Intermittent preventive therapy for malaria: arguments in favour of artesunate and sulphamethoxypyrazine - pyrimethamine combination.

Recent publications put a serious warning regarding the inefficacy of sulphadoxine-pyrimethamine (SP) for the intermittent preventive treatment of malaria in young children (IPTi). Recommendations for other therapies are being made. By using a different and better sulphonamide (sulphamethoxypyrazine), it is possible to manufacture fixed dose combination pills with artesunate and pyrimethamine. This combination permits a full therapy over 24 hours (dosing interval being 12 hours). It is recommended that this combination should be tested in future field studies of IPTi.

An open randomized clinical trial in comparing two artesunate-based combination treatments on Plasmodium falciparum malaria in Nigerian children: artesunate/sulphamethoxypyrazine/pyrimethamine (fixed dose over 24 hours) versus artesunate/amodiaquine (fixed dose over 48 hours).

BACKGROUND: Several studies have demonstrated the efficacy of artemisinin-combination therapy (ACT) across malaria zones of the world. Fixed dose ACT with shorter courses and fewer tablets may be key determinants to ease of administration and compliance. METHODS: Children aged one year to 13 years presenting with uncomplicated Plasmodium falciparum malaria were recruited in Ibadan, south-western Nigeria. A total of 250 children each were randomly assigned to receive three doses of artesunate/sulphamethoxypyrazine/pyrimethamine (AS + SMP) (12 hourly doses over 24 hours) or three doses of artesunate/amodiaquine (AS + AQ) (daily doses over 48 hours). Efficacy and safety of the two drugs were assessed using a 28-day follow-up and the primary outcome was PCR- corrected parasitological cure rate and clinical response. RESULTS: There were two (0.4%) early treatment failures, one in each treatment arm. The PCR corrected cure rates for day 28 was 97.9% in the AS + AQ arm and 95.6% in the AS + SMP arm (p = 0.15). The re-infection rate was 1.7% in the AS + AQ arm and 5.7% in the AS + SMP arm (p = 0.021). The fever clearance time was similar in the two treatment groups: 1 - 2 days for both AS + SMP and AS + AQ (p = 0.271). The parasite clearance time was also similar in the two treatment groups with 1 - 7 days for AS + SMP and 1 - 4 days for AS + AQ (p = 0.941). The proportion of children with gametocytes over the follow-up period was similar in both treatment groups. Serious Adverse Events were not reported in any of the patients and in all children, laboratory values (packed cell volume, liver enzymes, bilirubin) remained within normal levels during the follow-up period but the packed cell volume was significantly lower in the AS + SMP group. CONCLUSIONS: This study demonstrates that AS + SMP FDC given as three doses over 24 hours (12-hour intervals) has similar efficacy as AS + AQ FDC given as three doses over 48 hours (24-hour interval) for the treatment of uncomplicated Plasmodium falciparum malaria in children in Nigeria. Both drugs also proved to be safe. Therefore, AS + SMP could be an alternative to currently recommended first-line ACT with continuous resistance surveillance.

Efficacy of artesunate + sulfamethoxypyrazine/pyrimethamine versus praziquantel in the treatment of Schistosoma haematobium in children.

BACKGROUND: This study was conducted to determine the efficacy of the antimalarial artemisinin-based combination therapy (ACT) artesunate +sulfamethoxypyrazine/pyrimethamine (As+SMP), administered in doses used for malaria, to treat Schistosoma haematobium in school aged children. METHODOLOGY/PRINCIPAL FINDINGS: The study was conducted in Djalakorodji, a peri-urban area of Bamako, Mali, using a double blind setup in which As+SMP was compared with praziquantel (PZQ). Urine samples were examined for Schistosoma haematobium on days -1, 0, 28 and 29. Detection of haematuria, and haematological and biochemical exams were conducted on day 0 and day 28. Clinical exams were performed on days 0, 1, 2, and 28. A total of 800 children were included in the trial. The cure rate obtained without viability testing was 43.9% in the As+SMP group versus 53% in the PZQ group (Chi(2) = 6.44, p = 0.011). Egg reduction rates were 95.6% with PZQ in comparison with 92.8% with As+SMP, p = 0.096. The proportion of participants who experienced adverse events related to the medication was 0.5% (2/400) in As+SMP treated children compared to 2.3% (9/399) in the PZQ group (p = 0.033). Abdominal pain and vomiting were the most frequent adverse events in both treatment arms. All adverse events were categorized as mild. CONCLUSIONS/SIGNIFICANCE: The study demonstrates that PZQ was more effective than As+SMP for treating Schistosoma haematobium. However, the safety and tolerability profile of As+SMP was similar to that seen with PZQ. Our findings suggest that further investigations seem justifiable to determine the dose/efficacy/safety pattern of As+SMP in the treatment of Schistosoma infections. TRIAL REGISTRATION: ClinicalTrials.gov NCT00510159.

