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At least 19 recordsLinked to original sources
PubMed1986

Potentiating effect of pyrimethamine and sulfadoxine against dihydrofolate reductase from pyrimethamine-sensitive and pyrimethamine-resistant Plasmodium chabaudi.

Dihydrofolate reductase was partially purified from a pyrimethamine-sensitive Plasmodium chabaudi clone and a pyrimethamine-resistant clone derived from it and used in a study of the inhibitory effect of pyrimethamine and sulfadoxine, both alone and in combination. Kinetic analysis of the inhibitory effect of sulfadoxine against the enzyme from pyrimethamine-sensitive and -resistant parasites revealed that the drug inhibited the former enzyme competitively, with an inhibition constant (Kis) of 0.7 +/- 0.4 mM, but inhibited the latter enzyme noncompetitively, with Kis and Kii of 8.9 +/- 1.2 and 4.1 +/- 1.2 mM, respectively. Previous studies also showed competitive inhibition by pyrimethamine on the former enzyme and noncompetitive inhibition on the latter enzyme, with some 200-fold-lower affinity. Sulfadoxine and pyrimethamine exhibited a mutually potentiating effect on the enzyme activity, as revealed by the concave isoboles and the fractional inhibitions of less than unity. A potentiating effect was observed for the enzymes from both sources and was not dependent on the degree of the purification of the enzyme. Our results can be explained by assuming simultaneous binding of two inhibitors on the enzyme.

Animals↗
PubMed2005

Efficacy of chloroquine, amodiaquine, sulfadoxine-pyrimethamine, chloroquine-sulfadoxine-pyrimethamine combination, and amodiaquine-sulfadoxine-pyrimethamine combination in Central African children with noncomplicated malaria.

This paper reports a two-phase study in Bangui, Central African Republic (CAR): first, we assessed the clinical efficacy to chloroquine (CQ), sulfadoxine-pyrimethamine (SP), and amodiaquine (AQ), then we tested the efficacy of two combinations: CQ + SP and AQ + SP. We used the standard 14-day WHO 2001 protocol to compare therapeutic responses in children under 5 years of age with acute uncomplicated Plasmodium falciparum malaria in Bangui between February 2002 and March 2004. The overall treatment failure rates with CQ, AQ, SP, CQ + SP, and AQ + SP were 40.9%, 20.0%, 22.8%, 7.2%, and 0%. These findings suggest that the Ministry of Health should recommend an interim policy with AQ + SP combination as the first-line antimalarial drug in Bangui until best alternative treatments like artemisinin-based combination therapies (ACTs) become available at low prices in the CAR.

Amodiaquine↗
PubMed2000

Chloroquine or amodiaquine combined with sulfadoxine-pyrimethamine for treating uncomplicated malaria.

BACKGROUND: Amodiaquine and chloroquine give fast relief from malaria symptoms, particularly fever. When used alone in areas where there is some parasite resistance they do not completely clear parasites from the blood in all cases, and so not all patients are cured of infection. The major disadvantage of using sulfadoxine-pyrimethamine alone is that it takes a relatively long time to relieve fever. OBJECTIVES: To assess the effectiveness of chloroquine or amodiaquine given with sulfadoxine-pyrimethamine to treat uncomplicated falciparum malaria. SEARCH STRATEGY: The Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, MEDLINE, EMBASE, Science Citation Index, African Index Medicus and LILACS were searched. Experts in the field and drug companies were contacted. SELECTION CRITERIA: Randomised and quasi-randomised trials of chloroquine or amodiaquine given with sulfadoxine-pyrimethamine compared with either drug alone in adults or children with confirmed uncomplicated falciparum malaria. DATA COLLECTION AND ANALYSIS: Two people independently applied the inclusion criteria. Data were extracted by the reviewer and checked independently by another person. MAIN RESULTS: Five trials were included. Fever clearance time was reduced by combination therapy compared with sulfadoxine-pyrimethamine alone. Parasite clearance at day seven follow-up was not significantly different for chloroquine or amodiaquine treatment with or without sulfadoxine-pyrimethamine. Parasite clearance at day 28 was better with combination therapy compared with chloroquine or amodiaquine alone (odds ratio 14.28, 95% confidence interval 6.76 to 30.19), but not significantly better than sulfadoxine-pyrimethamine alone (odds ratio 3.17, 95% confidence interval 0.96 to 10.43). There was no evidence from the included trials of serious side effects with combination treatment. REVIEWER'S CONCLUSIONS: In areas where chloroquine or amodiaquine are still effective, despite some degree of resistance, using these drugs in combination with sulfadoxine-pyrimethamine, rather than sulfadoxine-pyrimethamine alone, may make people feel better faster and improve sustained parasites clearance.

