不同剂量青蒿琥酯影响食蟹猴疟原虫配子体和孢子增殖的实验研究

目的：了解不同剂量青蒿琥酯对食触猴疟原虫孢子增殖的影响。方法：首剂药量加倍，随后24，48，72和96小时给实验猴各肌注一次，疗程5天，总剂量分别为15．0mg/kg、7．2mg/kg、3．6mg/kg、1．8mg/kg；在给药前及给药后6、12、24、30、36、48、54、60、72、84和108小时各用一批大劣按蚊叮咬实验猴，叮咬后第9天解剖蚊胃，第13天解剖涎腺。结果：在1．8－15mg/kg剂量范围内均能阻断食蟹猴疟原虫孢子增殖。结论：较低剂量青蒿琥酯亦能阻断孢子增殖，且随药物浓度增加，阻断速度会相应增快。     

Observations on early and late post-sporozoite tissue stages in primate malaria. V. The effect of pyrimethamine and proguanil upon tissue hypnozoites and schizonts of Plasmodium cynomolgi bastianellii

Two rhesus monkeys were each infected with 2.1 x 10(6) sporozoites of Plasmodium cynomolgi bastianellii; one was treated with 1.0 mg of pyrimethamine base per kg body weight for 5 d after sporozoite inoculation. A further 2 monkeys were each infected with 9.75 x 10(6) sporozoites of the same parasite; one was treated with 10 mg of proguanil per kg body weight for 4 out of 5 d after inoculation. The treated monkeys showed a delayed primary parasitaemia and relapses. In sections of liver biopsies taken 7.5 d after sporozoite inoculation, all monkeys showed numerous hypnozoites. However, there were no full grown schizonts and only rare retarded schizonts in the treated monkeys, in contrast to the untreated monkeys which had many mature or nearly mature schizonts. Later biopsies confirmed the continued presence of hypnozoites in all monkeys.     

Observations on early and late post-sporozoite tissue stages in primate malaria. III. Further attempts to find early forms and to correlate hypnozoites with growing exo-erythrocytic schizonts and parasitaemic relapses in Plasmodium cynomolgi bastianellii infections

Rhesus monkeys were heavily infected with sporozoites of Plasmodium cynomolgi bastianellii in an attempt to demonstrate the site of invasion of sporozoites into tissue cells and their growth there. Further attempts were made to correlate the appearance and loss of hypnozoites with parasitaemic relapses. Hypnozoites were demonstrated and once again shown to decrease in numbers over 229 days during which time the infection showed parasitaemic relapses. Liver biopsies taken at two-day intervals for 12 days showed that hypnozoites decreased in numbers over-all and growing schizonts were demonstrated in the liver. At this time a parasite the size of a hypnozoite was seen with two nuclei and another was seen with an elongate, possibly dividing nucleus in one monkey. an attempt to find the location of the early intracellular exoerythrocytic forms in the liver at various times less than 40 hours after infection using smears and immunological staining with newly prepared anti-sera failed. Large numbers of sporozoites of P. knowlesi were also injected into a rhesus monkey the liver of which on the fifth day after infection showed no hypnozoites among 157 sections of growing schizonts and no parasites at all on the 42nd day after infection. In P. cynomolgi bastianellii infections parasites, mostly hypnozoites, were found in the liver up to 229 days after infection.     

Characterizing the genetic diversity of the monkey malaria parasite Plasmodium cynomolgi

Plasmodium cynomolgi is a malaria parasite that typically infects Asian macaque monkeys, and humans on rare occasions. P. cynomolgi serves as a model system for the human malaria parasite Plasmodium vivax, with which it shares such important biological characteristics as formation of a dormant liver stage and a preference to invade reticulocytes. While genomes of three P. cynomolgi strains have been sequenced, genetic diversity of P. cynomolgi has not been widely investigated. To address this we developed the first panel of P. cynomolgi microsatellite markers to genotype eleven P. cynomolgi laboratory strains and 18 field isolates from Sarawak, Malaysian Borneo. We found diverse genotypes among most of the laboratory strains, though two nominally different strains were found to be genetically identical. We also investigated sequence polymorphism in two erythrocyte invasion gene families, the reticulocyte binding protein and Duffy binding protein genes, in these strains. We also observed copy number variation in rbp genes.     

