New drugs are needed for preventing drug-resistant Plasmodium falciparum malaria. The prophylactic efficacy of azithromycin against P. falciparum in malaria-immune Kenyans was 83%. We conducted a double-blind, placebo-controlled trial to determine the prophylactic efficacy of azithromycin against multidrug-resistant P. falciparum malaria and chloroquine-resistant Plasmodium vivax malaria in Indonesian adults with limited immunity. After radical cure therapy, 300 randomized subjects received azithromycin (148 subjects, 750-mg loading dose followed by 250 mg/d), placebo (77), or doxycycline (75, 100 mg/d). The end point was slide-proven parasitemia. There were 58 P. falciparum and 29 P. vivax prophylaxis failures over 20 weeks. Using incidence rates, the protective efficacy of azithromycin relative to placebo was 71.6% (95% confidence interval [CI], 50.3 -83.8) against P. falciparum malaria and 98.9% (95% CI, 93.1 -99.9) against P. vivax malaria. Corresponding figures for doxycycline were 96.3% (95% CI, 85.4 -99.6) and 98% (95% CI, 88.0 -99.9), respectively. Daily azithromycin offered excellent protection against P. vivax malaria but modest protection against P. falciparum malaria.Malaria is a serious global public health problem. The World chloroquine-resistant Plasmodium vivax is now an emerging Health Organization estimates that there are 300 -500 million threat [7,8]. cases of clinical malaria each year worldwide with 1.5 to 2.7Prophylactic drugs must have high efficacy and low toxicity. million deaths attributable to Plasmodium falciparum [1,2].Mefloquine, doxycycline, and chloroquine/proguanil are curChemoprophylaxis for malaria is aimed at two distinct rently recommended as prophylaxis for chloroquine-resistant groups: nonimmune individuals of all ages who travel to areas P. falciparum malaria [3,9, 10]. None of these drugs is ideal. where malaria is endemic [3] and pregnant women living in Doxycycline is contraindicated in pregnancy [3, 10] and chilareas of endemicity [4]. Antimalarial drugs for prophylaxis and dren younger than 8 years of age [9]. Mefloquine is contrainditreatment are becoming increasingly ineffective because of the cated for patients with a history of epilepsy or serious psychiatcontinuing rise of multidrug-resistant P. falciparum malaria in ric disease [9]. The World Health Organization [3] and the most areas where malaria is endemic [5,6] avoidable [9]. Chloroquine and proguanil are safe in pregnancyInformed consent was obtained from all study subjects, and the regulations [10,11], but this combination has low efficacy [12,13].governing the protection of human subjects of the Indonesian Ministry of Health, the Indonesian Army, and the U.S. Navy and Army were followed in Azithromycin, an azalide antibiotic similar to erythromycin, the conduct of this study.had good antimalarial activity in human malaria challenge stud-The views expressed in this article are those of the authors and do not in any way represent those of the Indonesian Army, the Indonesian Ministry of ies [14,15]. When azi...

Abstract. Combination therapy is one method of overcoming the global challenge of drug-resistant Plasmodium falciparum malaria. We conducted a hospital-based 28-day in vivo test comparing chloroquine/doxycycline to chloroquine or doxycycline alone for treating P. falciparum and Plasmodium vivax malaria in Irian Jaya, Indonesia. Eighty-nine patients with uncomplicated falciparum malaria were randomized to standard dose chloroquine (n ϭ 30), doxycycline (100 mg every 12 hours [7 days], n ϭ 20), or chloroquine with doxycycline (n ϭ 39); corresponding numbers for vivax malaria (n ϭ 63) were 23, 16, 24. Endpoints were parasite sensitivity (S) or resistance (RI/RII/ RIII Chloroquine/doxycycline was effective against P. falciparum but only modestly effective against P. vivax. These findings support the use of chloroquine/doxycycline as an inexpensive alternative to mefloquine for treating chloroquine-resistant P. falciparum but not chloroquine-resistant P. vivax in this setting.