Adult↗
PubMed2001

Therapy of uncomplicated falciparum malaria: a randomized trial comparing artesunate plus sulfadoxine-pyrimethamine versus sulfadoxine-pyrimethamine alone in Irian Jaya, Indonesia.

Combining artesunate with existing antimalarial drugs may improve cure rates, delay emergence of resistance, and reduce transmission. We performed a randomized comparative trial to quantify the effect of adding artesunate to sulfadoxine-pyrimethamine in the treatment of uncomplicated falciparum malaria in Indonesia. Using a modified 1997 World Health Organization protocol for assessment of therapeutic efficacy of antimalarial drugs, 105 patients (stratified by age/ethnic group) were randomized: 53 received artesunate orally, 4 mg/kg of body weight, a single daily dose for three days, plus sulfadoxine-pyrimethamine orally (1.25 mg of pyrimethamine/kg of body weight), a single dose on day 0, and 52 patients received sulfadoxine-pyrimethamine alone. Six from the combination group were withdrawn from analysis, as were six of the sulfadoxine-pyrimethamine group. Treatment failure rates on day 14 were 0% in the artesunate plus sulfadoxine-pyrimethamine group and 8.7% in the sulfadoxine-pyrimethamine group (P = 0.12). Treatment failure rates on day 28 were 4.4% and 15.2%, respectively (P = 0.16). Relative risk of treatment failure at 28 days was 0.3 (95% confidence interval [CI] = 0.1-1.3). Mean fever clearance time (1.3 versus 1.7 days) and mean parasite clearance time (1.4 versus 2.0 days) were both faster in the artesunate plus sulfadoxine-pyrimethamine group than in the sulfadoxine-pyrimethamine group (P = 0.08 and P < 0.0001, respectively). Only 20 (39.2%) of 51 patients treated with artesunate plus sulfadoxine-pyrimethamine were still parasitemic on day 1 compared with 45 (86.5%) of 52 patients treated with sulfadoxine-pyrimethamine alone (P = 0.000001, relative risk [RR] = 0.4, 95% CI = 0.3-0.6). Gametocyte carriage was lower following artesunate plus sulfadoxine-pyrimethamine than following sulfadoxine-pyrimethamine (RR = 0.5, 95% CI = 0.2-1.0 on day 7 and RR = 0.5, 95% CI = 0.2-1.1 on day 14). Mild diarrhea, rash, and itching resolved without treatment. Combined artesunate plus sulfadoxine-pyrimethamine resulted in more rapid fever and parasiteclearance, was well tolerated, reduced risk of treatment failure, and lowered gametocyte carriage.

Administration, Oral↗
PubMed1996

Artemether-pyrimethamine in the treatment of pyrimethamine-resistant falciparum malaria.

