Enhanced drug metabolism in young children with cystic fibrosis

Parker, A.C.; Pritchard, P H; Preston, Tom; Smyth, Rosalind L; Choonara, Imti

doi:10.1136/adc.77.3.239

Cited by 28 publications

(26 citation statements)

References 15 publications

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“…Importantly, AEs were mostly transitory and occurred only during the first days of therapy. Although CF patients seem to have an altered metabolism in general [17], the frequency and nature of side effects related to amitriptyline in those patients did not differ from reported adverse drug reactions of the drug in non-CF patients.…”

Section: Discussionmentioning

confidence: 99%

Therapy of CF-Patients with Amitriptyline and Placebo - a Randomised, Double-Blind, Placebo-Controlled Phase IIb Multicenter, Cohort-Study

Naehrlich

Mainz

Adams

et al. 2013

Cell Physiol Biochem

1,958

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Background/Aims: Several recent studies revealed an accumulation of ceramide in bronchial, tracheal and intestinal epithelial cells of mice and patients with cystic fibrosis (CF). Normalization of ceramide concentrations in lungs of CF mice employing the functional acid sphingomyelinase inhibitor amitriptyline also normalized mucociliary clearance, chronic inflammation and infection susceptibility to pulmonary P. aeruginosa in these mice. Methods: To test for a beneficial effect of amitriptyline in vivo, we performed a phase IIb randomised, double-blind, placebo-controlled study. Twenty-one CF patients were treated with 25 mg/d amitriptyline twice daily for 28 days. The placebo consisted of 19 patients and was also treated twice per day. The primary endpoint was the change in lung function in the intention-to-treat (ITT) population. Secondary endpoints were ceramide levels in epithelial cells and safety. Results: After treatment, forced expiratory volume in 1 sec predicted (FEV₁) increased 6.3±11.5% (p=0.08) in the ITT population (36 of 40 CF patients) and 8.5±10% (p=0.013) in the per protocol (PP) population (29 of 40 patients). Ceramide levels decreased in nasal epithelial cells after amitriptyline treatment. Amitriptyline had no severe and only mild and mostly transient adverse effects, i.e. xerostomia and tiredness. Conclusion: Amitriptyline is safe in CF-patients, increases FEV₁ and reduces ceramide in lung cells of CF patients.

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Section: Discussionmentioning

confidence: 99%

Therapy of CF-Patients with Amitriptyline and Placebo - a Randomised, Double-Blind, Placebo-Controlled Phase IIb Multicenter, Cohort-Study

Naehrlich

Mainz

Adams

et al. 2013

Cell Physiol Biochem

1,958

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“…These involved taking multiple blood samples from each patient. Alternative approaches that involve the use of population pharmacokinetics where a fewer number of blood samples are collected from a larger number of patients [68] or non-invasive methods such as the caffeine breath test [69,70] may be necessary.…”

Section: Discussionmentioning

confidence: 99%

A systematic review of pharmacokinetics studies in children with protein-energy malnutrition

Oshikoya

Sammons

Choonara

2010

Eur J Clin Pharmacol

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“…Although the liver is the primary site of xenobiotic metabolism, the importance of the small intestine, which is a major site of drug absorption, is being increasingly recognized (31,43). In CF patients, metabolic clearance of some drugs has been reported to be increased (32,44,45), although those studies focused almost exclusively on hepatic clearance. Given the discrepancy between the downregulation of drug metabolism genes in the CF mouse intestine and the seemingly contradictory increase in drug clearance in CF patients, additional studies will be needed to understand the mechanisms underlying the changes in drug metabolism in CF and the relative roles of liver and intestinal xenobiotic metabolism.…”

Section: Nhe3mentioning

confidence: 99%

Reduced NHE3-mediated Na⁺ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice

Bradford¹,

Sartor²,

Gawenis³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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In cystic fibrosis, impaired secretion resulting from loss of activity of the cystic fibrosis transmembrane conductance regulator (CFTR) causes dehydration of intestinal contents and life-threatening obstructions. Conversely, impaired absorption resulting from loss of the NHE3 Na+/H+ exchanger causes increased fluidity of the intestinal contents and diarrhea. To test the hypothesis that reduced NHE3-mediated absorption could increase survival and prevent some of the intestinal pathologies of cystic fibrosis, Cftr/Nhe3 double heterozygous mice were mated and their offspring analyzed. Cftr-null mice lacking one or both copies of the NHE3 gene exhibited increased fluidity of their intestinal contents, which prevented the formation of obstructions and increased survival. Goblet cell hyperplasia was eliminated, but not the accumulation of Paneth cell granules or increased cell proliferation in the crypts. Microarray analysis of small intestine RNA from Cftr-null, NHE3-null, and double-null mice all revealed downregulation of genes involved in xenobiotic metabolism, including a cohort of genes involved in glutathione metabolism. Expression of energy metabolism genes was altered, but there were no changes in genes involved in inflammation. Total intracellular glutathione was increased in the jejunum of all of the mutants and the ratio of reduced to oxidized glutathione was reduced in Cftr-null mutants, indicating that CFTR deficiency affects intestinal glutathione metabolism. The data establish a major role for NHE3 in regulating the fluidity of the intestinal contents and show that reduced NHE3-mediated absorption reverses some of the intestinal pathologies of cystic fibrosis, thus suggesting that it may serve as a potential therapeutic target.

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Enhanced drug metabolism in young children with cystic fibrosis

Cited by 28 publications

References 15 publications

Therapy of CF-Patients with Amitriptyline and Placebo - a Randomised, Double-Blind, Placebo-Controlled Phase IIb Multicenter, Cohort-Study

Therapy of CF-Patients with Amitriptyline and Placebo - a Randomised, Double-Blind, Placebo-Controlled Phase IIb Multicenter, Cohort-Study

A systematic review of pharmacokinetics studies in children with protein-energy malnutrition

Reduced NHE3-mediated Na⁺ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice

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Enhanced drug metabolism in young children with cystic fibrosis

Cited by 28 publications

References 15 publications

Therapy of CF-Patients with Amitriptyline and Placebo - a Randomised, Double-Blind, Placebo-Controlled Phase IIb Multicenter, Cohort-Study

Therapy of CF-Patients with Amitriptyline and Placebo - a Randomised, Double-Blind, Placebo-Controlled Phase IIb Multicenter, Cohort-Study

A systematic review of pharmacokinetics studies in children with protein-energy malnutrition

Reduced NHE3-mediated Na+ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice

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Product

Resources

About

Reduced NHE3-mediated Na⁺ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice