Dornase alfa for cystic fibrosis. Patients should not be denied a safe, effective treatment.
Explore the source record for details and available documents.
Cystic Fibrosis↗
Biomedical subjects
D M Geddes
Publications and source records attributed to D M Geddes.
Inhaled budesonide for mild asthma.
Explore the source record for details and available documents.
Administration, Inhalation↗
Gene therapy for cystic fibrosis.
Explore the source record for details and available documents.
Animals↗
Two years experience with recombinant human DNase I in the treatment of pulmonary disease in cystic fibrosis.
Recombinant human DNase I (rhDNase) has been shown to improve pulmonary function in patients treated for up to 6 months. A cohort of 52 cystic fibrosis patients with a FVC > 40% predicted were enrolled into an open label study in order to evaluate longer-term effects of rhDNase. They received 2.5 mg rhDNase twice daily for 6 months followed by a 2-week wash-out period, and for the subsequent 18 months were treated with rhDNase once daily. Twenty-six male and 26 female patients with a mean FVC of 2.941 and FEV1 of 1.471 were recruited. Thirteen patients did not complete the study; there were seven deaths, three patients withdrew consent and three patients were lost to follow-up. Improvement in pulmonary function was seen following treatment and changes were evaluated as mean percent change from baseline. The maximum improvement occurred in the first month followed by a plateau at a lower level of improvement. The mean improvement in FEV1 over the first month was 13.3% (range 12-14.1%), followed by a plateau at around 7.1% (range 4.6-11.0%) for the subsequent 23 months. Mean FVC was improved by 12.03% (range 9.0-14.3%) over the first month and subsequently 4.2% (range - 2.2-10.2%). The effects on pulmonary function were similar for both treatment doses of rhDNase. There was also a steady improvement in weight from a mean of 54.2 kg to 55.7 kg at the end of the study.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Home treatment of patients with cystic fibrosis using the 'Intermate': the first year's experience.
Home treatment of patients with cystic fibrosis has many attractions and is becoming increasingly popular. The investigators have studied the use, results and costs of the first year of operation of a home-care intravenous antibiotic service using the 'Intermate' infusion device in a prospective study using questionnaires, spirometric and weight measurements. Ninety-three patients received 166 courses of intravenous antibiotics in full or in part at home during 1991. The average length of treatment was 12.5 days and on average 70% of the treatment was given at home. The mean percentage predicted FEV1 and FVC improved after treatment and the mean improvement was not significantly different to that produced by hospital treatment. Breathlessness, sputum volume, appetite, ability to sleep, mood, energy and overall well-being, as assessed by questionnaire, showed significant improvements after home treatment. The median time spent mixing and administering drugs was 10-19 hours and visiting the hospital was 7-12 hours. The median number of days of lost income to patients or their carers was 0 days. The majority of the patients were extremely satisfied with the treatment and supervision that they received. Using the home care service, 1442 inpatient days were saved. The investigators conclude that home care using 'Intermates' improves a patient's lung function and quality of life.
Adolescent↗
Recall lung pneumonitis due to carmustine after radiotherapy.
A patient who developed pneumonitis immediately after the administration of carmustine (BCNU), within exactly the same field as previous irradiation, is presented. The patient responded partially to corticosteroids. This case suggests that irradiation causes subclinical sensitisation of the lung and can therefore have an additive effect in precipitating lung damage when another pulmonary toxin is encountered at a later date.
Antineoplastic Agents, Alkylating↗
Medium term treatment of stable stage cystic fibrosis with recombinant human DNase I.
