Phase 2 trial of WR6026, an orally administered 8-aminoquinoline, in the treatment of visceral leishmaniasis caused by Leishmania chagasi.

Abstract

Abstract. There are no recognized orally administered treatments for any of the leishmaniases. The 8-aminoquinoline WR6026 is an orally administered analog of primaquine that cured 50% of patients with kala-azar in Kenya at a dose of 1 mg/kg/day for 28 days. A further phase 2, open-label, dose-escalating safety and efficacy study was performed for kala-azar in Brazil. Cure rates for Brazilian patients treated for 28 days were as follows: 1 mg/kg/day: 0 of 4 (0%); 1.5 mg/kg/day: 1 of 6 (17%); 2.0 mg/kg/day: 4 of 6 (67%); 2.5 mg/kg/day: 1 of 5 (20%); and 3.25 mg/ kg/day: 0 of 1 (0%). Nephrotoxicity that was not anticipated from preclinical animal studies or from phase 1 studies was seen at 2.5 mg/kg/day in 2 patients and in the single patient administered 3.25 mg/kg/day. WR6026 demonstrated the unusual clinical features of lack of increased efficacy against Brazilian kala-azar with increased dosing above 2 mg/kg/day and toxicity that was not present in previous investigations.

Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice

“…In conclusion, concerns about severe side effects from drug toxicity in the treatment of leishmaniasis, such as nephrotoxicity (74), pancreatitis (75), and hepatotoxicity (76,77) along with the development of drug resistance (78), have led to a need for the development of combined therapies for the leishmaniases, and notably for VL and drug-resistant cutaneous leishmaniasis. Our data suggest that a short-duration preconditioning regimen using broad-spectrum RTKIs, if proven safe in patients with active leishmaniasis, NO production by adherent splenocytes from infected mice treated as indicated.…”

Quantitative Analysis of Therapeutic Drugs in Dried Blood Spot Samples by Paper Spray Mass Spectrometry: An Avenue to Therapeutic Drug Monitoring

“…The sitamaquine sample with the lowest concentration analyzed here, 5 ng/mL, is sufficient to quantitate clinically relevant levels of sitamaquine in blood. In phase II clinical trials, the lowest dose administered gave mean plasma trough concentrations (i.e., concentration immediately before administration of the next dose) of 21 ng/mL after 28 d of administration [13].…”

Primaquine revisited six decades after its discovery

“…The relevant examples are those of two anti-malarial compounds, NPC 1161 [53] and, especially, sitamaquine that is already in an advanced phase of clinical trials (see Section 4.3) [54][55][56]. …”