"Preliminary Results of the Use of Inhaled Reduced Free Acid Glutathione by Twenty-Four Individuals with Cystic Fibrosis"

[The UVICF is grateful to all GSH users who so generously shared their "data" with us. We are thankful for the collective efforts of all members of the wlgroup, which has brought research on this topic forward in such an organized and timely fashion. This report is dedicated to the memory of Richard Andrew Young, one of the bravest and brightest who walked among us.]

***MUST READ BEFORE CONTINUING!***
DISCLAIMER AND NOTE:  1) The UVICF does not condone making changes to the treatment of any CF patients without the permission and supervision of that patient's medical professional!  Please consult your doctor before making any such changes.  2) It is to be explicitly noted that the following study was not a clinical trial by any stretch of the imagination.  Hudson and Allen merely asked CF persons who were using inhaled free acid GSH to report on their experiences so that patterns, if any, could be discerned.  3)  Now that buffered GSH suitable for inhalation is available, this study of the use of unbuffered free acid GSH is now no longer the ultimate word on the expected effects of this treatment.  Anecdotally, users of the new GSH Plus produced by Theranaturals, Inc. (theranat@fiber.net) experience none of the adverse side effects noted in this study, while continuing to experience all of the positive side effects.  This should be kept in mind by all who read this report.

INTRODUCTION

There are several means through which augmentation of GSH may be accomplished. One means involves inhalation of aerosolized GSH. The remainder of the essay will concentrate on that mode of augmentation. (For information on alternative means of augmentation, we refer you to the paper mentioned in the last paragraph.) Since 1989, it has been known that direct inhalation of reduced glutathione allows for GSH deficiency in the epithelial lining fluid (ELF) of the lung to be brought up to more normal levels for a period of time. By participation in the body's glutathione redox cycle, ELF GSH levels above the deficient baseline may be maintained for 3-4 hours, with duration of elevation dependent on dosage. At least six in vivo studies in humans of this treatment exist, though none involving CF patients was ever attempted, and this therapy never entered the treatment regimen of CF patients. (The above-mentioned paper contains full citation information for each of these six trials.)

It is important to note here that normalization of GSH levels in the ELF of CF patients is not a cure for CF, nor is it a panacea for all CF-related ills. It does represent, as we feel the data presented in this paper will show, a therapy with possible ameliorative effects of great significance and surprisingly wide range that deserves serious and timely investigation by medical professionals. The purpose of this essay is not to advocate the therapy per se, but to advocate that medical professionals begin such investigation as soon as possible. Having had the information in the first essay brought to their attention, a number of individuals with CF or parents of children with CF desired to attempt this therapy of their own free will and accord, many with the blessing of their doctors. Fortunately, since the use patent on inhaled reduced glutathione expired in the U.S. in 1997 and has not of the date of this writing been renewed, these individuals were legally free to do so. Furthermore, reduced glutathione is considered a nutritional supplement in the U.S., and thus individuals could freely purchase the substance on their own. Especially pure reduced glutathione is needed (minimum 98% pure pharmaceutical grade) for inhalation, and once a reliable supplier of such a pure grade was found (which supplier sells reduced glutathione as a nutritional supplement only), individuals already possessing a compressor and nebulizer could easily proceed with their plans. The supplier for most of the individuals in the sample was Theranaturals, Inc. ( theranat@fiber.net ). It should be noted that the UVICF, in disseminating information about the prospects of this therapy, has always emphasized that individuals should bring this information to the attention of their doctors and then discuss with their doctors whether the therapy would be appropriate for them to use or not. The UVICF does not endorse people making changes to their medical regime without consultation with their doctor. Nevertheless, since the UVICF is not an enforcement agency, it has no power to control the actions of individuals. An email discussion group unaffiliated with the UVICF was set up for CF users of inhaled glutathione to share their experiences. The UVICF has been observing the discussion on this group list, and it is from that observation that the data used in this analysis was collected.

