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At least 523 records · Page 29Linked to original sources
PubMed2002

Sulfadoxine-pyrimethamine monotherapy in Tanzanian children gives rapid parasite clearance but slow fever clearance that is improved by chloroquine in combination therapy.

Following widespread chloroquine (CQ) resistance, sulfadoxine plus pyrimethamine (SP) is now the first line antimalarial drug in a number of African countries including Tanzania. Unlike CQ, SP has no antipyretic effects, a feature that might delay fever clearance, and by acting on late stage parasites, SP could theoretical be slow in parasite clearance. We therefore assessed the antipyretic effects of CQ in therapeutic combination with SP, and the speed of parasite clearance by SP in an open-labelled, randomized trial of CQ alone (n=39), SP alone (n=39), SP plus CQ (n=37) and SP plus paracetamol (PCM) (n=38) in children with uncomplicated malaria. Over 72 h, there were eight (20.5%) treatment failures in the CQ group but none in the other groups. Although not significant (P > 0.1), irrespective of resistance CQ alone had a shorter median survival time to fever clearance than SP alone (54 vs. 60 h). SP plus CQ had a highly significantly shorter median survival time to fever clearance than SP alone (48 vs. 60 h) (P < 0.001). Although borderline (P=0.038), the median survival time to parasite clearance was significantly longer in SP plus PCM (72 h) than SP alone (48 h). Irrespective of resistance, CQ alone had a median survival time to parasite clearance equal to that of SP alone (48 h). Parasite clearance by SP was rapid and at the end of 72 h, most (77.3%, 95% confidence interval: 69.6, 85.0) of the children on SP (as a group) had become aparasitaemic. The findings rule out concerns on possible delayed parasitological and clinical responses to SP that could result from its action on late stage parasites. Despite its diminishing antimalarial activity, CQ has beneficial in vivo antipyretic effects in therapeutic combination with SP.

Acetaminophen↗
PubMed2002

Chloroquine and sulphadoxine-pyrimethamine efficacy for uncomplicated malaria treatment and haematological recovery in children in Bobo-Dioulasso, Burkina Faso during a 3-year period 1998-2000.

We determined the parasitological resistance and the clinical failure to chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) by the WHO 14-day in vivo test over three consecutive years in 948 children aged 6-59 months with uncomplicated malaria attending four health centres in the province of Houet, Burkina Faso. Children were alternatively allocated to either CQ or SP. Packed cell volume (PCV) was measured at days 0 and 14. Parasitological resistance (RI, RII and RIII) to CQ was 18% (83 of 455) and to SP <1% (two of 308). Clinical failure with CQ was 12% (53 of 455) with no evidence of increase over time. Only one case of clinical failure was detected among the children treated with SP. The prevalence of anaemia (PCV <25%) was about 40% at day 0 and had decreased substantially by day 14 in both groups. However, in children treated with SP the prevalence of anaemia at day 14 was significantly lower than in those treated with CQ:RR = 3.15 (95% CI: 1.33-7.42, P = 0.008). CQ and SP are still efficacious for the treatment of uncomplicated malaria in children, at least in this area of Burkina Faso. However, the prevalences of CQ resistance reported from other areas of the country are worrying because of its potential spread. Regular surveillance of resistance to commonly used antimalarial drugs should continue.

Anemia↗
PubMed2003

Treatment failure of pyrimethamine-sulphadoxine and induction of Plasmodium falciparum gametocytaemia in children in western Kenya.

Sub-Saharan Africa faces increasing levels of resistance of Plasmodium falciparum parasites to the first-line drug pyrimethamine-sulphadoxine (SP). Successful treatment with SP is reported to induce gametocytes and drug resistance may further increase gametocytaemia after treatment. Treatment success, gametocyte prevalence and gametocyte density were determined in 224 asymptomatic children in western Kenya on day 7 after treatment with SP. Treatment failure (R2 or R3 resistance) was observed in 22% of the children. The relative risk to show gametocytes on day 7 after treatment in children with treatment failure was 4.1 (95% CI 1.4-11.6) times higher compared to children with a sensitive infection, after adjustment for age and trophozoite density at the start of treatment. In addition, the gametocyte density was also higher upon SP treatment failure. These findings are reason for concern, as the increased gametocyte prevalence and density after SP treatment failure may increase the spread of SP-resistant strains in the population.

Adolescent↗
PubMed2003

Assessing the efficacy of chloroquine and sulfadoxine-pyrimethamine for treatment of uncomplicated Plasmodium falciparum malaria in the Democratic Republic of Congo.

