Gluzman I Y, Schlesinger P H, Krogstad D J
Antimicrob Agents Chemother. 1987 Jan;31(1):32-6. doi: 10.1128/AAC.31.1.32.
In the studies reported here, we examined the inoculum effect observed with chloroquine and Plasmodium falciparum. The 50% effective doses observed with both chloroquine-susceptible and -resistant parasites increased five- to sevenfold from their baseline values as the inoculum was increased from 2 X 10(5) to 2 X 10(7) parasitized erythrocytes per ml (parasitemias of 0.1 to 10% with a hematocrit of 2%). Increasing the inoculum also decreased the chloroquine uptake per parasitized erythrocyte 15- to 20-fold with both chloroquine-susceptible and -resistant parasites. However, because of the 100-fold increase in the inoculum, the total amount of chloroquine taken up actually increased sufficiently to reduce the extracellular chloroquine concentration in vitro by 60 to 90%. These studies suggest that a chloroquine uptake of greater than or equal to 2.0 pmol/10(6) parasitized erythrocytes is necessary for chloroquine to inhibit parasite growth. More marked reductions in the amount of chloroquine uptake per parasitized erythrocyte were observed with a hematocrit of 40% using similar parasitemias of 0.1 to 10% (inocula of 4 X 10(6) to 4 X 10(8) parasitized erythrocytes per ml). Thin-layer chromatography of [3H]chloroquine taken up by chloroquine-resistant P. falciparum revealed no evidence of drug alteration by the parasite. These studies define the mechanism responsible for the inoculum effect observed with chloroquine and P. falciparum in vitro.
在本文报道的研究中，我们检测了氯喹和恶性疟原虫的接种量效应。随着接种量从每毫升2×10⁵个感染红细胞增加到2×10⁷个感染红细胞（血细胞比容为2%时，疟原虫血症为0.1%至10%），氯喹敏感和耐药疟原虫的50%有效剂量从基线值增加了5至7倍。随着接种量增加，氯喹敏感和耐药疟原虫的每个感染红细胞对氯喹的摄取量均降低了15至20倍。然而，由于接种量增加了100倍，实际摄取的氯喹总量增加到足以使体外细胞外氯喹浓度降低60%至90%。这些研究表明，氯喹抑制疟原虫生长所需的摄取量为≥2.0 pmol/10⁶个感染红细胞。使用0.1%至10%的相似疟原虫血症（每毫升4×10⁶至4×10⁸个感染红细胞接种量），血细胞比容为40%时，每个感染红细胞的氯喹摄取量有更显著的降低。对氯喹耐药的恶性疟原虫摄取的[³H]氯喹进行薄层层析，未发现疟原虫对药物有改变的迹象。这些研究确定了体外观察到的氯喹和恶性疟原虫接种量效应的机制。