In vitro susceptibility and clinical response of multidrug resistant Plasmodium falciparum to the combination artemether-pyrimethamine were evaluated in patients with acute uncomplicated falciparum malaria. Sixty patients were randomized to receive 3 oral regimens of the combination artemether-pyrimethamine as follows: Regimen-I: artemether (300 mg) plus pyrimethamine (100 mg) on the first day, then placebo on the two consecutive days; Regimen-II: artemether (300 mg) plus pyrimethamine (100 mg) on the first day, then artemether (150 mg) plus pyrimethamine (50 mg) on the second day, and placebo on the third day; Regimen-III: artemether (300 mg) plus pyrimethamine (100 mg) on the first day, then artemether (150 mg) plus pyrimethamine (50 mg) on the second and third days. All patients had a rapid initial response to treatments with 95% of parasitemia being cleared within the first 24 hours. PCT24hours and PCT48hours were similar among the three drug regimens (11 vs 4, 6 vs 12, and 9 vs 11 patients for a 1-day, 2-day, and 3-day combination regimen, respectively). Fever was cleared within 48 hours in all patients in either group. Transient mild nausea, vomiting and loss of appetite were found in a few patients during the first 2 days of treatment. Seven patients did not complete the 28 day follow-up period (5 vs 2 in a 1-day vs 2-day regimen), the reason for withdrawal was not associated with drug-related adverse effects. Only 53 patients were therefore qualified for the efficacy assessment. There was 15, 13 and 5 patients in a 1-day, 2-day and 3-day combination regimens, respectively, who had reappearance of the parasitemia between days 11 and 21. The cure rates of the 3 treatment groups were statistically significantly different (0, 27.8, and 75% for a 1-day, 2-day and 3-day combination regimen, respectively). Two patients developed P. vivax malaria on days 20 and 24. All of the isolates were highly resistant to pyrimethamine, with MIC of 10(-5) M. There is potential advantage of this combination therapy in reducing the dosage and treatment period of artemisinin derivative, which is therefore likely to improve complaince in clinical practice. The use of a 3-day combination regimen (300 mg artemether plus 100 mg pyrimethamine on the first day, then 150 mg artemether plus 50 mg pyrimethamine on the second and third days) seems to be a good alternative regimen to sulfadoxine/ pyrimethamine in areas where P. falciparum is sensitive to pyrimethamine eg in Africa.

Adolescent↗
PubMed2004

Open randomized study of pyrimethamine-sulphadoxine vs. pyrimethamine-sulphadoxine plus probenecid for the treatment of uncomplicated Plasmodium falciparum malaria in children.

BACKGROUND: Increasing drug resistance in Plasmodium falciparum has necessitated renewed search for cheap, effective alternatives to commonly available antimalarials, chloroquine and pyrimethamine-sulphadoxine, for the treatment of malaria in Africa. Probenecid, an inhibitor of organic anion transporters and multiresistance-associated proteins, can chemosensitize P. falciparum to pyrimethamine and sulphadoxine in vitro, but the clinical significance is unclear. We assessed the safety, treatment efficacy, and effects on gametocyte carriage of adding probenecid to pyrimethamine-sulphadoxine. METHODS: We evaluated 151 children aged 12 years or younger who had uncomplicated P. falciparum malaria. Patients were randomly assigned pyrimethamine-sulphadoxine (25 mg/kg of the sulphadoxine component) or pyrimethamine-sulphadoxine as above plus probenecid 20-25 mg/kg of bodyweight in two divided doses daily for 3 days. The primary endpoints were parasitological cure rates on days 14 and 28. RESULTS: Both regimens were well tolerated; no child was withdrawn because of drug intolerance. Fever (1.9 +/- 1.1 vs. 2.4 +/- 1.2 days, P = 0.02) and parasite clearance (2.3 +/- 0.9 vs. 2.7 +/- 1.1 days, P = 0.04) were significantly shorter, and the parasitological cure rate on day 14 (96.2%vs. 83.5%, P = 0.02) but not day 28 (79.4%vs. 72.6%, P = 0.4), was significantly higher in children treated with pyrimethamine-sulphadoxine-probenecid than in those treated with pyrimethamine-sulphadoxine. Gametocyte carriage was similar with both treatment regimens. CONCLUSIONS: The combination of pyrimethamine-sulphadoxine, and probenecid, at a relatively moderate dose, improved treatment efficacy but had no effect on gametocyte carriage. The pyrimethamine-sulphadoxine-probenecid combination merits further evaluation as a potential treatment for use in Nigeria.

