Topical hydrophilic gel with itraconazole-loaded polymeric nanomicelles improves wound healing in the treatment of feline sporotrichosis.

Sporotrichosis is a superficial fungal disease that can affect animals and humans. The high number of infected cats has been associated with zoonotic transmission and contributed to sporotrichosis being considered by the World Health Organization as one of the main neglected tropical fungal diseases for 2021-2030. Oral administration of itraconazole (ITZ) is the first choice for treatment, but it is expensive, time-consuming, and often related to serious adverse effects. As a strategy to optimize the treatment, we proposed the development of a hydrophilic gel with nanomicelles loaded with ITZ (HGN-ITZ). The HGN-ITZ was developed using an I-optimal design and characterized for particle size, Zeta potential, drug content, microscopic aspects, viscosity, spreadability, in vitro drug release, in vitro antifungal activity, and clinical evaluation in cats. The HGN-ITZ showed a high content of ITZ (97.3 ± 2.1 mg/g); and characteristics suitable for topical application (viscosity, spreadability, globules size, Zeta potential, controlled drug release). In a pilot clinical study, cats with disseminated sporotrichosis were treated with oral ITZ or HGN-ITZ + oral ITZ. A mortality rate of 21.3% was observed for the oral ITZ group compared to 5.3% for the HGN-ITZ + oral ITZ group. In a cat with a single lesion, topical treatment alone (HGN-ITZ) provided complete healing of the lesion in 45 days. No signs of topical irritation were observed during the treatments, suggesting that HGN-ITZ can be a promising strategy in the treatment of sporotrichosis.

The GNE-KLH anti-cocaine vaccine protects dams and offspring from cocaine-induced effects during the prenatal and lactating periods.

Protecting children from prenatal cocaine exposure is a significant challenge for physicians and childbearing women with cocaine use disorder. Cocaine use is highly prevalent among reproductive-aged women and prenatal cocaine exposure produces obstetric, foetal neurodevelopmental and long-term behavioural impairments. Cocaine crosses the maternal and foetal blood-brain barrier and the placenta by diffusion. The best approach to prevent prenatal cocaine exposure is to stop cocaine use. However, only 25% of cocaine users can discontinue their use during pregnancy. Anti-cocaine vaccination decreases cocaine passage through the blood-brain barrier. This study describes an innovative approach for preventing prenatal cocaine exposure using the GNE-KLH anti-cocaine vaccine, a novel use for the named anti-drug vaccines. Here, we show that anti-cocaine vaccination with GNE-KLH produced and maintained anti-cocaine IgG antibody titres and avidity during pregnancy. These antibodies protected the pregnant rats and their pups against prenatal cocaine damage during pregnancy until weaning. The present work is the first preclinical evidence of the efficacy of an innovative mechanism to prevent prenatal cocaine exposure damage, a worldwide public health care issue. In the future, this mechanism may be useful in pregnant women with cocaine use disorder. Further studies to understand the mechanisms of how anti-cocaine antibodies exert their protective effects in pregnancy are warranted.

Inhibitory effects of dabigatran etexilate, a direct thrombin inhibitor, on osteoclasts and osteoblasts.

INTRODUCTION: Anticoagulants are widely used in orthopedic surgery to decrease the risk of deep vein thrombosis. While significant bone impairment is induced by long-term heparin therapy, little is known about the effects of direct oral anticoagulants (DOACs). Herein, we investigated the effects of dabigatran etexilate (Pradaxa®), a DOAC inhibitor of thrombin, on bone cells using in vitro and ex vivo cell culture models. MATERIALS AND METHODS: Osteoblasts and osteoclasts exposed to different concentrations of dabigatran etexilate and untreated cells were assayed for cell differentiation and activity. Favorable osteogenic conditions for osteoblasts were tested using titanium with nanotopography (Ti-Nano). In addition, mice treated with a dabigatran etexilate solution had bone marrow cells analyzed for the ability to generate osteoclasts. RESULTS: Dabigatran etexilate at concentrations of 1 µg/mL and 2 µg/mL did not impact osteoclast or osteoblast viability. The drug inhibited osteoclast differentiation and activity as observed by the reduction of TRAP+ cells, resorption pits and gene and protein expression of cathepsin K. Consistently, osteoclasts from mice treated with dabigatran showed decreased area, resorptive activity, as well as gene and protein expression of cathepsin K. In osteoblast cultures, grown both on polystyrene and Ti-Nano, dabigatran etexilate reduced alkaline phosphatase (ALP) activity, matrix mineralization, gene expression of ALP and osteocalcin. CONCLUSIONS: Dabigatran etexilate inhibited osteoclast differentiation in ex vivo and in vitro models in a dose-dependent manner. Moreover, the drug reduced osteoblast activity even under optimal osteogenic conditions. This study provides new evidence regarding the negative overall impact of DOACs on bone cells.