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The purpose of this study was to investigate the pharmacokinetic properties of colistin following intrapulmonary administration of colistin sulfate in rats. Colistin was infused or delivered in nebulized form at a dose of 0.35 mg/kg of body weight in rats, and plasma drug concentrations were measured for 4 h after administration. Bronchoalveolar lavages (BAL) were also conducted at 0.5, 2, and 4 h after intravenous (i.v.) administration and administration via nebulized drug to estimate epithelial lining fluid (ELF) drug concentrations. Unbound colistin plasma concentrations at distribution equilibrium (2 h postdosing) were almost identical after i.v. infusion and nebulized drug inhalation. ELF drug concentrations were undetectable in BAL samples after i.v. administration, but they were about 1,800 times higher than unbound plasma drug levels at 2 h and 4 h after administration of the nebulized drug. Simultaneous pharmacokinetic modeling of plasma and ELF drug concentrations was performed with a model characterized by a fixed physiological volume of ELF (V ELF ), a passive diffusion clearance (Q ELF ) between plasma and ELF, and a nonlinear influx transfer from ELF to the central compartment, which was assessed by reducing the nebulized dose of colistin by 10-fold (0.035 mg kg ؊1 ). The k m was estimated to be 133 g ml ؊1 , and the V max, in -to-K m ratio was equal to 2.5 ؋ 10 ؊3liter h ؊1 kg ؊1 , which was 37 times higher than the Q ELF (6.7 ؋ 10 ؊5 liter h ؊1 kg ؊1 ). This study showed that with the higher ELF drug concentrations after administration via nebulized aerosol than after intravenous administration, for antibiotics with low permeability such as colistin, nebulization offers a real potential over intravenous administration for the treatment of pulmonary infections.T reatment of lung infections by administration of antimicrobial agents using the pulmonary route presents potential clinical use, since it may afford higher drug concentrations at the site of infection with a reduction of systemic exposure (1, 2). Consequently, increased use of inhaled antibiotics, such as tobramycin, aztreonam, or colistin methansulfonate (CMS), has been observed to treat lung infections (3, 4).CMS is the inactive prodrug of colistin (5), which is a multicomponent cationic polypeptide that belongs to the class of polymyxins, comprised mainly of colistin A and colistin B (6). It is an old antibiotic that was abandoned in the 1970s due to its adverse effects (7). During the last 15 years, it has occasionally been used as "salvage" therapy for the treatment of infections engendered by multidrug-resistant bacteria, due to the lack of new antibiotics (8). When CMS was developed, controlled clinical trials and determination of pharmacokinetic and pharmacodynamic (PK/PD) properties were not required by drug-regulating agencies (6). However, the understanding of colistin pharmacokinetics after CMS intravenous (i.v.) administration to critically ill patients is progressing (9-13). But CMS is also nebulized for the treatment of pulm...

The aim of this study was to investigate the imipenem distribution in muscle and lung interstitial fluids by microdialysis in rats and to compare the free concentrations in tissue with the free concentrations in blood. Microdialysis probes were inserted into the jugular vein, hind leg muscle, and lung. Imipenem recoveries in these three media were determined in each rat by retrodialysis by drug period before drug administration. Imipenem was infused intravenously at a dose of 120 mg · kg ؊1 over 30 min, and microdialysis samples were collected for 150 min. The whole study was conducted with nonhydrated rats (n ‫؍‬ 4) and hydrated rats (n ‫؍‬ 6) while the animals were under isoflurane anesthesia. The decay of free concentrations in blood, muscle, and lung with time were monoexponential; and the concentration profiles in these three media were virtually superimposed in both groups. Accordingly, the ratios of the area under the curve (AUC) for tissue (muscle or lung) to the AUC for blood were always virtually equal to 1. Compared to values previously determined with awake rats, clearance was reduced by 2 and 1.5 in nonhydrated and hydrated rats, respectively, but the volume of distribution was unchanged. By combining microdialysis in blood and tissues, it was possible to demonstrate that free imipenem concentrations were virtually identical in blood, muscle, and lung.

