The oral agent miltefosine has demonstrated a >95% cure rate in Indian visceral leishmaniasis. We performed a large, placebo-controlled study of miltefosine therapy (2.5 mg/kg per day orally for 28 days) against cutaneous leishmaniasis in Colombia and Guatemala. In regions in Colombia where Leishmania vianna panamensis is common, the per-protocol cure rates for miltefosine and placebo were 91% (40 of 44 patients) and 38% (9 of 24). These values are similar to historic values for the antimony standard of care and placebo. In regions in Guatemala where L. v. braziliensis and L. mexicana mexicana are common, the per-protocol cure rates were 53% (20 of 38) for miltefosine and 21% (4 of 19) for placebo. The miltefosine rate was lower than historic antimony cure rates of >90%. Miltefosine was well tolerated. Miltefosine is a useful oral agent against cutaneous leishmaniasis due to L. v. panamensis in Colombia but not against leishmaniasis due to L. v. braziliensis in Guatemala.

There is no recognized oral treatment for American cutaneous leishmaniasis. A rising-dose, open-label phase I/II trial of the oral agent miltefosine against Colombian cutaneous leishmaniasis was conducted. Seventy-two male Colombian soldiers (mean weight, 67 kg) received miltefosine at 50-100 mg/day for 3 weeks (for 32 evaluable patients) or at 133-150 mg/day for 3-4 weeks (for 32 evaluable patients). The per-protocol cure rate for 50-100 mg/day was 21 (66%) of 32 patients. The per-protocol cure rate for 133-150 mg/day was 30 (94%) of 32 patients (P =.01, by use of Fisher's exact test). The historic per-protocol cure rate for standard injections of antimony is 93%. "Motion sickness" that did not interfere with normal duties was experienced by 40% of patients and was dose related. Vomiting and diarrhea were reported on approximately 2% of treatment days. In this uncontrolled study of oral miltefosine for treatment of patients with American cutaneous leishmaniasis, a dosage of approximately 2.25 mg/kg/day for 3-4 weeks was effective and tolerated.

Abstract. Chloroquine-resistant Plasmodium vivax has been the subject of numerous case reports and prospective studies from Oceania and Asia. In contrast, only case reports exist from the Americas. We performed a prospective study with 28-day follow-up of clinical responses to chloroquine in 2 P. vivax-endemic regions of Colombia. Three (11%) of 27 patients failed to respond to treatment with the standard regimen of chloroquine (1,500 mg of base over 3 days). One patient demonstrated RI resistance on Day 26; one patient demonstrated RI resistance due to recrudescence of blood stages on Day 11; and one patient demonstrated RII resistance of blood stages by never displaying clearing of peripheral parasitemia. All patients were successfully treated with primaquine, which has some blood stage efficacy against P. vivax, combined with a second course of chloroquine. Clinical resistance of P. vivax to chloroquine is present in Colombia and should be monitored in the Americas.

Abstract. We studied the efficacy of WR279396, a topical formulation of aminoglycosides that cures 100% of cutaneous leishmaniasis lesions in mice. We conducted what is to our knowledge the first controlled study of WR279396 therapy for clinical cutaneous leishmaniasis. A total of 45 Colombian soldiers, all men, were randomly assigned to treatment with WR279396 (33 patients) or placebo (12 patients). Each lesion was treated twice daily for 20 days. Lesions were measured at the end of therapy and at 45, 90, and 180 days after treatment began. A total of 17 (61%) of 28 assessable WR279396-treated patients were cured, and 5 (55%) of 9 assessable placebo-treated patients were cured (P ϭ 0.9). For the 36 lesions treated with WR279396 that were cured, cure took a mean of 35 days, whereas for the 6 lesions that were cured in the group of patients receiving placebo, cure time took a mean of 56 days (P ϭ 0.04). WR279396 is a nontoxic topical formulation that significantly accelerated cure time in patients with Leishmania panamensis cutaneous leishmaniasis.

The role of peroxisome proliferator activator receptor (PPAR)β/δ in the pathogenesis of Alzheimer's disease has only recently been explored through the use of PPARβ/δ agonists. Here we evaluated the effects of PPARβ/δ deficiency on the amyloidogenic pathway and tau hyperphosphorylation. PPARβ/δ-null mice showed cognitive impairment in the object recognition task, accompanied by enhanced DNA-binding activity of NF-κB in the cortex and increased expression of IL-6. In addition, two NF-κB-target genes involved in β-amyloid (Aβ) synthesis and deposition, the β site APP cleaving enzyme 1 (Bace1) and the receptor for advanced glycation endproducts (Rage), respectively, increased in PPARβ/δ-null mice compared to wild type animals. The protein levels of glial fibrillary acidic protein (GFAP) increased in the cortex of PPARβ/δ-null mice, which would suggest the presence of astrogliosis. Finally, tau hyperphosphorylation at Ser199 and enhanced levels of PHF-tau were associated with increased levels of the tau kinases CDK5 and phospho-ERK1/2 in the cortex of PPARβ/δ(-/-) mice. Collectively, our findings indicate that PPARβ/δ deficiency results in cognitive impairment associated with enhanced inflammation, astrogliosis and tau hyperphosphorylation in the cortex.

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