The UVICF has been tracking the progress of almost all of the individuals using inhaled GSH who converse on the email list, collecting baseline health information, as well as data on adverse reactions to inhalation and health benefits derived from the therapy. As of this writing, the UVICF has 31 active files and 2 inactive files. Knowing that the CF medical community would be interested in the preliminary results that follow from this data collection effort, the UVICF has compiled and analyzed the data on 24 individuals who have used inhaled GSH for a minimum of 2 weeks as of 13 January 1999. Median length of use for this sample is 38 days, and some individuals have used the therapy for approximately 4 months as of this writing.

Of course, we cannot over-emphasize the tentative and preliminary nature of these results. Since these individually-conducted "trials" were not orchestrated by anyone or any group, nor conducted in a clinical setting, there was no possibility of creating a control group to inhale a placebo for comparative purposes. Thus, a placebo effect may well be at work, even for infants and young children whose parents are reporting their data. Second, many individuals were unable to assess either pre- or post- clinical indicators (or both) that would have been of substantial importance in making the empirical case, such as peak flow, PFT scores, oxygen saturation, and so forth. In cases where such information was available, it will be presented. All of these scientific desiderata must await a clinical trial. As of this writing, two full-scale clinical trials are currently in the planning stage, and several clinic-based "mini-trials" are also being contemplated. Nevertheless, in the effort to encourage other CF medical professionals to seriously consider the merits of this therapy and to be open to a discussion of these merits with their individual patients, we present such results as we have.

This report is divided into four parts:

1. Protocol Information Overview
2. General Characteristics of the User Sample
3. Adverse Reactions to Inhalation
4. Health Effects Experienced

I. Protocol Information Overview

Age and health status appear to be the major factors to the email group in working out an appropriate dosage. Since the GSH deficiency in the ELF of young children is not as severe as older persons, children generally are started out at a relatively small dose. This dose increases with age, until one reaches young adulthood (some on the list suggest approximately age 15 as a cut-off point). After that time, the toll already taken on the lungs of the average CF person is severe enough that the dosage must be reduced substantially for all but the hardiest individuals. Thus, on the email list, a roughly bell-shaped curve for dosage by age appears to be in use. The younger you are, the smaller the dose; the older you are past young adulthood, the smaller the dose. Thus, the individuals inhaling the largest dosages tend to be in the 11-14 age category. However, there were one or two adults who did seem able to tolerate a fairly high dose of GSH (up to 500 mg). (These adults were quite atypical overall, and we note parenthetically that after this data collection effort ended, many of them substantially reduced their dose to below the dosage typical of the 11-14 age group.)

The following table demonstrates the range of doses for each age group.
 

According to the discussion on the email list, the chosen dose of GSH is given anywhere between one and four times during the waking hours. General preference tended to be for a minimum of three treatments a day (41.7% of the user sample), based on the evidence from the in vivo studies that the inhaled GSH participates in the redox cycle for approximately 3-4 hours, dependent on dose. We would like to point out that there may be an inconsistency in reasoning on dosage/number of treatments as far as the adults are concerned. If their doses tend to be relatively small compared to the other age groups, but their GSH deficit very large compared to the other age groups, then the length of time the adults' GSH level in the ELF will be elevated may in fact be much shorter than 3-4 hours. This is an issue that clinicians should address in future empirical investigations.

The users conversing on the email list describe that their dose of GSH is mixed with physiologic saline before nebulization. The amount of saline is adjusted according to user comfort and toleration, and we have found that the range of dilution used extends anywhere from 2 ccs to 10 ccs of saline per dose. We present more information on dilution in a moment. Persons with reactive airways knew from a previous in vivo trial that they might experience bronchoconstriction during inhalation. The use of a fast-acting bronchodilator was suggested by that in vivo study to preclude such an effect. Among the user group, of those reporting whether they used a bronchodilator or not (N=16), 50% did not use a bronchodilator and 50% did use a bronchodilator specifically with their GSH treatment. Those using a bronchodilator ranged in their manner of use from pre-inhalation to inhalation (i.e., the bronchodilator was mixed in with the GSH solution) to both pre- and post-inhalation.

