| Nitric Oxide (NO) is an effective dilator of the pulmonary arterial circulation for treatment of pulmonary hypertension. A wide range of inhalation breathing patterns and concentrations have proven effective, but the mechanisms underlying this variability are not known. We have developed a dynamic model of nitric oxide (NO) gas inhalation, which considers inhalation, diffusion, and reaction of NO in the pulmonary arteriolar region, and also considers disease progression. The response of the system (mean concentration of NO in the smooth muscle, c¯sm) is characterized using an overall transfer function. The model is used to simulate previously published experimental NO gas inhalation patterns in which a short pulse of 100 ppm of NO gas was applied at the start of inhalation. Our model predicts the clinically effective c¯sm to be 0.22–0.41 nM, which is far smaller than the equilibrium dissociation constant of soluble guanylyl cyclase previously estimated in vitro (<250 nM) and theoretically (23 nM). We conclude that the clinically effective c¯sm and the overall transfer function may be useful in the design of new NO-delivery strategies for the treatment of pulmonary hypertension.; Using the convenient framework of the dynamic model, any input function of NO gas can be simulated to generate the corresponding mean smooth muscle concentration. The simulations of various inhalation patterns and concentrations showed the limitation of NO gas therapy. Hence, NO-releasing molecules were suggested as an alternative therapy to NO gas, and the dynamic modeling and simulation for the system using NO-releasing molecules such as NONOates was performed. The simulations for the molecules having various releasing rates suggested the molecules having half-lives of around an hour were optimal.; A study for development of an inhalable drug delivery system for a small and hydrophilic prodrug molecule, PROLI/NO was performed. The prodrug molecule releases NO in a physiological aqueous condition, and was considered to be the safest NONOates. The system was designed to use hydrophilic and biodegradable polymers PLGA and PELA for entrapping the prodrug and forming inhalable microparticles that have proper size distribution. The prodrug and polymer PELA were synthesized and characterized. Also, microspheres containing the prodrug were prepared with double emulsion technique followed by the solvent evaporation method. Prepared microparticles were characterized for morphology with microscopy, for size distribution with Coulter counter, and for entrapment efficiency with Griess assay. The particles were freeze-dried, and NO releasing kinetics were monitored with an on-line NO measuring system. The prepared PELA-based microspheres showed about 50% prodrug entrapment efficiency, proper size distribution for the inhalable particle, and NO release in a physiological buffer solution. By addition of gelatin as a binder, the role of the hydrophilic moiety in the polymer matrix of the microsphere for NO release was explained.; With some variations in preparing microspheres, particles having large particle sizes with multi-chambered structure were found to have slow release kinetics, which could be used for NO release to a specific site at a sustained rate of NO release without systemic adverse effect. These particles are larger than inhalable microspheres, but still are small and biodegradable, and may represent an alternative to other implantable polymer matrices such as polyurethane. |
