A comparative clinical trial of sequential treatments of severe malaria with artesunate suppository followed by mefloquine in Thailand.

Sixty-three patients with severe falciparum malaria were randomly administered one of the two regimens of a sequential combination of artesunate suppository followed by an oral mefloquine tablet. Thirty-two patients received artesunate suppositories (200 mg/capsule) given rectally at 0, 4, 8, 12, 24, 36, 48, and 60 hr (total = 1,600 mg: Group I). Thirty-one patients received the same artesunate suppositories given rectally at 0, 12, 24, 36, 48, and 60 hr (total = 1,200 mg: Group II). Both regimens were followed by two doses of oral mefloquine, 750 mg given at 72 hr and 500 mg at 84 hr. Patient baseline characteristics were comparable in the two groups. All patients were admitted for 28 days to the Bangkok Hospital for Tropical Diseases to assess efficacy, tolerability, and delayed neuropsychiatric effects. The mean [SD] parasite clearance time was significantly shorter in Group I than Group II (47.3 [12.4] hr versus 55.3 [17.4] hr; P = 0.05) and the rate of parasite reduction was significantly faster in Group I (P = 0.05, by log-rank test). Mean [SD] fever clearance times were similar in the two Groups (71.1 [41.2] hr and 76.9 [47.9] hr, respectively). Twenty-two patients with unrousable coma on admission (median Glasgow Coma Score = 9) regained consciousness after 1-4 days. No deaths occurred. Sixty of sixty-three patients were parasitologically and clinically cured within 3-4 days of treatment. Three patients (5%) with deteriorating conditions required rescue treatment (one patient in Group I was administered intravenous artesunate, and two patients in Group II required two extra doses of suppository). No patients had major adverse drug effects. The cure rates at 28 days of follow-up in Group I were 96% (26 of 27 patients) and 89% (24 of 27 patients) in Group II. Artesunate suppository followed by mefloquine was well tolerated and effective. In severe malaria, the sequential treatment is a suitable alternative treatment to parenteral drugs. Further studies in a larger number of patients under field conditions are required.

PIP: The effectiveness of 2 treatment regimens for severe falciparum malaria was compared in a clinical trial involving 63 patients admitted to the Bangkok (Thailand) Hospital for Tropical Diseases in 1995. On admission, malaria patients were randomly assigned to receive artesunate rectal suppositories (200 mg/capsule) at 0, 4, 8, 12, 24, 36, 48, and 60 hours (total dose, 1600 mg) or the same drug administered at 0, 12, 24, 36, 48, and 60 hours (total dose, 1200 mg). Both regimens were followed by 2 doses of oral mefloquine (750 mg at 72 hours and 500 mg at 84 hours). The mean parasite clearance time was significantly shorter in the 1600 mg dose group than in the 1200 mg dose group (47.3 versus 55.3 hours) (p = 0.05) and the rate of parasite reduction was significantly faster in the former group (p = 0.05). The mean fever clearance time was similar in both groups (71.1 and 76.9 hours, respectively). The 22 patients with unrousable coma at admission regained consciousness after 1-4 days of treatment, and 60 patients (95.2%) were parasitologically and clinically cured within 3-4 days of admission. The cure rate after 28 days was 96% (26/27) in the higher-dose group and 89% (24/27) in the lower-dose group. There were no major adverse drug effects. Although further studies under field conditions are recommended, these findings suggest that sequential artesunate treatment is a suitable alternative to parenteral drugs in cases of severe malaria.

Monotherapy with sodium artesunate for uncomplicated falciparum malaria in Thailand: a comparison of 5- and 7-day regimens.

We compared the safety and efficacy of two treatment regimens using sodium artesunate in 91 randomized patients with uncomplicated falciparum malaria acquired in Thailand. One group of 45 patients received 400 mg of artesunate on the first day of treatment and then 200 mg daily for 4 days for a total of 1200 mg (group I: 5-day treatment). A second group of 46 patients received 400 mg of artesunate on the first day of treatment and then 200 mg daily for 6 days for a total of 1600 mg (group II: 7-day treatment). Both regimens were well tolerated. All patients were followed for a total of 28 days. By the third day of treatment, most patients were blood smear negative for parasites. Eighty-two patients completed the 28-day follow-up period and were used for describing the cure rate. All patients treated with the 5-day regimen were cured. In the 7-day treatment group, 98% (39 of 40) of the patients were cured; one patient developed late recrudescence (RI). There were no significant differences in fever clearance or parasite clearance between the two groups. However, 13 patients (five in group I and eight in group II) developed Plasmodium vivax infection during the follow-up period. We conclude that 5- or 7-day regimens of sodium artesunate with a total dose of 1200-1600 mg are effective and safe in treating falciparum malaria acquired in Thailand.

Comparative clinical trial of artesunate followed by mefloquine in the treatment of acute uncomplicated falciparum malaria: two- and three-day regimens.

