SEARCH · Search PubMed

Results for “Proguanil”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources

PubMed1995

Daily primaquine is effective for prophylaxis against falciparum malaria in Kenya: comparison with mefloquine, doxycycline, and chloroquine plus proguanil.

Primaquine was tested as a prophylactic drug against Plasmodium falciparum in a region in western Kenya in which malaria is holoendemic. Children 9-14 years old were randomized to receive regimens of daily primaquine, daily doxycycline, daily proguanil plus weekly chloroquine, daily vitamin plus weekly mefloquine, or daily vitamin alone. Primaquine, doxycycline, and mefloquine were equally effective in preventing both symptomatic and asymptomatic malarial infections. Chloroquine plus proguanil was the least effective regimen. There was no toxicity from daily primaquine during the 11 weeks of the study. Findings show that primaquine can be successfully used as a causal prophylactic regimen against falciparum malaria in western Kenya; chloroquine plus proguanil was not as efficacious as the three other preventive regimens; most Kenyan children receiving standard doses of mefloquine and doxycycline had lower than expected serum trough drug levels; and some volunteers with adequate mefloquine or doxycycline levels at trough developed asymptomatic parasitemias and clinical malaria.

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↗

PubMed1994

Oxidative activation of proguanil and dapsone acetylation in Thai soldiers.

The prevalence of putative poor metaboliser (PM) phenotypes of proguanil oxidation in Caucasian populations is 3-10%. The PM frequency in Oriental populations is unknown. In this study the plasma metabolic ratios of proguanil and dapsone to their principal metabolites cycloguanil and monoacetyldapsone were determined in Thai soldiers receiving antifolate drug combinations for malaria prophylaxis. The distribution ratio of proguanil to cycloguanil (PROG/CYC) was highly skewed with no evidence of bimodality. Assuming subjects with a PROG/CYC ratio greater than 10 are PMs from studies in Caucasians, the incidence of PMs in the soldiers would be 18% (30 of 170). The mean PROG/CYC ratio for PMs in the Thai soldiers was 31.2 +/- 28.9 (n = 30) compared with 25.5 +/- 2.5 (n = 3) in a study of Caucasians. The corresponding values for putative EMs were 5.4 +/- 2.1 (n = 140) and 2.4 +/- 0.2 (n = 134). Similar to other Oriental populations, Thais were found to be predominantly (76%, 173 of 228) rapid acetylators of dapsone.

Acetylation↗

PubMed1996

Pharmacokinetic evaluation of proguanil: a probe phenotyping drug for the mephenytoin hydroxylase polymorphism.

1. Proguanil (PG) oxidative metabolism to cycloguanil (CG) has been linked to the CYP2C19-mediated genetic polymorphism in S-mephenytoin oxidative metabolism. In many countries, rac-mephenytoin can no longer be administered to humans and hence proguanil may be a more suitable probe for phenotyping purposes. 2. There are limited data on the pharmacokinetics of PG and CG and in particular, whether there is a relationship between the urinary metabolic ratio of PG and its partial intrinsic clearance to CG. 3. The disposition of a 100 mg oral dose of PG was investigated in 10 subjects with widely varying metabolic ratios (pre-study urinary metabolic ratio CG to PG = 0.068 to 1.11). Blood samples and all urine were collected for 96 h and assayed for PG and CG by h.p.l.c. 4. The urinary recovery of PG ranged from 30 to 69% of the dose and for CG from 2.8 to 32% of the dose. The overall urinary recovery of PG plus CG ranged from 54 to 77% of the dose. The AUC for PG ranged from 3.2 to 9.5 mg l-1 h whereas for CG it was from 0.02 to 0.71 mg l-1 h. The partial intrinsic clearance to CG ranged 25-fold from 0.41 to 10.1 l h-1. 5. There was a highly significant (r2 = 0.96, P < 0.001) relationship between the urinary metabolic ratio for PG (as CG/PG) and its partial intrinsic clearance to CG. 6. These data have provided evidence for the justification of the use of the urinary metabolic ratio of proguanil for population phenotyping purposes, provided systematic variation in renal drug clearance between populations is considered.

