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PubMed1975

Polyamine alterations in blood of male homozygotes and heterozygotes for cystic fibrosis.

The polyamines, spermidine and spermine, have been measured in whole blood extracts from control volunteers, patients with cystic fibrosis, and obligate cystic fibrosis heterozygotes. Male homo- and heterozygotes for cystic fibrosis exhibit a consistent and significant decrease in blood spermine resulting in an elevated spermidine/spermine ratio when compared to control males. In contrast, control females exhibited reduced spermidine and spermine levels as compared to control males. Blood from female cystic fibrosis homo- and heterozygotes showed similar results. The sex difference is probably due to fluctiations of blood polyamines during the menstrual cycle. Abnormal polyamine levels are the first observation of an alteration of a low molecular weight metabolite characteristic of both male homo- and heterozygotes for cystic fibrosis.

Cystic Fibrosis↗
PubMed2000

Characterization of the oligosaccharide structures associated with the cystic fibrosis transmembrane conductance regulator.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a plasma membrane-associated glycoprotein. The protein can exist in three different molecular weight forms of approximately 127, 131, and 160 kDa, representing either nonglycosylated, core glycosylated, or fully mature, complex glycosylated CFTR, respectively. The most common mutation in cystic fibrosis (CF) results in the synthesis of a variant (DeltaF508-CFTR) that is incompletely glycosylated and defective in its trafficking to the cell surface. In this study, we have analyzed the oligosaccharide structures associated with the different forms of recombinant CFTR, by expressing and purifying the channel protein from either mammalian Chinese hamster ovary (CHO) or insect Sf9 cells. Using glycosidases and FACE analysis (fluorophore-assisted carbohydrate electrophoresis) we determined that purified CHO-CFTR contained polylactosaminoglycan (PL) sequences, while Sf9-CFTR had only oligomannosidic saccharides with fucosylation on the innermost GlcNAc. The presence of PL sequences on the recombinant CHO-CFTR is consistent with a normal feature of mammalian processing, since endogenous CFTR isolated from T84 cells displayed a similar pattern of glycosylation. The present study also reports on the use of FACE for the qualitative analysis of small amounts of glycoprotein oligosaccharides released enzymatically.

Amidohydrolases↗
PubMed1993

Comparison of Tc-99m DTPA aerosol ventilation studies with pulmonary function testing in cystic fibrosis.

In 43 patients with cystic fibrosis, the results of 122 Tc-99m DTPA aerosol ventilation (DAV) studies were compared with pulmonary function tests (PFTs) that were performed within 24 hours of the DAV studies. The DAV studies were evaluated blindly for (A) number of pulmonary segments showing little or no ventilation, (B) number of foci of bronchial deposition of aerosol, and (C) subjective overall improvement, lack of change, or worsening from the previous study. (A) and (B) correlated significantly with all PFTs (p's < .001, r's = -.51 to -.73). Changes in (A) and (B) also correlated with changes in PFTs (p's < or = .001, r's = -.37 to -.58). The three populations in (C) were significantly different from each other with respect to changes in all PFTs (p < or = .002). Intervals between studies showing subjective improvement, no change, and worsening averaged 60, 133, and 306 days, respectively. These results suggest that DAV is an indicator of both regional and global pulmonary function and may be useful in evaluating patients with cystic fibrosis.

Adolescent↗
PubMed2001

Pharmacotherapy of the ion transport defect in cystic fibrosis.

1. More than 1300 different mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF), a disease characterized by deficient epithelial Cl- secretion and enhanced Na+ absorption. The clinical course of the disease is determined by the progressive lung disease. Thus, novel approaches in pharmacotherapy are based primarily on correction of the ion transport defect in the airways. 2. The current therapeutic strategies try to counteract the deficiency in Cl- secretion and the enhanced Na+ absorption. A number of compounds have been identified, such as genistein and xanthine derivatives, which directly activate mutant CFTR. Other compounds may activate alternative Ca2+-activated Cl- channels or basolateral K+ channels, which supply the driving force for Cl- secretion. Apart from that, Na+ channel blockers, such as phenamil and benzamil, are being explored, which counteract the hyperabsorption of NaCl in CF airways. 3. Clinical trials are under way using purinergic compounds such as the P2Y(2) receptor agonist INS365. Activation of P2Y(2) receptors has been found to both activate Cl- secretion and inhibit Na+ absorption. 4. The ultimate goal is to recover Cl- channel activity of mutant CFTR by either enhancing synthesis and expression of the protein or by activating silent CFTR Cl- channels. Strategies combining these drugs with compounds facilitating Cl- secretion and inhibiting Na+ absorption in vivo may have the best chance to counteract the ion transport defect in cystic fibrosis.

