Artemisinin,,,from malaria to cancer treatment
- From: "4man12" <4mandr12@xxxxxxxxxx>
- Date: Mon, 18 Jul 2005 11:20:57 -0400
IT IS ALSO,AN EXELLANT CYST BUSTER
Artemisinin, the key ingredient obtained from Artemisia annua, has a long
history of use as an antimalarial remedy. Artemisia annua, or "sweet
wormwood," is mentioned in the Recipes For 52 Kinds Of Diseases found in the
Mawangdui Han Dynasty tomb, dating from 168 B.C. In that work, the herb is
recommended for use for hemorrhoids. It is also mentioned in the Zhou Hou
Bei Ji Fang (Handbook of Prescriptions for Emergency Treatments) written in
340 A. D. The major active principal was first isolated in l972, and
investigators at the Walter Reed Army Institute of Research located and
crystallized the active component in l984.1
Artemisinin and two synthetic derivatives, artemether and sodium artesunate,
were evaluated in the l970's. A number of the tropical countries have
conducted trials. In China in 1979, wherein 2,099 patients infected with P.
viva and P. falciparum, Artemisinin had good therapeutic effects and
improved or cured all patients. Furthermore, the treatment with Artemisinin
was without any obvious side effects. Artemisinin is also effective in
cerebral malaria. Body temperature of patients normalized within 72 hours,
and asexual parasites were eliminated within 72 hours. However, there was a
relapse rate of 21%.2
In clinical trials in Vietnam, children ages 1 to 15 years were randomly
selected to receive artemisinin suppositories or oral quinine. The results
indicated that the suppositories rapidly cleared asexual P. Falciparium
parasitemia in children and confirmed the problem reoccurrence rates.3
Artemisinin has been extensively researched for malaria, and has been used
on over a million patients, mostly in China and Vietnam. It is very helpful
for drug resistant malaria. Extensive review articles are available
documenting the extensive testing that has been done.4-6
Various oral dosage regimens have been adopted in treating over one million
patients. Early studies suggested that an optimum total dosage of 3 grams
(about 50 mg/kg) was administered over a 3 to 5 day period. In most cases
parasite and fever clearance times were in less than two days. Recurrence
were much more common with tablets than with parenteral formulations.
Because of the very rapid clearance time of fever and parasites, the use of
artemisinin was favored, and recurrences, which were common, were treated
with artemisinin again or with another drug.7
About twelve years ago, Dr. Leo Galland and Dr. Herman Bueno worked together
in New York City and began using artemisinin as a broad spectrum
antiparasitic agent.
"Artemisinin is a powerful oxidant. I have used it orally to treat small
bowel bacterial overgrowth, Clostridial overgrowth and (along with other
herbal extracts, such as berberine, grapefruit seed extract and oregano oil)
as a treatment for intestinal parasites." Leo Galland, MD.
Very recently, news reports have trumpeted Artemisinin as a leading
treatment for malaria. Affected nations are calling for it to be accepted as
the number one first line treatment, but the USA has blocked its acceptance
as the primary treatment, alleging yet more studies are needed.
For the past ten years, the Hoang medical family, with three generations of
sophisticated physicians, have used artemisinin in combination with several
other herbs to treat cancer, and eliminate necrosis material from the body;
for example, from wounds; from intestines of people who have ulcerative
colitis, and from Crohn's disease. The efficacy of the artemisinin compound
is very impressive for the treatment of breast cancer and possibly to
prevent it. It is not only because of direct anticancer activity, but also
due to hormonal balancing properties of the artemisinin. Herein, doses of
300 mg twice per day were adequate with other herbs.8
"The herb itself, Artemisia annua, is one of the best things for PMS,
cramping, excessive bleeding and all symptoms of hyper-estrogenemia and
hyperprolactinemia." Dr. Hoang, MD.
Artemisinin contains an internal peroxide group. Due to this group, reactive
oxygen is already present in the molecule. This belief is in agreement with
the observations that derivatives of artemisinin lacking the peroxide
moiety, are devoid of antimalaria activity.9
Additional support for oxygen-mediated toxicity of artemisinin is generated
from other studies. The antimalarial activity of artemisinin in vitro,
against P. falciparum, could be enhanced by increased oxygen tension. Drugs
such as miconazole and doxorubicin, which are known to work via oxygen
radical effects, enhance the activity of artesunate, a derivative of
artemisinin. The effectiveness of artemisinin is reduced by catalase,
dithiothreitol and alpha tocopherol.10
Furthermore, Levander, et al. found that manipulation of the host
antioxidant defense status could provide prophylactic or therapeutic
enhancement for the control of malaria. In this study, mice were fed with
diets deficient in vitamin E or a diet supplemented with cod liver oil,
which would deplete antioxidants. Vitamin E deficiency enhanced the
antimalarial action of artemisinin against P. yoelii, but selenium
deficiency did not. A diet containing 5% cod liver oil had a very strong
antimalarial action.11
Artemisinin has been shown to work through oxygen and carbon based free
radical mechanisms. Its structure includes an endoperoxide bridge. Peroxides
generate free radicals in a Fenton type reaction when exposed to unbound
ferrous iron. Malaria, which grows in the erythrocytes, has the opportunity
to accumulate much excess iron which can spill into the unbound form.