THE EVOLVING PROTOCOL FOR ADULTS

The CF adults in the user group tried numerous modifications to the protocol to insure tolerability, and the following summarizes their recommendations at the time of this writing. 1). Start with a very small dose, such as 80 mg of GSH per dose or even less. 2). Adjust dilution upwards to increase tolerability. One adult found his toleration increased if he used a .45% saline solution in conjunction with a normal .9% physiologic saline solution. The fact that this individual was able to increase his toleration by this strategy suggests that the issue of maintaining isotonicity may be one of the keys to the problem of tolerability. We urge clinicians to determine how to render a particular dosage of GSH into an isotonic solution, so that it may be determined whether tonicity is a crucial element of tolerability or not. 3). Use of a fast-acting bronchodilator by all CF adults using this therapy is highly recommended by the group of users. 4). Gradually increase the dose of GSH you are using, adjusting dilution as necessary, until intolerability begins to occur. 5). Realize that you may never be able to reach the recommended dose of the original in vivo studies of 600 mg of GSH per dose for adults. Nevertheless, many of the health benefits of GSH may still be realized at your personal tolerable dose even though that dose may be lower. (Note that at least one adult in the sample has in fact been able to use the 600 mg per dose of GSH.) 6). If there is no tolerable level of GSH inhalation for your body, do not continue to use it. (This situation had not occurred in the sample survey by 13 January 1999. But two adults, neither of whom were in the sample because they had started inhaled GSH too late for our study, did cease their use after that time.)

The adult users wondered if oral ingestion of GSH might provide an alternative route to elevating GSH levels in the ELF. GSH may be imported directly into the lung from the bloodstream via the large capillary system of the lung. However, this question must await clinical investigation.

Overall, we anticipate that the clinical trials on the use of inhaled GSH in CF patients will produce a much more accurate, sophisticated, and authoritative dosing protocol than that developed by the small group of users. We look forward to the day when that information becomes available.
 
 

II. General Characteristics of the User Sample

AGE AND GENDER

It is interesting to note that almost all of the adult users are male. Given the new and relatively untried nature of this therapy, only risk-tolerant or risk-acceptant adults would be attracted to its use. The social science literature indicates that risk orientation is highly correlated with gender, with males being much more risk-acceptant than females. Thus, the skewed sex ratio of the adult users at this time comes as no surprise.

GENOTYPE

CLINICAL INDICATORS

• peak flow
• full PFT scores
• FEV1% only
• oxygen saturation
• breaths per minute resting
• cough frequency
• sputum quantity/color/consistency
• medications usually used

Of the 13 users reporting baseline peak flow measurements, the range of scores was 150 to 460. Of the 14 users reporting baseline FEV1%, the range of scores was 21% to 107%.

Of the 17 users reporting their cough frequency, 12.5% have no cough or a rare cough; 20.8% have an occasional cough, and 29.2% have a persistent cough at baseline.

Of the 19 users reporting their sputum quantity, 20.8% report virtually no sputum production; 50% report a comparatively small amount; and 8.3% report the production of copious amounts of sputum. Virtually all patients reporting consistency of sputum (if they produced sputum) reported their sputum as thick. Of the 12 patients reporting the normal color of their sputum (if they in fact produced sputum), 25% reported clear or white sputum; 25% reported yellow sputum; 25% reported light green sputum; and 25% reported dark green sputum.

A veritable potpourri of medications are being consistently used by the patients in this sample. Average number of medications used per individual was four. Given the large number of possible medications and combinations thereof in use by the users, no overall tabulation will be presented. In light of the effects noted in Section IV, it should be noted that of the total sample of users, 37.5% used mucolytic agents before they started inhalation of GSH.

BACTERIA CULTURED

MISCELLANEOUS PERTINENT HEALTH INFORMATION

In addition, a few users mentioned other miscellaneous but potentially pertinent health facts. One user regularly required several liters of O2, another required O2 only at night. Another user is pancreatic sufficient. One user is also diabetic. Two users were reported as being tube-fed.

TWO INDICES OF OVERALL BASELINE HEALTH CONDITION OF THE USERS

The first is the AS score, standing for Age-Severity score. It inquires as to the relative age of the patient, plus whether the individual manifests none-mild or moderate-severe pulmonary symptoms. The AS score has three levels:

1. Relatively asymptomatic infants and children.
2. Symptomatic children.
3. Symptomatic adults.

Knowing that a three value index may not be nuanced enough to investigate variation in reactions and health effects, we also constructed a five value index which incorporates not only age and pulmonary symptom severity, but also the degree to which the individual's normal activities have been curtailed by their symptoms. Some individuals with, say, FEV1% in the 30s-50s are nevertheless very active and able to carry on a relatively normal schedule of work and play. Other individuals with the same scores may only be able to work a few hours a day or may need supplemental O2. To capture this variance, the ASA score was developed (Age-Severity-Activity). The five values of the ASA scale are:

1. Relatively asymptomatic infants and children with no curtailment of activity.
2. Symptomatic children with no curtailment of activity.
3. Symptomatic children with mild-moderate curtailment of activity.
4. Symptomatic adults with mild-moderate curtailment of activity.
5. Symptomatic adults with significant, lifestyle-altering curtailment of activity.

We will now proceed to an examination of reactions to inhalation of GSH among the user sample.
 
 

III. Analysis of Reactions to Inhalation of GSH

Before such detailed analysis, a few parameters of GSH use in the sample should be noted.

DURATION OF GSH USE IN SAMPLE

REACTIONS

Other reactions included a sinus headache, feeling of "dryness," post-nasal drip, shaky limbs, and the feeling of a "lump" in the chest or throat. These other reactions were each experienced by one or two individuals.

GENERAL OVERVIEW OF SEVERITY OF REACTION IN THE SAMPLE

1. No reaction
2. Mild reaction
3. Moderate Reaction
4. Severe Reaction

SUBSIDING OF REACTIONS

By adding together the percentage of the sample reporting no reactions, plus the percentage of the sample in whom reactions subsided either naturally or through adjustment of protocol, we determined that 70.8% of the total user sample now, generally speaking, experiences no significant reaction to inhaled GSH. That leaves 29.2% of the sample who still experience at least some reaction to inhaled GSH that has not subsided either naturally or by protocol adjustment.

WHO EXPERIENCED SIGNIFICANT ADVERSE REACTIONS?

We performed several cross-tabulations of the reaction severity scale with possible causal characteristics, using standard exploratory and confirmatory measures of association such as Pearson's chi-square, Kendall's tau-b, and gamma. The following characteristics were examined:

• age category
• AS score
• ASA score
• genotype (only where available)
• baseline FEV1% score (only where available)
• baseline peak flow (only where available)
• number of bacteria cultured
• culturing PA and/or B. cepacia
• number of medications consistently using
• reactive airways/asthma present
• frequency of cough
• darkness of sputum
• quantity of sputum produced

We found that four variables produced statistically significant results in each of three measures of association when crossed with reaction severity. They included: age category, AS score, ASA score, and culturing PA and/or B. cepacia. The remaining variables did not produce statistically significant results when similarly crossed with reaction severity. (One or two might have shown up as significant on one or two measures of association, but since the N size is so small, and the data "soft" in most respects, we chose a higher standard of significance. Significance had to be demonstrated for three chosen measures of association: Pearson's chi- square, Kendall's tau-b, and Gamma.). The cutoff point for significance was rho less than or equal to .10. Table 11 displays the measures of association and their significance for each significant variable.
 

We can see from the above results that reaction severity is significantly correlated with measures that are broad indicators of the degree to which the disease has progressed in a given individual. Generally speaking, the older and the more involved the pulmonary system of an individual, the more likely that they will experience an adverse reaction to inhalation of GSH. There are, of course exceptions to this general rule. Some adults have experienced little in the way of adverse reactions, and some children just shy of puberty have experienced significant reaction. Notice that the more nuanced the picture of the individual's health status, visible by examining the chi-square results for age category, then AS score, then ASA score, demonstrate that there is plenty of room for individual variance on these matters. Nevertheless, we will repeat that generally speaking, the older and the more involved the pulmonary system of an individual, the more likely it is that they will experience an adverse reaction to the inhalation of GSH. Indeed, effects not harmful in less ill individuals might become harmful in this sensitive group. For example, coughing during inhalation, if severe enough, could possibly lead to an effect such as pneumothorax. Medical professionals would have to carefully and diligently monitor the progress of such individuals if they were to use this treatment.