Chloride Channels↗
PubMed1987

Ciprofloxacin versus tobramycin plus azlocillin in pulmonary exacerbations in adult patients with cystic fibrosis.

Twenty adult patients with cystic fibrosis who were experiencing acute pulmonary exacerbations were enrolled in a randomized, controlled trial comparing oral ciprofloxacin with intravenous tobramycin plus azlocillin. Efficacy of the two treatments was compared based upon changes in clinical status, pulmonary function tests, white blood cell counts, and quantitative bacteriology of sputum. No statistically significant differences were detected in these parameters of response between the two treatment groups (p greater than 0.05). Ciprofloxacin appears to be therapeutically equivalent to intravenous antibiotics in the treatment of adult patients with cystic fibrosis who are experiencing pulmonary exacerbations associated with susceptible bacteria.

Adult↗
PubMed2001

Glycosylation and the cystic fibrosis transmembrane conductance regulator.

The cystic fibrosis transmembrane conductance regulator (CFTR) has been known for the past 11 years to be a membrane glycoprotein with chloride channel activity. Only recently has the glycosylation of CFTR been examined in detail, by O'Riordan et al in Glycobiology. Using cells that overexpress wild-type (wt)CFTR, the presence of polylactosamine was noted on the fully glycosylated form of CFTR. In the present commentary the results of that work are discussed in relation to the glycosylation phenotype of cystic fibrosis (CF), and the cellular localization and processing of DeltaF508 CFTR. The significance of the glycosylation will be known when endogenous CFTR from primary human tissue is examined.

Animals↗
PubMed1987

Lack of pancreatic [3H]estradiol-binding activity in cystic fibrosis.

A major characteristic of cystic fibrosis (CF) is the progressive degeneration of acinar cells in the pancreas. It is now well established that the normal pancreas contains an abundant amount of an [3H]estradiol-binding protein. Although the physiological function of this protein is unknown, available evidence suggests that it modulates resting secretion from acinar cells. Analysis of pancreatic autopsy samples from 13 patients who had CF demonstrated a high degree of correlation between loss of acinar cells and loss of [3H]estradiol-binding activity. Autopsy samples taken from individuals unaffected by CF contained large amounts of the [3H]estradiol-binding protein that were significantly correlated with the tissue content of amylase. This biological model demonstrates that the [3H]estradiol-binding protein in pancreas is localized primarily within acinar cells. Based on the presumed regulatory role this protein has on pancreatic secretion, an hypothesis is offered to account for acinar cell degeneration in individuals suffering from cystic fibrosis.

Adolescent↗
PubMed1995

An ultrasound scoring system for the diagnosis of liver disease in cystic fibrosis.

Advances in the management of the pulmonary complications of cystic fibrosis may result in an increasing prevalence of patients with chronic liver disease which may, therefore, become more important in the long-term management of cystic fibrosis patients. However, no simple and reliable test is available for the diagnosis of liver disease in cystic fibrosis. In particular percutaneous liver biopsy is highly inaccurate and potentially dangerous. Imaging techniques, including real-time ultrasound scanning, have been used to evaluate the hepato-biliary system in cystic fibrosis and may represent the best available techniques for documenting hepatic involvement. The purposes of this study were to construct an ultrasound scoring system using three cardinal features of hepatic ultrasound in cystic fibrosis: coarseness of the parenchyma, nodularity of the liver edge and increased periportal echogenicity, to enable the accurate, early diagnosis of liver involvement in cystic fibrosis. The scoring system was validated by correlating the results against ultrasound markers of portal hypertension, clinical and haematological data. The scoring system proved to be reproducible and to correlate well with the markers of hepatic disease detailed above. The results also suggest that the scoring system may allow the identification of patients with pre-cirrhotic chronic liver disease and so may prove of value in selecting a sub-group of patients more likely to respond to therapy.

Adult↗
PubMed1985

Adverse reactions to piperacillin in adults with cystic fibrosis.

Nine adult patients with cystic fibrosis, nearly a quarter of the 38 patients with this disease who were treated with piperacillin (59 courses in all) during 1981-3 at the Brompton Hospital, developed a swinging pyrexia after a mean of 13.5 days' treatment with this antibiotic. The fever resolved shortly after the piperacillin treatment was stopped, as did the widespread rashes in the two patients who developed them. Three of four patients who had probable reactions to azlocillin may have been sensitised by piperacillin. As piperacillin does not appear to be any more effective than other antipseudomonal penicillins in cystic fibrosis, it is no longer used at the hospital for treating bronchopulmonary exacerbations in such patients.

