proguanil alone, as a causal or suppressive prophylatic, has poor efficacy against P. falciparum. Side-effects were infrequent and generally mild, except for two subjects whose sulfisoxazole prophylaxis was discontinued because of urticarial rash.

Adolescent↗
PubMedDate not supplied

Proguanil-sulphonamide for malaria prophylaxis.

There are few safe, effective chemoprophylactic regimens for preventing Plasmodium falciparum infection in south-east Asia. In two randomized placebo-controlled trials, combinations of proguanil and sulphonamide were tested for chemoprophylactic activity in schoolchildren, aged 6-15 years, living near the Thai-Burmese border. Proguanil at an equivalent adult dose of 200 mg/d was combined with sulphafurazole (= sulfisoxazole) at 25 mg/kg/d or sulphamethoxazole at 25 and 10 mg/kg/d. Combinations of daily proguanil/sulphafurazole and proguanil/sulphamethoxazole were equally effective (greater than 75%) against both falciparum and vivax malaria when the sulphonamide component was used at 25 mg/kg/d. Proguanil and sulphamethoxazole at 10 mg/kg/d was ineffective. Approximately 1% of the children had sulphonamide-related skin rashes which resolved when treatment stopped. Proguanil/sulphonamide is a possible alternative chemoprophylactic regimen in areas with multiple drug-resistant P. falciparum.

Adolescent↗
PubMed1990

The pharmacokinetics and activation of proguanil in man: consequences of variability in drug metabolism.

1. Based on the ratio of drug to active metabolite excreted in urine approximately 3% of a healthy Caucasian population showed a reduced ability to convert proguanil to cycloguanil. 2. Pharmacokinetic analysis showed that this observation resulted from a reduced oral clearance of proguanil in these individuals (245, 534 and 552 ml min-1) compared with the rest of the population (858 +/- 482 ml min-1). 3. Peak plasma concentrations of active metabolite were significantly lower in these subjects (54.2, 26.8 and 51.7 ng ml-1) compared with the rest of the population (141 +/- 45.2 ng ml-1). 4. The observed variability may result from the polymorphic metabolism of proguanil in man.

Biotransformation↗
PubMed1991

How safe is proguanil? A post-marketing investigation of side-effects.

Side-effects of proguanil reported to the Swedish Adverse Drug Reaction (ADR) register from 1981 to 1988 are described and related to sales figures of the drug in Sweden during the same period. One serious reaction, thrombocytopenia, and 7 minor reactions, mainly urticaria and exanthema were believed to be causally related to proguanil intake in an estimated 60,000 users of the drug. Proguanil can be considered a very safe drug but rare hematological side-effects may possibly occur.

Adult↗
PubMed1991

The effect of prophylaxis with chloroquine and proguanil on delayed-type hypersensitivity and antibody production following vaccination with diphtheria, tetanus, polio, and pneumococcal vaccines.

In vitro studies have shown that anti-malarial drugs suppress immunity. In this study, the effects of chloroquine and proguanil (Paludrine) on the cellular and humoral immune system were measured by two in vivo methods: 1) cell-mediated immunity (delayed cutaneous hypersensitivity) i.e., skin tests with seven delayed-type common antigens (Multitest) and 2) humoral immunity by measurement of specific antibody response to vaccination. Sixty healthy young individuals were randomized into four groups and given 1) no treatment (controls), 2) chloroquine diphosphate (500 mg/week), 3) chloroquine diphosphate (1,000 mg/week), or 4) proguanil hydrochloride (200 mg/day) for six weeks. Skin testing was performed on days 0 and 28. Vaccinations with diphtheria, tetanus, polio, and pneumococcal polysaccharide antigen vaccines were performed on day 28, and the presence of specific antibodies was determined on days 0, 28, and 42. The skin tests induced a significant increase in skin reactive areas from day 0 to day 28 in all groups. Furthermore, the skin test induced an increase in the level of specific IgG for diphtheria and tetanus, but had no effect on antibodies to antigens not included in the skin test. The results showed that there were no significant differences among the four groups regarding skin test areas and increases in antibody titers following vaccination. Therefore, it is concluded that in healthy persons, six weeks intake of chloroquine, even in double doses, or proguanil in chemoprophylactic dosages, does not induce any detectable suppression of delayed-type hypersensitivity or vaccination responses to diphtheria, tetanus, polio, or pneumococcal polysaccharide antigens.

Adult↗
PubMed1990

Multiple-dose kinetics in healthy volunteers and in vitro antimalarial activity of proguanil plus dapsone.

The multiple-dose kinetics of a daily dose of proguanil (200 mg) coadministered with dapsone (10 mg) was investigated in 6 healthy adult male volunteers. The kinetics of dapsone (DDS), monoacetyldapsone (MADDS), proguanil (PROG) and its active metabolite cycloguanil (CYCLO) were derived from plasma drug concentrations after the last maintenance dose. The following kinetic parameters (mean values) were estimated for DDS and PROG, respectively: maximum concentration (Cmax) = 285 and 151 ng/ml, minimum concentration (Cmin) = 125 and 31 ng/ml, elimination half-life (t1/2) = 23.3 and 18.3 h, plasma clearance (Cl) = 0.032 and 1.27 l/h/kg and apparent volume of distribution (Vss) = 1.05 and 33.32 l/kg. The Cmax, Cmin and t1/2 of CYCLO were 56 ng/ml, 17 ng/ml and 15.0 h, respectively. The antimalarial activity of the proguanil/dapsone combination was assessed in vitro by measuring the inhibition of re-invasion of two Plasmodium falciparum isolates grown in the presence of volunteers' sera. Both FC-27 [chloroquine (CQ)- and pyrimethamine (PYR)-sensitive] and K1 (CQ- and PYR-resistant) isolates were completely inhibited by the drug combination at steady-state concentrations. These findings suggest that the drug regimen may be effective against drug-resistant falciparum malaria.

