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At least 451 records · Page 25Linked to original sources
PubMed2005

Misprocessing of the CFTR protein leads to mild cystic fibrosis phenotype.

Cystic fibrosis (CF) is mainly caused by mutations that interfere with the biosynthetic folding of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The aim of this study was to determine the mechanism of dysfunction of a disease-causing mutation associated with variable phenotypes. In order to attain these objectives, we studied the effect of the p.L206W mutation on CFTR protein production and function, and we examined the genotype-phenotype correlation of [p.L206W]+[p.F508del] patients. We showed that p.L206W is a processing (class II) mutation since the CFTR biosynthetic pathway was severely impaired, whereas single-channel measurements indicated ion conductance similar to the wild-type protein. These data raise the larger question of the phenotypic variability of class II mutants, including p.F508del. Since multiple potential partners could modify the processing of the CFTR protein during its course to the cell surface, environmental and other genetic factors might contribute to this variability.

Adolescent↗
PubMed2001

Regulation of gap junctional communication by a pro-inflammatory cytokine in cystic fibrosis transmembrane conductance regulator-expressing but not cystic fibrosis airway cells.

Airway inflammation is orchestrated by cell-cell interactions involving soluble mediators and cell adhesion molecules. Alterations in the coordination of the multicellular process of inflammation may play a major role in the chronic lung disease state of cystic fibrosis (CF). The aim of this study was to determine whether direct cell-cell interactions via gap junctional communication is affected during the inflammatory response of the airway epithelium. We have examined the strength of intercellular communication and the activation of nuclear factor-kappaB (NF-kappaB) in normal (non-CF) and CF human airway cell lines stimulated with tumor necrosis factor-alpha (TNF-alpha). TNF-alpha induced maximal translocation of NF-kappaB into the nucleus of non-CF as well as CF airway cells within 20 minutes. In non-CF cells, TNF-alpha progressively decreased the extent of intercellular communication. In contrast, gap junctional communication between CF cells exposed to TNF-alpha remained unaltered. CF results from mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Interestingly, transfer of wild-type CFTR into CF cells by adenovirus-mediated infection was associated with the recovery of TNF-alpha-induced uncoupling. These results suggest that expression of functional CFTR is necessary for regulation of gap junctional communication by TNF-alpha. Gap junction channels close during the inflammatory response, therefore limiting the intercellular diffusion of signaling molecules, and thereby the recruitment of neighboring cells. Defects in this mechanism may contribute to the excessive inflammatory response of CF airway epithelium.

Bronchi↗
PubMed1999

Lack of correlation between CFTR expression, CFTR Cl- currents, amiloride-sensitive Na+ conductance, and cystic fibrosis phenotype.

Cystic fibrosis (CF) is characterized by defective Cl- and enhanced Na+ conductance, both due to malfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in airway epithelial cells. In the present study we examined whether expression of CFTR mRNA (CFTR messenger ribonucleic acid) is different in airway epithelia derived from either CF patients or healthy volunteers. Moreover, we tried to correlate differences in epithelial Cl- and Na+ conductance with the level of CFTR mRNA expression and studied whether these properties correlate to the clinical phenotype of CF patients. To that end, CFTR mRNA was determined by means of quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and cyclic adenosine monophosphate (cAMP)-activated Cl- and epithelial Na+ conductances were examined in airway epithelial cells using microelectrode techniques. Complementary in vitro data were obtained from cultured CF and non-CF airway epithelial cell lines. Genotype and Shwachman score were assessed for each patient. We found variable levels of CFTR mRNA expression in airway cells of both CF patients and healthy volunteers. As expected, epithelial Na+ conductance was enhanced and CFTR Cl- conductance was absent in airway cells from CF patients. However, CFTR mRNA expression did not correlate with either electrophysiological properties or Shwachman scores obtained from CF patients. In addition, CFTR mRNA expression did not correlate to Cl- conductance in cultured CF and non-CF airway epithelial cells. These results indicate a lack of correlation between levels of CFTR mRNA and CFTR function, and that only small amounts of CFTR are required for expression of the CFTR Cl- conductance.

Amiloride↗
PubMed2001

Gene therapy in cystic fibrosis.