Indeed, we urge that end stage CF pateints not try inhalation of GSH at all, and use another means, such as oral ingestion, to promote GSH augmentation. One end stage patient who was not in the sample because he was not initially in contact with the email group, used inhaled GSH for 9 days, and began to develop a dry, nonproductive cough indicative of lung irritation. Even though cough intensity was not severe, the man developed a pneumothorax which was identified when he was admitted to the hospital one day after ceasing the GSH inhalation. In the hospital, medical professionals were able to control the pneumothorax, but a second one developed. Undergoing more medical procedures, the man's cepacia began to overwhelm his system and he died. Though it is highly unlikely the short period of GSH inhalation caused the pneumothorrax, the development of the dry, non-productive cough was not a positive development in his case, and thus GSH inhalation cannot be ruled out as a contributing factor. We urge CF clinicians to never allow end stage CF patients to use inhaled GSH until it has been more thoroughly investigated in clinical trials.

DISCUSSION: CAN TOLERABILITY BE INCREASED?

-- pH discrepancy of inhalant
-- tonicity discrepancy of inhalant
-- production of sulfites by the GSH solution

The addition of solids to physiologic saline increases its osmolarity, producing a hypertonic solution. The inhalation of a hypertonic solution may be irritating to the lungs of especially sensitive persons. One adult user found his reactions subsiding when he began using .45% saline. Several others have found alleviation of their reactions through increased dilution of the dose they were taking. Again, could this be the cause of the adverse reactions, and what could be done about the situation if that was the case? Members of the email group worked out an osmolarity table to assure isotonicity of the inhalant. We urge clinicians to do the same.

When GSH is placed in an aqueous solution, various sulfites may be produced, which account for the "rotten eggs" smell of the solution that some users have noted. Sulfites may cause bronchoconstriction in sensitive individuals. Once more, could this be the cause of the adverse reactions, and what could be done about the situation if that was the case?

We request that the medical community interested in the potential of this therapy for use in CF address these three possible causes of reaction, as well as any others that may be at work. If these reactions can be alleviated or prevented, a broader range of patients may be able to use this therapy -- and use it at more optimal doses -- than if not.

IV. Health Effects Experienced

EFFECTS

There were also a number of individuals who failed to respond to the question of whether they experienced a certain effect. Respondents were asked to answer either "yes", "no", "don't know", or "not applicable" with regard to whether they experienced a given effect. As with all such endeavors, some individuals did not answer with any response at all. Since it is impossible to tell whether their response would have been positive or negative, we have excluded missing data as well. When for a given effect the N size of the valid case pool drops below 15, we feel that calculation of percentages loses its meaning. So, we will display two different tables. Table 12 will display effects where the valid case pool at least 15, and percentages will be calculated. Table 13 will display effects where the valid case pool was less than 15. In Table 13, no percentages will be calculated, but the number of individuals in the sample reporting that effect will be noted.
 

Let us take the results displayed in Table 12 first. Notice that the most common effects presumably produced by inhalation of GSH (greater than or equal to 60% of the valid cases) were breathing easier/deeper, thinner mucus, clearing mucus easier, cough frequency diminished, increased energy, sinuses clearing, and a greater subjective feeling of wellness. Other effects occurring in a least a third of valid cases included increased stamina, significant weight gain, sleeps more soundly, and increased appetite. The first set of effects appears to be related to the action of GSH as a powerful mucolytic capable of cleaving disulfide bonds in sputum. The second set of effects appears to be related to the action of GSH in lowering the over-inflammation response of the CF body.

Before proceeding to a full discussion of Table 13, please note that for one of the variables, PFT increase, the number of "don't know" responses was very high. Since the median length of use of inhaled GSH at the time of this writing was 38 days for the sample, most individuals had not had the chance to return to their clinic to assess their PFT scores by the day the data collection effort was closed. Since that time, an additional 2 individuals beyond the two reported above have reported somewhat elevated PFT scores since use of inhaled GSH.

Turning to Table 13, we note that there were some other remarkable, though less common effects noted by the users and presumably due to the inhalation of GSH on their part. Effects worth notation by the medical community include: less enzymes needed, stools more normal, significant weight gain, more saliva, better color in cheeks/nail beds/gums, a disappearance of pains in the chest, air sounds in regions that had not had air sounds in a long while, diminishing of crackles, fewer and milder cold, lessened need for mucolytics, and gobs/chunk of old mucus being brought up. A few tentative observations are warranted at this point.

