11.2.1. Molecularly-derived Therapeutics
The lungs, directly accessible via the airways to the outside environment, were the target of one of the first molecularly-based medical therapies. Dornase alpha recombinant human deoxyribonuclease I (rhDNase), launched in 1994, is a proteinaceous enzyme that selectively cleaves DNA . Cystic fibrosis patients use rhDNAase, administered by inhalation of an aerosol mist, to cleave the sticky free DNA that has been released from destroyed inflammatory cells and that comprises a significant portion of mucous. This lysis of the DNA facilitates expectoration. DNAase therapy has contributed to improvements in the multi-component management of an autosomal recessive inherited disease that had previously resulted in near uniform mortality by the early teens to result in a life expectancy for these patients that may reach now into the mid-thirties and even beyond .
After having been originally applied to treat acute coronary syndromes in the late 1980's, tissue plasminogen activators have come to use in the lungs as treatment for large and life-threatening pulmonary emboli. Their value in this setting, though, continues to be questioned, plagued by complications related to inability to target their site of action, resulting in the potential for bleeding complications, and the sheer volume of clot that is often seen in acute thromboembolic disease. Thus, the role of tissue plasminogen activators in this setting is still under exploration .
Liposomes in many sizes and compositions are in fairly common use in cosmetic and medical applications and are continuing to undergo further refinement and testing for additional medical uses . The liposome refinements attempt to overcome early problems related to variability in size, amount of medication incorporation into the particles, integrity of payload encapsulation, and targeting to diseased tissue and organs. Encapsulation of drugs in liposomes has often resulted in improved therapeutic efficacy over that of the drug alone following administration by multiple routes, including topical, injection, and inhalation. Physicians are accustomed especially to intravenous use of liposomal formulations of toxic azole antifungal medications .
Additional non-cosmetic liposomal formulations are in various stages of testing. Lung deposition of the antibiotics gentamicin, amikacin, and tobramycin markedly improves when these antibiotics are administered in inhalable liposomal forms, compared to non-liposomal inhalation [18, 26, 35, 36, 41, 66, 71]. A liposomal form of ketotifen fumarate, an experimental asthma bronchodilator, is in human trials , as is liposomal cyclosporine. Cyclosporin is currently most often utilized as an anti-rejection medication for transplant patients in oral or intravenous form, where its potential for system-wide side effects is significant. When given via liposomal inhalation for lung transplants, the peak serum level of cyclosporin is on the order of 110 nanograms per milliliter, a fraction of that necessary if the drug is administered by other routes, thus reducing its toxic potential . Inter-leukin 2 has been in use for many years to combat various cancers. Its administration, usually intravenously or subcutaneously, is often complicated by uncomfortable and occasionally life-threatening infection-like symptoms. Liposome-encapsulated Interleukin 2 via inhalation has been tested with promising results in animal models of several cancers that metastasize to the lungs . Clodronate disodium encapsulated within liposomes administered via the airway in a murine model of Pseudomonas bacterial pneumonia and sepsis results in depletion of alveolar macrophages, thus reducing the initial inflammatory response and bringing about improvements in mortality . Evaluation of gene therapies with the genetic material introduced via liposomal inhalation is underway. Liposomal formulations of the gene for a-tocopherol, a naturally-occurring anti-oxidant, have been administered in rats in anticipation of severe hypoxia (low oxygen levels). After hypoxia, the treated rats show downregulation of caspases, resulting in a limitation of apoptosis in the lungs. Their mortality is reduced from 60 to 30 percent [67,86]. This approach also may be useful to protect the lungs during time-limited risks such as radiation therapy through the expression of manganese superoxide dismutase plasmids . These are but a few of the many liposomal delivery systems that are under current use and study.
Filters with pores of 15-40 nanometers have seen increased use in the manufacture of plasma-derived biopharmaceuticals as a means of size-excluding viral and other potentially infectious elements from therapeutic protein mixtures [13, 93]. Microarrays of many types and varieties are under development to aide in the identification of disease states or monitoring of disease activity. Many of the emerging systems utilize micron and nanometer scale manufactured features. Though these are still primarily a research tool, as the results become more reliable and the array results are correlated with particular disease states, we can anticipate more common use in the patient population.
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