Adult↗

PubMed2004

Modified fixed-ratio isobologram method for studying in vitro interactions between atovaquone and proguanil or dihydroartemisinin against drug-resistant strains of Plasmodium falciparum.

A modified fixed-ratio isobologram method for studying the in vitro interactions between antiplasmodial drugs is described. This method was used to examine the interactions between atovaquone, proguanil, and dihydroartemisinin. The interaction between atovaquone and proguanil was synergistic against atovaquone-sensitive strains K1 and T996; however, there was a loss of synergy against atovaquone-resistant strain NGATV01 isolated after Malarone (the combination of atovaquone and proguanil) treatment failure. While the interaction between atovaquone and dihydroartemisinin was indifferent against isolate NGATV01, the interaction displayed indifference tending toward antagonism against the atovaquone-sensitive strains tested. The relevance of in vitro interactions to in vivo treatment is discussed.

Animals↗

PubMed1974

Relapses after withdrawal of proguanil treatment in tropical splenomegaly syndrome.

After the remission of symptoms and reduction in spleen size while on proguanil therapy four patients with the tropical splenomegaly syndrome defaulted from treatment. The withdrawal of proguanil caused a recrudescence of original symptoms, splenomegaly, and a return of the initially raised serum IgM. Complete return to normal values was again effected with proguanil therapy.The role of the spleen in the tropical splenomegaly syndrome in the production of the raised serum IgM is discussed. These patients should be educated as to the nature of their disease and the importance of continued medical treatment.

Adult↗

PubMed2006

Confirmation of emergence of mutations associated with atovaquone-proguanil resistance in unexposed Plasmodium falciparum isolates from Africa.

BACKGROUND: In vitro and in vivo resistance of Plasmodium falciparum to atovaquone or atovaquone-proguanil hydrochloride combination has been associated to two point mutations in the parasite cytochrome b (cytb) gene (Tyr268Ser and Tyr268Asn). However, little is known about the prevalence of codon-268 mutations in natural populations of P. falciparum without previous exposure to the drug in Africa. METHODS: The prevalence of codon-268 mutations in the cytb gene of African P. falciparum isolates from Nigeria, Malawi and Senegal, where atovaquone-proguanil has not been introduced for treatment of malaria was assessed. Genotyping of the cytb gene in isolates of P. falciparum was performed by PCR-restriction fragment length polymorphism and confirmed by sequencing. RESULTS: 295 samples from Nigeria (111), Malawi (91) and Senegal (93) were successfully analyzed for detection of either mutant Tyr268Ser or Tyr268Asn. No case of Ser268 or Asn268 was detected in cytb gene of parasites from Malawi or Senegal. However, Asn268 was detected in five out of 111 (4.5%) unexposed P. falciparum isolates from Nigeria. In addition, one out of these five mutant Asn268 isolates showed an additional cytb mutation leading to a Pro266Thr substitution inside the ubiquinone reduction site. CONCLUSION: No Tyr268Ser mutation is found in cytb of P. falciparum isolates from Nigeria, Malawi or Senegal. This study reports for the first time cytb Tyr268Asn mutation in unexposed P. falciparum isolates from Nigeria. The emergence in Africa of P. falciparum isolates with cytb Tyr268Asn mutation is a matter of serious concern. Continuous monitoring of atovaquone-proguanil resistant P. falciparum in Africa is warranted for the rational use of this new antimalarial drug, especially in non-immune travelers.

Adult↗

PubMedDate not supplied

Atovaquone-proguanil (malarone): an effective treatment for uncomplicated Plasmodium falciparum malaria in travelers from Denmark.

BACKGROUND: Previous experience with unacceptable adverse effects with mefloquine as treatment for uncomplicated Plasmodium falciparum malaria prompted an evaluation of the effectiveness and side effects of atovaquone-proguanil (Malarone) in a hospital setting. METHODS: Atovaquone-proguanil was given as standard treatment (1,000/400 mgq.d. for 3 days) to 50 adults who had traveled in Africa and returned with uncomplicated Plasmodium falciparum malaria. Half of the treated patients were African and had lived outside Africa for varying periods of time; the other half were Danish-born persons without any previous immunity towards malaria. RESULTS: All patients treated with Malarone were cured without complications. The mean fever clearance times differed among the groups and according to various degrees of prior exposure to malaria and ranged from 1.3 to 2.2 days. Adverse effects during treatment were mild, and were likely to be due to the malaria itself. Fourteen people who had acquired falciparum malaria in spite of taking proguanil-chloroquine prophylaxis were also cured uneventfully without recrudescence. CONCLUSIONS: Malarone appears to be an effective, safe and acceptable oral treatment for uncomplicated malaria.