Theoretically, cystic fibrosis transmembrane conductance regulator (CFTR) gene replacement during the neonatal period can decrease morbidity and mortality from cystic fibrosis (CF). In vivo gene transfers have been accomplished in CF patients. Choice of vector, mode of delivery to airways, translocation of genetic information, and sufficient expression level of the normalized CFTR gene are issues that currently are being addressed in the field. The advantages and limitations of viral vectors are a function of the parent virus. Viral vectors used in this setting include adenovirus (Ad) and adeno-associated virus (AAV). Initial studies with Ad vectors resulted in a vector that was efficient for gene transfer with dose-limiting inflammatory effects due to the large amount of viral protein delivered. The next generation of Ad vectors, with more viral coding sequence deletions, has a longer duration of activity and elicits a lesser degree of cell-mediated immunity in mice. A more recent generation of Ad vectors has no viral genes remaining. Despite these changes, the problem of humoral immunity remains with Ad vectors. A variety of strategies such as vector systems requiring single, or widely spaced, administrations, pharmacologic immunosuppression at administration, creation of a stealth vector, modification of immunogenic epitopes, or tolerance induction are being considered to circumvent humoral immunity. AAV vectors have been studied in animal and human models. They do not appear to induce inflammatory changes over a wide range of doses. The level of CFTR messenger RNA expression is difficult to ascertain with AAV vectors since the small size of the vector relative to the CFTR gene leaves no space for vector-specific sequences on which to base assays to distinguish endogenous from vector-expressed messenger RNA. In general, AAV vectors appear to be safe and have superior duration profiles. Cationic liposomes are lipid-DNA complexes. These vectors generally have been less efficient than viral vectors but do not stimulate inflammatory and immunologic responses. Another challenge to the development of clinically feasible gene therapy is delivery mode. Early pulmonary delivery systems relied on the direct instillation of aerosolized vectors, which can result in the induction of adverse reactions because vector is delivered into the lung parenchyma. More recent studies have examined the potential for using spray technologies to target aerosolized AAV vectors to the larger central airways, thereby avoiding alveolar exposure and adverse effects. Comparisons of lung deposition with nebulized delivery of aerosol and spray delivery indicate that spraying results in a more localized deposition pattern (predominantly in the proximal airways) and significantly higher deposition fractions than nebulization. These findings could lead to more efficient and targeted lung delivery of aerosolized gene vectors in the future.

Aerosols↗
PubMed1992

Defective epithelial chloride transport in a gene-targeted mouse model of cystic fibrosis.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes an adenosine 3',5'-monophosphate (cyclic AMP)-activated chloride channel. In cystic fibrosis (CF) patients, loss of CFTR function because of a genetic mutation results in defective cyclic AMP-mediated chloride secretion across epithelia. Because of their potential role as an animal model for CF, mice with targeted disruption of the murine CFTR gene [CFTR(-/-)] were tested for abnormalities in epithelial chloride transport. In both freshly excised tissue from the intestine and in cultured epithelia from the proximal airways, the cyclic AMP-activated chloride secretory response was absent in CFTR(-/-) mice as compared to littermate controls. Thus, disruption of the murine CFTR gene results in the chloride transport abnormalities predicted from studies of human CF epithelia.

Amiloride↗
PubMedDate not supplied

Reduced number of CFTR molecules in erythrocyte plasma membrane of cystic fibrosis patients.

Cystic fibrosis (CF), the most common genetic disease among Caucasians, is caused by mutations in the gene encoding CFTR (cystic fibrosis transmembrane conductance regulator). The most frequent mutation, DeltaF508, results in protein misfolding and, as a consequence, prevents CFTR from reaching its final location at the cell surface. CFTR is expressed in various cell types including red blood cells. The functional role of CFTR in erythrocytes is still unclear. Since the number of CFTR copies in a single erythrocyte of healthy donors and CF patients with a homozygous DeltaF508 mutation is unknown, we counted CFTR, localized in erythrocyte plasma membrane, at the single molecule level. A novel experimental approach combining atomic force microscopy with quantum-dot-labeled anti-CFTR antibodies, used as topographic surface markers, was employed to detect individual CFTR molecules. Analysis of erythrocyte plasma membranes taken from healthy donors and CF patients with a homozygous DeltaF508 mutation reveals mean (SEM) values of 698 (12.8) (n=542) and 172 (3.8) (n=538) CFTR molecules per red blood cell, respectively. We conclude that erythrocytes reflect the CFTR status of the organism and that quantification of CFTR in a blood sample could be useful in the diagnosis of CFTR related diseases.