Adult↗
PubMed1990

Prospective study of mycobacterial infections in patients with cystic fibrosis.

Fifty four patients with cystic fibrosis, aged 3-67 years, were studied prospectively for pulmonary mycobacterial infection. Sputum smears and cultures were carried out and intradermal skin tests performed. Mycobacteria were cultured from six patients in association with clinical deterioration; four patients had positive direct smears. Mycobacterium tuberculosis, M aviumintracellulare, M kansasii, and M gordonae were isolated. There were no deaths and all improved with chemotherapy. A third of the other 48 patients had positive skin test responses (greater than 6 mm) to purified protein derivative (PPD) tuberculin and 21 to one or more antigens prepared from non-tuberculous mycobacteria. Sensitisation increased with age; before the age of 11 only one patient had a positive response to PPD tuberculin and none to any other antigen. This was less than in healthy control subjects of similar age. After age 11 the reactions in sensitised patients were stronger than in positive healthy control subjects. Our study indicates that it is important to consider mycobacterial infection in patients with cystic fibrosis who deteriorate without obvious cause.

Adolescent↗
PubMed1998

Restoration by intratracheal gene transfer of bicarbonate secretion in cystic fibrosis mouse gallbladder.

Gallbladders from cystic fibrosis (CF) mice (Cftrtm1Cam and Cftrtm2Cam) were examined with the short-circuit current technique. The tissues failed to show any electrogenic anion transport in response to forskolin (cAMP stimulus) but responded to the Ca2+ ionophore ionomycin. Administration of the plasmid pTrial10-CFTR2 complexed with cationic liposomes (3beta-[N-(dimethylaminoethane)-carbamoyl]cholesterol and L-alpha-phosphatidylethanolamine dioleolyl) to the airways restored the phenotype of CF gallbladders to that of the wild type, but did not do so when given orally. Formation of human CFTR mRNA in gallbladders of transfected CF null mice was demonstrated. Using the reporter genes pCMV-luc and pCMV-LacZ, we showed that 1) the intratracheal route was more effective than the oral,intravenous, intramuscular, subcutaneous, or intraperitoneal routes in expressing luciferase activity in the gallbladder and 2) beta-galactosidase staining after pCMV-LacZ was confined to the columnar epithelium lining the gallbladder without any discernible activity in it smooth muscle. The discovery of an unusual route for gene transfer to the biliary system may give useful insight into counteracting the consequences of biliary fibrosis in human CF patients.

Animals↗
PubMed2001

Nebulized heparin in Burkholderia cepacia colonized adult cystic fibrosis patients.

Viscous negatively charged cystic fibrosis (CF) sputum allows colonization by pathogens, inducing a chronic inflammatory response. Heparin thins sputum by decreasing the mucin molecule amino group negative charge, altering its intermolecular hydrogen bonding, and ionically shielding its polyionic moieties. It also has an anti-inflammatory effect within the lung. It may, therefore, be useful in the treatment of CF patients. In order to test this, six fully informed Burkholderia cepacia colonized stable adult CF patients, received 25,000 IU nebulized heparin sulphate daily for 7 days. Subjective sputum parameters, spirometry, platelets, coagulation parameters, and serum and sputum interleukin (IL)-6 and -8 were measured before and after treatment. All patients tolerated the heparin with no evidence of bleeding, thrombocytopenia or change in coagulation parameters. There was no change in spirometry, but a reduction in interleukins (sputum IL-6, p=0.01; sputum IL-8, p=0.002; serum IL-6, p=0.02; serum IL-8, p=0.02). Sputum was easier to expectorate (p < 0.04), with a trend towards thinner sputum (p=0.07) but no change in sputum volume. Heparin therapy was well tolerated and had an anti-inflammatory effect, with subjective sputum mucolysis. Further studies are necessary to define the role of heparin in the treatment of cystic fibrosis patients.

Adult↗
PubMed1992

Exhaustive screening of exon 10 CFTR gene mutations and polymorphisms by denaturing gradient gel electrophoresis: applications to genetic counselling in cystic fibrosis.

Several mutations in the cystic fibrosis (CF) gene have been reported. Ten, including the most prevalent mutation in Caucasians, delta F508, are located in exon 10 of the gene, in addition to five sequence polymorphisms. We have previously presented a strategy based on denaturing gradient gel analysis for the rapid detection of any nucleotide variation in all the exons and their immediate flanking regions. We now report the application of this method to the simultaneous detection of all mutations and polymorphisms located in exon 10, together with the use of exon 10 polymorphisms, especially the most frequent one (M470V), as intragenic markers for prenatal diagnosis of cystic fibrosis in families with at least one affected child and unknown disease-causing mutations.