Efficacy and safety of a fixed dose artesunate-sulphamethoxypyrazine-pyrimethamine compared to artemether-lumefantrine for the treatment of uncomplicated falciparum malaria across Africa: a randomized multi-centre trial.

BACKGROUND: The efficacy of artemisinin-based combination therapy has already been demonstrated in a number of studies all over the world, and some of them can be regarded as comparably effective. Ease of administration of anti-malarial treatments with shorter courses and fewer tablets may be key determinant of compliance. METHODS: Patients with uncomplicated falciparum malaria and over six months of age were recruited in Cameroon, Mali, Rwanda and Sudan. 1,384 patients were randomly assigned to receive artesunate-sulphamethoxypyrazine-pyrimethamine (AS-SMP) three-day (once daily for 3 days) regimen (N = 476) or AS-SMP 24-hour (0 h, 12 h, 24 h) regimen (N = 458) or artemether-lumefantrine (AL), the regular 6 doses regimen (N = 450). The primary objective was to demonstrate non-inferiority (using a margin of -6%) of AS-SMP 24 hours or AS-SMP three days versus AL on the PCR-corrected 28-day cure rate. RESULTS: The PCR corrected 28-day cure rate on the intention to treat (ITT) analysis population were: 96.0%(457/476) in the AS-SMP three-day group, 93.7%(429/458) in the AS-SMP 24-hour group and 92.0%(414/450) in the AL group. Likewise, the cure rates on the PP analysis population were high: 99.3%(432/437) in the AS-SMP three-day group, 99.5%(416/419) in the AS-SMP 24-hour group and 99.7(391/394)% in the AL group. Most common drug-related adverse events were gastrointestinal symptoms (such as vomiting and diarrhea) which were slightly higher in the AS-SMP 24-hour group. CONCLUSION: AS-SMP three days or AS-SMP 24 hours are safe, are as efficacious as AL, and are well tolerated. TRIAL REGISTRATION: NCT00484900 http://www.clinicaltrials.gov.

Single-day, three-dose treatment with fixed dose combination artesunate/sulfamethoxypyrazine/pyrimethamine to cure Plasmodium falciparum malaria.

OBJECTIVES: Malaria kills approximately 1.5 to 2.7 million people each year. Despite the introduction of artemisinin-based combination therapies (ACTs), the treatment of malaria is hampered by problems such as inadequate efficacy, recrudescence, early re-infection, low patient compliance, and high cost price of drugs. This study tested the hypothesis that the co-formulated fixed dose combination (FDC) artesunate/sulfamethoxypyrazine/pyrimethamine (As/SMP) administered as a 24-hour therapy with a dose interval of 12 hours is as efficacious and safe as the administration of the same drug over 3 days given with a dose interval of 24 hours, for the treatment of uncomplicated Plasmodium falciparum malaria in Ivory Coast. METHOD: Two hundred and twenty-one patients presenting with uncomplicated P. falciparum malaria were randomly assigned to either one of the two dosing schemes. Treatment efficacy was assessed using the current 28-day World Health Organization protocol, success being determined by absence of recrudescence and parasitemia on day 28. RESULTS: Both treatment regimens were highly efficacious, with a success rate of 100% (111/111) for the 3-day therapy and 99% (109/110) for the 24-hour therapy. Only one patient in the 24-hour therapy group showed late treatment failure. No serious adverse events or significant laboratory abnormalities were seen. CONCLUSION: The 24-hour therapy is as well tolerated and efficacious as the same medicament administered over 3 days. This low cost and simplified three-pill treatment is certain to improve compliance.

The effects of artemether-lumefantrine vs amodiaquine-sulfalene-pyrimethamine on the hepatomegaly associated with Plasmodium falciparum malaria in children.