Acute Disease↗
PubMed2002

A prospective, randomized trial of pyrimethamine and azithromycin vs pyrimethamine and sulfadiazine for the treatment of ocular toxoplasmosis.

OBJECTIVE: To compare the effects of two treatment regimens, one of which included azithromycin, for the treatment of sight-threatening (near optic disk or fovea) ocular toxoplasmosis. DESIGN: Prospective, randomized open-labeled multicenter study, masked in part with regard to evaluation. METHODS: PARTICIPANTS TOTAL ENROLLMENT: 46 patients with sight-threatening ocular toxoplasmosis; pyrimethamine and azithromycin group: 24 patients; pyrimethamine and sulfadiazine group: 22 patients. INTERVENTION: Patients were randomized into two treatment regimens. Group 1 was treated with pyrimethamine and azithromycin complemented with folinic acid and the addition of prednisone from day 3. Group 2 was treated with pyrimethamine and sulfadiazine complemented with folinic acid and the addition of prednisone from day 3. Patients used study medications daily for 4 weeks. Ocular and laboratory examinations were performed at least weekly during the observation period. The study was masked in part with regard to evaluation. MAIN OUTCOME MEASURES: An assessment was made of the time to resolution of the intraocular inflammatory activity, the size of the retinochoroidal lesion, and visual acuity before and after the treatment as well as all adverse effects of treatments. RESULTS: Adverse effects were more frequent in the pyrimethamine/sulfadiazine group (P <.04), and three patients in this group had to discontinue treatment. The time to resolution of inflammatory activity, decrease in size of retinochoroidal lesions, and optimal visual acuity did not differ between the two treatment groups. The number of patients who developed recurrences during the first year after treatment was similar for both groups. CONCLUSIONS: The efficacy of the multidrug regimen with pyrimethamine and azithromycin was similar to the standard treatment with pyrimethamine and sulfadiazine. However, the frequency and severity of adverse effects was significantly lower with a regimen containing pyrimethamine and azithromycin. Multidrug therapy with the combination of pyrimethamine and azithromycin appears to be an acceptable alternative for treatment of sight-threatening ocular toxoplasmosis.

Adolescent↗
PubMedDate not supplied

The disposition of pyrimethamine base and pyrimethamine pamoate in the mouse: effect of route of administration.

We have investigated the plasma pharmacokinetics and mass fate in mice, of pyrimethamine administered as either the base or as the poorly soluble pamoate salt, in each case by the intraperitoneal (i.p.) and subcutaneous (s.c.) routes. Following the administration of pyrimethamine base (i.p. and s.c.) and pyrimethamine pamoate (i.p.), maximum measured plasma levels of pyrimethamine were attained within 1 h, before declining monoexponentially. There was no significant difference between these three groups in the clearance (0.29 +/- 0.05, 0.30 +/- 0.03, 0.26 +/- 0.05 ml min-1), elimination half-life (4.5 +/- 0.5, 4.8 +/- 0.8, 4.9 +/- 0.5 h) and AUC (19.4 +/- 4.4, 17.3 +/- 2.2, 21.1 +/- 4.4 micrograms.h ml-1). By contrast, after s.c. dosage of pyrimethamine pamoate, drug absorption was significantly delayed, maximum plasma levels being reached after 4 h, these levels being approximately one-third of those in the other three groups. Absorption was however complete, as the values for AUC and clearance were not significantly different from the other groups. The pattern of faecal and urinary elimination of 14C radioactivity was unaffected by either dose site or formulation of pyrimethamine. The majority of the dose (44.5-64.2 per cent) was eliminated in the faeces suggesting extensive biliary excretion. Localization of 14C radioactivity in the major organs was negligible in all groups. Following each dose, between 85 and 98 per cent of the dose was accounted for. These studies indicate that of the four treatment groups only pyrimethamine pamoate on s.c. administration demonstrates a sustained release action from the dose site.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Kinetic and molecular properties of the dihydrofolate reductase from pyrimethamine-sensitive and pyrimethamine-resistant clones of the human malaria parasite Plasmodium falciparum.