We evaluated the in vivo responses to chloroquine (CQ), the first line antimalarial, and to sulfadoxine-pyrimethamine (SP), the most readily available and affordable alternative treatment, in children under 5 with acute uncomplicated Plasmodium falciparum malaria in seven sites of Democratic Republic of Congo (DRC) between May 2000 and November 2001, using the standard 14-day WHO protocol. In the CQ group, the overall treatment failure rate was 45.4% (95% CI: 40.1-50.8) of 350 infections successfully tested; in the SP group it was 7.5% (95% CI: 5.0-11.0) of 333 infections. Of 191 patients who had an adequate clinical response (ACR) in the CQ group, 127 (66.5%; range: 62.5-71.4) still had parasitaemia on day 14. In the SP group, only 21 (6.8%; range: 2.2-12.8) of 308 patients with an ACR were still parasitaemic on day 14. Using pooled data from three rural sites, haematological recovery was better in the SP group (mean of haematocrit difference between days 14 and 0 among anaemic children: 4.7 vs. 3.2; P < 0.01, Wilcoxon test). These findings suggest that CQ is no longer effective in DRC and that SP may be a good alternative for its replacement as first line antimalarial treatment. The Ministry of Health (MOH) therefore now recommends SP as the first line antimalarial drug in DRC, as an interim step, 18 months after launching the first study. Additional studies are needed to select alternative therapies that might replace SP or improve its efficacy, should it prove ineffective in the future.

Antimalarials↗
PubMed2004

Adherence to the combination of sulphadoxine-pyrimethamine and artesunate in the Maheba refugee settlement, Zambia.

Artemisinin-based combination therapy (ACT) is one strategy recommended to increase cure rates in malaria and to contain resistance to Plasmodium falciparum. In the Maheba refugee settlement, children aged 5 years or younger with a confirmed diagnosis of uncomplicated falciparum malaria are treated with the combination of sulphadoxine-pyrimethamine (1 day) and artesunate (3 days). To measure treatment adherence, home visits were carried out the day after the last treatment dose. Patients who had any treatment dose left were considered certainly non-adherent. Other patients' classification was based on the answers to the questionnaire: patients whose caretakers stated the child had received the treatment regimen exactly as prescribed were considered probably adherent; all other patients were considered probably non-adherent. Reasons for non-adherence were assessed. We found 21.2% (95% CI [15.0-28.4]) of the patients to be certainly non-adherent, 39.4% (95% CI [31.6-47.6]) probably non-adherent, and 39.4% (95% CI [31.6-47.6]) probably adherent. Insufficient explanation by the dispenser was identified as an important reason for non-adherence. When considering the use of ACT, the issue of patient adherence remains challenging. However, it should not be used as an argument against the introduction of ACT. For these treatment regimens to remain efficacious on a long-term basis, specific and locally adapted strategies need to be implemented to ensure completion of the treatment.

Antimalarials↗
PubMed2004

The efficacy of chloroquine, sulfadoxine-pyrimethamine and a combination of both for the treatment of uncomplicated Plasmodium falciparum malaria in an area of low transmission in western Uganda.

We conducted an efficacy study of chloroquine (CQ), sulfadoxine-pyrimethamine (SP) and a combination of both (SP+CQ) for the treatment of uncomplicated malaria in an area of low transmission with low drug pressure. On day 3, fever clearance was 97.4% (95% CI, 86.8-99.9), 100% (95% CI, 87.2-100) and 96.6% (95% CI, 82.2-99.9) in the CQ, SP and SP+CQ groups, respectively, (P=0.65). On day 14, clinical success was 92.5% (95% CI, 79.6-98.4), 100% (95% CI, 87.2-100) and 100% (95% CI, 88.1-100) in the CQ, SP and CQ+SP groups, respectively. Clinical failure was seen in 7.5% with 5% (95% CI, 0.61-16.9) early treatment failure and 2.5% (95% CI, 0.06-13.2) late treatment failure of cases in the CQ group and 0% in the SP and SP+CQ groups. Parasitological resistance was observed at RI level in 10% (95% CI, 2.8-23.7), 18.5% (95% CI, 6.3-38.1) and 6.9% (95% CI, 0.85-22.8) for the CQ, SP and SP+CQ, respectively (P=0.37). There was no age-dependent difference in clinical failure or parasitological resistance in any of the treatment groups and prior CQ use within the last 2 weeks did not affect CQ treatment outcome. The findings of this study suggest that CQ is still effective for the treatment of uncomplicated malaria in this area of low transmission and SP. However, combination therapy of SP+CQ is recommended to delay the development SP resistance, and regular surveillance for emerging CQ and SP resistance is needed to plan for alternative antimalarial drug regimens.

