Cystic fibrosis administration

The use of the aerosol route for delivery of antibiotics for pulmonary infections remains controversial. The majority of pediatric studies have been conducted in children with cystic fibrosis. In these patients distribution of the antibiotic to the desired tissue site is impeded because of the viscosity of the sputum in patients with acute exacerbations of their pulmonary infections [91,92], Long-term studies have demonstrated preventive benefits of aerosolized antibiotics in children with cystic fibrosis who are colonizing Pseudomonas aeruginosa in their lungs but are not acutely ill [93,94], Cyclic administration of tobramycin administered by nebulizer has received FDA approval [95],... 

A second approach involves direct injection/administration of the nucleic-acid-containing vector to the target cell, in situ in the body. Examples of this approach have included the direct injection of vectors into a tumour mass, as well as aerosol administration of vectors (e.g. containing the cystic fibrosis gene) to respiratory tract epithelial cells. 

Children with chronic illnesses require special consideration. For example, patients with cystic fibrosis have increased hepatic metabolism and therefore increased drug clearance. This may necessitate the administration of increased drug dosages. 

Pharmacokinetics Rapid, complete absorption after IM administration. Protein binding 0%-10%. Widely distributed (doesn t cross the blood-brain barrier, low concentrations in CSF). Excreted unchanged in urine. Removed by hemodialysis. Half-life 2-4 hr (increased in impaired renal function decreased in cystic fibrosis and burn or febrile patients). 

Perricone, M.A., Morris, J.E., Pavelka, K., et al. (2001). Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. II. Transfection efficiency in airway epithelium. Hum. Gene Ther., 12(11), 1383-1394. 

The ease of application, the minimization of systemic side effects, and the increased drug penetration directly into the target region resulted in extensive clinical use of iontophoresis mainly in the transdermal field. This technique has been utilized for administration of local anesthetics [2-5], sweat chloride testing in cystic fibrosis patients by transcutaneous delivery of pilocarpine [6,7], administration of vidarabine to patients with herpes orolabialis [8], fluoride administration to patients with hypersensitive dentin [9,10], and gentamicin delivery for the management of burned ears [11],... 

Flotte, T. R., Zeitlin, P. L., Reynolds, T. C., Heald, A. E., Pedersen, P., Beck, S., Conrad, C. K., Brass-Ernst, L., Humphries, M., Sullivan, K., Wetzel, R., Taylor, G., Carter, B. J. and Guggino, W. B. (2003). Phase I trial of intranasal and endobronchial administration of a recombinant adeno-associated virus serotype 2 (rAAV2)-CFTR vector in adult cystic fibrosis patients A two-part clinical study. Hum. Gene. Ther. 14, 1079-1088. 

F. W., McGhee, J. R., Kelly, D., Lyrene, R. K. and Sorscher, E. J. (2001). A clinical inflammatory syndrome attributable to aerosolized lipid-DNA administration in cystic fibrosis. Hum. Gene Ther. 12, 751-761. 

B. W. Ramsey, 8. J. Aslley, M. L. Ailken, W, Burke, A. A. Colin, H. L, Dorian, J. D. hisenbe, K. L. Gibson, I. R. Harwood, D. V. Schidlow, et al. Efficacy and safety of short-term administration of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis. Am. jfeu Reqtir. Dm, /4 ]45-l Jl (1993k... 

Bums, J.L., Van Dalfsen, J.M., Shawar, R.M., Otto, K.L., Garber, R.L., Quan, J.M., Montgomery, A.B., Albers, G.M., Ramsey, B.W., Smith, A.L. Effect of chronic intermittent administration of inhaled tobramycin on respiratory microbial flora in patients with cystic fibrosis. J Infect Dis 179 (1999) 1190-1196. 

Since that time, a significant number of variations on that theme have been placed into clinical trials and, in some cases, such as Aztreonam 28, into commerce. Recently (late 2007, early 2008), this compound was submitted for approval in the EU and the USA as the lysinate salt for the inhalation treatment of Pseudomonas aeruginosa in cystic fibrosis under an Orphan drug category. As of late 2008, the Food and Drug Administration (FDA) was requiring further information and the status of the EU application was not yet known. 

Ramsey, B. W., Pepe, M. S., Quan, J. M., et al. (1999), Intermittent administration of inhaled tobramycin in patients with cystic fibrosis, cystic fibrosis inhaled tobramycin study group, N. Engl. J. Med.., 340,23-30. 

Saprophytic colonization is found with increased incidence in patients with underlying pulmonary diseases, such as in advanced stages of chronic obstructive pulmonary disease, chronic asthma requiring administration of adrenal corticosteroids, primary ciliary dyskinesia syndrome and cystic fibrosis [4-7]. A.fumigatus is the predominant species cultured from the respiratory tract although other Aspergillus species may also be found occasionally. 

Although routine oral delivery of proteins has not been realized, some protein formulations have been developed for pulmonary delivery. Pulmonary delivery can result in either parenteral or local administration of the drug and, like oral delivery, is considered non-invasive. As with other routes of delivery, the size of the protein may limit its ability to be delivered systemi-cally via the pulmonary route of administration. Pulmozyme , a DNase-based formulation approved for the treatment of cystic fibrosis (CF), is delivered to the lungs by a nebulizer to clear blockage of the airways in the CF patient.Formulations for insulin to be administered by inhalation for systemic delivery of... 

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