Cystic Fibrosis

Cystic fibrosis (CF) is genetic autosomal recessive disease caused by reduced or absent function of CFTR protein.

CFTR stands for Cystic Fibrosis Transmembrane Conductance Regulator. The CFTR protein functions as a channel for the movement of chloride ions in and out of cells, which is important for the salt and water balance on epithelial surfaces, such as in the lungs or pancreas.

Treatment Challenges

– CF is so rare that there is very little funding for research
– Within this rare group are many subcategories which makes it even harder to get funding for research as each individual will often require a unique protocol to be created and constant monitoring and with changing treatments and doses. There is no “one” cure or target for CF
– CF tend to have extra fast detoxification systems and burn so many calories with every day function. Being such fast metabolisers they quickly become resistant to treatment and need to constantly change medication and/or dose.

Naturopathic strategies for CF

– B2 agonists – grapefruit essential oil, stimulants like PEA’s and DMAA, caffeine
– cAMP stimulation with forskolin
– inhibit PDE2 with caffeine
– enhance cAMP induction of CFTR protein with menthol from peppermint oil
– PPAR receptor modulation – Conjugated linolenic acid (pomegranate seed oil) and conjugated linoleic acid (safflower seed oil)
– Slow phase 1 cytochrome p450 pathways in particular CYP1A2 – Turmeric and schisandra, brassicas, mustard and watercress.

Some interesting reading for CF

CFTR

Eur Respir J. 2016 Sep;48(3):768-79. doi: 10.1183/13993003.01661-2015. Epub 2016 Jul 28. β2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis. Vijftigschild LA et al.

We hypothesized that people with cystic fibrosis (CF) who express CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations associated with residual function may benefit from G-protein coupled receptor (GPCR)-targeting drugs that can activate and enhance CFTR function.We used intestinal organoids to screen a GPCR-modulating compound library and identified β2-adrenergic receptor agonists as the most potent inducers of CFTR function.β2-Agonist-induced organoid swelling correlated with the CFTR genotype, and could be induced in homozygous CFTR-F508del organoids and highly differentiated primary CF airway epithelial cells after rescue of CFTR trafficking by small molecules. The in vivo response to treatment with an oral or inhaled β2-agonist (salbutamol) in CF patients with residual CFTR function was evaluated in a pilot study. 10 subjects with a R117H or A455E mutation were included and showed changes in the nasal potential difference measurement after treatment with oral salbutamol, including a significant improvement of the baseline potential difference of the nasal mucosa (+6.35 mV, p<0.05), suggesting that this treatment might be effective in vivo Furthermore, plasma that was collected after oral salbutamol treatment induced CFTR activation when administered ex vivo to organoids.This proof-of-concept study suggests that organoids can be used to identify drugs that activate CFTR function in vivo and to select route of administration.

CYP450

Arch Dis Child. 1997 Sep;77(3):239-41. Enhanced drug metabolism in young children with cystic fibrosis. Parker AC1, Pritchard P, Preston T, Smyth RL, Choonara I.

The effect of cystic fibrosis on caffeine metabolism was studied in young children using the caffeine breath test. Eight children with cystic fibrosis aged 2-6 years and nine age matched controls were studied on a single occasion, and the cumulative percentage of labelled caffeine exhaled as carbon dioxide measured over two hours. This was significantly higher in the patients with cystic fibrosis than in controls, suggesting an increase in the CYP1A2 metabolic pathway in the former. The fact that these were young children with minimal lung and liver disease suggests that enhanced drug metabolism in children with cystic fibrosis is hereditary rather than secondary to lung and liver damage.

Clin Pharmacol Ther. 1996 May;59(5):529-40. Hepatic drug clearance in patients with mild cystic fibrosis. Kearns GL1, Crom WR, Karlson KH Jr, Mallory GB Jr, Evans WE.

The plasma disposition of three model substrates (lorazepam, indocyanine green, and antipyrine) and the formation clearance of antipyrine metabolites (3-hydroxymethylantipyrine, norantipyrine, and 4-hydroxyantipyrine) were evaluated in 15 subjects with mild cystic fibrosis and in 15 healthy control subjects. Plasma clearance was significantly greater in patients with cystic fibrosis for both lorazepam (1.7 +/- 0.4 versus 1.2 +/- 0.5 ml/min/kg) and indocyanine green (14.2 +/- 6.1 versus 9.1 +/- 3.0 ml/min/kg). In contrast, the clearance of antipyrine was not significantly different (1.0 +/- 0.7 versus 0.8 +/- 0.3 ml/min/kg), but the formation clearance for 3-hydroxymethylantipyrine was significantly greater in patients with cystic fibrosis. Lorazepam and antipyrine apparent steady-state volume of distribution were not different between groups. These results suggest that clearance of drugs that undergo conjugation (e.g., lorazepam) or biliary excretion (e.g., indocyanine green) is increased in patients with mild cystic fibrosis. In contrast, the increased formation clearance of only one antipyrine metabolite suggests that alterations in clearance of drugs metabolized by cytochrome P450 enzymes are substrate specific and isoform specific in patients with cystic fibrosis.

Med Hypotheses. 1986 Jun;20(2):233-43. Cystic fibrosis: a casualty of “detoxification”? Braganza JM.
It is proposed that excessive and/or aberrant function of cytochromes P450, due to a combination of genetic and environmental influences, is the basic defect in cystic fibrosis. Organs that are involved in oxidative detoxification reactions in foetal life are thus at risk: tissue damage is initiated by excessive production of oxygen free radicals which deplete cellular antioxidants and provoke the secretion of mucus.

Clin Pharmacol Ther. 1994 Nov;56(5):521-9. Caffeine metabolism in cystic fibrosis: enhanced xanthine oxidase activity. Hamelin BA1, Xu K, Vallé F, Manseau L, Richer M, LeBel M.

To characterize the activities of the P450 mixed-function oxidase CYP1A2 as well as the cytosolic enzymes N-acetyltransferase and xanthine oxidase using caffeine as a probe in children with cystic fibrosis compared to age-matched healthy control subjects.

The indexes for CYP1A2, N-acetyltransferase, and 8-hydroxylation were similar in both groups of subjects. In contrast, there was a significant difference in the frequency distribution of the xanthine oxidase activity between the two groups. Nine of 12 patients with cystic fibrosis but only one of 12 healthy volunteers had xanthine oxidase activities above 0.42 (Kolmogorov-Smirnov two-sample test, p < 0.01).

CONCLUSIONS:

Differences in xanthine oxidase may have clinical implications with regard to interindividual variation in xenobiotic biotransformation and the exposure to lung tissue-damaging oxygen radicals. Hepatic enzyme activities appear to be selectively altered in patients with cystic fibrosis.