Thymomodulin
Thymomodulin, a preparation made from the thymus glands ofcalves, is an approved drug in Italy, and is used in Europe
as an immune treatment. Human trials have shown good results
with a number of conditions involving immune deficiency or
dysfunction -- for example, in treating hepatitis B,(1) in
reducing recurrent respiratory infections in children,(2,3)
and in reducing fever and sepsis after surgery in patients
who were immune deficient (as shown by lack of response to
skin tests of delayed-type hypersensitivity); thymomodulin
also helped to restore skin-test responsiveness.(4) Other
studies have shown that the drug reduced certain immune
deficiencies of aging,(5) helped cancer patients tolerate
chemotherapy,(6) and was useful in treating certain allergic
conditions, including food allergies in children.(7,8) Many
laboratory and animal studies have demonstrated various
mechanisms by which thymomodulin might improve certain immune
responses (see bibliography sections, below).
A small, observational study in persons with HIV, conducted
in Europe several years ago, reported striking improvement in
clinical condition, as well as improvement in blood work.(9)
But this early result was not followed up. The entire area of
thymus treatments for HIV has been seriously neglected -- and
all but completely neglected in the United States.
AIDS TREATMENT NEWS recently reported on another thymus
preparation, thymosin a1 (thymosin alpha 1), which recently
showed good results in a small trial in Italy (see "Thymosin
Alpha 1: Sustained T-helper Count Rise in Three-Drug
Combination," AIDS TREATMENT NEWS # 194, March 4, 1994).
Thymosin a1 is now tied up in a business dispute, and is
unavailable anywhere in the world, except to a few patients
in clinical trials. But while researching thymosin a1, we
learned that three people we know personally have been using
thymomodulin for over two years. All have been able to
reverse declining blood counts, especially total lymphocyte
and CD8 counts, bringing them from dangerous levels to normal
or near normal, where they have remained for the last two
years. The one person of the three who has advanced AIDS
continued to have a decline in his CD4 (T-helper) count, but
had a dramatic improvement in his CD8 count. These people
referred us to others, who have used thymomodulin for a
shorter time, but have also had good results. Since
thymomodulin is the only scientifically studied thymus
product which does not need to be injected but can be taken
orally -- and one of the few which is available to patients
today -- we focused this article on it. Thymomodulin is not
approved in the United States, but patients can obtain a
personal supply.
We are fortunate to have the anecdotal reports, summarized
later in this article, because, when combined with the
medical literature on thymomodulin, they provide enough
rationale to bring this treatment to the attention of the
AIDS community. The scientific studies of thymomodulin and
HIV infection are small, uncontrolled, and usually several
years old; they may not provide a strong enough rationale to
get new studies going. But several cases of sustained
improvement in blood counts, on top of the scientific work,
makes this potential treatment hard to ignore. And since we
personally know three people who have used thymomodulin for
over two years, we can be confident that they are credible.
Human Studies of Thymomodulin
to Treat HIV
Thymomodulin is one of at least six substances produced by
the thymus gland which have been scientifically examined as a
possible HIV/AIDS treatment: the others are thymosin a1, THF
(thymic humoral factor), TP-5 (thymopentin), thym-uvocal, and
thymostimulin. Of the six, thymomodulin, thym-uvocal, and
thymostimulin are crude, or "natural," thymic extracts,
containing a number of chemically distinct substances; the
other three are made synthetically, each consisting of a
single molecule.
* The largest published study of thymomodulin and HIV was
conducted in Italy, and published in 1987. It reported on 15
patients with HIV who were treated with the drug (60 mg per
day orally, as a syrup) for more than 50 days. Two of the
patients with late-stage AIDS had no change in their
condition, and died shortly after the end of the study. The
only one with Kaposi's sarcoma who entered the study was
reported to have had "an evident clinical and laboratory
improvement with remission of the neoplasia."(9)
All of the other 12 showed resolution of fever. All of them
started the study with chronic lymphadenopathy, which
disappeared in six of them. Six started with thrush, which
disappeared in all but one case. The CD4/CD8 ratio (a measure
no longer considered useful) increased; and the average CD8
count decreased. (This CD8 result is opposite from all of the
anecdotal reports we have heard, a discrepancy which is
unexplained.) There was also a statistically significant
increase in T-helper cells. No side effects of thymomodulin
were seen. And there was no increase in neopterin, an
indicator of T-cell activation.