Adult↗

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↗

PubMed1994

Proguanil plus sulfamethoxazole is not causally prophylactic in the Macaca mulatta--Plasmodium cynomolgi model.

New drugs for causal prophylaxis of malaria are needed. A proguanil/sulfamethoxazole combination was investigated using a rhesus monkey model (Macaca mulatta infected with Plasmodium cynomolgi) to determine whether causal prophylaxis could be achieved. When a five-day regimen of proguanil (40 mg/kg/day) combined with sulfamethoxazole (100 mg/kg/day) was used, infection of all animals (6 of 6) was observed, with an extended prepatent period (median 40 days). Two control animals became infected on days 9 and 23 following sporozoite inoculation. Plasma concentrations indicated that proguanil and sulfamethoxazole were adequately absorbed and metabolized to cycloguanil and N4-acetylsulfamethoxazole, respectively. Analysis of liver biopsy specimens demonstrated that the drugs were present two days following sporozoite inoculation but were not detectable one week later. Proguanil plus sulfamethoxazole does not eliminate exoerythrocytic-stage parasites in the rhesus monkey--P. cynomolgi model.

Animals↗

PubMed2002

Polyclonal Plasmodium falciparum malaria in travelers and selection of antifolate mutations after proguanil prophylaxis.

The polymorphism of malaria parasites will greatly influence the efficiency of antimalarial drugs and vaccines. This study determined the genetic diversity of Plasmodium falciparum infections in 107 travelers and estimated the importance of mutations in the parasite dihydrofolate reductase (dhfr) gene for clinical breakthrough during proguanil prophylaxis. Genotyping with regards to the three highly polymorphic antigen-coding regions (merozoite surface protein-1 [msp-1], msp-2, and the glutamate-rich protein [glurp]) revealed multiple genotypes (up to five) in 64% of the patients. Single genotype infections were mainly associated with prior intake of antimalarial drugs, but also with a shorter stay in a malaria-endemic area and low parasite density. Malaria breakthrough despite proguanil prophylaxis was always associated with mutations in the dhfr gene; always the Asn-108 mutation and often the Ile-51 and Arg-59 mutations. The Leu-164 mutation was found in four travelers from Africa. Travelers with limited time in an endemic area were often infected with polyclonal P. falciparum infections, which suggests that single mosquito inoculations are often composed of several genetically diverse parasites. Chemoprophylaxis reduces the number of infecting clones and selects for resistant parasites as shown for proguanil through mutations in the dhfr gene.

Adolescent↗

PubMed2002

Molecular epidemiology of malaria in Cameroon. XII. In vitro drug assays and molecular surveillance of chloroquine and proguanil resistance.

Chloroquine-proguanil combination is one of the options for chemoprophylaxis. The rapid evolution of drug resistance status requires a constant upgrade of epidemiologic data. Due to various difficulties in conducting prospective clinical studies on the prophylactic efficacy of the drug combination, especially in highly chloroquine-resistant zones, in vitro drug sensitivity assays and specific molecular markers for chloroquine (Plasmodium falciparum chloroquine-resistance transporter, pfcrt) and cycloguanil (a biologically active metabolite of proguanil; dihydrofolate reductase, dhfr) resistance were evaluated as an alternative approach in this study. Of 116 isolates, 62 (53.4%) were doubly resistant in vitro to chloroquine (IC50 > or = 100 nM) and cycloguanil (IC50 > or = 15 nM). Likewise, 62 of 118 isolates (52.5%) carried both the mutant Thr-76 pfcrt allele and at least one dhfr mutant allele (1 with a single Asn-108 allele, 8 with double Arg-59 and Asn-108 mutations, and 53 with triple Ile-51, Arg-59, and Asn-108 mutations). The in vitro drug response corresponded with the presence or absence of key mutation(s) in the pfcrt and dhfr genes. These results suggest the high proportion of P. falciparum isolates in southern Cameroon that may not respond to chloroquine-proguanil combination.