Potentiation of activity of diaphenylsulfone and pyrimethamine against Plasmodium gallinaceum and Plasmodium cynomolgi bastianellii

In view of the fact that diaphenylsulfone has been shown to have low schizontocidal activity against Plasmodium gallinaceum and to lead to resistance in strains of P. cynomolgi, investigations were undertaken into the joint action of diaphenylsulfone and pyrimethamine against P. gallinaceum in chicks and P. cynomolgi bastianellii in monkeys. These drugs were assayed separately and in various combinations. It was found that at certain dose levels combination of the two drugs led to potentiation of their plasmocidal activity. On the other hand, this synergistic effect was not noted with combinations containing lower dosages of either drug; with these, a simple additive effect occurred. The authors suggest that the two drugs probably act on the same metabolic pathway but that their points of attack may be different. They note also that there was a difference in the response of P. gallinaceum in chicks and of P. cynomolgi bastianellii in monkeys to the combined use of the two drugs.     

Plasmodium cynomolgi Co-infections among Symptomatic Malaria Patients,Thailand

Among 1,180 symptomatic malaria patients, 9 (0.76%) infected with Plasmodium cynomolgi were co-infected with P. vivax (n = 7), P. falciparum (n = 1), or P. vivax and P. knowlesi (n = 1). Patients were from Tak, Chanthaburi, Ubon Ratchathani, Yala, and Narathiwat Provinces, suggesting P. cynomolgi is widespread in this country.     

Studies on the prophylactic and radical curative activity of RC-12 against Plasmodium cynomolgi in Macaca mulatta

The compound 4-(2-bromo-4,5-dimethoxyphenyl)-1,1,7,7-tetraethyldiethylenetriamine (RC-12) has been shown to be active against the exoerythrocytic (EE) stages of the malaria parasite. Experiments on Plasmodium cynomolgi in rhesus monkeys showed that single weekly doses of 25 mg per kg of body weight would prevent the development and/or maturation of EE stages. The usefulness of RC-12 for effecting radical cures is, however, still open to doubt.     

Orangutans Not Infected with Plasmodium vivax or P. cynomolgi, Indonesia

After orangutans in Indonesia were reported as infected with Plasmodium cynomolgi and P. vivax, we conducted phylogenetic analyses of small subunit ribosomal RNA gene sequences of Plasmodium spp. We found that these orangutans are not hosts of P. cynomolgi and P. vivax. Analysis of >1 genes is needed to identify Plasmodium spp. infecting orangutans.     

Comparative susceptibility of Southeast Asian Anopheles mosquitoes to the simian malaria parasite Plasmodium cynomolgi.

Seven Anopheles species/isolates were compared with Anopheles dirus (control) for susceptibility to Plasmodium cynomolgi B strain. The mean numbers of oocysts in paired replicates of An. dirus and An. takasagoensis were not significantly different. The remaining test species had significantly fewer mean numbers of oocysts than Anopheles dirus (P less than 0.01). Anopheles dirus had the highest percentage of mosquitoes infected with P. cynomolgi sporozoites (82%). Of the test groups, Anopheles dirus B and An. takasagoensis had the highest percentage of mosquitoes with sporozoites, 77 and 78%, respectively. Fewer than 50% of Anopheles maculatus E and An. maculatus B (NN isolate) had sporozoites in the salivary glands. Anopheles maculatus B (HK isolate) and Anopheles philippinensis were the least susceptible, with fewer than 30% having sporozoites in the salivary glands.     

Quinoline esters as potential antimalarial drugs: effect on relapses of Plasmodium cynomolgi infections in monkeys

Two compounds of the quinoline ester series, WR 197236 (6-butyl-4-hydroxy-3-methoxycarbonyl-7-beta-phenoxyethoxyquinoline ) and WR 194905 (4-acetoxy-6-decyloxy-7-isopropoxy-3-methoxycarbonylquinoline++ +), exhibit anti-relapse activity against sporozoite-induced Plasmodium cynomolgi B infections in rhesus monkeys. Both the compounds have been found to be curative when given intramuscularly in 7 daily doses of 15 mg/kg, and no relapses were observed during the observation period of 120 d.