Electron microscopy has confirmed destruction of plasmodium membranes with
morphology typical of free radical mechanisms.
With the knowledge of a high accumulation of iron in cancer cells,
researchers Henry Lai and Narenda Singh of the University of Washington
became interested in possible Artemisinin activity against malignant cells.
In 1995, they published a paper in Cancer Letters concerning the use of
artemisinin against numerous cancer cell lines in vitro. This article has
mobilized interest in artemisinin as an addition to anticancer treatment.12
There are a number of properties shared by cancer cells, which favor the
selective toxicity of artemisinin against cancer cell lines, and against
cancer in vivo. In addition to higher rates of iron flux via transferren
receptors than normal cells, cancers are particularly sensitive to oxygen
radicals.13
A subsequent article appeared in Life Science in 2001 by Singh and Lai on
the selective toxicity of artemisinin and holotransferrin towards human
breast cancer cells.14 In this article, rapid and complete destruction of a
radiation-resistant breast cancer cell line was achieved when the in vitro
cell system was supported in iron uptake with holotransferrin. The cancer
cell line was completely nonviable within 8 hours of combined incubation
with minimal effect on the normal cells.
Artemisinin becomes cytotoxic in the presence of ferrous iron. Since iron
influx is naturally high in cancer cells, artemisinin and its analogs
selectively kill cancer cells under conditions in vivo. Further, it is
possible to increase or enhance iron flux in cancer cells using the
conditions that increase intracellular iron concentrations. However, intact
in vivo systems do not need holotransferrin, the living body provides all
the necessary iron transport proteins.
A third paper, by Efferth et al., published in Oncology in 2001 stated that
the antimalarial artesunate is also active against cancer.15 This article
described dramatic cytotoxic activity against a wide variety of cancers
including drug resistant cell lines. Artesunate (ART) is a semi-synthetic
derivative of artemisinin, and has been analyzed for its anticancer activity
against 55 cell lines by the Developmental Therapeutics program of the
National Cancer Institute, USA. ART was most active against leukemia and
colon cancer cell lines. Mean growth inhibition 50% (GI 50) 1.11microM and
2.13 microM respectively. Non-small cell lung cancer cell lines showed the
highest mean (GI50 26.62 microM) indicating the lowest sensitivity towards
ART. Intermediate GI 50 values were obtained for melanomas, breast, ovarian,
prostate, CNS, and renal cancer cell lines. Most important, a comparison of
ART's cytotoxicity with those standard cytostatic drugs showed that ART was
active in molar ranges comparable to those of established antitumor drugs.
Leukemia lines resistant to either doxorubicin, vincristine, methotrexate,
or hydroxyurea were tested. Remarkably, none of these drug resistant lines
showed resistance to ART. The theorized reason for this is the absence of a
tertiary amine in ART, present in virtually all other chemotherapy agents,
which is required for cellular transport systems to usher the drug outside
the cell.
Cancer Cells Are Deficient in Antioxidant Enzymes
Cancer cells are notoriously deficient in antioxidant enzymes - both forms
of superoxide dismutase, the manganese form in mitochondria, and the copper
zinc form in the cell cytoplasm are generally low in cancer cells. Cancer
cells are grossly deficient in catalase and glutathione peroxidase, both of
which degrade hydrogen peroxide. It is these deficiencies in antioxidant
enzymes which lead to the use of many of the common chemotherapeutics which
are superoxide generators.16
The higher iron fluxes, especially associated with the reproductive phase of
tumor cells, should render these cells even more susceptible to oxidative
damage via hydrogen peroxide and superoxides. Normally, the profound
catalase deficiency in cancer cells is credited with creating vulnerability
to oxidants, in relationship to IV vitamin C or IV hydrogen peroxide.
However, since all of these protective antioxidant enzymes are most often
deficient in transformed cells, the oxidant vulnerability should be enhanced
dramatically, and further so, due to enhanced unbound iron during cell
division.
Dr. Hugh Riordan has suggested that very high doses of IV vitamin C can kill
cancer cells via conversion of vitamin C to hydrogen peroxide, and due to
deficiency of catalase. For this procedure to work, very high levels of IV
vitamin C are required to reach "kill concentrations." IV vitamin C may be
one of the best-documented alternative cancer treatments.17
Artemisinin may be a most effective method, and certainly one of the
easiest, of delivering a knockout oxidative stress to cancer cells.
Artemisinin is appealing for oral use in that the pharmacodynamics, dosage
and toxicity have been well studied for use in relationship to the treatment
of malaria. Artemisinin is relatively safe with little side effects even at
high dosages (70 mg/kg per day) in short term malaria use.