* A later study, conducted in Argentina and reported at the
International Conference on AIDS in Amsterdam, in July 1992,
treated 11 patients with HIV -- ten of whom had AIDS -- with a
combination of thymomodulin, AZT, and lithium carbonate
"which stimulates granulocytic colony forming units." Two of
the patients had died by the time the results were reported;
the other nine were still on the treatment. "All have a
better life-style, weight gaining, less opportunistic
infection episodes, and half of them returned to work...
Overall, they all improved their CD4 count."(10)
Unfortunately this study was only accepted for publication of
the abstract; it was not even among the thousands of
submissions given space for a poster presentation, and
therefore it received little attention at the conference or
afterwards.
* A paper from Germany, published in 1990, may have reported
on an additional study.(11) We could not obtain a copy or
abstract by press time, however, so we have only the title --
Immunoprophylaxis and/or Immunotherapy with Thymic Hormones
in HIV-Seropositive Asymptomatic Subjects and in AIDS
Patients -- and the fact that it was indexed under
thymomodulin.
Aside from clinical trials, a number of laboratory and animal
studies have described effects of thymomodulin on
immunological measurements, outlining potential mechanisms of
action.(12-18)
Anecdotal Reports
We have received four anecdotal reports, three from persons
well known to us, who have used thymomodulin for about two
and a half years. All four are still using the treatment.
The three we know (patient #1, patient #2, and patient #3
below) have tried both the oral and the injectable forms of
the drug, and find about the same effects with each. Usually
they use the injectable, but only because it costs less.
Patient #1 believes he is the first person to try
thymomodulin as an HIV treatment in the U.S. He has kept
careful records of his blood work, and has T-cell subsets
measured 28 times since November 1987. His T-helper count
started at 630 and then declined, going as low as 380, 344,
and 340 (three successive measurements, the last in November,
1990). Then he began high-dose compound Q in November or
December 1990, and began thymomodulin in the fall of 1991. In
December 1990 his T-helper count rose to about 500 and
stabilized there. His CD8 count showed a similar pattern,
reaching a low of about 700 to 800, then rising and
stabilizing at about 1000 in December 1990 (although there is
considerable variation in the numbers). Total lymphocyte
count was similar, starting at about 2000, declining to 1400
to 1500, and currently at about 1600.
His blood work also includes the percentage of activated T-
cells. An abnormally high value is a bad sign, because HIV
can reproduce in activated cells, but not in resting cells.
Activation increased to about 40 percent in 1990 (on six
separate measurements). But then it fell to 8 percent (within
the normal range) in February 1991 -- shortly after he began
high-dose compound Q -- and remained under 10 percent for at
least a year, through February 1992. By July 1992 it was 26
percent, however, a rise he suspects may have been due to
starting thymomodulin. Then the activation fell back
gradually, to 9 percent in March 1994.
Patient #1 is very concerned that people not use thymomodulin
or other thymus extract without an antiviral. He strongly
believes that compound Q has been helpful for him. (That
particular antiviral is not feasible for most people,
however, since there few physicians with the training and
experience to use it safely.)
Patient #2 has also used thymomodulin for two and a half
years, mainly to increase his total lymphocyte count. Before
starting thymomodulin, his lymphocyte count had declined
fairly consistently, from a high of 1900 in August 1988 to
951 in September 1991. After several months of using the
thymosin, his total lymphocyte count went up to the 1200
range. His last three counts were 1789, 1248, and 1264. T-
helper and CD8 cells have shown similar reversals of decline.
Patient #2 is also using compound Q, which he started taking
about two years ago.
Patient #3 has also used thymomodulin for two and a half
years. His T-helper count has continued to decline; it was
150 before he began thymomodulin, and is 35 now. But his CD8
count went up greatly, from about 400 (a seriously low level)
to about 1200 after ten months. Now he maintains a level of
around 900 -- unusually high for a person with advanced HIV
disease. While using thymomodulin he has also used d4T, and
other treatments.
