Ema
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Below is my first draft for the rationale to submit with the paperwork to try Adagen...any suggestions? Does it make sense logically to someone without a scientific background?
Thank you for your comments!
Ema
My adenosine deaminase level was 8.3 (0-15) through LabCorp. I decided to investigate this range further because a level of "0" would almost certainly mean SCID and that is decidedly NOT normal.
My investigations led me to a number of articles that did specify a normal range for ADA. While there is some variation, It turns out that a better range for healthy, control individuals is 15-23 U/L (supposing that Saudi women and American women don't differ significantly in this regard).
In the current study, the normal range for adenosine deaminase totalled 15.0 - 23.2, 14.8 - 23.6, 15.0 - 23.0 and 16.7 - 24.6 U/l for the overall population, all males, females, and children, respectively.
http://www.ncbi.nlm.nih.gov/m/pubmed/17587984/
Another study indicated that the average for healthy controls was 10.69. My value is at the very bottom, then, of this range as well.
The average (SD) of serum ADA in TB and non-TB patients were 20.88 (±5.97) and 10.69 (±2.98) U/L, respectively (P value < 0.05). The best cut-off point was 14 U/L.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732909/
This study got me thinking though because it seems that adenosine and consequently ADA levels are typically increased in people with varying types of infection. The study above references TB and I found another study that examines measuring ADA as a way to assess treatment outcomes in brucellosis.
Serum ADA levels were found to be significantly higher in patients with brucellosis than in healthy individuals (43.45 ± 24.19 IU/l and 27.5 ± 9.3 IU/l, respectively) (P < 0.01). Serum ADA activity did not show any correlation between the Brucella agglutination titer and CRP level.
http://journals.tubitak.gov.tr/medical/issues/sag-04-34-5/sag-34-5-5-0404-3.pdf
So it seems that someone like me, with multiple chronic infections, would be more likely to have an elevated level of ADA as opposed to a low level.
This journal article tells us that there is a relationship between lymphocytes and serum ADA level. When lymphocytes are high, as mine consistently (see panel on labs dated 11/27), the ADA level should also be high, and mine is not.
Among lymphocytes, it is mainly associated with T-lymphocytes [1] and studies have shown increased serum ADA levels in diseases characterized by T cell proliferation or activation [2, 3].
http://www.jle.com/e-docs/00/01/8a/26/article.phtml
I think this is further evidence that my ADA level is too low to adequately manage the level of high level of adenosine. According to these studies, my labs should show a high level of ADA activity and they actually show a low level.
Technically speaking, adenosine deaminase deficiency causes an increase of dATP, which inhibits S-adenosyl-homocysteine hydrolase, causing an increase in S-adenosylhomocysteine. Both dATP and S-adenosylhomocysteine have toxic affects on lymphocytes, causing them to be functionally defective. The defective function is caused by a depletion of all of the dNTP pools. This causes a breakdown in DNA synthesis and repair of breaks occurring in the DNA. This makes for a very serious disease and that is why the presence of ICL in CFIDS/ME patients causes a severe immunodeficiency where patients become prone to repeated infections. In CFIDS/ME, this is an acquired condition due to the disease progression itself. I should point out that one treatment option for adenosine deaminase deficiency involves the replacement of the enzyme adenosine deaminase itself. The drug used for this is called Adagen by Enzon Pharmaceuticals and it has been used for the treatment of severe combined immunodeficiency disease, known also as SCID, due to adenosine deaminase deficiency.
I believe at this time that my chronic infections have induced a sort of hibernation syndrome caused by a high level of adenosine without a sufficient amount of adenosine deaminase enzyme to break it down. This high level of adenosine causes a vicious cycle that is devastating to the immune system and allows the infections to continue to gain ground.
This study has shown that adenosine is the "switch" that turns on hibernation.
Turns out, the hibernation switch in squirrels is a receptor on brain cells for the ‘drowsiness’ neurotransmitter adenosine, which sends us to sleep by building up gradually in the brain during the day, New Scientist explains.
