For the treatment of American cutaneous leishmaniasis, the combination of allopurinol and meglumine antimoniate is significantly more effective than meglumine antimoniate alone, probably because of the efficacy of allopurinol alone, which appears to be as good as the combination.

Summary The Pseudomonas syringae DC3000 type III effector HopAM1 suppresses plant immunity and contains a Toll/interleukin‐1 receptor (TIR) domain homologous to immunity‐related TIR domains of plant nucleotide‐binding leucine‐rich repeat receptors that hydrolyze nicotinamide adenine dinucleotide (NAD+) and activate immunity. In vitro and in vivo assays were conducted to determine if HopAM1 hydrolyzes NAD+ and if the activity is essential for HopAM1’s suppression of plant immunity and contribution to virulence. HPLC and LC‐MS were utilized to analyze metabolites produced from NAD+ by HopAM1 in vitro and in both yeast and plants. Agrobacterium‐mediated transient expression and in planta inoculation assays were performed to determine HopAM1’s intrinsic enzymatic activity and virulence contribution. HopAM1 is catalytically active and hydrolyzes NAD+ to produce nicotinamide and a novel cADPR variant (v2‐cADPR). Expression of HopAM1 triggers cell death in yeast and plants dependent on the putative catalytic residue glutamic acid 191 (E191) within the TIR domain. Furthermore, HopAM1’s E191 residue is required to suppress both pattern‐triggered immunity and effector‐triggered immunity and promote P. syringae virulence. HopAM1 manipulates endogenous NAD+ to produce v2‐cADPR and promote pathogenesis. This work suggests that HopAM1’s TIR domain possesses different catalytic specificity than other TIR domain‐containing NAD+ hydrolases and that pathogens exploit this activity to sabotage NAD+ metabolism for immune suppression and virulence.

We conducted a randomized, controlled study in southern Colombia to determine if the addition of allopurinol to stibogluconate was superior to stibogluconate alone in the treatment of cutaneous leishmaniasis. Lesions that healed after a 3-month course of therapy and remained so during a 1-year period of follow-up were considered cured. The cure rate for patients treated with stibogluconate was 39%; the addition of allopurinol increased this rate to 71% (P = .005). For the treatment of cutaneous leishmaniasis, the combination of allopurinol and stibogluconate is significantly more effective than is stibogluconate alone. These results support those of other clinical studies in which allopurinol and stibogluconate were shown to be superior to stibogluconate alone. The aggregate data support the use of allopurinol as an inexpensive, orally administered agent that can be used as an adjunct to stibogluconate or, perhaps, other oral agents in the treatment of cutaneous leishmaniasis.

We have developed a simple and reproducible system for infecting a human macrophage cell line (U937) with stationary-phase Leishmania donovani promastigotes. Four days after infection, greater than 90% of the promastigotes had transformed to amastigotes. The antileishmanial agents allopurinol riboside, formycin B, 9-deazainosine, and sodium stibogluconate effectively inhibited the growth of L. donovani amastigotes in this cell line. To study the capability of amastigotes in the U937 cell line to carry out biochemical reactions that could be monitored experimentally, we incubated the cells with radiolabeled 9-deazainosine. This purine analogue underwent metabolism in the amastigote phase similar to that occurring in the promastigote phase. This cell line should be useful for studies of parasite maturation and differentiation, parasite-human interactions, and antiparasitic drugs.

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