Antibodies↗
PubMed1998

Vector-specific complementation profiles of two independent primary defects in cystic fibrosis airways.

Cystic fibrosis (CF) lung disease has been linked to multiple primary defects in airway epithelia caused by a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) gene. These defects include altered Cl- and Na+ permeability as well as intracellular defects in glycoprotein processing. This apparent diversity in CFTR function is reflected in the complex patterning of CFTR expression in airway epithelia. Such complexities present challenges in the design of CF gene therapies that are capable of reconstituting the endogenous patterns of CFTR gene expression in appropriate target cells. Using a human bronchial xenograft model of the CF airway, we have evaluated the efficacy of recombinant adenoviral and cationic liposome-mediated gene transfer to correct Cl- permeability and mucous sulfation defects found in CF lung disease. Results from these studies demonstrated a clear vector-specific complementation profile for these two defects that was dependent on the type of cell transduced and the level of transgene expression. Single-dose administration of recombinant adenovirus effectively transduced high levels of CFTR transgene expression in 11 +/- 1% of epithelial cells and was capable of correcting cAMP-induced changes in Cl- permeability to 91 +/- 14% that seen in non-CF airways. However, this level of transgene expression was incapable of reversing defects in mucous sulfation due to the lack of efficient targeting to goblet cells. In contrast, cationic liposome-mediated delivery of CFTR encoding plasmids to CF airways achieved extremely low levels of transgene expression with insignificant correction (7.4 +/- 2.4%) of cAMP-induced Cl- permeability. This low level of transgene expression, however, efficiently reduced mucous sulfation to levels seen in non-CF airways. Differences in the complementation profiles of these two vectors in correcting Cl- permeability and mucous sulfation defects mirror the ability of recombinant adenovirus and liposomes to reconstitute only certain features of the endogenous distribution and abundance of CFTR protein expression. Such findings suggest that the level of intracellular CFTR required to facilitate proper glycoprotein processing may be much lower than that needed to mediate bulk Cl- flow across the airway epithelium. In summary, these data present the first example by which two different vector systems can efficiently complement independent primary defects associated with a single dysfunctional gene.

Adenoviridae↗
PubMed1994

Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model.

The effect of the number of cystic fibrosis (CF) alleles on cholera toxin (CT)-induced intestinal secretion was examined in the CF mouse model. CF mice that expressed no CF transmembrane conductance regulator (CFTR) protein did not secrete fluid in response to CT. Heterozygotes expressed 50 percent of the normal amount of CFTR protein in the intestinal epithelium and secreted 50 percent of the normal fluid and chloride ion in intestinal epithelium and secreted 50 percent of the normal fluid and chloride ion and fluid secretion suggests that CF heterozygotes might possess a selective advantage of resistance to cholera.

Alleles↗
PubMed1996

Genotype-phenotype correlation in cystic fibrosis patients.

Cystic fibrosis (CF) is the most common severe recessive disease in Caucasians. The gene responsible for the disease encodes a protein named cystic fibrosis transmembrane conductance regulator, which is predicted to function as a cAMP-regulated chloride channel. Reduced chloride secretion is at the basis of insufficient hydratation of ductural mucus in the airways, reproductive system and pancreas, leading to progressive obstructive damage. The clinical expression of the disease is heterogeneous but most CF patients typically present with chronic obstructive lung disease, elevated electrolyte concentration in sweat and insufficient pancreatic exocrine function. Approximately 10-15% of CF patients have pancreatic sufficiency, 2 to 5% of patients have liver disease and infertility is present in almost all adult males, due to congenital bilateral absence of the vas deferens, and frequently in females. To date, over 500 mutations have been identified in the CFTR gene. A genotype-phenotype correlation has been observed only with pancreas status, while severity of lung involvement is not clearly related to the CFTR genotype, suggesting that this phenotype might be modulated by additional genetic or environmental factors; liver disease in general is not genetically determined. A large proportion of sterile healthy men with congenital bilateral absence of the vas deferens carry a mutation in at least one of their CFTR genes. The data collected so far suggest that the relationship between the CFTR genotype and the clinical manifestation is multiple and complex.

Adult↗
PubMed1995

Long term prognosis of patients with cystic fibrosis in relation to early detection by neonatal screening and treatment in a cystic fibrosis centre.