By blocking it using a chemical called cyclopentyltheophylline, the researchers could wake hibernating squirrels up; stimulating it using a chemical called cyclohexyladenosine sent them back to sleep.
http://www.jneurosci.org/content/31/30/10752
Theoretically, at least, high levels of adenosine, as shown on my methylation panel, could cause a sort of hibernation syndrome that may be exacerbated by the fact that I am carry the recessive allele for ADA deaminase. This may account for the lowered levels of ADA and my inability to fight chronic infections normally.
Finally, I also found a pilot study that contends that Valtrex modulates adenosine levels.
Dr. Sid Baker, in cooperation with Jill James Ph.D., conducted a pilot study of 10 children with autism. Nine children were treated with acyclovir and one child was not treated.
Note: Valtex is quickly converted to acyclovir in the intestines and the liver5. From a viral treatment perspective many viruses that Valtrex can affect can also take up residence in the liver. Valtrex is also more bioavailable than oral acyclovir6 (more similar to IV acyclovir) and has what seems to be a safer side-effect profile.
In all the 9 children adenosine levels were seemingly improved. Some children had higher levels of adenosine and they were lowered. Some children had lower levels and they were raised. The untreated child’s level remained unchanged. This striking normalizing effect is not very common in medicine.
I wonder if this is actually why antivirals seem to help - they may not only be stopping the viral replication, but they are modulating adenosine levels. I know that I have found improvement from high doses of AVs.
Based on my high levels of adenosine, the demonstrated problems with my purinergic pathway from adenosine to uric acid, and my genetic predisposition concerning adenosine deaminase, I really think that this should be enough to convince the makers of Adagen that there is a solid clinical rationale supported by the available literature to try Adagen in my case. The shots are easily administered and I have not come across any significant side effects. There is significant room in my results to raise my level that would still not approach the top of the range observed in those with illness. I think it might only take a few months of therapy to "clear the backlog" of adenosine, so to speak. At that point, I might make *enough* ADA on my own to keep myself out of adenosine induced hibernation and infection.
Thank you for your comments!
Ema
My adenosine deaminase level was 8.3 (0-15) through LabCorp. I decided to investigate this range further because a level of "0" would almost certainly mean SCID and that is decidedly NOT normal.
My investigations led me to a number of articles that did specify a normal range for ADA. While there is some variation, It turns out that a better range for healthy, control individuals is 15-23 U/L (supposing that Saudi women and American women don't differ significantly in this regard).
In the current study, the normal range for adenosine deaminase totalled 15.0 - 23.2, 14.8 - 23.6, 15.0 - 23.0 and 16.7 - 24.6 U/l for the overall population, all males, females, and children, respectively.
http://www.ncbi.nlm.nih.gov/m/pubmed/17587984/
Another study indicated that the average for healthy controls was 10.69. My value is at the very bottom, then, of this range as well.
The average (SD) of serum ADA in TB and non-TB patients were 20.88 (±5.97) and 10.69 (±2.98) U/L, respectively (P value < 0.05). The best cut-off point was 14 U/L.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732909/
This study got me thinking though because it seems that adenosine and consequently ADA levels are typically increased in people with varying types of infection. The study above references TB and I found another study that examines measuring ADA as a way to assess treatment outcomes in brucellosis.
Serum ADA levels were found to be significantly higher in patients with brucellosis than in healthy individuals (43.45 ± 24.19 IU/l and 27.5 ± 9.3 IU/l, respectively) (P < 0.01). Serum ADA activity did not show any correlation between the Brucella agglutination titer and CRP level.
http://journals.tubitak.gov.tr/medical/issues/sag-04-34-5/sag-34-5-5-0404-3.pdf
So it seems that someone like me, with multiple chronic infections, would be more likely to have an elevated level of ADA as opposed to a low level.
This journal article tells us that there is a relationship between lymphocytes and serum ADA level. When lymphocytes are high, as mine consistently (see panel on labs dated 11/27), the ADA level should also be high, and mine is not.
