Cystic fibrosis Indicator

A number of clinical symptoms characterize cystic fibrosis. Predominant among these is the presence of excess sodium chloride in cystic fibrosis patient sweat. Indeed, measurement of chloride levels in sweat remains the major diagnostic indicator of this disease. Another characteristic is the production of an extremely viscous, custard-like mucus in various body glands/organs that severely compromises their function. Particularly affected are ... 

The 12-transmembrane-spanning domain topology of the adenylyl cyclase enzymes is similar to that found in the ABC family of transporters (see Ch. 5), which includes the cystic fibrosis transmembrane rectifier and the P-glyco-protein. However, there is currently no convincing evidence of a transporter or channel function for mammalian adenylyl cyclases. The structural similarity may indicate that these functionally divergent protein families are derived in an evolutionary sense from related proteins. 

To date, cellular and gene therapy products submitted to FDA have included clinical studies indicated for bone marrow marking, cancer, cystic fibrosis, AIDS, and inborn errors of metabolism and infectious diseases. Of the current active INDs approximately 78% have been sponsored by individual investigators or academic institutions and 22% have also been industry sponsored. In addition to the variety of clinical indications the cell types have also been varied. Examples include tumor infiltrating lymphocytes (TIL) and lymphocyte activated killer (LAK) cells, selected cells from bone marrow and peripheral blood lymphocytes, for example, stem cells, myoblasts, tumor cells and encapsulated cells (e.g., islet cells and adrenal chromaffin cells). 

Mucous airway obstruction. Mu-colytics, such as acetylcysteine, split disulfide bonds in mucus, hence reduce its viscosity and promote clearing of bronchial mucus. Other expectorants (e.g., hot beverages, potassium iodide, and ipecac) stimulate production of watery mucus. Acetylcysteine is indicated in cystic fibrosis patients and inhaled as an aerosol. Whether mucolytics are indicated in the common cold and whether expectorants like bromohexine or am-broxole effectively lower viscosity of bronchial secretions may be questioned. 

Children Safety and efficacy of IV aztreonam have been established children 9 months to 16 years of age. Sufficient data are not available for pediatric patients younger than 9 months of age or for treatment of the following indications/pathogens Septicemia and skin and skin-structure infections (where the skin infection is caused by H. influenzae type b). In pediatric patients with cystic fibrosis, higher doses of aztreonam may be warranted. 

Indications Management of cystic fibrosis patients to improve pulmonary function and protection against respiratory tract infections... 

Map of restriction fragment length polymorphisms (RFLPs) closely linked to the cystic fibrosis (CF) gene. The inverted triangle near the right-hand end indicates the location of the AF508 mutation characteristic of most persons with cystic fibrosis disease. (Source ... 

Domase-oc, which is indicated for the treatment of cystic fibrosis, is another example of a protein drug successfully administered through the inhalation route. 

The routes of delivery of rAAV in animal models have been largely based upon the specific needs dictated by the disease process to be treated. For example, rAAV-cystic fibrosis transmembrane conductance regulator (CFTR) vectors that have been developed for treatment of cystic fibrosis (CF) were tested in New Zealand white rabbits and in rhesus macaques by the endobronchial route (Flotte et al., 1993 Afione et al., 1996 Conrad et al., 1996). In each instance aliquots of vector were instilled directly into the lumen of a bronchus through a fiberoptic bronchoscope. Vector DNA transfer and mRNA expression were detectable (albeit at low levels) for more than 6 months in each instance, without any indication of inflammation or any other toxicity. Studies in rhesus monkeys also indicated that the likelihood of rescue of rAAV by concomitant wild-type AAV and adenovirus infection was low. These studies... 

Figure 14 Duodenal pH values in control subjects during basal, meal, and drink periods (left) basil duodenal pH values In patientt with cystic fibrosis [right). Irreversible inactivation of panacea lipase occurs at pH 4 Ranges are indicated by a broken line, deviation by a solid line n is the number of subjects studied. (From Refs. 68-72.)...

Fig. 11.3 Biosynthesis of P. aeruginosa lipid A in cystic fibrosis patient isolates. For all structures, the mass/charge ratio of the singly charged lipid A species is indicated...

Singh, P.K., Schaefer, A.L., Parsek, M.R., Moninger, T.O., Welsh, M.J., Greenberg, E.P. Quorumsensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature 407 (2000) 762-764. 

The rationale for the need of recovery animals was frequently discussed. For drag substances which require chronic (live time) treatment (e.g. oral anti-diabetics, drags for treatment of hypertension, anti-Parkinson drugs, etc.) the question of recovery is less important than in the case of anti-infectives with, in most cases, short treatment periods where mild symptoms of intolerance, e.g. diarrhoea, are observed. However, inclusion of recovery animals is recommended in general because at the stage of development where first clinical studies are conducted, the whole set of indications is not finally known and line extensions can happen. One example is the use of quinolones and other anti-infectives for the treatment of cystic fibrosis. Another example is drugs used for chemotherapy of malignant diseases where recovery has to be studies anyway. 

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