The Treatment of Pulmonary Diseases and Respiratory-Related Conditions With Inhaled (Nebulized or Aerosolized) Glutathione

Jonathan Prousky

Evid Based Complement Alternat Med. 2008;5(1):27-35.

Conclusions

GSH inhalation is an effective treatment for a variety of pulmonary diseases and respiratory-related conditions. Even very serious and difficult-to-treat diseases (e.g., CF, IPF) yielded benefits from this novel treatment. GSH inhalation is very safe, and rarely causes major or life-threatening side effects. The potential applications are numerous when one considers just how many pulmonary diseases and respiratory-related conditions are affected by deficient antioxidant status, poor oxygenation and/or impaired host defenses. More studies are clearly warranted.

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Acknowledgments

The author would like to thank Mr Glen Carr and Mr Andrew Dick for their wonderful illustration of GSH's mechanism of action.

Reprint Address

Jonathan Prousky, 1255 Sheppard Avenue East, Toronto, Ontario, Canada MK2 1E2. Tel: 416-498-1255, ext. 235; Fax: 416-498-1611; E-mail: jprousky@ccnm.edu

References

Enzyme Systems Involving Glutathione
Enzyme system	Function
Glutathione synthetase	Gamma-glutamyl cycle.
Riboflavin-containing glutathione reductase	Catalyzes the conversion of oxidized glutathione (glutathione disulfide; GSSG) to its reduced form.
GSH transferase isoenzymes	Conjugation of GSH with fat-soluble substances for liver detoxification and the detoxification of environmental carcinogens, such as those found in tobacco smoke.
Selenium-containing glutathione peroxidase (GPX)	Protects cells from hydrogen peroxides and lipid hydroperoxides. If not neutralized, these peroxides will damage cellular membranes and other vital cellular components.
Leukotriene C₄ synthase	Conjugation of leukotriene A₄ with GSH, resulting in the generation of leukotrienes C₄. Gamma-glutamyl transpeptidase then metabolizes leukotrienes C₄ to leukotrienes D₄.

Grades of Evidence
A	Systematic reviews of randomized controlled trials and/or randomized controlled trials with or without double-blind placebo control.
B	Systematic reviews of observational studies and/or high-quality observational studies including cohort and case-control studies and/or cohort 'outcomes' research and/or nonrandomized controlled trials.
C	Case-series, case-reports, and/or poor-quality cohort and case-control studies.
D	Expert opinion without explicit critical appraisal or based on physiology, bench research or 'first principles.'

Summary of Articles Demonstrating The Effectiveness Of Inhaled Glutathione for The Treatment of Pulmonary Diseases And Respiratory-Related Conditions
Reference	Condition	N	Dosages of inhaled GSH	Outcome	Evidence grade
(21)	Asthma	Eight asthma patients [mean age, 29 ± 7 (standard deviation; SD) years]	600 mg once weekly for 3 months	A subset of patients with clinically stable mild asthma experienced a bronchoconstrictor effect when treated with inhaled GSH.	A: Randomized placebo-controlled trial
(23)	Chronic otitis media with effusion (chronic OME)	30 patients (3-12 years of age; mean age, 5.8 years) and 30 controls (3-12 years of age; mean age, 6.1 years)	600mg of GSH in 4 ml of saline subdivided into five 2-min sessions by nasal aerosol every 3-4 waking h for 2 weeks	GSH should be considered for the nonsurgical management of chronic OME.	A: Randomized placebo-controlled trial
(24)	Cystic fibrosis (CF)	Nine patients [mean age, 16.1 ± 1.44 (SD) years] received the S-nitrosoglutathione (GSNO) and 11 patients [mean age, 19.9 ± 3.45 (SD) years] received the phosphate- buffered saline (PBS) solution	0.05 ml/kg of 10 mM GSNO	The treatment group showed a modest improvement in oxygenation that was thought to be independent of the physiological effects of nitric oxide.	A: Randomized placebo-controlled trial
(27)	CF	19 patients (6-19 years of age) were randomized to treatment [mean age, 13.3 ± 4.1 (SD) years] or placebo groups [mean age, 12.9 ± 4.9 (SD) years]	Total daily dose administered to the patients in the treatment group was 66 mg/kg of body weight	GSH can improve clinical parameters in CF patients, and that effective treatment should include the correction of GSH deficiency.	A: Randomized placebo-controlled trial
(9)	Idiopathic pulmonary fibrosis (IPF)	10 patients with IPF [mean age, 46 ± 3 (SD) years] and 19 normal nonsmokers [mean age, 36 ± 3 (SD) years]	600 mg twice daily for 3 days	Inhaled GSH might be beneficial among IPF patients by reversing the oxidant-antioxidant imbalance.	B: Nonrandomized controlled trial
(19)	Human immunodeficiency virus (HIV) seropositive individuals	14 HIV seropositive individuals [mean age, 32 ± 2 (SD) years]	600 mg twice daily for 3 days	It is a reasonable therapeutic strategy to augment the deficient GSH levels of the lower respiratory tracts of HIV seropositive individuals.	B: Cohort 'outcomes' research
(20)	Chronic rhinitis	13 patients with chronic rhinitis and 13 healthy subjects (4-15 years of age for all subjects; mean age, 8.2 years)	600 mg daily for 14 days	Statistically significant improvement in nasal obstruction, rhinorrhea and ear fullness.	B: Nonrandomized controlled trial
(10)	CF	Seven CF patients [mean age, 25 ± 1 (SD) years]	600 mg of GSH for 3 days	Inhalation therapy with GSH does normalize the respiratory epithelial surface oxidant-antioxidant balance in CF patients.	B: Cohort 'outcomes' research
(25)	CF	21 patients with CF (16-37 years of age for all subjects)	300 or 450 mg three times daily for 14 days	Inhaled GSH can permeate the lower airways of the lungs and improve important parameters of lung function in CF patients despite not having any effect upon markers of oxidative injury.	B: Cohort 'outcomes' research
(26)	CF	17 patients with CF (18-29 years of age for all subjects; mean age, 24 years)	450 mg three times daily for 14 days	Inhaled GSH did not affect the oxidative status of the patients who were tested, but it did favorably modulate their immune responses.	B: Cohort 'outcomes' research
(22)	Emphysema	One (95 year-old male)	120 mg of GSH in office, then 120 mg twice daily for 3 days, and continuation of treatment (dose unknown) for 2 years	When the patient returned for a follow-up visit, he no longer required the use of his wheelchair and oxygen. The striking results were unexpected and unlikely to be due to placebo alone.	C: Case report