Dihydrofolate reductase (DHFR) (5,6,7,8-tetrahydrofolate: NADPH+-oxidoreductase; EC 1.5.1.3) was partially purified by affinity chromatography from three clones of the human malaria parasite Plasmodium falciparum. The three clones were representative of pyrimethamine-sensitive (clone 3D7) and pyrimethamine-resistant (clone HB3 and clone 7G8) parasites with ID50 values of 0.53 nM (3D7), 210 nM (HB3), and 540 nM (7G8), when tested in vitro against the drug. The specific activities of the partially purified DHFR differed by less than a factor of 2 between the sensitive clone 3D7 (442 +/- 39 nmol min-1 mg-1 protein) and the resistant clones HB3 (634 +/- 25 nmol min-1 mg-1 protein) and 7G8 (565 +/- 85 nmol min-1 mg-1 protein). The number of catalytic sites in partially purified DHFR from the three clones was similar and ranged from 151 to 194 pmol mg-1 protein. The Km value for NADPH was similar in all three clones (4.5-11.6 microM). The Km value for dihydrofolate was altered 13-fold comparing the sensitive clone 3D7 (3.2 +/- 0.6 microM) with the resistant clone HB3 (42.6 +/- 1.6 microM), with the Km for the resistant clone 7G8 falling in between (11.9 +/- 1.2 microM). The inhibition constants for pyrimethamine increased from 0.19 +/- 0.08 nM (3D7) to 2.0 +/- 0.3 nM (HB3) to 8.9 +/- 0.8 nM (7G8). The inhibition by pyrimethamine of the sensitive clone 3D7 was noncompetitive and competitive for the two other clones. The titration of partially purified DHFR with pyrimethamine revealed a 500-fold increase in the concentration of the drug needed to inhibit the DHFR activity by 50%, when the sensitive clone 3D7 (0.18 +/- 0.02 nM) was compared to the resistant clone 7G8 (95 +/- 16 nM). From the comparison of the specific activities and the catalytic center activities with the Km values for the substrate and the inhibition constants for pyrimethamine, both of which are altered in the resistant clones, we conclude that the molecular mechanism for pyrimethamine resistance in the three clones studied is not based on an overproduction of the DHFR but is due to a decreased affinity to antifolates by a structurally altered enzyme.

Chromatography, Affinity↗
PubMed2003

DHFR and DHPS genotypes of Plasmodium falciparum isolates from Gabon correlate with in vitro activity of pyrimethamine and cycloguanil, but not with sulfadoxine-pyrimethamine treatment efficacy.

OBJECTIVES: To assess the relationship between the presence of DHFR and DHPS mutations in Plasmodium falciparum, parasite in vitro resistance, and in vivo efficacy of sulfadoxine-pyrimethamine (SP) treatment. PATIENTS AND METHODS: Measurement of SP treatment efficacy in malaria-infected children in Gabon was combined with in vitro tests of susceptibility to pyrimethamine and cycloguanil, and molecular genotyping at several DHFR and DHPS loci of parasites isolated before treatment. DHFR was studied at codons 108, 51, and 59, whereas DHPS gene was typed at positions 436, 437, 540 and 581. RESULTS: SP treatment was effective in 86% of children by day 28. Seventy-five percent of isolates were in vitro resistant to pyrimethamine and 65.5% to cycloguanil. No mutation was detected at codons 540 and 581 of the DHPS gene. Most isolates (71.8%) presented with the triple mutant DHFR genotype, whereas 64.3% combined at least three DHFR and one DHPS mutations. The increase in the number of DHFR mutations was associated with an increase in in vitro resistance to pyrimethamine and cycloguanil; three DHFR mutations conferred pyrimethamine and to a lesser extent cycloguanil resistance. Treatment failures only occurred with isolates presenting at least two DHFR mutations (S108N and C59R) and one DHPS mutation (S436A or A437G), but SP treatment of infections with such parasites gave treatment success in 82.0% of children. CONCLUSIONS: DHFR mutations that lead to high-level in vitro resistance to pyrimethamine plus 1-2 DHPS mutations are not sufficient to induce in vivo failure of SP treatment in young children from Gabon.

