IV glutathione

[Guest guest]

if anyone is interested in our personal story with IV glutathione

therapy please feel free to mail me .. pls put " IV glut questions " in

the subject line.. I just want to do my part to make info more easily

available on an archive search.. we had a hard time finding any..

just wanting to share info.. certainly NOT trying to be

controversial..

PS in case spelling is a prob on a search! here are some keywords!..

glut glutithione Kane IVG IV intravenous push

[Guest guest]

Andy,

There certainly may be indications for IV glutathione in developmentally

impaired children. I've talked to numerous parents for whom this

treatment proved to be a key to significant gains, not only in neurological

issues, but also in general health.

It would be valuable to collect stories from parents who feel this has been

a key effective therapy for their children, and that would allow the other

side of the story to get an airing here, allowing parents to draw their own

conclusions. I'm just worried that those who had positive experiences may

feel reluctant to speak up after what you've said, Andy. For that reason,

I'd be glad to gather such comments offlist, and repost them incognito, if

that would be helpful to other parents.

But while we are on the subject, Andy, you addressed the issue of blood

concentrations after glutathione infusions the other day, and said:

=========================

You go inject a gram of glutathione (I believe this is typical).

Kid started at 300. Kid now has 1,300. Unless the kid is over about

80#, he just went from LOW total thiols and LOW individual thiols to

HIGH total thiols.

If it is a little kid, they might be blasted up to 2 or 3 times the

upper normal limit in terms of total thiol equivalent. It is not my

impression doctors adjust the glutathione dose based on body weight.

===========================

I am going to see if I can find out what sort of doses are typical and how

they are calculated

Glutathione is not going to be elminated via the sort of kinetics that you

would see when talking about a foreign substance to the body, because it is

a very normal thing for glutathione to be rapidly processed by the body,

and especially by the kidneys. The body knows exactly what to do with it

without making any special arrangements. Since glutathione doesn't have to

be detoxified, and since it needs to be utilized rather than disposed, it

would not be constrained by the same rules as would effect the levels of a

drug in the blood, ie. something that would be processed by sulfation or

acetylation or whatever to be eliminated.

The blood also isn't a closed system. Papers I have read that did the

necessary science showed that the blood cannot reach homeostasis on

something like glutathione because of the speed at which glutathione and

other thiols are broken down and/or transported out of the blood into

cells. The ectoenzyme, GGT, acting mainly in the kidney and pancreas, and

sulfur transporters of various sorts can work at a very rapid rate.

The blood's compartment, in this situation, doesn't work like an innertube

which will get too much pressure with too much air, but it is more like

that same innertube with holes all over it where that GSH can " escape "

about as fast as you can put it in. If there is too much of the sulfur

from glutathione getting into the cells, the body at that point has a very

good system to get rid of the excess, but it will first convert that

glutathione into something else besides glutathione. For that reason it

just doesn't make sense to watch the glutathione levels solo, and it also

doesn't make sense to watch only thiols. The disposal pathway of excess

sulfur is sulfate or taurine, not plasma cysteine.

I use the generic term, " sulfur " because there are many types of

transporters that would transport glutathione's sulfur back into the blood

in the various forms that the sulfur in glutathione would take after it was

processed by cells. I'm talking about a rapid covnversion into things like

cysteine, proteins, molecules with metal/sulfur centers, misc. thiols, or

taurine, or sulfate, etc. Some of it would stay in the cell in which it

was imported, and some of it would leave, but the whole body is a quite

capable " sulfur sink " , especially if sulfur has been lacking.

In order to help think about the capacity issues, I offer the first study

below which gave IV glutathione to some adults at a continuous rate

amounting to 10 mg/kg/hour, so it would be about 680 mg/hr for a grownup of

about 150 pounds, or about a third of that for a fifty pound child. At

that rate, the study said that the cysteine flux was essentially equivalent

to the rate of infusion, and the glutathione they infused accounted for all

of the measured increase in cysteine turnover. They didn't exceed that

rate of infusion, but it sounds like they might have been able to keep it

up at that rate for a long, long time without creating a problem. I

haven't gotten this study yet, but after I do, I will see what they say

about this issue and if they have charts that show the changes in blood

levels of glutathione and its components.

