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Medical Forum / Diseases and Disorders / Herpes / November 2005

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The inhibition of TK transcription by canavanine

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Perl Molson - 08 Nov 2005 16:06 GMT
"This result suggests that
the transcription of the thymidine kinase gene
was inhibited by canavanine, and thymidine kinase
can therefore be classified as a member of
the ,B2 group. These data are in agreement with
the previous observation that expression of the
thymidine kinase polypeptide is inhibited by
canavanine in the cistron-specific enzyme-forming
assay."

http://www.pubmedcentral.gov/picrender.fcgi?artid=353652&blobtype=pdf
Tim Fitzmaurice - 09 Nov 2005 07:56 GMT
> "This result suggests that
> the transcription of the thymidine kinase gene
> was inhibited by canavanine, and thymidine kinase
> can therefore be classified as a member of

Erm, thats not necessarily a good thing. Deletion of the TK gene is
probably the commonest method of generation of resistance to
ACV/PCV/VACV/FCV. Now gene deletion is about as profound a method of
inhibiting transcription as you can manage.

So two issues. 1) If you start supplementing a drug regime with something
that inhibits TK and the person is on one of the above drugs you
presumably run a heck of a risk of completely losing any drug efficiacy.
2) TK deleted HSV's are less viable than normal (wildtype) ones but can
still survive and replicate in a host, albeit less
effectively than a wildtype (less of an issue than above but still to be
thought about). Resistance mechanisms will be the same, too.

Tim
--
When playing rugby, its not the winning that counts, but the taking apart
ICQ: 5178568
Perl Molson - 10 Nov 2005 07:49 GMT
> > "This result suggests that
> > the transcription of the thymidine kinase gene
[quoted text clipped - 5 lines]
> ACV/PCV/VACV/FCV. Now gene deletion is about as profound a method of
> inhibiting transcription as you can manage.

> So two issues. 1) If you start supplementing a drug regime with something
> that inhibits TK and the person is on one of the above drugs you
[quoted text clipped - 8 lines]
> When playing rugby, its not the winning that counts, but the taking apart
> ICQ: 5178568

Well, if I was to take prescription drugs for herpes, I would not have
spent so much
time looking for answers on folk treatments.

I've always emphasized, if someone is taking prescription drugs, he/she
can
forget about other methods that may even interfere with the former.

Meanwhile, I've found an article about L-canavanine:

http://www.freepatentsonline.com/5110600.html

Method of treating viral infections with amino acid analogs

Amino acid analogs may also be effective in killing cells infected with
a variety of DNA viruses, for example Herpes Simplex Virus (HSV).

Because L-canavanine has been determined not to be mutagenic (Ames,
Science 204:587 (1979)), it is also likely that it is not carcinogenic.
Moreover, the toxic effects of the analog may be quickly reversed by
administering the natural amino acid arginine over a suitable period of
time. (Green et al., Cancer Res. 43:4180-4182 (1983)).

Since L-canavanine has been demonstrated to kill tumor cells in live
animals (Green et al., 1980, supra and Thomas et al., supra) and as
demonstrated herein, can selectively kill retrovirally infected human
cells in vitro, it shows promise for treatment of retrovirally infected
cells in vivo in humans as well as animals suffering from viral
diseases. Treatment with the analogs will irreversibly halt viral
production in infected cells as a result of cell death. Because the
amino acid analogs such as L-canavanine will be incorporated into newly
synthesized cellular and viral proteins, the present method should
further result in lowered subsequent cell infection by the newly
synthesized virus because of altered structure and lowered numbers of
the viruses. The fact that L-canavanine has been found to be tolerable
when administered orally in primates (Malinkow, supra) suggests that
humans may tolerate the drug when administered in an appropriate form
and dosage.

L-canavanine as well as other natural and synthetic amino acid analogs
that are readily incorporated into newly synthesized proteins, may be
used to treat retroviral disease in a mammal by administration of
effective amounts of the pharmaceutical preparations containing the
analogs. In this respect, it is important to note that the relative
ratios of L-canavanine to arginine appeared significant in the in vitro
cell toxicity studies described herein. These ratios may determine the
amount of canavanine relative to arginine that is incorporated into
proteins. Therefore, in determining the appropriate dosage for an
individual subject the amount of arginine present in the blood of the
subject must be measured and the ratio of L-canavanine to arginine
optimized. Based on the in vitro results described herein, ratios in
the range of from 1:1 to 10:1 L-canavanine to arginine are preferable.
Appropriate dosages will also depend on the body weight of the mammal
and stage and severity of infection.

For initial treatment it may be necessary to maintain relatively high
and constant levels of the L-canavanine in the mammal's body to obtain
maximum kill of the virally infected cells. In addition, since the
virus produced by the infected cells may itself be killed as a result
of L-canavanine incorporation during viral replication, the continued
presence of L-canavanine may be necessary to control the spread of the
virus. Therefore, continuous infusion of the amino acid analog or
frequent injections or other form of sustained release of the analog
may be warranted. Because the half-life of L-canavanine in the blood of
mice has been determined to be relatively short (Green et al., 1980,
supra) the frequency and amount of L-canavanine to be administered
should be calculated so as to attain a sufficient level of L-canavanine
to achieve optimal selective cell kill for virally infected cells in
vivo. This calculation should also take into account the amount of
arginine present in the blood serum of a subject to achieve the desired
ratios of arginine to L-canavanine described above, in vivo. The exact
regimen for administration of the analogs disclosed herein will
necessarily be dependent upon the needs of the individual subject being
treated, the type of treatment and, of course, the judgment of the
attending practitioner.