BACKGROUND: A study was undertaken to evaluate whether an early diagnosis by neonatal screening may improve the long term prognosis of patients with cystic fibrosis and to assess the influence of expert management started immediately after the diagnosis. METHODS: Comparative clinical follow up in three birth cohorts of patients with cystic fibrosis was performed at the Cystic Fibrosis centre in Groningen in close collaboration with paediatricians in general hospitals in the north-eastern part of the Netherlands. The first birth cohort (n = 19) was detected by screening and the two other cohorts were detected clinically, one (n = 30) consisting of patients born during the screening programme and the other (n = 32) of patients born during the six years immediately after the screening programme ended. The total number of patients in the three birth cohorts included all patients with cystic fibrosis born in this area during a 12 year period. Cumulative survival rates and the variation with time of lung function, the levels of immunoglobulins, and growth patterns were used as main outcome measures. RESULTS: Patients born during the screening programme but detected clinically appeared to have a reduced life expectancy compared with patients detected by screening. The patients detected by screening showed less deterioration in lung function (annual decrease 1.2% of FEV1 % pred), a smaller increase in immunoglobulin levels, and minimal catch-up growth compared with an annual decrease of 3.25% of FEV1 % pred in the non-screened birth cohort of the same age, a higher rise in immunoglobulins leading to increased levels at the end of the observation period, and catch-up growth for weight as well as height. Differences between patients treated in a cystic fibrosis centre and those not referred to a specialist centre were smaller but similar, in favour of treatment at a cystic fibrosis clinic. CONCLUSIONS: Expert management started immediately after an early diagnosis of cystic fibrosis by neonatal screening results in important beneficial effects on the outcome and clinical course of the condition. The institution of very early treatment may be critical for the outcome and long term prognosis for most patients with cystic fibrosis. Neonatal screening programmes for cystic fibrosis should be introduced more widely.

Age Factors↗
PubMed1990

[Colonization by pyocyanic bacillus and its treatment in cystic fibrosis].

In cystic fibrosis infection is localized to the bronchi and self-perpetuated by a disorder of mucociliary clearance. At a certain stage of the disease infection is caused by Pseudomonas aeruginosa (PA), and the patient cannot get rid of it as cystic fibrosis reduces his defence mechanisms against this organism, a naturally weak pathogen. The presence and significance of persistent bronchial PA infection result from complex phenomena which have been summarized as "an opportunistic organism in a host whose defences have been very peculiarly compromised". The toxicity of PA and the inappropriate inflammatory response of the host concur to create permanent alveolar lesions which are gradually spreading out. The effectiveness of antibiotics depends on the organism and its resistance, on pharmacokinetic factors bringing the drug in situ and on local conditions of redox, physico-chemical environment and nutrition. Other factors intervene more roughly, including patient's age, liver impairment, lung anatomy (excluded areas), general malnutrition and vitamin deficiencies. Thus, the part played by other treatments in the antibiotic therapy of cystic fibrosis can no longer be ignored, just as it is no longer sensible to limit the use of antibiotics to obvious infections. To evaluate the effectiveness of antibiotics is not easy, but it can be demonstrated beyond any doubt when the above mentioned factors are taken into account. The use of antibiotics creates practical problems relating to their cost, their dosage, their side-effects, the adequacy of therapeutic infrastructures and, above all, it raises the question of short- and long-term changes in microbial ecology.

Adolescent↗
PubMed1977

Membrane function in cystic fibrosis. I. Putrescine transport in normal and cystic fibrosis fibroblasts.

Putrescine transport was examined in normal and cystic fibrosis fibroblasts. No differences were observed in accumulation pattern, kinetics of uptake, or efflux between CF and normal cells. In both growing and growth-arrested CF and normal fibroblasts, exogenously supplied putrescine remained unchanged for at least 60 min. Some differences were observed in the response of CF and normal cells to environmental (media) changes.

Biological Transport↗
PubMed2000

Expression of cystic fibrosis transmembrane conductance regulator in liver tissue from patients with cystic fibrosis.