Base Sequence↗
PubMed2006

alpha1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients.

The airways of cystic fibrosis (CF) patients are characterised by neutrophils that release high amounts of elastase overwhelming the local antiprotease shield. Inhalation of alpha(1)-antitrypsin (AAT) may restore the protease-antiprotease balance and attenuate airway inflammation in CF airways. The aims of the present study were: 1) to assess the best deposition region for inhaled AAT by two different inhalation strategies; and 2) to examine the effect of 4 weeks of AAT inhalation on lung function, protease-antiprotease balance and airway inflammation in CF patients. In a prospective, randomised study, 52 CF patients received a daily deposition by inhalation of 25 mg AAT for 4 weeks targeting their peripheral or bronchial compartment. The levels of elastase activity, AAT, pro-inflammatory cytokines, neutrophils, immunoglobulin G fragments and the numbers of Pseudomonas aeruginosa were assessed in induced sputum before and after the inhalation period. Inhalation of AAT increased AAT levels and decreased the levels of elastase activity, neutrophils, pro-inflammatory cytokines and the numbers of P. aeruginosa. However, it had no effect on lung function. No difference was found between the peripheral and bronchial inhalation mode. In conclusion, although no effect on lung function was observed, the clear reduction of airway inflammation after alpha(1)-antitrypsin treatment may precede pulmonary structural changes. The alpha(1)-antitrypsin deposition region may play a minor role for alpha(1)-antitrypsin inhalation in cystic fibrosis patients.

Administration, Inhalation↗
PubMed1992

Increased oral bioavailability of ciprofloxacin in cystic fibrosis patients.

The altered pharmacokinetic properties of, e.g., aminoglycosides in cystic fibrosis patients have to be considered when pulmonary exacerbations are treated. Since reported data on ciprofloxacin, a fluorinated quinolone, are conflicting, we compared intravenous and oral administration in cystic fibrosis patients when treating them for mild symptoms of pulmonary infection. All of the patients were colonized with Pseudomonas species. Ciprofloxacin was administered orally (15 mg/kg of body weight) or intravenously (6 mg/kg) twice a day for at least 10 days during separate treatment periods. Five healthy volunteers received single intravenous and oral doses. Pharmacokinetic evaluations were performed at first dose and at steady state. The results showed that cystic fibrosis patients have increased oral bioavailability of ciprofloxacin (80% in cystic fibrosis patients versus 57% in volunteers) and increased total clearance (688 ml/min in CF patients versus 528 ml/min in volunteers). Our data indicate that the pharmacokinetic properties of ciprofloxacin are altered in cystic fibrosis patients with mild symptoms of pulmonary exacerbations and that the changes most probably are due to cystic fibrosis per se or to the impact of chronic infection.

Administration, Oral↗
PubMed1988

Prenatal diagnostic options in cystic fibrosis.

There are currently two diagnostic options in cystic fibrosis. These involve assays for certain microvillar enzyme activities in amniotic fluid and recombinant deoxyribonucleic acid studies of markers linked to the cystic fibrosis gene on chromosome 7. The former are reduced in cystic fibrosis homozygotes; the latter make it possible to determine the particular pattern of chromosome 7 markers predictive of a cystic fibrosis homozygote in a specific family. However, neither test is appropriate for, applicable to, or informative in all families. The problems and potential of each approach are discussed.

Adult↗
PubMed1991

Toxicity of colistin in cystic fibrosis patients.

Pulmonary exacerbations of cystic fibrosis associated with strains of Pseudomonas aeruginosa that are resistant to multiple antibiotics are becoming increasingly common. The search for treatment alternatives continues and may include the reexamination of older antibiotics. Colistin sulfate is a polypeptide antibiotic with good activity against P. aeruginosa. Although its use was largely discontinued in the early 1970s because of reports of frequent renal and neurologic toxicity, intravenous colistin is often prescribed at our institution for patients with P. aeruginosa resistant to multiple-drug therapy. We prospectively monitored 19 patients during 21 courses of colistin therapy to identify the character and incidence of this agent's toxicity. Only one case of renal toxicity occurred. Six cases of neurotoxicity occurred, which were characterized by perioral paresthesia, ataxia, or both. The rate of intolerable renal adverse effects secondary to colistin therapy was appreciably lower among these patients than that reported previously for other patients. It appears that intravenous colistin can be considered for cystic fibrosis patients with strains of P. aeruginosa that are resistant to more commonly used antibiotics.

Adolescent↗