The present study was undertaken to evaluate in vitro the relative importance of tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) in the mitogenic and chemotactic potential of bovine fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF)-BB for smooth muscle cells (SMC). Aortic SMC were isolated from transgenic mice showing single inactivations of the t-PA, u-PA, plasminogen activator inhibitor-1, or urokinase-type plasminogen activator receptor (u-PAR) genes. With regard to serum-induced proliferation, all cell types showed similar responses. However, SMC isolated from t-PA-deficient mice did not proliferate or migrate in response to PDGF, whereas SMC isolated from u-PA-deficient animals appeared to be much less sensitive to bFGF than the cells isolated from the other animals. Supplementation of cells from deficient animals with exogenous murine t-PA or u-PA restored the normal response of the growth factors with regard to both migration and proliferation. The mitogenic and chemotactic responses of bFGF were specifically inhibited in u-PAR-deficient cells or in wild-type SMC, cultured in the presence of antibodies to u-PAR. The role of u-PA and t-PA in bFGF and PDGF-induced growth and migration of SMC was not dependent on plasmin generation and activity as demonstrated by the inactivity of ⑀-aminocaproic acid and aprotinin. A 4 -5-fold increase in the steady-state levels of u-PA and t-PA mRNA and proteins were observed after 24 h of incubation of the cell cultures with bFGF and PDGF-BB, respectively. These results therefore indicate that, at least in vitro, t-PA is an important element of the activity of PDGF-BB with regard to the proliferation and migration of SMC whereas u-PA is a key factor in the effect of bFGF on SMC.The accumulation of neointimal SMC 1 resulting from media smooth muscle proliferation and migration in response to vascular injury is believed to be one of the main events involved in the initiation of atherosclerosis or during restenosis following angioplasty (1, 2). Although the general contribution of thrombosis to the development of atherosclerosis has been acknowledged for a long time, recent investigations suggested that the fibrinolytic system may also play an important role in the process of cell proliferation or migration (3, 4). Indeed, several authors described both a mitogenic and a chemotactic effect of two types of plasminogen activators: t-PA and u-PA for several cell types including vascular smooth muscle cells (5-8) 2 and a recent study (10) showed that both u-PA and t-PA produced by endothelial cells were sequestered in an active form by the subendothelial extracellular matrix suggesting that they may participate in sequential matrix degradation during cell invasion but also function in the release of extracellular matrixbound growth factor-like bFGF, that will stimulate SMC growth, a crucial step in atherogenesis or post-percutaneous transluminal coronary angioplasty restenosis.Most interesting were the works of Clow...

The synthetic peptide, SFLLRNPNDKYEPF, has been recently described as a peptide mimicking the new amino-terminus created by cleavage of the thrombin receptor, therefore acting as an agonist of the thrombin receptor. This peptide was a porect mitogen for rdbbit arterial smooth muscle -ells (SMC) and exhibited the same activity as that of native a-thrombin. Both compounds stimulated the proliferation of growth-arrested SMCs with half-maximum mitogenic responses at I nM. NAPAP. a synthetic inhibitor of the enzymatic activity of thrombin, specifically inhibitad thrombin-induced SMC growth (I& = 0.35 + 0.04pM) but was without effect on the mitogenic effect of the agonist peptide. These results therefore demonstrate that the mitogenic effect of a-thrombin for SMCs is intimately linked to its esterolytic activity. Heparin, which inhibited fetal calf serum-induced SMC growth, was without effect or. thrombin-induced SMC growth but strongly reduced the mitogenic effect of the agonist peptide (ICS = 32 5 5 rf@ml). This effect wa:: not relatd to the anti-coagulant activity of heparin but was highly dependent on molecular mass and on the global charge of the molecule and WGE alsc observed for other sulphated polysaccharides such as pentosan polysulphate.

The aim of this study was to evaluate the biopharmaceutical characteristics of three fluoroquinolones (FQs), ciprofloxacin (CIP), moxifloxacin (MXF), and grepafloxacin (GRX), after delivery via a nebulized aerosol to rats. Bronchoalveolar lavages (BAL) were conducted 0.5, 2, 4, and 6 h after FQ intravenous administration and nebulized aerosol delivery to estimate epithelial lining fluid (ELF) drug concentrations. Plasma drug concentrations were also measured, and profiles of drug concentrations versus time after intravenous administration and nebulized aerosol delivery were virtually superimposable, attesting for rapid and complete systemic absorption of FQs. ELF drug concentrations were systematically higher than corresponding plasma drug concentrations, whatever the route of administration, and average ELF-to-unbound plasma drug concentration ratios post-distribution equilibrium did not change significantly between the ways of administration and were equal: 4.0 ؎ 5.3 for CIP, 12.6 ؎ 7.3 for MXF, and 19.1 ؎ 10.5 for GRX (means ؎ standard deviations). The impact of macrophage lysis on estimated ELF drug concentrations was significant for GRX but reduced for MXF and CIP; therefore, simultaneous pharmacokinetic modeling of plasma and ELF drug concentrations was only performed for the latter two drugs. The model was characterized by a fixed volume of ELF (V ELF ), passive diffusion clearance (Q ELF ), and active efflux clearance (CL out ) between plasma and ELF, indicating active efflux transport systems. In conclusion, this study demonstrates that ELF drug concentrations of these three FQs are several times higher than plasma drug concentrations, probably due to the presence of efflux transporters at the pulmonary barrier level, but no biopharmaceutical advantage of FQ nebulization was observed compared with intravenous administration.

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