Animals↗

PubMed2001

[symbol: see text] Atovaquone + proguanil for malaria prophylaxis.

[symbol: see text] Atovaquone + proguanil (Malarone--GlaxoSmithKline) is a fixed-dose combination of two antiparasitic drugs. In 1996, it was licensed in the UK for the treatment of acute, uncomplicated falciparum malaria. Earlier this year, the combination was licensed additionally for prophylaxis of falciparum malaria. The manufacturer claims that, when used for prophylaxis, atovaquone + proguanil "offers 97% efficacy with a side effect profile similar to placebo". Here, we assess these claims and review the place of atovaquone + proguanil as prophylaxis for non-immune people travelling from the UK.

Antimalarials↗

PubMed2003

[Three newly registered drugs in the Netherlands for the treatment and chemoprophylaxis of malaria: atovaquone-proguanil, artemether-lumefantrine and artemotil].

Three new antimalarial drugs have recently been registered in the Netherlands: atovaquone-proguanil, artemether-lumefantrine and artemotil. These drugs are effective against parasites with multiple resistance. Atovaquone-proguanil and artemether-lumefantrine seem in practice to be equivalent for the treatment of non-severe Plasmodium falciparum infections for respectively persons of more than 11 kg and persons aged 12 years and older (35 kg). Artemotil (intramuscular injection) is registered for the treatment of severe malaria in children up to 17 years of age. Atovaquone-proguanil is also registered for prophylactic use in adults. The intravenous administration of quinine is preferable in the case of seriously ill patients. In patients with non-severe malaria for whom parenteral treatment is indicated, artemotil is a good alternative for quinine.

Antimalarials↗

PubMed1987

The pharmacokinetics of proguanil in human subjects following a single oral dose.

The pharmacokinetics of orally administered 200-mg dose of proguanil in volunteers, one African and one Caucasian, is described. The drug was rapidly absorbed reaching a peak concentration in the blood within 3 h, and declining slowly thereafter to give a terminal phase elimination half life of 11.20 +/- 4.10 h and a systemic clearance of 1.270 +/- 0.020 l/h/kg. The small apparent volume of distribution shows that the drug is confined mainly to the blood and is not extensively bound to tissues; it undergoes cyclic oxidation in the liver to cycloguanil--the active metabolite responsible for antimalarial activity. Cycloguanil was detected in the plasma 3 h after proguanil ingestion and reached peak concentration between 5 h and 6 h. Excretion of proguanil was rapid, 60% of the single dose passing through the renal system within 24 h.

Administration, Oral↗

PubMed1985

Effect of proguanil and cycloguanil on human lymphocytes in vitro.

The in vitro effect of proguanil and its active metabolite cycloguanil on proliferating human blood mononuclear cells was studied. Proguanil had no effect on 14C-thymidine incorporation or on the number of cells. Cycloguanil, in concentrations corresponding to the plasma levels found in clinical practice, blocked the endogenous synthesis of thymidine and decreased the number of mitogen- and antigen-stimulated cells. The effect on phytohaemagglutinin-stimulated cells was transient. Higher concentrations of cycloguanil, corresponding to intralymphocytic levels in clinical practice, permanently suppressed the growth of lymphocytes. The effect of cycloguanil could be reversed by low doses of folinic acid and high doses of folic acid.

Humans↗

PubMed1986

Failure of malaria chemoprophylaxis with a proguanil-chloroquine combination in Papua New Guinea.

Proguanil 200 mg daily and chloroquine base 300 mg weekly were used as prophylaxis for 120 British Army soldiers from Hong Kong on a seven-week jungle exercise in the highly malarious Sepik district of Papua New Guinea. Compliance was rigidly enforced. Four men developed falciparum malaria whilst in Papua New Guinea and one within a few days of returning to Hong Kong. After stopping chloroquine four weeks after returning to Hong Kong 11 cases of mixed vivax and falciparum malaria and three cases of falciparum alone occurred within a 16-week period. This proguanil-chloroquine combination allows an unacceptably high level of breakthrough malaria and cannot be recommended for visitors to the highly malarious areas of Papua New Guinea.

Chloroquine↗