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The production of superoxide by the peripheral blood neutrophils of 19 patients with active rheumatoid arthritis was measured during treatment with sulphasalazine (SASP). The response to drug treatment was determined by change in plasma viscosity, CRP, early morning stiffness and articular index over a 10-point scale. Of the 19 patients studied, eight were considered to have responded well to SASP and seven to have responded poorly or not at all. Over the treatment period, plateau levels of superoxide production fell in seven of the eight responders (P = 0.028) compared with a non-significant fall in 3/7 of the non-responder groups. The initial rate of superoxide production also fell in the responder group, but this was not statistically significant. Initial values in both the responder and non-responder groups were comparable with those seen for normal controls. Analysis of drug levels showed all patients to be compliant with drug treatment; however, drug levels and neutrophil activity were not correlated. Studies of the effect of SASP and sulphapyridine on superoxide production in vitro showed no difference between good and poor responders. These results suggest that there is no inherent difference between good and poor responders regarding the susceptibility of their neutrophils to SASP. SASP's action on neutrophils, therefore, appears not to be its main mechanism of disease-modifying activity in RA.

In 120 adult Vietnamese patients with uncomplicated falciparum malaria the efficacy of, and tolerance to, mefloquine (M) vs the combination of mefloquine + sulfadoxine + pyrimethamine (MSP) was studied in a double-blind, randomized comparative trial with chloroquine. Also, a double-blind dose finding study of MSP was performed in 120 Vietnamese children with uncomplicated falciparum malaria. In the adults the mean parasite clearance time with M was 3.8 d and with MSP 3.6 d. Defervescence occurred in 2.9 and 3.0 d respectively for M and MSP. There was a 36.8% resistance rate in 38 patients treated with chloroquine. 96% of the children were sensitive or showed a delayed RI response. The lowest dose of MSP (10 mg/kg M + 20 mg/kg S + 1.0 mg/kg P, 1 tablet Fansimef) was as effective as 1.5-2x this dose in children weighing 23-30 kg. Side effects were mild, except for vomiting which required alternative therapy in 4 patients.

In Malawi, where high levels of chloroquine resistance were shown using a modified 7-day in vivo test, amodiaquine and pyrimethamine-sulfadoxine were evaluated as alternative initial therapies for Plasmodium falciparum infections in children under 5 years old. Therapy success rates, judged by parasite clearance by day 7 after initiation of therapy, were significantly greater among 39 children treated with amodiaquine at 10 mg/kg (90%), 37 receiving amodiaquine at 25 mg/kg (97%), and 34 receiving pyrimethamine-sulfadoxine (100%) at a dose of 25 mg sulfadoxine/kg, than among those treated with chloroquine at a dose of 25 mg/kg (59%) (P = 0.01). Extension of the follow-up period of those receiving amodiaquine (25 mg/kg) and pyrimethamine-sulfadoxine to 21 d revealed a progressively increasing rate of parasite recrudescence in the amodiaquine group (34%), but no recrudescence in the pyrimethamine-sulfadoxine group. These results suggest that, in Malawi, amodiaquine and pyrimethamine-sulfadoxine are superior to chloroquine in producing prompt clearance of P. falciparum parasites among young children, and that pyrimethamine-sulfadoxine alone is superior to the 4-aminoquinolines in sustaining P. falciparum clearance.

A case of Plasmodium falciparum malaria resistant to Fansidar (sulphadoxine plus pyrimethamine) at a level corresponding to R III and resistant to chloroquine is reported. The infection was most certainly acquired in Malaysia, but diagnosed and treated in a non-malarious area. Normal resorption and elimination rates of the Fansidar components excludes cure failure due to abnormal drug fate in the host. P. falciparum parasites from the patient have been maintained in vitro cultures. The patient was permanently cured with mefloquine.

The sensitivity of Plasmodium falciparum infections to pyrimethamine-sulfadoxine was studied in 18 Indonesian patients in Jayapura, Irian Jaya. In 16 of the 18 patients parasitaemia was cleared by day 6 and the patients remained without parasitaemia through day 28. Two of the 18 patients had late recrudescences consistent with RI-type resistance; one each on days 14 and 21. Pyrimethamine-sulfadoxine is still an effective antimalarial for most patients with falciparum malaria in Jayapura.

The anti-malarial drug pyrimethamine suppresses in vitro mitogenic lectin-induced blast transformation by human peripheral blood mononuclear cells (MNC) when the drug is added to cells (1 X 10(-5) M/culture). Sulphadoxine, a second widely used anti-malarial drug has no suppressive effect on the MNC. MNC responsiveness in the mixed leucocyte reaction and cellular viability are not altered by either pyrimethamine or sulphadoxine. In addition, no significant suppression is found when serum obtained from individuals on pyrimethamine-sulphadoxine chemoprophylaxis is added to MNC in the assays. The data, however, do not totally rule out any clinically significant suppressive effect by the anti-malarial drugs on human cellular immune responses.