Adolescent↗
PubMed2004

Efficacy of chloroquine, amodiaquine, sulphadoxine-pyrimethamine and combination therapy with artesunate in Mozambican children with non-complicated malaria.

This paper reports a two-phase study in Manhiça district, Mozambique: first we assessed the clinical efficacy and parasitological response of Plasmodium falciparum to chloroquine (CQ), sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ), then we tested the safety and efficacy in the treatment of uncomplicated malaria, of three combinations: AQ + SP, artesunate (AR) + SP and AQ + AR. Based on the WHO (1996, WHO/MAL/96.1077) in vivo protocol, we conducted two open, randomized, clinical trials. Children aged 6-59 months with axillary body temperature > or = 37.5 degrees C and non-complicated malaria were randomly allocated to treatment groups and followed up for 21 days (first and second trial) and 28 days (first trial). The therapeutic efficacy of AQ (91.6%) was better than that of SP (82.7%) and CQ (47.1%). After 14 days, 69% of the strains were parasitologically resistant to CQ, 21.4% to SP and 26% to AQ. Co-administration of AQ + SP, AR + SP and AQ + AR was safe and had 100% clinical efficacy at 14-day follow-up. The combination therapies affected rapid fever clearance time and reduced the incidence of gametocytaemia during follow-up.

Amodiaquine↗
PubMed2004

Efficacy of sulphadoxine-pyrimethamine alone or combined with amodiaquine or chloroquine for the treatment of uncomplicated falciparum malaria in Ugandan children.

The rapid development of falciparum resistance to sulphadoxine-pyrimethamine (SP) in East and Central Africa has raised concerns as to the efficacy of combining it with another drug. In 2002, we assessed the efficacy of SP alone and combined with amodiaquine (AQ/SP) or chloroquine (CQ/SP) in Ugandan children with uncomplicated falciparum malaria. At day 14, adequate clinical response was 100% (84/84) for AQ/SP, 93% (92/101) for CQ/SP and 91% (73/80) for SP. At day 28, parasitological failure (RI-RIII) occurred in 16% (13/80) of children treated with AQ/SP, in 48% (48/100) of those treated with CQ/SP and in 61% (48/79) of those treated with SP alone. Compared with the AQ/SP arm, the odds for parasitological failure at day 28 were five times higher (95% CI, 2-10) in the CQ/SP group and sevenfold higher (95% CI, 3-17) in that of SP alone. CQ/SP does not offer any significant added benefit over SP alone while AQ/SP is an efficacious low-cost combination. These findings have important policy implications for Uganda and other resource-constrained African countries faced with the problematic choice of a new first-line antimalarial treatment in a context of high CQ resistance.

Amodiaquine↗
PubMed2001

Gametocytaemia in Senegalese children with uncomplicated falciparum malaria treated with chloroquine, amodiaquine or sulfadoxine + pyrimethamine.

Plasmodium falciparum gametocytaemia was studied in 266 Senegalese children (median 4 years, range 0.5-16) with uncomplicated malaria treated with chloroquine (CQ), amodiaquine (AQ) or sulfadoxine + pyrimethamine (SP). The proportion of resistant infections in vivo to these drugs was 44%, 16% and 7%, respectively. Gametocytes were counted by microscopy in thick smears on days 0, 4, 7 and 14 after treatment. There was a peak of gametocytaemia one week after treatment; on days 0, 7 and 14 the gametocyte prevalences were 35%, 73% and 63%, and the geometric means of gametocyte densities were 1.3, 12.5 and 5.6/microliter of blood. Three factors were found to influence gametocytaemia: treatment, efficacy of treatment, and duration of symptoms before treatment. Gametocyte prevalence and density significantly appeared higher in children treated with SP than with CQ, and higher with CQ than with AQ. Gametocyte prevalence and density were higher in resistant than in sensitive infections. The period between the appearance of the first clinical symptoms and treatment was positively and significantly linked to gametocyte prevalence and density on days 0 and 4. Early treatment with AQ, against sensitive infection, was followed by the lowest gametocytaemia. By contrast, treatment with SP against resistant infection was followed by the highest gametocytaemia. No clear relationship was observed between the density of asexual stages on day 0 and the gametocytaemia at any day between days 0 and 14. The epidemiological significance of post-therapeutic gametocytaemia and its possible role in the spread of resistant parasites are underlined. Solutions are proposed in order to avoid or reduce this gametocytaemia.

Adolescent↗
PubMed1994

Folate deficiency and congenital malformations induced by pyrimethamine in the rat.

