We report an improved, nonhazardous, high-throughput assay for in vitro quantification of antimalarial drug inhibition of ␤-hematin (hemozoin) crystallization performed under conditions that are more physiological relative to previous assays. The assay uses the differential detergent solubility of crystalline and noncrystalline forms of heme and is optimized via the use of lipid catalyst. Using this assay, we quantify the effect of pH on the crystal growth-inhibitory activities of current quinoline antimalarials, evaluate the catalytic efficiencies of different lipids, and test for a possible correlation between hemozoin inhibition by drugs versus their antiplasmodial activity. Consistent with several previous reports, we found a good correlation between hemozoin inhibition potency versus cytostatic antiplasmodial potency (50% inhibitory concentration) for a series of chloroquine (CQ) analogues. However, we found no correlation between hemozoin inhibition potency and cytocidal antiplasmodial potency (50% lethal dose) for the same drugs, suggesting that cellular targets for these two layers of 4-aminoquinoline drug activity differ. This important concept is also explored further for QN and its stereoisomers in the accompanying paper (A. P. Gorka, K. S. Sherlach, A. C. de Dios, and P. D. Roepe, Antimicrob. Agents Chemother. 57:365-374, 2013). There are an estimated 350 million to 500 million Plasmodium falciparum malaria infections annually, with at least 1 million of these being fatal (1). The continued spread and evolution of resistance to currently used antimalarials (2-5) have generated renewed effort to design drugs effective against chloroquine (CQ)-resistant (CQR) malaria. This effort benefits from further development of rapid, inexpensive screens that more reliably estimate antiplasmodial activity.During the trophozoite stage of the intraerythrocytic cycle, P. falciparum actively degrades host red blood cell hemoglobin, producing millimolar quantities of toxic ferriprotoporphyrin IX (FPIX) heme within the digestive vacuole (DV) of the parasite (6, 7). Due to the lack of a heme oxygenase pathway (8), the malarial parasite maintains a low concentration of toxic free heme by sequestration into inert, nontoxic crystalline hemozoin (Hz) (9-12). The Hz crystallization pathway is an important target for antimalarial chemotherapy. Quinoline antimalarials, such as CQ and amodiaquine (AQ), are known to bind to multiple precrystalline forms of heme in different ways and thus presumably inhibit crystal growth by sequestration of monomeric and/or dimeric heme (13)(14)(15)(16)(17)(18). Quantifying drug inhibition of Hz formation in vitro has often been viewed as a faster and more economical way to predict and even quantify drug antiplasmodial activity in vivo (15, 16,(19)(20)(21)(22)(23)(24)(25)(26). However, the assays that have been used in this manner are typically done under conditions that are far from physiological. Also, it is becoming increasingly clear that some antimalarial drugs possess both cytostatic (growt...

Objectives: A variety of sclerotherapy agents are used to treat macrocystic lymphatic malformations (LMs). This retrospective study at a single institution was performed to compare the outcomes of pediatric macrocystic LMs of the head and neck that were treated with doxycycline or with OK432. Methods:The outcomes measured included early response to therapy, number of treatments required, operating room time, and adverse events. Results:The rates of clinical success for OK432 and doxycycline were similar (83% and 82%, respectively; p > 0.05), although OK432-treated patients required more treatments than did doxycycline-treated patients (1.9 versus 1.0 injections; p = 0.01; 95% confidence interval, 1.57 to 0.27). The average operating room time for a single OK432 injection was significantly shorter than that for doxycycline (53.2 versus 98.1 minutes; p < 0.001); however, when the total number of treatments administered was considered, the overall times in the operating room were similar. Adverse events in the early postoperative period were more common in OK432-treated patients, who experienced marked postoperative swelling compared to doxycycline-treated patients.Conclusions: OK432 and doxycycline are both effective sclerosants for the treatment of predominantly macrocystic LMs. The administration time for OK432 is shorter than that for doxycycline, but OK432 required more treatments overall to achieve clinical success. Early adverse events were more common in OK432-treated patients, but longer follow-up is necessary to determine whether rates of recurrence and adverse events are similar, particularly in light of the risk of tooth discoloration in doxycycline-treated patients.