The respiratory system, as well as the skin, are organs in direct contact with the environment and it they represent possible doors for the entrance of therapeutic agents into the body. Because of the increasing incidence of pulmonary diseases with high mortality and morbidity, pulmonary drug delivery is emerging as a non-invasive and attractive approach for the treatment of several pathologies. It must be pointed out that the development of drug delivery systems for pulmonary application requires a detailed knowledge of the lung, both in its healthy and disease state. Among the various drug delivery systems considered for pulmonary application, nanocarriers show several advantages over other conventional approaches for the treatment of respiratory diseases, for example prolonged drug release and cell-specific targeted drug delivery. Nano-size drug carriers can incorporate various therapeutics (e.g., poorly water soluble drugs, macromolecules) and show interesting features as drug delivery systems to the lung, such as: controlled release, protection from metabolism and degradation, decreased drug toxicity and targeting capabilities. Since gene therapy (e.g. small interfering RNA, siRNA) is currently being developed for a wide range of acute and chronic lung diseases, including CF, cancer and asthma, the use of nanocarriers for lung release/targeting represents a promising application of such nano-sized structures. Despite the many promising proof of concepts of various delivery technologies reported in this review, further efforts are needed to ensure the safety of long-term in vivo applications and the development of scale up from laboratory to industry in order to reach, together with safety, large - scale production at affordable costs of innovative lung delivery technologies

The Fas/Fas ligand system is involved in uncontrolled apoptosis, which ultimately leads to the loss of T lymphocytes in human immunodeficiency virus (HIV)-infected individuals. The signal transduced by Fas receptor involves the activation of an acidic sphingomyelinase, sphingomyelin breakdown, and ceramide production. Our recent reports have shown that L-carnitine inhibits Fas-induced apoptosis and ceramide production both in vitro and in vivo. The aim of this study was to study, in a preliminary fashion, the impact of long-term L-carnitine administration on CD4 and CD8 absolute counts, rate, and apoptosis in HIV-1–infected subjects. The generation of cell-associated ceramide and HIV-1 viremia was also investigated. Eleven, asymptomatic, HIV-1–infected subjects, who refused any antiretroviral treatment despite experiencing a progressive decline of CD4 counts, were treated with daily infusions of L-carnitine (6 g) for 4 months. Immunologic and virologic measures and safety were monitored at the start of the treatment and then on days 15, 30, 90, and 150. L-carnitine therapy resulted in an increase of absolute CD4 counts, which was statistically significant on day 90 and 150 (P = .010 and P = .019, respectively). A positive, not significant trend was also observed even in the change in absolute counts of CD8 lymphocytes. L-carnitine therapy also led to a drop in the frequency of apoptotic CD4 and CD8 lymphocytes. This reduction occurred gradually, but changes in actual values between each time point and baseline were strongly significant (P = .001 at the end of the study compared with the baseline). A strong reduction (P = .001) in cell-associated ceramide levels was found at the end of the study. In general, HIV-1 viremia increased slightly. No toxicity related to L-carnitine therapy was observed and dose reductions were not necessary. In HIV-1–infected subjects, long-term infusions of L-carnitine produced substantial increases in the rate and absolute counts of CD4 and, to a lesser degree, of CD8 lymphocytes. This was paralleled by a reduced frequency of apoptotic cells of both subgroups and a decline in the levels of ceramide. No clinically relevant change of HIV-1 viremia was observed.

No abstract