Summary of Articles Demonstrating The Effectiveness Of Inhaled Glutathione for The Treatment of Pulmonary Diseases And Respiratory-Related Conditions
Reference	Condition	N	Dosages of inhaled GSH	Outcome	Evidence grade
(21)	Asthma	Eight asthma patients [mean age, 29 ± 7 (standard deviation; SD) years]	600 mg once weekly for 3 months	A subset of patients with clinically stable mild asthma experienced a bronchoconstrictor effect when treated with inhaled GSH.	A: Randomized placebo-controlled trial
(23)	Chronic otitis media with effusion (chronic OME)	30 patients (3-12 years of age; mean age, 5.8 years) and 30 controls (3-12 years of age; mean age, 6.1 years)	600mg of GSH in 4 ml of saline subdivided into five 2-min sessions by nasal aerosol every 3-4 waking h for 2 weeks	GSH should be considered for the nonsurgical management of chronic OME.	A: Randomized placebo-controlled trial
(24)	Cystic fibrosis (CF)	Nine patients [mean age, 16.1 ± 1.44 (SD) years] received the S-nitrosoglutathione (GSNO) and 11 patients [mean age, 19.9 ± 3.45 (SD) years] received the phosphate- buffered saline (PBS) solution	0.05 ml/kg of 10 mM GSNO	The treatment group showed a modest improvement in oxygenation that was thought to be independent of the physiological effects of nitric oxide.	A: Randomized placebo-controlled trial
(27)	CF	19 patients (6-19 years of age) were randomized to treatment [mean age, 13.3 ± 4.1 (SD) years] or placebo groups [mean age, 12.9 ± 4.9 (SD) years]	Total daily dose administered to the patients in the treatment group was 66 mg/kg of body weight	GSH can improve clinical parameters in CF patients, and that effective treatment should include the correction of GSH deficiency.	A: Randomized placebo-controlled trial
(9)	Idiopathic pulmonary fibrosis (IPF)	10 patients with IPF [mean age, 46 ± 3 (SD) years] and 19 normal nonsmokers [mean age, 36 ± 3 (SD) years]	600 mg twice daily for 3 days	Inhaled GSH might be beneficial among IPF patients by reversing the oxidant-antioxidant imbalance.	B: Nonrandomized controlled trial
(19)	Human immunodeficiency virus (HIV) seropositive individuals	14 HIV seropositive individuals [mean age, 32 ± 2 (SD) years]	600 mg twice daily for 3 days	It is a reasonable therapeutic strategy to augment the deficient GSH levels of the lower respiratory tracts of HIV seropositive individuals.	B: Cohort 'outcomes' research
(20)	Chronic rhinitis	13 patients with chronic rhinitis and 13 healthy subjects (4-15 years of age for all subjects; mean age, 8.2 years)	600 mg daily for 14 days	Statistically significant improvement in nasal obstruction, rhinorrhea and ear fullness.	B: Nonrandomized controlled trial
(10)	CF	Seven CF patients [mean age, 25 ± 1 (SD) years]	600 mg of GSH for 3 days	Inhalation therapy with GSH does normalize the respiratory epithelial surface oxidant-antioxidant balance in CF patients.	B: Cohort 'outcomes' research
(25)	CF	21 patients with CF (16-37 years of age for all subjects)	300 or 450 mg three times daily for 14 days	Inhaled GSH can permeate the lower airways of the lungs and improve important parameters of lung function in CF patients despite not having any effect upon markers of oxidative injury.	B: Cohort 'outcomes' research
(26)	CF	17 patients with CF (18-29 years of age for all subjects; mean age, 24 years)	450 mg three times daily for 14 days	Inhaled GSH did not affect the oxidative status of the patients who were tested, but it did favorably modulate their immune responses.	B: Cohort 'outcomes' research
(22)	Emphysema	One (95 year-old male)	120 mg of GSH in office, then 120 mg twice daily for 3 days, and continuation of treatment (dose unknown) for 2 years	When the patient returned for a follow-up visit, he no longer required the use of his wheelchair and oxygen. The striking results were unexpected and unlikely to be due to placebo alone.	C: Case report

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