Schistosomiasis control in the people's Republic of China.

Evidence exists that schitosomiasis japonica has been present in China for more than 2,200 years. The first parasitologically confirmed clinical case was reported in 1905. Fragmentary surveys before 1949 suggested that there were 5 million schistosomiasis patients distributed in 138 hsiens (counties); however, a more systematic survey after the founding of the People's Republic showed that these figures represented only 50% of patients and 40% of infected hsiens. Based on the epidemiological pattern and ecological characteristics of the snail intermediate host, endemic areas have been divided into three strata: plain region, mountainous and hill region, and marshland and lake region. Following comprehensive control measures, with stress on applied research and integrating technical work with involvement of the population, in 204 hsiens the snail control programs are now considered to be relatively consolidated and the number of patients needing treatment is relatively few. In the marshland and lake region and mountainous region eradication of schistosomiasis remains a difficult problem.

Experimental studies on combinations of pyronaridine/primaquine versus chloroquine/primaquine.

The toxicity of combined use of blood schizontocide pyronaridine (PND) and primaquine (PQ) in mice and rats was significantly lower than that of chloroquine (CQ) plus primaquine (PQ). PND 1/2 LD50 (ca 600 mg/kg) in combination with PQ reduced the toxic action of PQ in mice, while CQ 1/2 LD50 (ca 300 mg/kg) plus PQ produced synergistic toxic effect. In animal models such as Plasmodium yoelii sporozoite infection in mice and P. cynomolgi sporozoite infection in rhesus monkeys, the tissue schizontocidal action of PQ was not affected by PND. Therefore, clinical evaluation of PND/PQ in comparison with CQ/PQ in treating vivax malaria is suggested.

Tissue schizontocidal effect of trifluoroacetyl primaquine in Plasmodium yoelii infected mice and Plasmodium cynomolgi infected monkeys.

Trifluoroacetyl primaquine oxalate (M8506) was compared with primaquine phosphate for tissue schizontocidal action in rodent and simian malaria. In Plasmodium yoelii sporozoites infected mice, the causal prophylactic effects of M8506 at 5, 10 and 20 mg(base)/kg were 56.7%, 87.2% and 100%, respectively, comparable to those of primaquine (54.4%, 90.8% and 100%). In P. cynomolgi sporozoites infected rhesus monkeys 4 dosage regimens of the two agents were compared for radical curative effect. On the first day of treatment pyronaridine phosphate 10 mg(base)/kg twice a day were intramuscularly injected to eliminate erythrocytic stages of P. cynomolgi. At the dosage of 3.0 mg(base)/kg/day x 3, both M8506 and primaquine radically cured the monkeys. At 0.75 mg/kg/day x 3, 12 of 13 (92.3%) monkeys cured by M8506, 5 of 9 (55.6%) cured by primaquine. At 1.5 and 0.375 mg/kg/day x 3, the radical curative effects of M8506 were also better than those of primaquine. Since the toxicity of M8506 was significantly milder in mice, rats and dogs than that of primaquine, M8506 has potential as a tissue schizontocide.

Comparison of effects of pyronaridine, amodiaquine, mefloquine and qinghaosu on rodent malaria.

Blood schizontocidal effect of antimalarials were compared by 4-day suppressive test with an extended observation period of 31 days. On a drug-sensitive Plasmodium berghei ANKA strain, pyronaridine (PND) exhibited the best effect, followed by amodiaquine (ADQ), mefloquine (MFQ), and qinghaosu (QHS). On a moderately chloroquine-resistant P. berghei NS line, the order of effects was the same, PND greater than ADQ greater than MFQ greater than QHS. On a highly pyronaridine-resistant P. berghei RP line, ADQ, MFQ and QHS showed cross resistance with PND.

A 5-year surveillance of sensitivity in vivo of Plasmodium falciparum to pyronaridine/sulfadoxine/pyrimethamine in Diaoluo area, Hainan Province.

The surveillance of sensitivity of P. falciparum to pyronaridine/sulfadoxine/pyrimethamine has been carried out in Diaoluo area in Hainan Province where chloroquine-resistant falciparum malaria is endemic, covering an area of 406 square kilometers, with a population of 3745 in 1986. From 1986 all outpatients diagnosed as falciparum malaria were administered with PND/S/P as the only antimalarial. In vivo sensitivity of P. falciparum was measured in some patients who were treated in hospital. It was demonstrated that P. falciparum in the Diaoluo area has retained its sensitivity to a single oral dose of PND/S/P of 500/1,000/50 mg with 100% cure rate for at least 5 years.

Antimalarial and toxic effect of triple combination of pyronaridine, sulfadoxine and pyrimethamine.

The triple combination of pyronaridine, sulfadoxine and pyrimethamine which has been proven to be efficient in delaying emergence of drug resistance of rodent malarial parasites was further studied for potential application to malaria control. The antimalarial effect of the triple combination on Plasmodium berghei ANKA-infected mice and the toxic effects in mice and rats were additive. A single dose of pyronaridine 500 mg in combination with sulfadoxine, 1000 or 1500 mg, and pyrimethamine, 50 or 75 mg, given to 72 acute falciparum malaria patients resulted in a 100% cure rate with nil or mild side effects, and no recrudescence of asexual parasite over 4-week follow-up. Preliminary experiments on the drug effect on sporogony showed that the drug combination at the dose used could not completely interrupt the sporozoite formation although many retarded oocysts were found.

[The blood schizontocidal effects of pyronaridine, amodiaquine, mefloquine and qinghaosu on mice infected with Plasmodium berghei].

The asexual stages of P. berghei ANKA were completely eliminated as revealed in a "4-day suppressive test" with the daily dose of pyronaridine 12.5 mg base/kg or amodiaquine 25 mg base/kg. Mefloquine 25 mg base/kg and qinghaosu 100 mg/kg though exerted obvious suppressive effect, the cure rates were only 50% and 0%, respectively. In treating chloroquine-sensitive P. berghei ANKA strain pyronaridine exhibited the best therapeutic activity, which was followed by amodiaquine, mefloquine and quinghaosu. In treating moderately chloroquine-resistant P. berghei NS line the cure rate of pyronaridine 12.5 mg/kg.d x 4 was 70%, but none of the 10 infected mice from any group was cured by amodiaquine 100 mg/kg.d, mefloquine 100 mg/kg.d or qinghaosu 200 mg/kg.d. Though the latter 3 drugs showed prominent suppressive effects, parasitemia remained positive or recrudesced after dosing. We demonstrate that parasites resistant to chloroquine had cross resistance to amodiaquine, mefloquine and inghaosu at various degrees. Amodiaquine 100 mg/kg.d, mefloquine 100 mg/kg.d and qinghaosu 200 mg/kg.d exhibited no obvious suppressive activity on highly pyronaridine-resistant line of P. berghei, indicating the existence of cross resistance to pyronaridine.