Animals↗
PubMed1990

Serious adverse drug reactions to pyrimethamine-sulphadoxine, pyrimethamine-dapsone and to amodiaquine in Britain.

All reports of adverse reactions with pyrimethamine-sulphadoxine (Fansidar), pyrimethamine-dapsone (Maloprim), and amodiaquine spontaneously reported through the UK national post-marketing system were reviewed. Retrospective reporting rates of serious reactions associated with these drugs were analysed using prescription data from the Department of Health, derived from the Prescription Pricing Authority, and relevant pharmaceutical companies. Whilst interpretation of these data requires caution, they allowed comparison with reporting rates from other studies. The reported rate for all serious reactions to pyrimethamine-sulphadoxine was 1:2100 prescriptions, and for cutaneous reactions was 1:4900 prescriptions, with a fatality rate of 1:11,100. The reported rate for serious reactions to pyrimethamine-dapsone was 1:9100 prescriptions, and for blood dyscrasias was 1:20,000 prescriptions, with a fatality rate of 1:75,000. The reported rate of blood dyscrasias associated with amodiaquine was 1:2100 users with a fatality rate of 1:31,000. Serious hepatic disorders occurred in 1:11 1000 pyrimethamine-sulphadoxine prescriptions, 1:75,200 pyrimethamine-dapsone prescriptions, and in 1:15,650 amodiaquine users. 35% of cases received these drugs needlessly as they were not exposed to drug resistant strains of Plasmodium falciparum. Since few serious reactions have been reported to chloroquine plus proguanil, these data support guidelines which restrict the use of reviewed drugs for those at greatest risk of infection. Dosage data indicated that fatalities had taken higher doses and continued prophylaxis after onset of symptoms. Two thirds of serious reactions to the compound antimalarials were reported in females.

Adolescent↗
PubMed1979

Treatment of vivax malaria with sulfadoxine-pyrimethamine and with pyrimethamine alone.

The effect of pyrimethamine and the combination of pyrimethamine-sulfadoxine (Fansidar) upon the termination of the acute attack of vivax malaria was studied in Thailand. Pyrimethamine was found to be ineffective, providing clearance of parasitaemia in only two of six patients by the end of seven days following treatment. The combination, administered in a two-tablet single dose (sulfadoxine 1 gm, pyrimethamine 50 mg) eliminated parasitaemia in only six of ten patients within seven days. Three tablets (sulfadoxine 1 . 5 gm, pyrimethamine 75 mg) given to 11 patients, provided clearance of parasitaemia in all within seven days; however, mean parasite and fever clearance times in this group were prolonged at 90 and 50 hours respectively. Chloroquine remains the drug of choice for the termination of the acute attack of vivax malaria. Subsequent primaquine is necessary for the prevention of relapse.

Acute Disease↗
PubMed1982

Comparison of in vitro pyrimethamine assays and in vivo response to sulphadoxine-pyrimethamine in Plasmodium falciparum from Papua New Guinea.

The in vitro pyrimethamine sensitivity of 20 Plasmodium falciparum isolates from Papua New Guinea children was determined. The children were treated with sulphadoxine-pyrimethamine and six were found to have clinically resistant malaria. The P. falciparum isolated from these subjects were more resistant to pyrimethamine in vitro than 13 of the isolates from sensitive cases. These results suggest that pyrimethamine sensitivity alone may be a good indicator of in vitro response to sulphadoxine-pyrimethamine.