So the real question is not how much sulfur would be in the blood after

this treatment, as the blood would be very quickly losing this sulfur in

glutathione since it is only a very temporary transport system,

representing a small part of the where that glutathione is going

immediately...The plasma represents just 3.38 liters in someone 150

pounds. If you assumed that this sulfur might only be distributed to the

body's water compartments (which is actually not the whole case), then it

would be distributed to 60% of the body's weight for a man, or 50% for a

woman. In both cases, 20% of that is extracellular, so 40% or 30% is

intracellular, respectively.

Dr. Stipanuk wrote a very useful article where they installed canulas at

either side of major organs in the body of rats so that her lab could

actually measure the blood in front of various organs to see what sulfur

forms it contained going in, and then compared that to what came out of

circulation on the other side of the organ, and then computed the

difference in those two compartments to calculate what each organ did with

the sulfur that came in, and how it was repackaged. What she found is that

a very tiny amount of GSH was taken out of circulation by the GI tract, but

the most significant amount of glutathione disappeared at the kidney, and

what replaced it on the other side of the kidney's circulation was

cysteine. Implicated here is the enzyme on the cell surface of renal cells

called gamma glutamyl transpeptidase which breaks GSH apart.

But at what rate? One article below talks about losing that activity with

a drug called acivicin, and in that case the amount of glutathione that was

excreted to the urine was 7200 times the normal rate, and the thols were at

390 times the normal rate. Obviously, if the kidney isn't repackaging the

sulfur in glutathione, it loses a lot of that sulfur to the urine.

Another article I've put below looked at what happened to cysteine in the

blood during sepsis. It found that the cytsteine in the blood was

elevated, but at the same time the formation of glutathione in cells was

down. Some of the extra cysteine in the blood seemed to be coming from

increased protein breakdown...so the extra need for sulfur at this time led

to a period of catabolism of muscle which elevated the plasma

cysteine...not something you would want to sustain for long and certainly

something that by no means could be interpreted as the body having enough

or too much sulfur.

So measuring sulfur in the blood has to be met by careful interpretation

with a lot of caveats. Probably the best measure of whether the sulfur

chemistry is adequate or not is whether the child is growing at a normal

rate and keeping his amount of muscle in proper proportion to his

size. Why? Because it takes a lot of sulfur to grow, and growing is

expendible in a way that other sulfur functions are not. This is why

measuring growth and muscle size is a much better way to evaluate overall

sulfur status in a child compared to any sort of blood or urine test

BECAUSE the liver asks the muscles to sacrifice themselves when the sulfur

the liver needs is not in sufficient supply.

It is this sort of growth and muscle problem that is what I have heard

parents talk about improving on IV glutathione. Now THAT is an issue that

you cannot address by measuring sulfur in the blood as cysteine or glutathione!

Am J Physiol. 1996 Feb;270(2 Pt 1):E209-14. Related Articles, Links

Plasma methionine and cysteine kinetics in response to an intravenous

glutathione infusion in adult humans.

Fukagawa NK, Ajami AM, Young VR.

Clinical Research Center, Rockefeller University, New York, New York

10021, USA.

Glutathione (GSH), a tripeptide (gamma-glutamyl-cysteinyl-glycine), is

thought to be both a storage and a transport form of cysteine (Cys). In a

previous study (T. Hiramatsu, N.K. Fukagawa, J.S. Marchini, J. Cortiella,

Y.-M. Yu, T.E. Chapman, and V.R. Young. Am. J. Clin. Nutr. 60: 525-533,

1994), the direct tracer-derived estimate of Cys flux was considerably

higher than that predicted from estimates of protein turnover. To further

examine the components of plasma Cys flux, seven normal-weight healthy

adult men and women (26 +/- 2 yr) received stable isotope tracer infusions

of L-[methyl-2H3;1-13C]methionine, L-[3,3-2H2]cysteine, and

L-[methyl-2H3]leucine for 460 min. After a 3-h baseline period, GSH was

administered at approximately 32 mumol.kg-1.h-1 until the end of the study.

Expired breath and blood samples were obtained at timed intervals and

analyzed for isotope enrichment using mass spectrometry. Leucine,

alpha-ketoisocaproate, and methionine (carboxyl carbon, methyl moiety,

remethylation, and transsulfuration) turnover were reduced during GSH

administration (P < 0.01). In the final hour of GSH administration, Cys

flux increased by 61% from 55.1 +/- 1.7 to 88.7 +/- 5.2 mumol.kg-1.h-1 (P <

0.01), which was essentially equivalent to the rate of exogenous GSH

infusion. These data suggest that GSH breakdown accounts for approximately

50% of tracer-derived Cys flux basally and for all of the increase in

measured Cys turnover during exogenous GSH infusion.

PMID: 8779940 [PubMed - indexed for MEDLINE]

Prog Neuropsychopharmacol Biol Psychiatry. 1996 Oct;20(7):1159-70.

Related Articles, Links

[Click here to read]

Reduced intravenous glutathione in the treatment of early Parkinson's

disease.

Sechi G, Deledda MG, Bua G, Satta WM, Deiana GA, Pes GM, ti G.

Department of Neurology, University of Sassari, Italy.

1. Several studies have demonstrated a deficiency in reduced

glutathione (GSH) in the nigra of patients with Parkinson's Disease (PD).

In particular, the magnitude of reduction in GSH seems to parallel the

severity of the disease. This finding may indicate a means by which the

nigra cells could be therapeutically supported. 2. The authors studied the

effects of GSH in nine patients with early, untreated PD. GSH was

administered intravenous, 600 mg twice daily, for 30 days, in an open label

fashion. Then, the drug was discontinued and a follow-up examination

carried-out at 1-month interval for 2-4 months. Thereafter, the patients

were treated with carbidopa-levodopa. 3. The clinical disability was

assessed by using two different rating scale and the Webster Step-Second

Test at baseline and at 1-month interval for 4-6 months. All patients

improved significantly after GSH therapy, with a 42% decline in disability.

Once GSH was stopped the therapeutic effect lasted for 2-4 months. 4. Our

data indicate that in untreated PD patients GSH has symptomatic efficacy

and possibly retards the progression of the disease.

Publication Types:

* Clinical Trial

PMID: 8938817 [PubMed - indexed for MEDLINE]

J Pharmacol Exp Ther. 1987 Jul;242(1):27-32. Related Articles, Links

Effect of inhibition of gamma-glutamyltranspeptidase on biliary and

urinary excretion of glutathione-derived thiols and methylmercury.

Gregus Z, Stein AF, Klaassen CD.

Acivicin (AT-125; 6.25-200 mumol/kg i.v.) inhibited hepatic, biliary

and renal gamma-glutamyltranspeptidase (GGT) activity up to 88, 99 and 97%,

respectively, in 4-week-old rats. This inhibition of GGT by acivicin

resulted in a 10- to 12-fold increase in the biliary excretion of reduced

(GSH) and oxidized glutathione. Because the biliary excretion of

cysteinylglycine (Cys-Gly), Cys-Gly disulfide, cysteine (Cys) and cystine

concomitantly decreased (63-99%), the biliary excretion rate of total

glutathione-derived thiols and disulfides did not change. In contrast,

acivicin treatment dramatically elevated the urinary excretion rate of

glutathione-derived thiols in a dose-dependent fashion, resulting in a

390-fold increase at the highest dosage. This mainly originated from

enhancement of urinary excretion of GSH (up to 7200-fold), although the

excretion of Cys and Cys-Gly into urine was also increased. Acivicin

treatment did not affect hepatic and renal levels of GSH but, at high

dosages, reduced the concentration of Cys in these organs. GSH and oxidized

glutathione concentrations in serum were increased, whereas cystine was

diminished in acivicin-treated rats. Inhibition of GGT by acivicin (100

mumol/kg i.v.) failed to influence the biliary excretion of methylmercury

but increased urinary excretion 34-fold. Even though the urinary thiol

excretion was much higher than the biliary thiol excretion in the

acivicin-treated rats, methylmercury was preferentially excreted into bile

rather than urine, indicating the importance of the liver as an excretory

organ for methylmercury.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 2886637 [PubMed - indexed for MEDLINE]

Crit Care Med. 2001 Apr;29(4):870-7. Related Articles, Links

[Click here to read]

Cysteine metabolism and whole blood glutathione synthesis in septic

pediatric patients.