In order to establish a relationship between the appearance of congenital malformations and the decrease of folic acid in rat mothers and embryos, a folic acid antagonist, pyrimethamine (PY), was administered. On the 12th day of gestation/pregnant rats received an intraperitoneal injection of 12.5, 15.63, 18.75 or 25 mg/kg PY. On the 13th day of gestation folic acid was measured in different maternal and embryonic tissues obtained after surgical hysterectomy of 1 uterine horn. On the 21st day of gestation malformations were studied on live fetuses remaining in the opposite horn. The folate levels were identical in all maternal tissues. The concentration of folic acid significantly decreased (50%) within the embryonic tissues in all PY-treated groups. A decrease of fetal weight occurred in the 18.75 and 25 mg/kg PY groups. Malformations were observed in the same groups. A dysfunction of the placental transfer of folates is hypothesized.

Animals↗
PubMed2001

Twice-weekly pyrimethamine-sulfadoxine effectively prevents Pneumocystis carinii pneumonia relapse and toxoplasmic encephalitis in patients with AIDS.

OBJECTIVE: To evaluate the safety and efficacy of a fixed 25mg pyrimethamine--500mg sulfadoxine combination plus 15mg folinic acid given twice weekly for the prevention of relapses of Pneumocystis carinii pneumonia (PCP) and primary episodes of toxoplasmic encephalitis. METHODS: Ninety-five HIV-infected patients with successfully treated PCP and without history of toxoplasmic encephalitis were enrolled between January 1990 and October 1995 in a single-arm open-label prospective study. No patient was receiving highly active antiretroviral treatment, including protease inhibitors or non-nucleoside reverse transcriptase inhibitors, while on study medication. Efficacy was analysed on an "as-treated" basis. RESULTS: Five patients (5.3%) suffered a PCP relapse while on study medication, three of whom had been non-compliant. No relapse occurred in the first year. Probabilities of freedom from relapse were 0.96 after 24 months and 0.90 after 36 months. Of 69 patients positive for anti-toxoplasma IgG antibodies, one (1.5%) developed cerebral lesions compatible with toxoplasmic encephalitis after 50 months. Cutaneous allergic reactions were observed in 16 patients (16.8%) resulting in permanent discontinuation in six patients (6.3%). Two patients (2.1%) developed serious adverse reactions (Stevens-Johnson syndrome), both of whom had continued prophylaxis despite progressive hypersensitivity reactions. CONCLUSIONS: The prophylactic regimen used is effective in preventing PCP relapses and toxoplasmic encephalitis. The regimen appears to be safe. Severe adverse events can likely be prevented by discontinuation of prophylaxis at the time allergic reactions are noted. Rechallenge frequently results in tolerance of the regimen. Efficacy and safety compare favourably with previously studied regimens. This simple prophylactic regimen may provide a convenient alternative for patients unable to tolerate approved regimens.

AIDS-Related Opportunistic Infections↗
PubMed1983

[Falciparum malaria in East African tourists in spite of fansidar prevention. A contribution on increased chloroquine and pyrimethamine-sulfadoxine resistance in areas of East Africa].

A decreased chloroquine (Resochin) sensitivity of strains of Plasmodium falciparum in certain areas of East Africa has given rise to an inappropriate change of chemoprophylaxis to pyrimethamine-sulfadoxine (Fansidar). Falciparum malaria occurred in five tourists during or after Fansidar prophylaxis. A therapeutic chloroquine-R2-resistance was observed in one seriously ill patient. In some patients the course of disease was prolonged to such an extent that the diagnosis could be established only after as much as 4 months after the end of the journey. This was in part surely caused by intake of anti-plasmodial drugs such as sulfonamides, tetracyclines and co-trimoxazol. The high mortality of falciparum malaria of nearly 10% in this country does not depend on the choice of drug prophylaxis or on problems of resistance, but still on a missed or delayed diagnosis.

Adult↗
PubMed2005

Crystal structure of dihydrofolate reductase from Plasmodium vivax: pyrimethamine displacement linked with mutation-induced resistance.

Pyrimethamine (Pyr) targets dihydrofolate reductase of Plasmodium vivax (PvDHFR) as well as other malarial parasites, but its use as antimalarial is hampered by the widespread high resistance. Comparison of the crystal structures of PvDHFR from wild-type and the Pyr-resistant (SP21, Ser-58 --> Arg + Ser-117 --> Asn) strain as complexes with NADPH and Pyr or its analog lacking p-Cl (Pyr20) clearly shows that the steric conflict arising from the side chain of Asn-117 in the mutant enzyme, accompanied by the loss of binding to Ser-120, is mainly responsible for the reduction in binding of Pyr. Pyr20 still effectively inhibits both the wild-type and SP21 proteins, and the x-ray structures of these complexes show how Pyr20 fits into both active sites without steric strain. These structural insights suggest a general approach for developing new generations of antimalarial DHFR inhibitors that, by only occupying substrate space of the active site, would retain binding affinity with the mutant enzymes.

