Pulmonary disposition of vancomycin nebulized as lipid vesicles in rats.

Formulation of antibiotics as inhalable products is proposed to improve their therapeutic index when intended for the treatment of pulmonary infections; as vancomycin shows reduced values of lung partition coefficient, pulmonary administration might be an interesting alternative to conventional administration routes. An experimental study has been performed to compare the pulmonary disposition of vancomycin after inhalation of the drug formulated as a solution and as lipid vesicles (conventional liposomes or liposomes modified with chitosan). Vancomycin concentrations were determined in bronchoalveolar fluid, pulmonary tissue and blood samples from 27 Wistar rats distributed in three groups subjected to nebulisation of the drug formulated as a solution, conventional liposomes or chitosomes. Statistically significant differences between the mean drug concentrations in bronchoalveolar lavage (BALF) and lung tissue were found upon comparing the solution to lipid vesicles (116.95 µg ml(-1)±62.13 versus 68.34 µg ml(-1)±28.90 for liposomes and 65.36±22.11 µg g(-1) for chitosomes in BALF; 222.74±37.15 µg g(-1) versus 357.17±65.37 µg g(-1) for liposomes and 378.83±85.87 µg g(-1) for chitosomes in pulmonary tissue). The amount of available drug estimated by mass balance reached the highest values for chitosomes followed by liposomes (24289.66±4795.48 µg and 20207.91±5318.29 µg, respectively) and the lowest for the solution (18971.64±4765.38 µg). The drug transport and tissue uptake processes showed to be dependent on the nebulized formulation, being facilitated by the lipid vesicles that improved drug passage from the airway space to the pulmonary tissue and systemic circulation.

Full survival of paraquat-exposed rats after treatment with sodium salicylate.

Over the past decades, there have been numerous fatalities resulting from accidental or voluntary ingestion of the widely used herbicide paraquat dichloride (methyl viologen; PQ). Considering that the main target organ for PQ toxicity is the lung and involves the production of reactive oxygen and nitrogen species, inflammation, disseminated intravascular coagulation, and activation of transcriptional regulatory mechanisms, it may be hypothesized that an antidote against PQ poisonings should counteract all these effects. For this purpose, sodium salicylate (NaSAL) may constitute an adequate therapeutic drug, due to its ability to modulate inflammatory signaling systems and to prevent oxidative stress. To test this hypothesis, NaSAL (200 mg/kg ip) was injected in rats 2 h after exposure to a toxic dose of PQ (25 mg/kg, ip). NaSAL treatment caused a significant reduction in PQ-induced oxidative stress, platelet activation, and nuclear factor (NF)-kappaB activation in lung. In addition, histopathological lesions induced by PQ in lung were strongly attenuated and the oxidant-induced increases of glutathione peroxidase and catalase expression became absent. These effects were associated with a full survival of the PQ-treated rats (extended for more than 30 days) in comparison with 100% of mortality by Day 6 in animals exposed only to PQ, suggesting that NaSAL constitutes an important and valuable therapeutic drug to be used against PQ-induced toxicity. Indeed, NaSAL constitutes the first compound with such degree of success (100% survival).

Paraquat exposure as an etiological factor of Parkinson's disease.

Parkinson's disease (PD) is a multifactorial chronic progressive neurodegenerative disease influenced by age, and by genetic and environmental factors. The role of genetic predisposition in PD has been increasingly acknowledged and a number of relevant genes have been identified (e.g., genes encoding alpha-synuclein, parkin, and dardarin), while the search for environmental factors that influence the pathogenesis of PD has only recently begun to escalate. In recent years, the investigation on paraquat (PQ) toxicity has suggested that this herbicide might be an environmental factor contributing to this neurodegenerative disorder. Although the biochemical mechanism through which PQ causes neurodegeneration in PD is not yet fully understood, PQ-induced lipid peroxidation and consequent cell death of dopaminergic neurons can be responsible for the onset of the Parkinsonian syndrome, thus indicating that this herbicide may induce PD or influence its natural course. PQ has also been recently considered as an eligible candidate for inducing the Parkinsonian syndrome in laboratory animals, and can therefore constitute an alternative tool in suitable animal models for the study of PD. In the present review, the recent evidences linking PQ exposure with PD development are discussed, with the aim of encouraging new perspectives and further investigation on the involvement of environmental agents in PD.