Lyons J, Rauh-Pfeiffer A, Ming-Yu Y, Lu XM, Zurakowski D, Curley M,

Collier S, Duggan C, Nurko S, J, Ajami A, Borgonha S, Young VR,

Castillo L.

Department of Anesthesia, Children's Hospital, Boston, MA, USA.

OBJECTIVE: To investigate whole body in vivo cysteine kinetics and its

relationship to whole blood glutathione (GSH) synthesis rates in septic,

critically ill pediatric patients and controls. DESIGN: Prospective cohort

study. SETTING: Multidisciplinary intensive care unit and pediatric

inpatient units at a children's hospital. PATIENTS: Ten septic pediatric

patients and ten controls (children admitted to the hospital for elective

surgery). INTERVENTIONS: Septic patients (age, 31 months to 17 yrs) and

controls (age, 24 months to 21 yrs) received a 6-hr primed, constant,

intravenous tracer infusion of l-[1-13C]cysteine. Blood samples were

obtained to determine isotopic enrichment of plasma cysteine and whole

blood [1-13C]cysteinyl-glutathione by gas-chromatography mass spectrometric

techniques. The plasma flux and oxidation rate of cysteine and the

fractional and absolute synthesis rates of GSH were determined. Septic

patients received variable protein and energy intake, as per routine

clinical management, and controls were studied in the early postabsorptive

state. MEASUREMENTS AND MAIN RESULTS: Plasma cysteine fluxes were increased

in the septic patients when compared with the controls (68.2 +/- 17.5 [sd]

vs. 48.7 +/- 8.8 micromol x kg(-1) x hr(-1); p <.01), and the fraction of

plasma cysteine flux associated with oxidative disposal was similar among

the groups. The absolute rates of GSH synthesis in whole blood were

decreased (p <.01) in the septic patients (368 +/- 156 vs. 909 +/- 272

micromol x L(-1) x day(-1)). The concentration of whole blood GSH also was

decreased in the septic group (665.4 +/- 194 vs. 1059 +/- 334 microM; p

<.01) CONCLUSIONS: Whole blood glutathione synthesis rates are decreased,

by about 60%, in critically ill septic children receiving limited

nutritional support. Plasma cysteine fluxes and concentration of cysteine

were increased in the septic patients, suggesting a hypermetabolic state

with increased protein breakdown. The mechanisms whereby GSH synthesis

rates are decreased in these patients are probably multifactorial,

presumably involving an inflammatory response in the presence of limited

nutritional support. The role of nutritional modulation and the use of

cysteine prodrugs in maintaining GSH concentration and synthesis remain to

be established.

PMID: 11373484 [PubMed - indexed for MEDLINE]

Neurochem Res. 2004 Jan;29(1):105-10. Related Articles, Links

Role of the liver in regulation of body cysteine and taurine levels: a

brief review.

Stipanuk MH.

227 Savage Hall, Division of Nutritional Sciences, Cornell University,

Ithaca, New York 14853, USA. mhs6@...

The first-pass metabolism of dietary sulfur amino acids by the liver

and the robust upregulation of hepatic cysteine dioxygenase activity in

response to an increase in dietary protein or sulfur amino acid level gives

the liver a primary role in the removal of excess cysteine and in the

synthesis of taurine. Hepatic taurine synthesis is largely restricted by

the low availability of cysteinesulfinate as substrate for

cysteinesulfinate decarboxylase, and taurine production is increased when

cysteinesulfinate increases in response to an increase in the hepatic

cysteine concentration and the associated increase in cysteine dioxygenase

activity. The upregulation of cysteine dioxygenase in the presence of

cysteine is a consequence of diminished ubiquitination of cysteine

dioxygenase and a slower rate of degradation by the 26S proteasome.

PMID: 14992268 [PubMed - in process]

..At 08:58 PM 6/12/2004 +0000, you wrote:

>Do not do intravenous glutathione.

>

>There is no rational protective strategy.

>

>There is no legitimate indication for it in developmentally impaired

>children.

>

>The use of chelators with it is not going to make it safer and might

>make it more dangerous.

>

>There are never any circumstances where low plasma cysteine and

>glutathione can be an indication for intravenous injection of

>glutatione. Low cysteine is only an indication for increasing dietary

>and supplemetntal thiols and their precursors (sulfur foods).

>

>Andy . .. . .. . . .