Amino Acid Substitution↗
PubMed1990

Pyrimethamine: an approach to the development of a male contraceptive.

With the human population of the world currently more than 5.2 billion and growing at an explosive rate, the need for additional forms of readily available contraception appears paramount. To date, contraception techniques in the male have been very limited. The present study demonstrates the ability of pyrimethamine (PYR) to cause spermatogenic arrest and male infertility in mice in a dose-dependent manner. Furthermore, upon cessation of drug administration all animals returned to normal fertility status. It is also suggested that the action of PYR is due to its antifolate action. Thus, PYR represents another approach toward development of a male contraceptive.

Animals↗
PubMed2000

Comparative efficacy of chloroquine plus chlorpheniramine alone and in a sequential combination with sulfadoxine-pyrimethamine, for the treatment of acute, uncomplicated, falciparum malaria in children.

One hundred and eight children with acute, symptomatic, uncomplicated, falciparum malaria were randomized to receive chloroquine (for 3 days) plus chlorpheniramine alone (for seven days) (CQ-CP group; N = 55) or, in a sequential treatment, chloroquine plus chlorpheniramine for 3 days followed, on the fourth day, by a single oral dose of sulfadoxine-pyrimethamine (25 mg sulfadoxine/kg) (CQ-CP-SP group; N = 53). The mean (S.D.) parasite-clearance time in the CQ-CP group [2.1 (0.7) days; range = 1-5 days] was similar to that in the CQ-CP-SP [2.1 (0.8) days; range = 1-5 days]. The fever-clearance times were also similar: 1.2 (0.1) days (range = 1-3 days) v. 1.1 (0.4) days (range = 1-3 days). The cure rates on days 14, 21 and 28 were 98.2%, 96.3% and 92.7%, respectively in the CQ-CP group, and 100%, 100% and 96.2%, respectively, in the CQ-CP-SP group. The rates of gametocyte carriage were low and similar (5.4% in the CQ-CP group and 3.8% in the CQ-CP-SP group) throughout the duration of the study. Both treatment regimens were relatively well tolerated, the main adverse reactions being similar: sleepiness (on day 1) and pruritus (on days 1-3). No adverse effect was attributable to SP. The results indicate that sequential treatment, for 3 days with CQ and CP, followed by a single dose of SP, is effective and well tolerated in children with acute, uncomplicated, falciparum malaria and may be an alternative treatment for CQ- and/or SP-resistant falciparum malaria. Treatment with a CQ-CP combination (CQ and CP for 3 days and then CP alone for another 4 days) is also effective but requires continuing administration after the signs and symptoms of acute malaria have disappeared.

Animals↗
PubMed2000

A randomized, parallel-group study in Mumbai (Bombay), comparing chloroquine with chloroquine plus sulfadoxine-pyrimethamine in the treatment of adults with acute, uncomplicated, Plasmodium falciparum malaria.

A major problem in the control of malaria is the development of resistance, of the parasites to the existing drugs and of the vectors to insecticides. With few new drugs in the pipeline, in an era of declining resources, it is imperative to make judicious use of the existing antimalarials. In the city of Mumbai, resistance exists to chloroquine (CQ) and to sulfadoxine-pyrimethamine (SP). Use of a combination of CQ with SP would theoretically slow down the development of resistance to each of the drugs and increase their useful lives. The effectiveness of this combination in the treatment of adults from Mumbai, who had acute, uncomplicated Plasmodium falciparum malaria, was compared with that of CQ alone. The combination was found to be significantly more effective, in terms of 28- or 42-day cure rates, and to be more cost-effective.

Acute Disease↗
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↗
PubMed1985

A comparison of the pyrimethamine and cycloguanil sensitivities of the pre-erythrocytic and erythrocytic stages of drug-sensitive and -resistant strains of Plasmodium yoelii.

The cycloguanil and pyrimethamine sensitivities of the pre-erythrocytic and erythrocytic stages of a drug-sensitive and drug-resistant strain of Plasmodium yoelii have been compared. With both compounds, and in both parasite strains, the pre-erythrocytic stages were more sensitive to inhibition than were the erythrocytic stages. In the resistant strain the increase in the level of drug tolerance in the erythrocytic stages was paralleled by a corresponding loss of sensitivity in the pre-erythrocytic stages.

Animals↗