The analogs may be administered in association with a pharmaceutically
acceptable carrier. The text Remington's Pharmaceutical Sciences, 15th
Ed. by E. W. Martin (Mark Publ. Co., 1975) discloses typical carriers
and methods of preparation, which disclosure is incorporated herein by
reference. The pharmaceutical amino acid analog preparations may be
administered orally, parenterally (e.g. intravenously (i.v.), intra
muscularly, or intraperitoneal (i.p.) or the like depending on the
nature of the viral infection being treated and at dose levels
appropriate for the body weight of the mammal. In addition, the
preparations may be applied topically to treat viral infections of
exposed tissues such as the skin and eyes or mouth, for example by HSV
and other viruses for which L-canavanine has been demonstrated to be
effective. Since the compounds are amino acids, it is also possible to
incorporate the analogs into normal food products for oral intake.

In addition to the use of L-canavanine, effective retroviral therapy
may be accomplished by combining administration of amino acid analogs
such as L-canavanine with other chemotherapeutic or antiviral agents
that act by other mechanisms directed against retroviruses. For
example, the analogs may be administered along with drugs such as
interferons or base analogs such as AZT, and antibodies to the virus or
to cellular receptors for the virus, to retard viral replication as
well as to kill virally infected cells. In addition, virally infected
cells may be targeted in vivo for treatment with the amino acid analogs
using targeting agents. For example, the analogs may be encapsulated
within liposomes that selectively interact with the virally infected
cells. Furthermore, such targeting agents may be associated with an
additional chemotherapeutic agent and then administered along with or
complexed to the amino acid analogs for enhanced treatment of a viral
infection.

The foregoing examples have been presented to illustrate the present
invention and are not to be construed as limitations on the invention's
scope which is instead defined by the following claims.
Perl Molson - 10 Nov 2005 13:51 GMT
an example is Astragalus root; it contains L-canavanine.
it was to me, one of the most effective anti-herpes herb I've ever
taken, together
with Prunella Vulgaris (Self Heal) infussion.

Perl von Molson

http://www.thorne.com/altmedrev/.fulltext/8/1/72.pdf

Other Constituents
Phytosterols, a volatile oil, and amino
acids, including gamma-aminobutyric acid
(GABA) and L-canavanine, have been isolated
from the root.11 Zinc, iron, copper, magnesium,
manganese, calcium, potassium, sodium, cobalt,
rubidium, molybdenum, chromium, vanadium, tin,
and silver have also been found in the root of Astragalus,
as well as traces of tantalum, hafnium,
europium, and thorium. Organic compounds identified
in the roots include choline, betaine, gluconic
acid, and ß-sitosterols, as well as aromatic
compounds, essential oil, linoleic acid, a-
aminobutyric acid, bitter compounds, and asparagine.
4
Mechanisms of Action
Research shows Astragalus root
stimulates the immune system in many ways. It
increases the number of stem cells in bone marrow
and lymph tissue and encourages their
development into active immune cells. It appears
to help trigger immune cells from a "resting" state
into heightened activity. One study showed
Astragalus root helps promote and maintain
respiratory health. It also enhances the body's
production of immunoglobulin and stimulates
macrophages. Astragalus can help activate T-cells
and natural killer (NK) cells.12
Several studies also show Astragalus proffers
heart-protecting effects, including protection
against oxidative damage. Additionally, the flavonoids,
saponins, and polysaccharides found in
Astragalus root help minimize free radical damage
to membranes.13-15
The flavonoids and saponins in Astragalus
can significantly inhibit membrane lipid
peroxidation generated by superoxide (O2-), hydrogen
peroxide (H2O2), and ultraviolet rays, while
the polysaccharides of Astragalus possess weaker
protective activity.14
Astragalus has been shown to have inhibitory
effects on lipid peroxidation and protein oxidative
modification by copper. The results of a
study showed the free radical scavenging effects
were similar to, and stronger than, those of mannitol
and superoxide dismutase, respectively, demonstrating
inhibitory effects on oxidative stress
induced by copper.13
Clinical Indications
Current Western applications of Astragalus
are primarily for restoring and strengthening
the immune response, enhancing cardiovascular
function, and increasing vitality. Indications supported
by clinical trials include impaired immunity,
adjunctive cancer treatment, and viral infections,
including the common cold and cervical
erosion associated with Herpes simplex. Western
preparations include dried root for decoction, liquid
extract, tablets, and powdered root.
Immune Modulation
In mice, oral doses of Astragalus enhanced
several aspects of immunity, including superoxide
anion production by peritoneal macrophages,

> > > "This result suggests that
> > > the transcription of the thymidine kinase gene
[quoted text clipped - 129 lines]
> invention and are not to be construed as limitations on the invention's
> scope which is instead defined by the following claims.
 
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