An open randomized controlled study of artemether-lumefantrine (AL) and amodiaquine-sulfalene-pyrimethamine (ASP) for the treatment of uncomplicated Plasmodium falciparum malaria was carried out in 181 children. In 79 children, the hepatomegaly reduction ratios (HRR) and the speed of resolution of hepatomegaly, the hepatomegaly resolution rates (HRSR), were calculated and compared between the two treatment groups. HRR and HRSR were similar in the two treatment groups. HRSR was 71% and 62% in AL- and ASP-treated children, respectively, 14 days after commencing treatment. There was no significant correlation between HRR and parasite reduction ratio in the same patient. In children in whom parasitaemia cleared and hepatomegaly resolved within 14 days, recurrence of parasitaemia was associated with reoccurrence of hepatomegaly, suggesting that the propensity for recurrence of infection drives the malaria-attributable hepatomegaly in children from this endemic area. Combination therapy may provide additional beneficial effects on pathophysiological processes and changes associated with falciparum malaria by rapid clearing of asexual parasitaemia and reducing the propensity for recurrence of infection.

A fixed-dose 24-hour regimen of artesunate plus sulfamethoxypyrazine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum malaria in eastern Sudan.

BACKGROUND: Artemisinin-based combination therapy is increasingly being adopted as first-line antimalarial therapy. The choice of appropriate therapy depends on efficacy, cost, side effects, and simplicity of administration. METHODS: the efficacy of fixed co-formulated (f) artesunate-sulfamethoxypyrazine-pyrimethamine (AS+SMP f) administered at time intervals of 12 hours for a 24-hour therapy was compared with the efficacy of the same drug given as a loose combination (AS+SMP l) with a dose interval of 24 hours for 3 days for the treatment of uncomplicated Plasmodium falciparum malaria in eastern Sudan. RESULTS: seventy-three patients (39 and 34 in the fixed and the loose regimen of AS+SMP respectively) completed the 28-days of follow-up. On day 3; all patients in both groups were a parasitaemic but one patient in the fixed group of AS+SMP f was still febrile. Polymerase chain reaction genotyping adjusted cure rates on day 28 were 92.3% and 97.1% (P > 0.05) for the fixed and loose combination of AS+SMP respectively. Three (4.1%) patients (one in the fixed and two patients in the loose group of AS+SMP) in the study suffered drug-related adverse effects. Gametocytaemia was not detected during follow-up in any of the patients. CONCLUSION: both regimens of AS+SMP were effective and safe for the treatment of uncomplicated P. falciparum malaria in eastern Sudan. Due to its simplicity, the fixed dose one-day treatment regimen may improve compliance and therefore may be the preferred choice.

Determination of sulfalene in plasma, red blood cells and whole blood by high-performance liquid chromatography.

A normal phase high-performance liquid chromatographic method using dichloromethane-methanol-perchloric acid (1 M) (96:9:1, v/v) at a flow-rate of 1 ml/min on a Nucleosil 100-7 column (250 x 8 x 4 mm) and UV detection at 254 nm, has been developed to determine the concentration of sulfalene in plasma, red blood cells and whole blood after oral administration of the antimalarial drug metakelfin. The coefficient of variation was 7.1% and the extraction recovery was 82%. Mean concentrations of sulfalene on days 1, 7 and 15 were: 49.56, 10.46 and 2.24 micrograms/ml in plasma, 25.02, 4.34 and 0.84 micrograms/ml in red blood cells and 21.12, 4.44 and 1.00 micrograms/ml in whole blood, respectively. Quinine, chloroquine, desethylchloroquine, mefloquine, primaquine, sulfadoxine, pyrimethamine and dapsone did not interfere in the detection of sulfalene.

Efficacy of sulfalene and pyrimethamine combination drugs alone and with quinine in treatment of P. falciparum cases in chloroquine resistant areas of north east India.

Studies were carried out in some areas of Assam, Nagaland, West Bengal and Mizoram where chloroquine resistant strains of Plasmodium falciparum were present during 1983 and 1984, to see the efficacy of treatment of P. falciparum cases with SLP alone or with quinine sulphate. The findings have indicated that SLP in the dosage of sulfalene (1000 mg) + Pyrimethamine (50 mg) is suitable for treatment of P. falciparum cases not responding to chloroquine therapy in N.E. India. Treatment with sulfalene (1500 mg) + Pyrimethamine (75 mg) has no advantage over the SLP (1000 + 50) mg. Combination of quinine (1000 mg x 3 days) + SLP (1000 + 50) mg is better with 100 per cent cure rate. In Karhi Anglong district (Manja PHC) of Assam response to these drug combination is however less.