The authors examined the expression of cystic fibrosis transmembrane conductance regulator (CFTR) and its relationship to histopathological changes in cystic fibrosis (CF) liver tissue. Immunohistochemistry was used to examine expression of CFTR, intercellular adhesion molecule-1 (ICAM-1) and liver cell-type markers in liver cryosections in 11 patients with CF-associated liver disease, and non-CF controls with (n = 17) and without (n = 3) liver disease. In CF patients prominent inflammatory infiltrates were not found, yet hepatic stellate cells were identified within fibrotic areas around bile ducts. Proliferating bile ducts displayed ICAM-1 immunoreactivity in 3 cases, but bile ducts were otherwise negative. In 2 patients homozygous for R764X and for 1112delT no CFTR immunoreactivity was detected. Bile-duct epithelial cells in patients carrying the DeltaF508 mutation displayed aberrant cytoplasmic immunolocalization of CFTR, as determined with confocal laser scanning microscopy, in contrast to the distinct CFTR expression at the luminal surface seen in controls. No clear relationship between CFTR expression and fibrosis or inflammation was evidenced in CF patients. In conclusion, these findings are consistent with an impairment of DeltaF508 CFTR processing in intrahepatic biliary epithelium. ICAM-1 expression on bile-duct epithelial cells and inflammatory infiltrates were rare findings in CF liver tissue, indicating that immunological mechanisms are unlikely to be involved in initiation of CF-associated liver disease.

Adolescent↗
PubMed1997

Sequential ciprofloxacin therapy in pediatric cystic fibrosis: comparative study vs. ceftazidime/tobramycin in the treatment of acute pulmonary exacerbations. The Cystic Fibrosis Study Group.

BACKGROUND: Cystic fibrosis patients have chronic bacterial infections of the respiratory tract, most commonly Pseudomonas aeruginosa. Although controversial, administration of antibiotic therapy during acute pulmonary exacerbations is standard practice. Fluoroquinolones are currently not indicated for use in young children because of the observation of arthropathy and damage to growing cartilage in beagle puppies. Because of its activity against P. aeruginosa and excellent oral bioavailability, ciprofloxacin offers a unique therapeutic alternative for this patient population. OBJECTIVE: This prospective, randomized, double blind study compared the efficacy and safety of sequential intravenous/oral ciprofloxacin vs. ceftazidime/tobramycin in hospitalized pediatric cystic fibrosis patients with an acute pulmonary exacerbation associated with P. aeruginosa infection. METHODS: One hundred thirty patients (ages 5 to 17 years) were randomized to receive either i.v. ciprofloxacin 10 mg/kg every 8 h for 7 days followed by oral ciprofloxacin 20 mg/kg every 12 h for a minimum of 3 days or i.v. ceftazidime 50 mg/kg every 8 h plus i.v. tobramycin 3 mg/kg every 8 h for a minimum of 10 days. Clinical, bacteriologic and safety responses were assessed throughout the study. RESULTS: All 84 patients (median age, 11 years; range, 5 to 17 years) valid for efficacy in both treatment groups demonstrated clinical improvement. Five patients experienced clinical relapses (3 ciprofloxacin, 2 ceftazidime/tobramycin) by the 2- to 4-week follow-up. Intent-to-treat analysis demonstrated similar clinical findings between the two treatment groups at both the end of therapy and follow-up. Clinical improvement correlated with improvement in pulmonary function studies and the acute clinical scoring system but not with bacteriologic eradication of Pseudomonas. DNA profiles demonstrated that irrespective of colony morphology, usually one clonal strain was associated with each patient's pulmonary exacerbation. Treatment-associated musculoskeletal events occurred with equal frequency (22% vs. 21%) in both study drug groups (n = 129), and arthralgias were within the range of rates for cystic fibrosis arthropathy. None of these events required study drug discontinuation. CONCLUSION: Sequential i.v./oral ciprofloxacin monotherapy offers a safe and efficacious alternative to standard parenteral therapy for acute pulmonary exacerbations in pediatric cystic fibrosis patients.

Acute Disease↗
PubMedDate not supplied

Identification of three novel cystic fibrosis mutations in a sample of Italian cystic fibrosis patients.

An analysis of 274 non-delta F508 Italian cystic fibrosis chromosomes was carried out to determine their molecular defect. In a first step, the delta F508 and 59 other mutations were detected by polyacrylamide gel electrophoresis, restriction digestion, and the amplification refractory mutation system (ARMS) technique. The molecular defects of the other chromosomes were screened for by denaturing gradient gel electrophoresis analysis of exons 3, 4, 7, 11, 12, 13, 14a, 17b, 19 and 20. Direct sequencing was carried out if necessary. This approach allowed us to identify 3 novel mutations, namely M348K, D614G and F693L.