Adult↗
PubMed1991

Proguanil daily or chlorproguanil twice weekly are efficacious against falciparum malaria in a holoendemic area of Tanzania.

The prophylactic efficacy of proguanil 100 mg (Paludrine) daily was compared to that of chlorproguanil 20 mg (Lapudrine) twice weekly in school children from Nyamisathi village, in a coastal area of Tanzania, 160 km south of Dar es Salaam. A total of 80 children were randomly allocated to three groups after radical treatment with a curative dose of mefloquine (Lariam). Seventy-six children were then followed up with daily prophylaxis and/or placebo for 13 weeks. All children in the group taking placebo prophylaxis were reinfected within 10 weeks whereas no parasites were detected in the children taking proguanil or chlorproguanil for prophylaxis. We conclude that both regimens were efficacious and that chlorproguanil represents an important alternative for chemoprophylaxis if taken at least twice weekly instead of the recommended once weekly regimen.

Adolescent↗
PubMed1991

[Chemoprophylaxis of Plasmodium falciparum malaria by a combination of 100 mg of chloroquine and 200 mg of proguanil per day in a zone III of chloroquine resistance (Gabon). Study of 431 French soldiers].

Incidence of P. falciparum malaria in french non-immune soldiers serving in Gabon for four months has increased from 21% in 1987 to 37% in 1988. Since 1989, in a first step, the personal protection measures were reinforced. Thereafter, the usual chemoprophylaxis (chloroquine 100 mg daily) was replaced by a daily association of chloroquine 100 mg and proguanil 200 mg. A 85% decrease of malaria incidence was observed in 431 soldiers. The effects of the personal protection strengthening and of the new chemoprophylaxis can be evaluated to be respectively responsible for 50% and 71% decrease. Among the secondary effects, gastric pain was the most frequent, but it was never a cause of chemoprophylaxis stopping. The mouth ulcer frequency was far lower than that elsewhere reported. No significant biological abnormalities could be related to the chloroquine-proguanil association.

Animals↗
PubMed1977

Experimental studies of the potentiation of proguanil and pyrimethamine by dapsone using Plasmodium berghei in white mice.

An accurate system with stringent criteria has been established to test antimalarial drugs and drug combinations against Plasmodium berghei in mice. Minimum effective doses for a number of antimalarial drugs have been determined when used in this system. Considerable potentiation of the activity of pyrimethamine and to a somewhat less extent of proguanil by dapsone has been demonstrated. The need to extend studies of these combinations to the parasites of human malaria is discussed in terms of establishing a safe chemoprophylactic regime in the presence of drug-resistant strains of parasites.

Animals↗
PubMed1991

The activation of the biguanide antimalarial proguanil co-segregates with the mephenytoin oxidation polymorphism--a panel study.

The activation of the antimalarial drug proguanil (PG) to the active metabolite cycloguanil (CG) has been evaluated in a panel of 18 subjects. These subjects had previously been screened and classified as mephenytoin poor (PMm) or extensive metabolisers (EMm) and sparteine poor (PMs) or extensive metabolisers (EMs). Five subjects had the phenotype PMm/EMs, one was PMm/PMs, six subjects were EMm/PMs and six were EMm/EMs. The PG/CG ratio in urine (8 h) was significantly higher in PMm than in EMm (P = 0.0013). This study shows that the P450-isozyme involved in the polymorphic oxidation of mephenytoin is of critical importance in the activation of PG to CG and this may explain the large intersubject variability in CG concentrations in man. PMm make up about 3% of Caucasians, but up to about 20% of Orientals. From the present study, it may be anticipated that the antimalarial effect of PG is absent or impaired in this phenotype. The sparteine polymorphism appeared not to influence the activation of PG to CG significantly.

Adult↗
PubMed1991

Prolonged malaria prophylaxis with chloroquine and proguanil (chloroguanide) in a nonimmune resident population of an endemic area with a high prevalence of chloroquine resistance.

One hundred thirty nonimmune subjects living in Yaoundé, Cameroon, completed an 18-month prospective study on the efficacy and safety of weekly chloroquine and daily proguanil (chloroguanide) (Ch-P) in malaria prevention. A total of 9 of 78 Ch-P-treated subjects and 26 of 52 subjects who received no prophylaxis contracted Plasmodium falciparum infection during this period (P less than 0.00005). These two groups were comparable for demographic parameters and degree of exposure. Clinical manifestations were of similar severities in the two groups, but parasite counts were significantly higher in the subjects who received no prophylaxis (P less than 0.00005). Side effects of prophylaxis were frequent (31%), minor, and related to chloroquine, and they usually resolved within 4 to 6 weeks. Prolonged administration of Ch-P is safe and effectively prevents P. falciparum malaria in an endemic area with a high prevalence of chloroquine resistance.

Adult↗