BACKGROUND: A phase II multicentre double blind placebo controlled study in 1993 showed that short term treatment (10 days) with recombinant human DNase I (rhDNase) was safe and improved pulmonary function in patients with cystic fibrosis with stable stage lung disease. A six month open label treatment study was conducted in some of the patients who participated in the short term study to assess the medium term effects of rhDNase. METHODS: Patients who completed the phase II study and were stable for 14 days prior to treatment were eligible. They were treated with rhDNase 2.5 mg twice daily for six months and reviewed at regular intervals to assess safety and efficacy. RESULTS: Fifty nine patients (31M,28F) of age range 16-55 years were recruited. Mean baseline values for forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were 41.5% and 72.4% of predicted, respectively. The mean increase in FEV1 over the first month of treatment was 13.1% (range 12-14.1%) and then stabilised at 6.2% (4.6-7.8%) for the subsequent five months. FVC was similarly improved. Administration of rhDNase improved the severity of dyspnoea, cystic fibrosis related symptoms, and the modified Taussig/NIH score (not statistically significant). Fifty seven of the 59 patients completed the study; two died from progression of their pulmonary disease unrelated to treatment with rhDNase. The adverse events and intercurrent illnesses were no different from those expected in a cystic fibrosis population. Pharyngitis was the only possible drug related adverse event which occurred at least once in 14% of patients during the six month period. CONCLUSIONS: Administration of rhDNase was safe, well tolerated, and improved pulmonary function in patients with cystic fibrosis. When rhDNase was stopped at day 169 there was a deterioration in pulmonary function and dyspnoea score.
Adolescent↗
Gene therapy for respiratory diseases: potential applications and difficulties.
Explore the source record for details and available documents.
Cystic Fibrosis↗
Bioelectric characteristics of exon 10 insertional cystic fibrosis mouse: comparison with humans.
Two important issues that can be addressed by animal models are disease pathogenesis and the testing of new treatments, including gene therapy. How closely these models mimic the relevant disorder in humans will determine their usefulness. This study examines how closely the characteristic bioelectric features of cystic fibrosis (CF) are reproduced in the airways and intestinal tract of the exon 10 insertional mutant mouse (cf/cf). In agreement with CF subjects these cf/cf mutant mice demonstrate the following: 1) reduced adenosine 3',5'-cyclic monophosphate-related chloride secretion throughout the respiratory and intestinal tracts both in vivo and in vitro, 2) calcium-related chloride secretion that is preserved in the airways but reduced in the intestine, and 3) a more negative nasal potential difference and increased amiloride response compared with wild-type animals, likely to relate to increased sodium absorption. In contrast to humans, sodium absorption is not increased in the small intestine and is reduced in the trachea of the cf/cf mice. We conclude that the majority of the salient electrophysiological features of CF required for studies of pathogenesis or testing of new treatments are present in these cf/cf mice.
Animals↗
Fatal haemorrhage from mesenchymal cystic hamartoma of the lung.
A 34 year old women was admitted to the hospital with a 9 year history of intermittent haemoptysis associated with increasing breathlessness. A working diagnosis of lymphangioleiomyomatosis was made, based on clinical, radiological and histological findings. Three years later, the patient was admitted to hospital with worsening haemoptysis, which rapidly progressed and resulted in death from massive pulmonary haemorrhage. Postmortem examination and histology revealed findings consistent with multiple mesenchymal cystic hamartomas of the lungs. This is a rare condition which has previously been described as having a good prognosis. This case is the first fatality resulting directly from the disease to be reported.
Adult↗
Gene therapy for cystic fibrosis: a clinical perspective.
Since the isolation of the cystic fibrosis (CF) gene in 1989, the potential for gene therapy for this disease has existed. Although current treatments have resulted in a mean life expectancy of approximately 30 years, there is clearly a need for more effective therapy. A large number of studies have now assessed both in vitro and in vivo CFTR gene transfer into cell lines, animal models and most recently in CF subjects. Despite this rapid progress several difficulties remain including efficient in vivo gene transfer and the measurement of end-points to assess such gene transfer. This article reviews some of the clinically related aspects of gene therapy for CF.
Animals↗
Recombinant human DNase I in cystic fibrosis patients with severe pulmonary disease: a short-term, double-blind study followed by six months open-label treatment.