[Effect of sulfalene and furosemide on benzylpenicillin kinetics in rats with aseptic inflammation]. / Vliianie sul'falena i furosemida na kinetiku benzilpenitsillina u krys s asepticheskim vospaleniem.

The effect of sulfalen and furosemide on benzylpenicillin kinetics in blood serum, intact tissues and aseptic inflammation foci was studied on rats. It was shown that under the action of sulfalen and furosemide protein binding of benzylpenicillin lowered by 30 per cent. The changes in the antibiotic kinetics after combined use with sulfalen and furosemide were of the same type: markedly increased concentrations in blood serum and tissues and retarded elimination.

[Interactions of sulfanilamides, penicillins and acetylsalicylic acid in serum protein binding]. / Vzaimodeistvie sul'fanilamidov, penitsillinov i atsetilsalitsilovoi kisloty pri sviazyvanii ikh syvorotochnymi belkami.

Combined use of sulfalen and sulfadimethoxine with benzylpenicillin and ampicillin resulted in increased binding of sulfalen to serum proteins of man. Acetylsalicylic acid promoted a decrease in the sulfanilamide binding to the serum proteins. The observed changes in the sulfanilamide binding to proteins of human blood serum were due to increased or decreased affinity of the drugs to the protein molecules.

[Pharmacokinetics of benzylpenicillin and ampicillin in patients after combined administration with sulfalen and sulfadimethoxine]. / Farmakokinetika benzilpenitsillina i ampitsillina u bol'nykh pri kombinirovannom primenenii s sul'falenom i sul'fadimetoksinom.

Combined use of the penicillins and sulfanylamides in patients resulted in increased antibiotic blood levels and circulation. Retarded elimination of the penicillins was mainly due to the depositing effect of the sulfanylamides on the antibiotics at the account of increasing levels of the latter in peripheral tissues which was realized through increasing the drug distribution volume. It is not excluded that the primary mechanism of changing the penicillin kinetics in patients is lowered antibiotic binding to plasma proteins.

Distribution of trimethoprim and sulfametopyrazine in the female reproductive tract.

A combination of trimethoprim (TMP) 250 mg and sulfametopyrazine (SMP) 200 mg (dose ratio 5:4) in capsules was administered to ten patients undergoing hysterectomy for uterine leiomyoma. Each patient received a total of 3 of these Kelfiprim capsules: 2 capsules in a single administration 36 hours before surgery and 1 capsule 24 hours later. TMP and SMP concentrations were analyzed in plasma and also in the ovary, Fallopian tube and uterus, removed during surgery. The results indicated that in the reproductive organs of the female genital tract TMP reaches the same concentrations as in plasma. In contrast SMP is 3 to 3.5 times less concentrated in these tissues compared with plasma. At the TMP/SMP ratios obtained in these various organs synergism of the two compounds is reported to be particularly prominent for most bacterial strains. These findings indicate that this TMP-SMP combination may be useful in the treatment of female reproductive tract infections.

A single dose of sulfametopyrazine versus 7 days of ampicillin in acute on chronic bronchitis.

Forty-two patients with acute on chronic bronchitis received in double-blind fashion either a single dose of 2 g of sulfametopyrazine or ampicillin 250 mg thrice daily for 7 days. There were no significant differences between treatments in the number of patients achieving white sputum, the time to do so, or the incidence of pathogens at the end of treatment. Blood levels of sulfametopyrazine between 8 and 24 hours and on the seventh day were likely to result in sputum concentration adequate to kill Haemophilus influenzae.

Effect of a new sulfa-trimethoprim combination (trimethoprim-sulfamethopyrazine) in typhoid fever. A double-blind study on 72 adult patients.

A double-blind study on 72 adult patients affected by typhoid fever was done utilizing a new sulfa-trimethoprim combination (trimethoprim-sulfamethopyrazine) versus the well-known combination trimethoprim-sulfamethoxazole. The dosage used for the new drug was 2 capsules (250 mg trimethoprim + 200 mg sulfamethopyrazine per capsule) the 1st day and 1 capsule for the following 14 days or 2 capsules (trimethoprim 80 mg + sulfamethoxazole 400 mg per capsule) twice daily for 15 days. Both drugs proved to be very effective according to the parameters considered. No complications (intestinal bleeding, perforation, etc.) occurred in any of the patients, and untoward effects were not observed. It is therefore our opinion that treatment of typhoid fever with a sulfa-trimethoprim combination is both effective and safe.