Preclinical Development and In Vivo Efficacy of Ceftiofur-PLGA Microparticles.

Drug delivery systems based on polymeric microparticles represent an interesting field of development for the treatment of several infectious diseases for humans and animals. In this work, we developed PLGA microparticles loaded with ceftiofur (PLGA-cef), a third- generation cephalosporin that is used exclusively used in animals. PLGA-cef was prepared by the double emulsion w/o/w method, and exhibited a diameter in the range of 1.5-2.2 µm, and a negative ζ potential in the range of -35 to -55 mV. The loading yield of PLGA-cef was ~7% and encapsulation efficiency was approximately 40%. The pharmacokinetic study demonstrated a sustained release profile of ceftiofur for 20 days. PLGA-cef administrated in a single dose was more effective than ceftiofur non-encapsulated in rats challenged with S. Typhimurium. The in vivo toxicological evaluation showed that PLGA-cef did not affect the blood biochemical, hematological and hemostasis parameters. Overall, the PLGA-cef showed slow in vivo release profile, high antibacterial efficacy, and low toxicity. The results obtained supports the safe application of PLGA-cef as sustained release platform in the veterinary industry.

Leishmanicidal and trypanocidal activity of Sapindus saponaria / Actividad leishmanicida y tripanocida de Sapindus saponaria

Leishmaniasis and trypanosomiasis are parasitic diseases with a high infection rate, being a serious public health issue in the new world. Unfortunately, there are few available commercial drugs, poorly efficient and with increasing parasite resistance. Under these condi- tions, there is a need for new molecules to develop new and better drugs. One approach to carry out this search is using traditional medicine as information source to obtain new molecules or extracts to control these parasite diseases. Sapindus saponaria (Sapindaceae) fruit resin is used in Colombia to treat ulcers caused by Leishmaniasis. In a bioguided study, we have analyzed the in vitro effect of fruit resin, chroma- tographical fractions from fruit resin and also pure compounds against Leishmania species (L. panamensis, L. braziliensis, L. amazonensis and L. donovani) and Trypanosoma cruzi. The in vivo antileishmanial effect was established under the hamster model for cutaneous leish- maniasis by L. panamensis; refined extract of S. saponaria and pure saponins displayed high in vitro and in vivo activity as leishmanicides. In addition, extracts caused low viability on T. cruzi amastigotes. The use of the crude extract can be a good alternative against cutaneous leishmaniasis, due to its activity, reduced hemolytic effect, and easy production procedures.

La Leishmaniasis y la tripanosomiasis son enfermedades parasitarias con una alta incidencia, siendo un serio asunto de salud pública en el nuevo mundo. Desafortunadamente, hay pocas drogas comerciales disponibles, con pobre eficiencia y con una creciente resis- tencia parasitaria. Bajo esas condiciones, se necesitan nuevas moléculas para desarrollar nuevas y mejores drogas. Una aproximación para llevar a cabo esa búsqueda es usar la medicina tradicional como fuente de información para obtener nuevas moléculas o extractos para con- trolar esas enfermedades parasitarias. La resina de Sapindus saponaria (Sapindaceae) se usa en Colombia para tratar úlceras causadas por la Leishmaniasis. En un estudio bioguiado, se analizó el efecto in vitro de varios extractos de la resina, sus fracciones cromatográficas y algu- nos compuestos puros, contra varias especies de Leishmania (L. panamensis, L. braziliensis, L. amazonensis y L. donovani) panamensis y Trypanosoma cruzi. El efecto lesihmanicida in vivo fue establecido usando el modelo en hamster de leishmaniasis cutánea producida por L. panamensis; los extractos refinados de S. saponaria y las saponinas puras mostraron alta actividad in vitro e in vivo como leishmanicidas. Además, los extractos causaron una baja viabilidad en amastigotes de T. cruzi. El uso de extractos refinados en vez de saponinas puras podría ser una buena alternativa contra leishmaniasis cutánea debido a su actividad, poco efecto hemolítico y procedimientos de producción mucho más fáciles.

Evaluation of ceftiofur-PHBV microparticles in rats.

Despite the high number of antibiotics used for the treatment of infectious disease in animals, the development of slow release formulations presents a significant challenge, particularly in using novel biomaterials with low cost. In this report, we studied the pharmacokinetics, toxicity, and therapeutic activity of ceftiofur-PHBV (ceftiofur-poly(3-hydroxybutyrate-co-3-hydroxyvalerate)) in rats. The pharmacokinetic study demonstrated a sustained release of ceftiofur into the bloodstream, with detectable levels over the minimum inhibitory concentration for at least 17 days after a single intramuscular injection of ceftiofur-PHBV (10 mg/kg weight). In addition, the toxicological evaluation of biochemical, hematological, and coagulation blood parameters at the therapeutic dose demonstrated the safety of ceftiofur-PHBV, with no adverse effects. In addition, ceftiofur-PHBV exhibited a therapeutic effect for a longer time period than the nonencapsulated ceftiofur in rats challenged with Salmonella Typhimurium. The slow release of ceftiofur from the ceftiofur-PHBV, its low toxicity in the blood parameters evaluated, and the efficacy in the rats infected with Salmonella Typhimurium make ceftiofur-PHBV a strong candidate for biotechnological applications in the veterinary industry.

Paclitaxel-PHBV nanoparticles and their toxicity to endometrial and primary ovarian cancer cells.

This report is an integrated study to include the molecular simulation, physicochemical characterization and biological analysis of a paclitaxel-loaded PHBV nanoparticle that demonstrates uptake, release and cytotoxicity in cancer cell lines. Taking this nanoparticle one step closer to its use in a clinical setting, we demonstrate that it causes significant cell death in primary cultures of stage IIIc serous ovarian cancer cells isolated from six patients. Molecular simulations revealed a high affinity of paclitaxel for the water-polymer interface, thus the drug is delivered only when the polymer near it is degraded. The Fourier transform infrared spectroscopy suggests the formation of a short-lived crystalline phase, also observed in the CG simulations, and transmission electron microscopy revealed branched structures on the surface of particles, which disappeared after 4 days. Biological analyses indicated that these particles have a 48-h window of toxicity protection, allowing for the endocytosis of the particle by the cells; this finding was corroborated by confocal microscopy and flow cytometry. The low cost to synthesize PHBV using microorganisms and the potential chemical modifications of the polymer make it attractive for inexpensive, large-scale pharmaceutical production.