Child↗
PubMed2002

Therapeutic efficacy of sulfadoxine-pyrimethamine, amodiaquine and the sulfadoxine-pyrimethamine-amodiaquine combination against uncomplicated Plasmodium falciparum malaria in young children in Cameroon.

OBJECTIVE: To evaluate the therapeutic efficacy of sulfadoxine-pyrimethamine, amodiaquine, and the sulfadoxine-pyrimethamine-amodiaquine combination for the treatment of uncomplicated Plasmodium falciparum malaria in young children in Cameroon. METHODS: In a randomized study we evaluated the effectiveness and tolerance of (i) sulfadoxine-pyrimethamine (SP) (25 mg/kg body weight of sulfadoxine and 1.25 mg/kg of pyrimethamine in a single oral dose), (ii) amodiaquine (AQ) (30 mg/kg body weight in three divided daily doses), and (iii) the sulfadoxine-pyrimethamine-amodiaquine combination (SP+AQ) (same doses as in the other two treatment groups, given simultaneously on day 0) in young children in southern Cameroon. The parasitological and clinical responses were studied until day 28 in accordance with the modified 1996 WHO protocol for the evaluation of the therapeutic efficacy of antimalarial drugs. FINDINGS: Of 191 enrolled patients, 6 and 8 were excluded or lost to follow-up before day 14 and between day 14 and day 28, respectively. For the AQ-treated patients, parasitological and clinical evaluation on day 14 showed late treatment failure in 2 of 61 (3.3%) and adequate clinical response with parasitological failure in one (1.6%). There was an adequate clinical response in all patients treated with SP or SP+AQ. Therapeutic failure rates on day 28 were 13.6%, 10.2% and 0% in the SP, AQ, and SP+AQ groups, respectively. Anaemia improved in all three regimens. AQ produced faster fever clearance but was associated with more transient minor side-effects than SP. SP+AQ reduced the risk of recrudescence between day 14 and day 28 but increased the incidence of minor side-effects. CONCLUSION: SP+AQ can be recommended as a temporary means of slowing the spread of multidrug resistance in Plasmodium falciparum in Africa while the introduction of other combinations, including artemisinin derivatives, is awaited.

Administration, Oral↗
PubMed2006

Sulfadoxine-pyrimethamine plus artesunate versus sulfadoxine-pyrimethamine plus amodiaquine for treating uncomplicated malaria.

BACKGROUND: Artemisinin-based combination treatments are strongly advocated, but supplies are limited. Sulfadoxine combined with amodiaquine is an alternative non-artemisinin combination. OBJECTIVES: To compare sulfadoxine-pyrimethamine plus amodiaquine (SP plus AQ) with sulfadoxine-pyrimethamine plus artesunate (SP plus AS) for treating uncomplicated Plasmodium falciparum malaria. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group Specialized Register (October 2005), CENTRAL (The Cochrane Library 2005, Issue 4), MEDLINE (1966 to October 2005), EMBASE (1988 to October 2005), LILACS (October 2005), and reference lists. We also contacted researchers and organizations working in this field. SELECTION CRITERIA: Randomized controlled trials comparing SP plus AS with SP plus AQ for treating uncomplicated P. falciparum malaria. DATA COLLECTION AND ANALYSIS: Two authors independently applied the inclusion criteria, extracted data, and assessed methodological quality. The primary outcome measure was treatment failure (parasitological or clinical evidence of treatment failure between start of treatment and day 28). We calculated the relative risk (RR) with 95% confidence intervals (CI) for dichotomous data. MAIN RESULTS: Four trials (775 participants) met the inclusion criteria. All were from areas of high and seasonal malaria transmission in Africa. Fewer participants using SP plus AQ failed treatment by day 28 (RR 0.59, 95% CI 0.42 to 0.83; 652 participants, 3 trials). Even excluding new infections, SP plus AQ performed better (RR 0.62, 95% CI 0.40 to 0.96; 649 participants, 3 trials). There was no statistically significant difference between the two treatments for treatment failure at day 14 (RR 1.14, 95% CI 0.47 to 2.78; 775 participants, 4 trials). SP plus AS was more effective at reducing gametocyte carriage at day seven (RR 2.31, 95% CI 1.36 to 3.92; 220 participants, 1 trial). One trial reported that one person - in the SP plus AQ group - developed severe malaria. Adverse events were poorly reported, but did not seem to differ in type and number between the two treatment combinations. AUTHORS' CONCLUSIONS: SP plus AQ performed better at controlling treatment failure at day 28, but was not as good as SP plus AS at reducing gametocyte carriage at day seven. Careful consideration of local resistance patterns is required because resistance to sulfadoxine-pyrimethamine and amodiaquine are high in many areas. In order to delay development of resistance to artesunate, the combination with sulfadoxine-pyrimethamine should only be considered where both drugs are known to be effective. Data on adverse events are still lacking.