First, inhalation of GSH apparently affects more than simply the pulmonary system of a CF person. In some cases, a broader systemic effect appears to be at work, resulting in the amelioration of GI symptoms commonly experienced by CF persons. Those needing less enzymes report needing from ´ to 3/4 less enzymes than they had traditionally needed. Weight gain in infants and children without significant lung involvement was almost uniformly noted (80% of AS score 1 individuals report this phenomenon) and relatively dramatic in the first 7-10 days, with gain ranging from 1-3 pounds over that short period of time. Adults reporting weight gain did not experience that same type of short term burst, and only found themselves gaining weight more gradually over time. Other assorted GI benefits were reported, from increased appetite to more normal stools, to more saliva. It appears that the inhaled GSH is either lessening the inflamed state of a CF person's GI tract leading to better absorption of food, or the inhaled GSH is allowing (perhaps through its powerful mucolytic properties) greater excretion of enzymes from the pancreas and/or bile from the liver. It may be that both phenomena are in fact occurring. This is certainly an exciting area for further research by medical professionals. (As a tangential note, these observations may argue also for an investigation of the health effects to be derived by CF persons from the ingestion of GSH as versus only the inhalation of it. GSH is not broken down in the jejunum and duodenum, but is rather transported from that region directly into the bloodstream.)

Second something more profound than mere mucolysis is apparently going on as an effect of inhaled GSH. Better color in cheeks/nail beds/gums is a sign of better oxygenation. More than that, some have observed chest pains of long duration disappearing with GSH use, and others report a diminishment of crackles and even the presence of air sounds where no such sounds could be detected before. Several report they experience fewer or milder colds than they once did. A few have even reported the clearing of obviously old, dark, hardened chunks or gobs of mucus. One person, reporting after this data collection effort ended, reported a lessened need for use of bronchodilators (indicating the NO system in his body might be undergoing rectification). Something significant appears to be occurring in the lungs of these users, and we hope that serious investigation by medical professionals will determine whether GSH is, in fact, causing such effects, and if so, reveal the precise mechanisms involved.

OVERVIEW OF DIRECTION AND INTENSITY OF EFFECTS

1 = significant negative effects
2 = mild-moderate negative effects
3 = no effects one way or the other
4 = mild-moderate positive effects
5 = significant positive effects

We see several things from the above tables. Let us examine Table 14 first. The first observation to be made is that no user stated they had seen harmful health effects from the use of GSH (this in contrast to reactions to inhalation itself, covered in Section III). Two users did indicate they saw neither benefit nor harm to themselves from the use of this treatment, representing 8.3% of the sample. Intensity of effects was evenly split between those seeing mild-moderate improvement and those professing significant improvement in their health.

Turning to Table 15 and 16, we see that asymptomatic children dominated the category of mild-moderate improvement (perhaps as a result of coding inadequacy, as explained above). The category of significant improvement was dominated by symptomatic children, with the worst-affected children (in terms of curtailment of activity) reporting the most consistently and intensely positive results. However, it is also noteworthy that all three of the adults whose health and activity were described as very seriously affected by CF saw significant improvement by use of inhaled GSH.

Another interesting comparison of data is that displaying Effect Score cross-tabulated by Reaction Severity score. Are those who experienced the worst reactions to inhalation denied positive health effects? Table 17 provides the results.
 

From the above Table 17, we see that even persons who experienced adverse reactions to the inhalation of GSH saw themselves at the same time experiencing positive health effects. The cross-tabulation produced no statistically significant associations and we conclude that reaction severity and direction/intensity of health effects experienced are unrelated.

MISCELLANEOUS STATISTICAL INVESTIGATION OF EFFECTS

These are interesting results, worthy of further investigation. It does appear that, generally speaking, the worse off in overall health an individual is, the greater the positive health effects noticed. Now this may be a statistical artifact, due to the lack of ability to code the improvement of relatively asymptomatic infants and children. It may simply be the that the positive effects are more noticeable when the background health context is poorer. Sputum quantity may also be tapping into this phenomenon, as well. We hope the medical community will address this issue in greater detail in formal clinical trials.