Patient #4 has used thymomodulin for one year -- one 80 mg
capsule every other day. He also takes low-dose aspirin on
the alternate days, because of research suggesting that low-
dose aspirin can increase production of IL-2 and gamma
interferon, and lower the level of prostaglandin E2 -- effects
which might be beneficial in HIV disease. His last counts
before starting the treatment, in March 1993, were CD4 330,
CD8 572, and total lymphocytes 1786. Shortly after starting,
in August, his CD4 was 351, CD8 715, and lymphocytes 2040.
His last blood draw, in February 1994, was CD4 624, CD8 1508,
and lymphocytes 3089.
On the negative side, patient #4 has also had signs of
possible viral activation -- despite continuing use of ddI
(which he had been using for 66 weeks). His beta 2
microglobulin went up, from 2.1 to 3.6. He was able to get a
Roche PCR test for HIV RNA, and the result was 186,000 copies
per ml, which is high. He has no baseline RNA copies from
before starting thymomodulin, however.
Besides these four, we have also heard of several other U.S.
patients who have used thymomodulin and had CD8 count
increases, but we do not have details.
The CD8 count may be at least as important as the CD4 (T-
helper) count as an indicator of disease progression. It has
been known for several years that some CD8 cells produce a
substance (as yet unidentified) which inhibits HIV. The CD8
count has also been found to help predict (independently of
the T-helper count) the risk of death or certain
opportunistic infections in late-stage HIV disease.(19,20)
These patients also used a number of other experimental and
standard treatments while they were using thymomodulin; we do
not have the full information. For this and other reasons,
these anecdotal reports are only a guide to further research,
not proof of benefit of the treatment.
Side Effects and Risks
Thymomodulin is widely considered to be nontoxic; we could
not find any reference to toxicity in the literature.
However, this safety information is from HIV-negative
persons, and from animal studies.
For persons with HIV, there is a concern that immune
stimulation might stimulate growth of the virus. No one knows
if this danger is real, because there is so little human
experience with the drug in treating persons with HIV.
Patient #1 above, who is probably as familiar with
thymomodulin as anyone in the U.S., strongly believes that no
one with HIV should use thymomodulin unless they are also
using anti-HIV treatment.
Anecdotal reports have said that the drug often causes an
aggravated, unpleasantly stimulated feeling, and that there
can also be redness of the skin, and sometimes headache.
These effects may mean that one is using too high a dose.
Incidentally, patients #1, #2, and #3 reported that
thymomodulin causes them to feel warmth in the chest, where
the thymus is located, shortly after it is taken. We have not
heard from the others about this.
How to Obtain Thymomodulin
Thymomodulin is not approved in the United States. However,
it is possible to obtain a supply for personal use.
The Atlanta Buyers' Club (404/874-4845) carries thymomodulin
capsules; a prescription is required. It does not carry the
injectable form.
It may also be possible to get the drug through pharmacies in
Italy, England, Switzerland, or some other countries. Again,
a prescription is required.
The four patients whose use of the drug is described above
suggest that the drug be taken on an empty stomach. They
started with a loading dose, two 80 mg capsule per day (or
one, if the larger dose cannot be tolerated) for two to four
weeks. Then they reduced the dose to one capsule every other
day, or one capsule three times a week. (The lowest price we
have heard is about $4 per 80 mg. capsule.)
Comment
Clearly more research is needed -- work which could easily be
done by a community-based research organization. Some
possible studies:
* Can consistent improvement in blood work -- especially CD8
count, T-helper count, or total lymphocyte count -- be shown
in a prospective trial, for any group of patients? (This
effect might be easiest to show in those at a fairly early
stage of HIV disease, but who show evidence of impaired
thymus function on certain blood tests.)
* Does such immune improvement (if found) lead to reduced
viral measurements, by helping the immune system to keep the
virus under control?
* Could thymomodulin help to reduce certain chronic or
repeated infections -- as has been reported for both HIV-
positive and HIV-negative patients?
* Would thymomodulin work better if combined with alpha
interferon (as well as with an antiviral).
* Could thymomodulin have any role in the treatment of KS --
or was the single case reported so far only a coincidence?
Acknowledgment
The authors thank Curtis Ponzi for his help with this
article.
References
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source: AIDS Treatment News