Among lymphocytes, it is mainly associated with T-lymphocytes [1] and studies have shown increased serum ADA levels in diseases characterized by T cell proliferation or activation [2, 3].
http://www.jle.com/e-docs/00/01/8a/26/article.phtml
I think this is further evidence that my ADA level is too low to adequately manage the level of high level of adenosine. According to these studies, my labs should show a high level of ADA activity and they actually show a low level.
Technically speaking, adenosine deaminase deficiency causes an increase of dATP, which inhibits S-adenosyl-homocysteine hydrolase, causing an increase in S-adenosylhomocysteine. Both dATP and S-adenosylhomocysteine have toxic affects on lymphocytes, causing them to be functionally defective. The defective function is caused by a depletion of all of the dNTP pools. This causes a breakdown in DNA synthesis and repair of breaks occurring in the DNA. This makes for a very serious disease and that is why the presence of ICL in CFIDS/ME patients causes a severe immunodeficiency where patients become prone to repeated infections. In CFIDS/ME, this is an acquired condition due to the disease progression itself. I should point out that one treatment option for adenosine deaminase deficiency involves the replacement of the enzyme adenosine deaminase itself. The drug used for this is called Adagen by Enzon Pharmaceuticals and it has been used for the treatment of severe combined immunodeficiency disease, known also as SCID, due to adenosine deaminase deficiency.
I believe at this time that my chronic infections have induced a sort of hibernation syndrome caused by a high level of adenosine without a sufficient amount of adenosine deaminase enzyme to break it down. This high level of adenosine causes a vicious cycle that is devastating to the immune system and allows the infections to continue to gain ground.
This study has shown that adenosine is the "switch" that turns on hibernation.
Turns out, the hibernation switch in squirrels is a receptor on brain cells for the ‘drowsiness’ neurotransmitter adenosine, which sends us to sleep by building up gradually in the brain during the day, New Scientist explains.
By blocking it using a chemical called cyclopentyltheophylline, the researchers could wake hibernating squirrels up; stimulating it using a chemical called cyclohexyladenosine sent them back to sleep.
http://www.jneurosci.org/content/31/30/10752
Theoretically, at least, high levels of adenosine, as shown on my methylation panel, could cause a sort of hibernation syndrome that may be exacerbated by the fact that I am carry the recessive allele for ADA deaminase. This may account for the lowered levels of ADA and my inability to fight chronic infections normally.
Finally, I also found a pilot study that contends that Valtrex modulates adenosine levels.
Dr. Sid Baker, in cooperation with Jill James Ph.D., conducted a pilot study of 10 children with autism. Nine children were treated with acyclovir and one child was not treated.
Note: Valtex is quickly converted to acyclovir in the intestines and the liver5. From a viral treatment perspective many viruses that Valtrex can affect can also take up residence in the liver. Valtrex is also more bioavailable than oral acyclovir6 (more similar to IV acyclovir) and has what seems to be a safer side-effect profile.
In all the 9 children adenosine levels were seemingly improved. Some children had higher levels of adenosine and they were lowered. Some children had lower levels and they were raised. The untreated child’s level remained unchanged. This striking normalizing effect is not very common in medicine.
I wonder if this is actually why antivirals seem to help - they may not only be stopping the viral replication, but they are modulating adenosine levels. I know that I have found improvement from high doses of AVs.
Based on my high levels of adenosine, the demonstrated problems with my purinergic pathway from adenosine to uric acid, and my genetic predisposition concerning adenosine deaminase, I really think that this should be enough to convince the makers of Adagen that there is a solid clinical rationale supported by the available literature to try Adagen in my case. The shots are easily administered and I have not come across any significant side effects. There is significant room in my results to raise my level that would still not approach the top of the range observed in those with illness. I think it might only take a few months of therapy to "clear the backlog" of adenosine, so to speak. At that point, I might make *enough* ADA on my own to keep myself out of adenosine induced hibernation and infection.