ADDITIONAL DISCUSSION

REPORT SUMMARY

1) Buhl's (et al.) original protocol is inappropriate for CF users of inhaled GSH, and substantial modifications became necessary for the users to make.

2) The majority of the sample experienced none-mild reactions to the inhalation itself (75%). Of the remaining 25% who experienced moderate-severe reactions, the majority (66.6%) found their reactions to subside fully or partially over time or with adjustment of the protocol (dosing, dilution, bronchodilator use). Users most at risk for significant reaction were older and/or had significant pulmonary involvement. Medical professionals would have to be especially cautious about the use of inhaled GSH in such persons. Another mode of GSH augmentation should be contemplated for these individuals. No end stage CF patient should use inhaled GSH until clinical trials have been conducted.

3) The health effects of inhaled GSH use in this user sample appeared to be positive, with 45.8% reporting mild-moderate positive effects, and 45.8% reporting significant and sometimes dramatic positive effects. Thus, 91.6% of the sample reported experiencing at least some positive health effects from the use of inhaled GSH.

4) A few remarkable and unexpected positive effects occurred in several user cases, including significant amelioration of GI symptoms and seemingly significant alteration of pulmonary status. Both of these provocative syndromes bear further investigation by skilled clinicians.

DIRECTIONS FOR FUTURE RESEARCH

a) What is the optimum dose and dosing regimen for the use of inhaled GSH by CF patients? Only the investigation of degree and duration of elevated ELF GSH levels following inhalation can answer this question, and this demands clinical investigation.

b) Can adverse reactions to inhalation of GSH be minimized or prevented entirely? Could discrepancy in pH and/or tonicity of the inhalant be at fault? Could the production of sulfites when GSH is dissolved in water be part of the problem? Are there other factors at work? What are the precise mechanisms by which reactions are felt during inhalation of GSH? Might another form of administration be more appropriate, such as inhalation of a liposomal form of GSH or IV or oral administration of GSH? Again, the answers to these questions must await clinical investigation.

c) The positive health effects of inhaled GSH use in CF persons must be scientifically documented through careful clinical trials which include a control group. Furthermore, subjective indicators used here must be buttressed by objective indicators such as PFT or other lung function scores, testing of GSH levels in the ELF, the ESR/SED test and other tests to determine if inflammatory burden is decreasing as a result of GSH use, measurement of exhaled NO to ascertain whether inhaled GSH rectifies the NO system of CF individuals, measurement of T-cell activity and effectiveness of other parts of the immune response system before and after GSH use, and so forth. This type of rigorous scientific clinical investigation is essential in determining the efficacy of this treatment.

d) What are the precise mechanisms by which GSH, if it is in fact producing any of these beneficial health effects, is doing so? We must leave these questions to the theorists among our research and medical community.

e) If adoption of this therapy is one day warranted through careful clinical investigation, what aspects of a CF person's medical regime will change? Will the need for other anti-inflammatory agents, such as steroids and high dose ibuprofen, be obviated? Will the need for other mucolytic agents, such as NAC/Mucomyst and DNase/Pulmozyme, lessen? Will colonization of CF lungs with bacteria and fungi be less common in CF patients using inhaled GSH as a maintenance agent prior to culture of these organisms? (Of course, use of antibiotics when such organisms have been cultured will still be essential even with inhalation of GSH.) Will inhaled GSH cause a change in the GI medical maintenance regime of CF patients? Will we see as many cases of diabetes and/or liver failure if inhaled GSH is used as part of a maintenance regime early on in life? Indeed, when is the optimal point of introduction for supplemental GSH? Will women pregnant with CF fetuses be asked to take GSH in some form to alleviate damage that may occur in utero, such as meconium ileus/peritonitis and fibrosization of the vas deferens? Will GSH in some form be one of the very first treatments recommended upon diagnosis of CF? Only if rigorous clinical investigation bears out the potential of this treatment will medical professionals begin to ask and to answer some of these provocative questions.

Our final statement and only statement of advocacy in the entire report is this: Let clinical trials begin, and the sooner the better!