Chronic pulmonary infection is the major cause of morbidity and mortality in cystic fibrosis (CF). Recombinant human deoxyribonuclease (rhDNase) in vitro has been shown to dramatically reduce the viscoelasticity of the sputum from CF patients. Phase II and III clinical trials have shown the drug to be safe, and that patients with a forced vital capacity (FVC) of > 40% predicted show an improvement in pulmonary function when receiving rhDNase. The current study evaluates the safety and efficacy of rhDNase in the most severly ill CF patients (FVC < 40% predicted). A double-blind, randomized, placebo-controlled trial in which patients received either 2.5 mg rhDNase twice daily or placebo for a period of 14 days followed by a 6 month open extension period (OEP) is reported. Seventy patients were recruited for the double-blind study, and 64 entered the OEP of whom 38 completed. During the OEP, all patients received 2.5 mg rhDNase twice daily. In both the double-blind period and the OEP the drug appeared to be safe. During the double-blind study, forced expiratory volume in one second (FEV1) and FVC improved in both groups but there was no statistically significant difference between the groups. In the OEP, there was mean improvement in percentage predicted FEV1 and FVC, 9 and 18%, respectively, for all patients participating. In conclusion, DNase is safe when administered in conjunction with a rigorous regimen of chest physiotherapy to severely ill patients (FVC < 40% predicted) with CF. The double-blind, 14 day study showed no significant improvement in pulmonary function but some patients may have improved after longer administration of rhDNase.
Administration, Inhalation↗
Gene therapy for alpha 1-antitrypsin deficiency.
Alpha 1-antitrypsin deficiency is associated with pulmonary emphysema and liver cirrhosis. The pathogenesis and treatment is reviewed with particular emphasis on gene therapy for emphysema. The technology of gene transfer using viruses and liposomes is developing fast and animal experiments have confirmed the feasibility of gene therapy for alpha 1-antitrypsin deficiency (AATD). So far only subtherapeutic levels of protein have been produced but human trials are starting and progress can be expected.
Animals↗
Quantitative fluorescence measurements of chloride secretion in native airway epithelium from CF and non-CF subjects.
Functional assessment of the efficacy of CFTR gene transfer protocols in humans has previously involved measurement of in vivo potential difference. We have studied whether freshly obtained airway epithelial cells may provide suitable tissue for studies of in vivo gene transfer using fluorescent digital imaging microscopy. Nasal epithelial cells from non-cystic fibrosis subjects (n = 6) and from cystic fibrosis (CF) patients (delta F508: delta F508, n = 5) were obtained by brushing and loaded with 6-methoxy-N-(3-sulfopropyl)quinolinium (SPQ). Addition of the cAMP-agonists forskolin (20 microM) and 3-isobutyl-1-methylxanthine (IBMX, 100 microM) produced an increased efflux of iodide from the cells which was significantly (P < 0.05) greater in non-CF than in CF cells. Efflux following addition of the calcium ionophore, ionomycin (100 microM) was similar in both non-CF and CF cells. Liposome-mediated transfection of CF nasal epithelial cells in vitro with CFTR-cDNA restored the cAMP-stimulated efflux to non-CF values. Bronchial epithelial cells from non-CF subjects showed responses to forskolin and ionomycin that were not different to those in non-CF nasal epithelia. These data demonstrate that the assay provides a useful method for assessing correction of abnormal ion transport in non-cultured CF epithelium and is likely to provide a further assay for assessment of in vivo gene transfer efficiency in protocols of gene therapy for CF.
Adult↗
Lack of inhibition by dideoxy-forskolin and verapamil of DIDS-sensitive volume-activated Cl- secretion in human squamous lung carcinoma epithelial cells.
The effect of osmotic stress on Cl- permeability in human squamous lung carcinoma epithelial (S1) cells was investigated using a macroscopic 125I efflux assay. Hypotonic challenge of monolayers led to a significant (P < 0.01) dose-related increase in efflux from pre-loaded cells, returning to pre-activation rates within 10 min. A similar magnitude of response could be produced by challenge with an isotonic low chloride-containing solution. Neither 100 mM dideoxy-forskolin nor 100 mM verapamil inhibited the increase in Cl- secretion after hypotonic challenge, whereas 100 mM DIDS inhibited volume-activated Cl- secretion by 55%. Both Northern and Western blot analysis confirmed the absence of MDR1 mRNA and P-glycoprotein in the S1 cells. We conclude that these cells have a volume-regulated Cl- secretory pathway that is independent of the ABC transporter, P-glycoprotein.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Nasal application of the cationic liposome DC-Chol:DOPE does not alter ion transport, lung function or bacterial growth.
