Absorptive Clearance After Inhaled Osmotics in Cystic Fibrosis
| Status: | Completed |
|---|---|
| Conditions: | Pulmonary |
| Therapuetic Areas: | Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 12/1/2018 |
| Start Date: | September 2010 |
| End Date: | December 2012 |
Blockage of the breathing tubes of the lungs by thick, sticky mucus is a major cause of lung
problems for people with cystic fibrosis (CF). Many researchers now believe that people with
CF absorb too much water from the insides of their lungs, and that the mucus in their lungs
becomes so thick and sticky because there is not enough water in it. The investigators are
trying to develop ways to measure how fast water is absorbed from the breathing tubes in the
lung so that the investigators can more quickly test new medications that are being developed
to fix this problem for CF patients. The investigators have already done studies showing that
people with CF absorb a particular radioactive drug (Indium-111 diethylenetriaminepentaacetic
acid or In-DTPA) from their lungs more quickly than people without CF. Now the investigators
are trying to prove that the absorption of this drug is related to the absorption of water.
The investigators measure the absorption of In-DTPA by delivering it in an aerosol (inhaled
mist) along with another radioactive drug (Technetium 99m sulfur colloid or Tc-SC). This
other drug helps us measure how much material is cleared from the lungs in other ways (like
coughing) without being absorbed. In this study, the investigators will measure how the
absorption of In-DTPA is affected by inhaling isotonic saline and hypertonic saline (salt
water), both of which the investigators know affect the absorption of water in the airways.
problems for people with cystic fibrosis (CF). Many researchers now believe that people with
CF absorb too much water from the insides of their lungs, and that the mucus in their lungs
becomes so thick and sticky because there is not enough water in it. The investigators are
trying to develop ways to measure how fast water is absorbed from the breathing tubes in the
lung so that the investigators can more quickly test new medications that are being developed
to fix this problem for CF patients. The investigators have already done studies showing that
people with CF absorb a particular radioactive drug (Indium-111 diethylenetriaminepentaacetic
acid or In-DTPA) from their lungs more quickly than people without CF. Now the investigators
are trying to prove that the absorption of this drug is related to the absorption of water.
The investigators measure the absorption of In-DTPA by delivering it in an aerosol (inhaled
mist) along with another radioactive drug (Technetium 99m sulfur colloid or Tc-SC). This
other drug helps us measure how much material is cleared from the lungs in other ways (like
coughing) without being absorbed. In this study, the investigators will measure how the
absorption of In-DTPA is affected by inhaling isotonic saline and hypertonic saline (salt
water), both of which the investigators know affect the absorption of water in the airways.
There is a substantial need for new biomarkers in the study of cystic fibrosis (CF) lung
disease. Conventional endpoints, such as rate of FEV1 decline, require prolonged trials and
large sample sizes to demonstrate therapeutic efficacy. Ideally such biomarkers would provide
a quantitative window to the most basic aspects of CF pathophysiology, allowing for the
development and evaluation of therapies prior to large scale clinical trials. The basic
defect of CF lung disease occurs in the airways where dysfunction of the cystic fibrosis
transmembrane conductance regulator (CFTR) and epithelial sodium (ENaC) channels is thought
to create an ionic gradient that causes excessive liquid absorption across the epithelium.
This results in a dehydrated airway surface liquid (ASL) layer, defective mucociliary
clearance, and an increased proclivity for infection and inflammation.
Aerosol-based methods have been developed to measure mucociliary clearance in the lung and
used to demonstrate the efficacy of inhaled osmotic therapies. We have developed an aerosol
technique to measure both mucociliary clearance and the absorptive clearance of a hydrophilic
small molecule (diethylenetriaminepentaacetic acid or DTPA) in whole, central, and peripheral
lung regions. We estimate DTPA absorption by delivering an aerosol containing both Indium 111
DTPA (In-DTPA) and Technetium 99m sulfur colloid (Tc-SC) to the airways. The clearance of
each radiopharmaceutical is imaged independently and two separate clearance curves are
calculated. In-DTPA is cleared through both absorption and mucociliary clearance while Tc-SC
is cleared only through the mucociliary route. The difference between the clearance rates of
the radiopharmaceuticals provides an estimate of In-DTPA absorption rate.
Our previous studies have demonstrated that absorption of In-DTPA occurs at a higher rate in
central (airway dominated) lung zones of CF subjects compared to controls (42 vs. 32 %/hr, CF
n= 9, control n=10, p=0.03). We believe that this increased In-DTPA absorption is being
caused by the increased liquid absorption occurring in these airways, however there are other
potential causes such as increase in tight junction permeability or epithelial denuding.
In this study we propose to measure In-DTPA absorption after the delivery of interventions
known to affect liquid absorption in the airways to see if changes in In-DTPA absorption
mirror the changes in liquid absorption known to be caused by the interventions.
disease. Conventional endpoints, such as rate of FEV1 decline, require prolonged trials and
large sample sizes to demonstrate therapeutic efficacy. Ideally such biomarkers would provide
a quantitative window to the most basic aspects of CF pathophysiology, allowing for the
development and evaluation of therapies prior to large scale clinical trials. The basic
defect of CF lung disease occurs in the airways where dysfunction of the cystic fibrosis
transmembrane conductance regulator (CFTR) and epithelial sodium (ENaC) channels is thought
to create an ionic gradient that causes excessive liquid absorption across the epithelium.
This results in a dehydrated airway surface liquid (ASL) layer, defective mucociliary
clearance, and an increased proclivity for infection and inflammation.
Aerosol-based methods have been developed to measure mucociliary clearance in the lung and
used to demonstrate the efficacy of inhaled osmotic therapies. We have developed an aerosol
technique to measure both mucociliary clearance and the absorptive clearance of a hydrophilic
small molecule (diethylenetriaminepentaacetic acid or DTPA) in whole, central, and peripheral
lung regions. We estimate DTPA absorption by delivering an aerosol containing both Indium 111
DTPA (In-DTPA) and Technetium 99m sulfur colloid (Tc-SC) to the airways. The clearance of
each radiopharmaceutical is imaged independently and two separate clearance curves are
calculated. In-DTPA is cleared through both absorption and mucociliary clearance while Tc-SC
is cleared only through the mucociliary route. The difference between the clearance rates of
the radiopharmaceuticals provides an estimate of In-DTPA absorption rate.
Our previous studies have demonstrated that absorption of In-DTPA occurs at a higher rate in
central (airway dominated) lung zones of CF subjects compared to controls (42 vs. 32 %/hr, CF
n= 9, control n=10, p=0.03). We believe that this increased In-DTPA absorption is being
caused by the increased liquid absorption occurring in these airways, however there are other
potential causes such as increase in tight junction permeability or epithelial denuding.
In this study we propose to measure In-DTPA absorption after the delivery of interventions
known to affect liquid absorption in the airways to see if changes in In-DTPA absorption
mirror the changes in liquid absorption known to be caused by the interventions.
Inclusion Criteria:
- age ≥ 18 years
- diagnosis of cystic fibrosis as determined by sweat test or genotype and clinical
symptoms
- clinically stable as determined by the investigator (pulmonologist)
Exclusion Criteria:
- intolerant to hypertonic saline.
- FEV1%p <40% of predicted
- nursing mother
- positive urine pregnancy test
- unwilling to stop hypertonic saline therapy for 72 hours prior to each test day
- cigarette smoker (regular smoking within 6 months of study)
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