Cystic Fibrosis↗
PubMed2004

Compacted DNA nanoparticles administered to the nasal mucosa of cystic fibrosis subjects are safe and demonstrate partial to complete cystic fibrosis transmembrane regulator reconstitution.

A double-blind, dose escalation gene transfer trial was conducted in subjects with cystic fibrosis (CF), among whom placebo (saline) or compacted DNA was superfused onto the inferior turbinate of the right or left nostril. The vector consisted of single molecules of plasmid DNA carrying the cystic fibrosis transmembrane regulator- encoding gene compacted into DNA nanoparticles, using polyethylene glycol-substituted 30-mer lysine peptides. Entry criteria included age greater than 18 years, FEV1 exceeding 50% predicted, and basal nasal potential difference (NPD) isoproterenol responses (> or = -5 mV) that are typical for subjects with classic CF. Twelve subjects were enrolled: 2 in dose level I (DLI) (0.8 mg DNA), 4 in DLII (2.67 mg), and 6 in DLIII (8.0 mg). The primary trial end points were safety and tolerability, and secondary gene transfer end points were assessed. In addition to routine clinical assessments and laboratory tests, subjects were serially evaluated for serum IL-6, complement, and C-reactive protein; nasal washings were taken for cell counts, protein, IL-6, and IL-8; and pulmonary function and hearing tests were performed. No serious adverse events occurred, and no events were attributed to compacted DNA. There was no association of serum or nasal washing inflammatory mediators with administration of compacted DNA. Day 14 vector polymerase chain reaction analysis showed a mean value in DLIII nasal scraping samples of 0.58 copy per cell. Partial to complete NPD isoproterenol responses were observed in eight subjects: one of two in DLI, three of four in DLII, and four of six in DLIII. Corrections persisted for as long as 6 days (1 subject to day 28) after gene transfer. In conclusion, compacted DNA nanoparticles can be safely administered to the nares of CF subjects, with evidence of vector gene transfer and partial NPD correction.

Administration, Intranasal↗
PubMed1993

Disposition of drugs in cystic fibrosis. V. In vivo CYP2C9 activity as probed by (S)-warfarin is not enhanced in cystic fibrosis.

Enhanced metabolism of theophylline in subjects with cystic fibrosis suggests that the activity of certain cytochrome P450 isoforms is affected in subjects with this genetic disease. To determine whether this effect on the P450 enzymes is selective, the in vivo activity of the cytochrome P450 isoform CYP2C9 was determined in adult subjects with cystic fibrosis (n = 6) and in control subjects (n = 8). Subjects were administered (S)-warfarin as a single intravenous bolus dose (0.375 mg/kg), and urine and plasma samples were collected for 96 hours. Plasma (S)-warfarin concentrations were determined by HPLC; urinary concentrations of (S)-warfarin and its metabolites were determined by gas chromatography-mass spectrometry. The total plasma clearance of (S)-warfarin (subjects with cystic fibrosis, 3.6 +/- 0.48 ml/hr/kg; control subjects, 3.82 +/- 0.73 ml/hr/kg), elimination half-life (subjects with cystic fibrosis, 29.5 +/- 4.2 hours; control subjects, 25.9 +/- 5.4 hours); and steady-state volume of distribution (subjects with cystic fibrosis, 153 +/- 18 ml/kg; control subjects, 138 +/- 22 ml/kg) were similar in the two groups (p > 0.05). The metabolic clearance of (S)-warfarin to its major metabolites mediated by CYP2C9, 6-hydroxywarfarin and 7-hydroxywarfarin, was not significantly (p > 0.05) different between the two groups (6-hydroxywarfarin: subjects with cystic fibrosis, 0.33 +/- 0.1 ml/hr/kg; control subjects, 0.41 +/- 0.1 ml/hr/kg; 7-hydroxywarfarin: subjects with cystic fibrosis, 1.34 +/- 0.49 ml/hr/kg; control subjects, 1.8 +/- 0.45 ml/hr/kg). On the basis of these data, we conclude that the in vivo cytochrome P450 activity is selectively affected in persons with cystic fibrosis.

Adult↗