RESUMO
Benznidazole (BZ) tablets are the currently prescribed treatment for Chagas disease. However, BZ presents limited efficacy and a prolonged treatment regimen with dose-dependent side effects. The design and development of new BZ subcutaneous (SC) implants based on the biodegradable poly-É-caprolactone (PCL) is proposed in this study for a controlled release of BZ and to improve patient compliance. The BZ-PCL implants were characterized by X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy, which indicated that BZ remains in its crystalline state dispersed in the polymer matrix with no polymorphic transitions. BZ-PCL implants, even at the highest doses, induce no alteration of the levels of hepatic enzymes in treated animals. BZ release from implants to blood was monitored in plasma during and after treatment in healthy and infected animals. Implants at equivalent oral doses increase the body's exposure to BZ in the first days compared with oral therapy, exhibiting a safe profile and allowing sustained BZ concentrations in plasma to induce a cure of all mice in the experimental model of acute infection by the Y strain of T. cruzi. BZ-PCL implants have the same efficacy as 40 daily oral doses of BZ. Biodegradable BZ implants are a promising option to reduce failures related to poor adherence to treatment, with more comfort for patients, and with sustained BZ plasma concentration in the blood. These results are relevant for optimizing human Chagas disease treatment regimens.
RESUMO
PURPOSE: To evaluate the in vivo release, retinal safety and antiangiogenic effect of a thalidomide-loaded poly-lactide-co-glycolide intravitreal implant. METHODS: New Zealand white rabbits, divided into two groups, I and II, received an intravitreal implant containing or not thalidomide, respectively (n = 12). Intravitreal drug levels were determined during a six-week study period. The potential for toxicity associated with the implants was evaluated by electroretinography and light microscopy (n = 8). Twelve chorioallantoic membranes (CAMs) from chicken eggs were incubated with thalidomide dispersion, implants containing or not thalidomide and vitreous samples and analyzed after two days regarding the percentage of vessels regression. RESULTS: Intravitreal concentrations of thalidomide (ng/ml) were 690.21 ± 177.95, 372.51 ± 185.56, 240.59 ± 133.48, 327.54 ± 169.71, 294.26 ± 142.41 and 465.18 ± 157.51 at 1, 2, 3, 4, 5 and 6 weeks, respectively, after implantation in group I rabbits. No drug was detected in group II samples. Electroretinography and histological evaluations did not show any sign of retina toxicity. There was significant regression of vessels in CAM incubated with thalidomide dispersion, thalidomide-loaded implants and vitreous samples from group I when compared to control. CONCLUSION: The intravitreal implants delivered safe doses of thalidomide that were also effective to induce vessels regression in CAMs.