The difficulties in treating drug-resistant falciparum malaria in Thailand are compounded by the necessity of giving antimalarials over long periods of time. The resultant decrease in patient compliance not only lowers cure rates but also predisposes to the further spread of drug resistance. We compared the efficacy of two sequential treatment regimens given over two and three days in 111 patients with acute uncomplicated falciparum malaria. Sixty-seven patients received two 400-mg doses of artesunate (total dose = 800 mg) followed by two doses of mefloquine (750 mg given immediately and 500 mg 12 hr later; total dose = 1,250 mg) in Group 1. Forty-four patients (Group II) received four 200-mg doses of artesunate (total dose = 800 mg) given 12 hr apart followed by a mefloquine regimen similar to that for Group I. All patients were admitted to hospital in Bangkok for 28 days to preclude reinfection. Ninety-six patients completed the study. Cure rates for the two groups were 84% (49 of 58) for Group I and 100% (38 of 38) for Group II. The mean parasite clearance time and fever clearance time were significantly shorter in Group II (P < 0.02). There were no serious adverse reactions. All nine of the treatment failures in Group I were of the RI types. The results indicate that the sequential treatment with artesunate followed by mefloquine given over three days is effective and well-tolerated in patients with acute, uncomplicated falciparum malaria and suitable as an alternative treatment for multidrug-resistant falciparum malaria.

Efficacy and tolerability of a sequential, artesunate suppository plus mefloquine, treatment of severe falciparum malaria.

Thirty patients with severe falciparum malaria were each given a total of 1600-mg artesunate suppository over three consecutive days followed by 1250 mg mefloquine per os, divided into two doses which were given 12 h apart. All patients were admitted for 28 days to the Bangkok Hospital for Tropical Diseases, so that the efficacy and tolerability of the treatment could be assessed. All the patients showed clinical improvement, with mean (S.D.) parasite and fever clearance times of 50.4 (13.0) and 70.7 (44.9) h, respectively. Two patients with unrousable coma (Glasgow coma score < or = 8) on admittance regained consciousness 46 and 48 h post-treatment. One other patient had acute renal failure and required dialysis. Most patients (80%) were initially hyperparasitaemic, with a mean density of 184,344 parasites/microliters blood. No deaths occurred. Efficacy was evaluated in 25 of the patients. The cure rate 28 days post-treatment was 92%. None of the patients had major adverse effects although two had tenesmus and passed stools immediately after each suppository was administered. A fresh suppository had to be inserted when this occurred. The results indicate that artesunate suppositories followed by oral mefloquine constitute a well-tolerated regimen with a high cure rate. The combination is suitable as an alternative treatment for severe malaria, particularly in children. Further, large-scale studies are required.

Randomized trial of mefloquine alone and artesunate followed by mefloquine for the treatment of acute uncomplicated falciparum malaria.

Mefloquine is the main antimalarial used for treatment of falciparum malaria patients at the malaria clinics in Thailand. However, the cure rate with mefloquine alone has declined seriously in recent years. The efficacy and tolerability of a sequential treatment of artesunate followed by mefloquine was therefore compared with those of mefloquine alone, in a randomized therapeutic trial involving 125 patients with acute uncomplicated falciparum malaria. Sixty-three patients received mefloquine alone (750 mg given immediately, followed by 500 mg 6 h later) and 62 each received 800 mg artesunate over 2 days (200 mg every 12 h) followed 6 h later by a single, 750-mg dose of mefloquine. All patients were admitted to the hospital in Bangkok for 28 days to exclude re-infection. Most patients (107) completed the study; 18 left the hospital prior to completion of follow-up for reasons unrelated to their treatment. Cure rates for the two groups were 74% (42/57) for mefloquine alone and 92% (46/50) for artesunate followed by mefloquine. The mean parasite clearance time was significantly shorter (P < 0.001) in the group treated with the sequential combination than in the group treated with mefloquine alone, but the mean fever clearance times were not significantly different (P = 0.26). Most patients responded well to the treatment regimens and none suffered from serious toxic adverse reactions. Only four patients who were treated with mefloquine alone had parasitaemia persisting to day 7 (RII), thus requiring alternative follow-up treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Protection by a polyvalent vaccine against challenge infection and pyelonephritis.

The protective effect of immunization with a polyvalent vaccine (SolcoUrovac) was studied in the mouse and the rat. The i.m. immunization increased the resistance of mice to challenge infection with all homologous strains of bacteria. The LD50 values for E. coli, Proteus mirabilis and Streptococcus were 3.5-4.5 times and that of Klebsiella as much as 600 times that in nonimmunized mice. Protection against challenge with heterologous E. coli was also achieved and persisted for about 20 weeks. Immunization with the vaccine also provided marked protection against pyelonephritis in rats. Kidneys with abscesses were seen only one-third as often as in controls, and the size of the individual abscesses was substantially smaller in the vaccinated animals. Based on the quantity of bacteria in the kidneys it was postulated that the vaccination increased the clearance of bacteria.

Urinary antibody response after immunisation with a vaccine against urinary tract infection.

Immunisation of mice with SolcoUrovac vaccine induced an approximately 10-fold increase of the total amount of IgG and a 2-fold increase of IgA immunoglobulins in urine. IgG antibodies to SolcoUrovac antigens appeared in urine after the first injection, and booster injections caused a further increase of the titer. IgA antibodies appeared in the urine after the second injection, and the third injection doubled the titer. IgM immunoglobulins and specific IgM class antibodies to SolcoUrovac were not found in any urine tested. The exact origin of the immunoglobulins in the urine as well as the specificity of immune response is discussed.