Liposome-mediated gene transfer is commonly used for in vitro transfection of deoxyribonucleic acid (DNA) into mammalian cells. We and others have recently demonstrated that this can be an effective method for in vivo delivery of plasmid DNA containing the human cystic fibrosis transmembrane conductance regulator (CFTR) gene to mouse models of cystic fibrosis (CF). This suggests that cationic liposomes may be useful for transferring CFTR complementary DNA (cDNA) into the airways of CF subjects. In such trials, measurement of nasal potential difference (PD) will be used to monitor the efficacy of correction of the CF bioelectric defect and to provide a sensitive assay of epithelial integrity [corrected]. We therefore assessed whether the cationic liposome DC-Chol: DOPE altered nasal ion transport parameters, in six normal and three CF subjects. Lung function was also measured as a further marker of safety. Finally, as CF airways are chronically infected, we studied whether DC-Chol:DOPE or DC-Chol:DOPE-DNA complexes altered the bacterial growth and sensitivities of CF sputum. No significant effect was seen on any of these parameters, suggesting that DC-Chol:DOPE may be appropriate for use in human trials of liposome-mediated gene therapy for CF.
Administration, Intranasal↗
Protocols for in vivo measurement of the ion transport defects in cystic fibrosis nasal epithelium.
New treatments for cystic fibrosis (CF), including gene therapy, are currently being assessed. These aim to correct the basic defects of increased sodium absorption and decreased chloride secretion in airway epithelia. Assessment of these bioelectric parameters, particularly in the nasal epithelium, is likely to be used as a measure of treatment efficacy. However, the optimal in vivo protocol to discriminate cystic fibrosis from non-cystic fibrosis subjects is unclear. We have, therefore, compared three protocols for measurement of the cystic fibrosis ion transport defects in vivo in the nasal epithelium. Sodium absorption was measured using both the baseline potential difference and the response to the sodium channel blocker, amiloride. Chloride secretion was assessed in the presence of amiloride, using perfusion with isoprenaline, or terbutaline, or a low chloride solution followed by isoprenaline. Baseline potential difference (PD) and the absolute response to amiloride clearly differentiated the increased sodium absorption in the cystic fibrosis subjects. The responses both to terbutaline (delta PD: non-CF: -0.8 (SEM 0.7) mV; CF: -3.6 (0.5) mV) and isoprenaline (non-CF: 1.5 (0.6) mV; CF: -2.9 (0.6) mV) differentiated the two groups of subjects, but there was considerable overlap of values. Perfusion with a low chloride solution (non-CF: 12.6 (1.2) mV; CF: 0.6 (0.4) mV), as well as subsequent perfusion with isoprenaline (non-CF: 10.0 (1.1) mV; CF: -1.4 (0.4) mV) allowed clear separation of the two groups, with no overlap of values. Some CF subjects showed a transient hyperpolarization to these stimuli, which could clearly be differentiated from the sustained responses seen in non-cystic fibrosis subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Characterization and comparison of ion transport across sheep and human airway epithelium.
This study aimed to assess the suitability of sheep tracheal epithelium as a model for studies of human airway ion transport. Ovine and human airway epithelium were mounted in Ussing chambers under short circuit conditions. Bumetanide (100 microM) reduced short-circuit current (Isc) by a mean of 21.3% +/- SEM 2.0, n = 8, in sheep, and 30.4% +/- 9.7, n = 3, in human airway epithelium. Acetazolamide (100 microM) decreased Isc by 10.6% +/- 1.2, n = 18, in sheep, and 5.8% +/- 2.9, n = 3, in human airways. Phloridzin (200 microM) reduced Isc by 4.7% +/- 0.8, n = 7, and 3.1% +/- 5.1, n = 3 in sheep and human tissue respectively. Amiloride (100 microM) decreased Isc by 42.9% +/- 3.5, n = 12, in sheep airways, whilst bathing the mucosal surface with Na(+)-free solutions reduced Isc by 67.4% +/- 4.2, n = 18. The sequential addition of acetazolamide, bumetanide, phloridzin, amiloride and mucosal Na(+)-free solutions totally inhibited the basal Isc in both sheep and human tissues, suggesting that Cl- and HCO3- secretion, Na(+)-glucose co-transport and amiloride-sensitive and -insensitive Na+ absorption contribute to the Isc. The similarities between the species suggest that sheep tracheal epithelium is a useful model for basal studies of airway ion transport, and may prove a valuable tool for further regulatory studies.
4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