Amodiaquine↗
PubMedDate not supplied

A randomized safety and tolerability trial of artesunate plus sulfadoxine--pyrimethamine versus sulfadoxine-pyrimethamine alone for the treatment of uncomplicated malaria in Gambian children.

Artemisinin derivatives, such as artesunate, have a short half-life and very rapid anti-malarial activity. Theoretically, using such agents in conjunction with well-established anti-malarial drugs such as sulfadoxine-pyrimethamine may reduce the rate of drug resistance. Such a combination has not previously been used in Africa. We have conducted a pilot safety trial of artesunate (4 mg/kg for 3 days) given with a single dose of sulfadoxine-pyrimethamine (25 mg/kg sulfadoxine) compared to sulfadoxine-pyrimethamine alone among 40 Gambian children with uncomplicated malaria. Both regimens were safe and well tolerated and there were no adverse experiences attributed to the combination. The addition of artesunate resulted in a higher proportion of afebrile children and children with a negative blood film on Day 2, and a reduction in the proportion of gametocyte carriers, when compared to sulfadoxine-pyrimethamine alone.

Antimalarials↗
PubMed1996

Pyrimethamine-clindamycin vs. pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients with AIDS.

This European multicenter study compares the efficacy and tolerance of the combination of pyrimethamine-clindamycin (Pyr-Cm) with the standard therapy pyrimethamine-sulfadiazine (Pyr-Sdz) for the treatment of toxoplasmic encephalitis (TE) in patients with AIDS. Two hundred ninety-nine human immunodeficiency virus-infected patients with TE were randomly assigned to receive 50 mg of pyrimethamine daily combined with either 2,400 mg of clindamycin or 4 g of sulfadiazine for 6 weeks followed by maintenance therapy with 25 mg of pyrimethamine daily with either 1,200 mg of clindamycin or 2 g of sulfadiazine. An intent-to-treat analysis showed that Pyr-Cm was less effective than Pyr-Sdz; the overall risk of progression of TE was 1.84 times higher for patients receiving Pyr-Cm therapy. There was no statistically significant difference in efficacy during acute therapy, although the rate of crossover motivated by a lack of response was higher among Pyr-Cm recipients. The difference in efficacy was evidenced during the maintenance phase of treatment; the relapse rate was twice as high among patients in the Pyr-Cm group (P = .02). The rate of side effects due to both regimens was similar, although the toxic effects of Pyr-Cm led to fewer discontinuations of therapy than did those of Pyr-Sdz (11% vs. 30%, respectively; P = .001). Pyr-Sdz appears to be the most effective treatment of TE. Pyr-Cm is a valuable alternative but is less effective for long-term prevention of relapses.

AIDS-Related Opportunistic Infections↗