Background: There are limited data on the evolution of the leukocyte and platelet counts in malaria patients.

Drug tolerability affects compliance. We evaluated the tolerability levels of azithromycin (750-mg loading dose plus 250 mg/day; n ‫؍‬ 148 subjects), doxycycline (100 mg/day; n ‫؍‬ 75), and placebo (n ‫؍‬ 77) as prophylaxis against malaria in Indonesian adults over 20 weeks. Self-reported and elicited symptoms, health perception, hearing, hematology, and biochemistry were assessed. The loading dose was well tolerated. Prolonged drug use for disease prophylaxis, treatment, or suppression should be well tolerated. This is especially true for healthy recipients of prophylaxis, such as travelers and pregnant women, for whom the risk-to-benefit ratio requires both safe and easily tolerable regimens.Azithromycin has several clinical indications that include the treatment and prophylaxis of Mycobacterium avium-M. intracellulare complex (MAC) infection and the treatment of community-acquired pneumonia and genital or ocular Chlamydia trachomatis infection (25). The standard doses of azithromycin (30 mg/kg of body weight for children and 1.5 g total dose for adults) are well tolerated. Up to 12% of patients report any symptom, Ͻ10% report gastrointestinal symptoms, and 0.7 to 1.3% discontinue therapy. Such tolerability compares favorably to that of other antibiotics (7,11,12,22). High doses of azithromycin, 1 g/kg for adults and 20 mg/kg for children, are also well tolerated (2, 16). However, doses used for MAC infections (1.2 g/week or 300 to 600 mg/day) are less well tolerated (3, 9, 10, 17). Gastrointestinal symptoms are reported by a high proportion of patients (e.g., by 71 [78.9%] of 85 recipients of weekly azithromycin, resulting in six [7%] withdrawals [17]). Hearing loss in the speech frequency range has also been reported in 13 to 17% of patients with MAC infections. It is dose dependent and recovers within 2 to 11 weeks after discontinuation of the drug (3,9,23,24). Irreversible high-frequency-hearing loss has also been reported following treatment with 750 mg of oral azithromycin in a 37-year-old woman (19). Biochemical and hematological assessments in large clinical series have been unremarkable. Mild elevations of liver enzymes (0.3 to 1.7%) and transient neutropenia (1.5%) or neutrophilia (1.5%) have been documented (11). Significant hepatotoxicity (e.g., hypersensitivity hepatitis, cholestasis) is rare (4, 15), as are anaphylaxis, pseudomembranous colitis, erythema multiforme, and Churg-Strauss syndrome (12,13,22).One trial has previously assessed azithromycin as prophylaxis against malaria. Azithromycin was administered daily (250 mg) or weekly (1 g) for 13 weeks to Kenyan adults. The reported symptoms were similar to those of placebo recipients, and there was no evidence of toxicity on routine hematological or biochemical testing (1).We report the tolerability of daily-administered azithromycin as prophylaxis against malaria in Indonesian adults. MATERIALS AND METHODSSubjects and study conduct. This double-blind, placebo-controlled trial assessed the prophylactic efficacy and tolerability of azithromycin ...

Ecto-nucleotidases are plasma membrane-bound enzymes that sequentially dephosphorylate extracellular nucleotides such as ATP. This breakdown of ATP and other nucleotides obscures the characterization and classification of P2 (nucleotide) receptors. We therefore studied suramin and several of its analogs, divalent cations and ATP gamma S for their ability to inhibit ecto-ATPase in human blood cells. Suramin itself and Ni2+ were the more potent, non-competitive inhibitors with micromolar affinity. ATP gamma S also displayed micromolar affinity and inhibited ecto-ATPase competitively. The data obtained with the divalent cations demonstrate that coordination of the phosphate chain but not the N7 of the adenine ring is required for the breakdown of ATP by ecto-ATPase. Divalent cations that coordinate both the phosphate chain and N7 inhibit ecto-ATPase in a non-competitive manner.