A randomized double blind study was performed to evaluate the tolerance and the acceptance of mefloquine alone (Lariam) compared to a combined drug regimen consisting of mefloquine, sulfadoxine and pyrimethamine (MSP; Fansimef) in the prophylaxis of malaria. 175 Europeans travelling to different malaria endemic areas received either mefloquine alone (250 mg/week) or its combination with sulfadoxine (500 mg/week) plus pyrimethamine (25 mg/week). One person taking mefloquine and two taking MSP discontinued the drug intake because of moderate clinical side effects. Mild and moderate adverse clinical reactions predominantly concerning the gastro-intestinal tract and the autonomous nervous system were reported with a significantly higher occurrence in the MSP group. With both prophylactic regimens, reversibly elevated liver enzyme activities (glutamate oxalate transaminase and glutamate pyruvate transaminase [GPT]) were observed after prophylaxis. The increase of GPT serum activity correlated significantly with relatively high GPT levels before prophylaxis in both groups. This finding suggests a limited use of both regimens in cases of liver dysfunction. One case of mefloquine-resistant Plasmodium falciparum malaria was observed from West Africa; this patient was cured by a standard regimen of chloroquine.

A randomized, double-blind field trial was carried out to compare the effectiveness of mefloquine plus sulfadoxine-pyrimethamine (MSP) with that of sulfadoxine-pyrimethamine (SP) in chemoprophylaxis against malaria. The study was conducted in 193 migrant workers in the eastern rural areas of Thailand which are known to be highly endemic for multidrug-resistant Plasmodium falciparum infection. MSP was found to be more effective than SP in the suppression of both P. falciparum and P. vivax parasitaemias, when administered weekly for 12 weeks (P = 0.0014). Complete suppression of P. falciparum was achieved by MSP while 8 subjects receiving SP developed parasitaemia. One subject in the MSP group developed P. vivax parasitaemia, compared with 4 in the SP group. However, in view of the reported complications associated with the use of long-acting sulphonamides, some of which can be life threatening, prophylactic regimens containing sulfadoxine, though proved efficacious, must be used with extreme caution.

The sensitivity of Plasmodium falciparum strains to Fansidar (500 mg sulphadoxine/25 mg pyrimethamine) was tested in vivo in six localities in the United Republic of Tanzania where chloroquine-resistant P. falciparum strains have been demonstrated by both in vivo and in vitro tests. Single doses as recommended by the manufacturers achieved 100% clearance of parasitaemia in five localities with mean clearance period of between 2.2 and 2.9 days. In one locality (Gonja) the recommended dose failed to clear parasitaemia in two of the 38 cases (5.3%) within seven days. The possibility of using this drug combination for the treatment of chloroquine-resistant P. falciparum strains in the United Republic of Tanzania is discussed.

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.

29 male patients (14 from Taunggyi, 6 from Rangoon and 9 from Tharrawaddy in Burma) were treated simultaneously with 200 mg artemether (Single intramuscular dose), 1500 mg sulfadoxine and 75 mg [corrected] pyrimethamine (orally). The mean parasite clearance time was 106.7 +/- 48.7 h. Side effects were few and self-limiting. 13 of 29 patients had recrudescences before day 28; as all the patients were living in towns, reinfection was unlikely. This parasite clearance time was longer than that in patients treated with artemether alone (600 mg total dose), and the recrudescence rate was higher. This drug combination is not recommended for patients in areas where sulfadoxine/pyrimethamine resistance is already established.

The in vivo response of Plasmodium falciparum to standard treatment with sulphadoxine/pyrimethamine was studied in 19 hospital patients from Yekepa town with hypoendemic malaria and in 28 children, two to nine years old, living in a village with holoendemic malaria. In vitro tests were performed on eight isolates. In the hospital patients all parasites cleared with mean clearance time of 2.2 (range one to three) days and no recrudescence occurred during a 28-day follow-up period. In the village children, despite a high sporozoite inoculation rate, recurrent parasitaemias were only recorded after 28 days, suggesting a rather long-lasting prophylactic effect against reinfection by the drug combination. In vitro, inhibition of parasite multiplication was achieved by 3 X 10(-7) M sulphadoxine and 3.8 X 10(-9) M pyrimethamine.

Malaria, particularly that due to chloroquine-resistant Plasmodium falciparum, which requires management with antimalarial drugs capable of protecting against multiresistant strains, has emerged in Malaysia. A study was carried out to assess the efficacy and tolerability of 2 dosages of mefloquine/sulfadoxine/pyrimethamine (MSP; RO 13-5112) compared to Fansidar in a malaria endemic area. 914 subjects in 3 random groups were studied. Occurrence of malaria was assessed both clinically as well as by blood films. Plasma drug levels were also measured. The results showed that the low dose of MSP was completely effective in suppressing parasitaemia. 2.7% of the study population reported adverse drug reactions, the lowest incidence being in subjects on the low dose; their blood chemical profiles were also the least affected. The plasma levels of pyrimethamine and sulfadoxine achieved in the low dose group were slightly higher than expected, but there was no significant difference in bioavailability. The study showed that, for chemoprophylaxis, a low dose of MSP provided effective protection with minimal side effects.

A randomized double blind study in long term malaria chemoprophylaxis was performed to compare the tolerability of Fansimef (1 tablet containing 250 mg mefloquine + 500 mg sulfadoxine + 25 mg pyrimethamine per week) with chloroquine (300 mg per week). 211 Austrian industrial workers and their families in Warri, Nigeria, participated in this study; 101 received Fansimef and 110 chloroquine for 3-18 months (mean 41 weeks). Prophylaxis was discontinued because of adverse effects in 7 volunteers in the Fansimef group (mainly insomnia, palpitations, dizziness, nausea and headache) and in 2 volunteers of the chloroquine group (headache and loss of hair in one volunteer, nausea, dizziness and vomiting in the other). Most of the adverse effects could be due to the mefloquine component. A few minor complaints of burning eyes, nausea and gastric pain were reported in both groups. Laboratory checks performed at 3-monthly intervals showed a slight, transient and clinically irrelevant (but statistically significant) increase of serum glutamic-oxalacetic transaminase and gamma-glutamyl transpeptidase at month 3 in the Fansimef group. An attack of acute Plasmodium falciparum malaria occurred in one volunteer 6 weeks after discontinuation of prophylaxis with Fansimef. Antibodies against blood stage parasites could be demonstrated by the indirect immunofluorescence test at different stages of the study, indicating that these two antimalarials are not causal prophylactic agents.

Falciparum malaria in 104 Thai patients was treated with either Mefloquine or Fansidar and patients were examined for parasitaemia for the next 28 days. All but one of the 40 patients treated with Mefloquine were cured, but the cure rates for Fansidar were only 9 . 1% for the two-tablet regimen and 19 . 4% for the three-tablet regimen. Most failures were classified as RII. Serum sulpha levels indicated that the Fansidar was being absorbed. Immediate steps should be taken to eliminate this focus of resistance and to protect against further resistance to Fansidar by using it in combination with another effective anti-malarial and by vigorous vector control measures.

Fifty-eight Nigerian children with Plasmodium falciparum malaria were allocated randomly into two groups and treated with either chloroquine (25 mg/kg over three days) or Fansidar (35 mg sulphadoxin (+ 1/20 pyrimethamine) per kg single dose)). They were observed for 28 days during which blood films were examined periodically for malaria parasites. Asexual forms of P. falciparum, which were present in the blood films of all the patients in both groups before commencing treatment, disappeared rapidly from the blood so that by the fourth day after starting treatment no parasites were seen in the blood films. The blood films thereafter remained negative in both groups throughout the rest of the 28-day observation period. The rate of fever clearance was also similar in both groups. The study did not show resistance to Fansidar or to chloroquine. There is therefore, at present, no case for the indiscriminate use of Fansidar on the basis of suspected chloroquine resistance.

The protective effect of malaria chemoprophylaxis with either Fansidar (pyrimethamine-sulfadoxine) or chloroquine was estimated by determining the attack rates of Plasmodium falciparum infections acquired in Kenya and imported by U.S. and Swiss travelers who had used no chemoprophylaxis, who had used only chloroquine for prophylaxis, and who had used Fansidar weekly, either alone or in combination with chloroquine. The estimated attack rates were almost identical in U.S. and Swiss travelers. The attack rate per 100,000 travelers averaged 280 in those who did not use chemoprophylaxis, 162 in those who took 4-aminoquinolines (P greater than .05), and 27 in those who used Fansidar for prophylaxis (P less than .001). Non-immune travelers to Kenya have an appreciable risk of acquiring a P. falciparum infection and need to be informed of current guidelines for chemoprophylaxis. The changing drug susceptibility patterns in Africa require continuous evaluation of the efficacy of recommended drug regimens for malaria prophylaxis.

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.

The response of Plasmodium falciparum isolates to dihydrofolate reductase inhibitors (DHFRI) was examined in Malindi, Kenya. All 20 infected children treated with pyrimethamine/sulphadoxine responded. In contrast, after treatment with pyrimethamine, parasitaemia in 9 of 14 infections failed to clear or recrudesced during the seven-day follow-up. In a 48-hour in vitro test, five of six isolates resistant to pyrimethamine in vivo had a minimal inhibitory concentration (MIC) to pyrimethamine greater than or equal to 300 nmoles/1 compared with less than or equal to 100 nmoles/1 for the four sensitive isolates; four isolates did not grow. MIC to M-B 35769, an experimental DHFRI structurally similar to pyrimethamine were the same (six isolates) or 10-fold lower (three isolates). In the laboratory four of five isolates adapted to in vitro culture had the same MICs as in the field while one isolate became less responsive to both drugs. Cycloguanil (the active metabolite of proguanil) was more active in vitro in the laboratory than pyrimethamine or M-B 35769.