Artemisinin has two semisynthetic derivatives. Artesunate is a water-soluble
derivative with no reported toxicity at usual levels. However, its serum
half-life is relatively short. Artemether is a lipid soluble derivative,
effective in cerebral malaria, and therefore may be more effective in brain
cancers by better penetration of the blood-brain barrier. Artemether,
however, has been reported to cause some neural toxicity in laboratory
models in rather high doses. Artemisinin has an intermediate half life and
can cross the blood-brain barrier. The two semisynthetic derivatives are
available overseas in both oral and injectable for artesuante and
artemether.
As mentioned, Lai used holotransferrin, which is iron-loaded transferrin, to
further sensitize tumor cell lines to the oxidizing properties of
dihydroartemisinin, which is derived from the parent compound metabolically
in vivo. A human leukemia cell culture, Molt-4-lymphblastoid cells, and
normal human lymphocytes were used in this experiment.
A significant decrease in cell count was noted with artemisinin alone, with
p<.035. Greater effects were noted when transferrin and dihydroartemeisin
were used together. In combined treatment, considerable tumor cell death was
observed at a concentration of dihydroartemisinin of 1 uM after 8 hours of
incubation. Furthermore, there is reason to believe that artemisinin can
work at lower concentrations in vivo than in vitro, due to destruction of
the artemisinin molecule in vitro.
Lai suggests that this procedure would be most effective for the treatment
of aggressive cancers, in which large numbers of transferrin receptors are
expressed on the cell surface. It may not be effective for T cell leukemias,
which have defective internalization of transferrin receptors, and therefore
may not be susceptible to this treatment.12
Case reports
1. Patient D.A. a 47 year-old mechanic who presented with a 4.5 cm.
Non-Hodgkin's lymphoma on the right side of his head, with gaping incision
from a recent biopsy, and tremendous inflammatory erythema. Artesunate, 60mg
was administered IM 14 consecutive days and he switched diets to high
protein/vegetable (Kelley parasympathetic type diet). At the end of two
weeks, a depression appeared at the apex of the tumor. Four weeks later, the
mass was completely gone, skull surface smooth, incision totally healed and
erythema virtually cleared. Apparantly cancer-free as of this writing 6
months later.
2. Patient V.M. an 83 year old Toronto resident. Healthy most of her life,
she now had a non-small cell lung carcinoma in the right lower lobe,
considered non-resectable because of heart failure and circulatory problems.
She received Artemisinin 500mg BID from Allergy Research Group and Carnivora
oral, via nebulizer, 5cc BID. In 4 months the tumor shrunk to 1x2 cm and her
oncologist felt this represented scar tissue and declared her cancer free.
(Her heart condition improved considerably with CoQ10, 600mg daily).
3. Patient D.E., a 47 year-old Alaska resident with stage 4 breast cancer
and metastases to T1 with significant pain, vertebral collapse and local
neurological impairment. First seen May 2001, she received a series of IPT
(insulin potentiation therapy-low dose chemotherapy), high dose vitamin C
infusions, supplements, and dendritic cell vaccine, dietary management
(Kelly sympathetic type diet), and detoxification strategies. Most symptoms
had cleared within 4 months (October 2001). In January 2002, she received
artesunate IV (source: mainland China), plus oral artemisinin 300 mg BID
(ARG and Wellcare Pharma) which has been continued. Six months later she was
happy to report she has no symptoms whatsoever and is living a normal life.
Her local provider believes the regressed mass is now scar tissue.
4. Patient F.A., an 81 year-old Californian with multiple skin cancers
including one active recurrent quarter-sized lesion that had been burned 4
times previously. Topical artemisinin (one capsule ARG artemisinin in 50%
DMSO) applied twice daily caused the large lesion to fall off within 5 days
and other smaller skin cancers to regress. His wife reported the same with
her skin cancers.
5. L.L. is a West Coast woman in her 40's with breast cancer and extremely
painful metasteses all over her spine. She had received limited radiation
therapy to reduce the pain in the thoracic spine prior to consulting me. She
began artemisinin, and a variety of complementary strategies, including
diet, detoxification and Kelly type proteolytic enzymes (from Allergy
Research Group). Immediately, her energy exploded. Her pain level took a
dive when she received treatment from an Edgar Cayce Foundation healer. Her
comment after two weeks on artemisinin was "Last week I thought I was dying,
and today for the first time in months, I believe I am going to live." Four
months into therapy using oral supplements alone (no IV therapy), diet and
detoxification strategies, a PET scan, the most efficient and sensitive
study for spread of cancer, did not show any activity anywhere in her spine,
even in places that were present before and not radiated! Further, the scan
did not confirm definite cancer activity anywhere else!
All patients who took oral artemisinin did so in the morning and evening on
an empty stomach with either conjugated linoleic acid and/or omega 3
supplements and/or some full fat cultured organic dairy product to enhance
absorption. Simultaneous iron in the stomach might neutralize its
effectiveness.
Conclusion
Artemisinin has been used for about 30 years in Vietnam and China for cancer
treatment. And the experience with artemisinin for this purpose is
increasing. This history probably led to the recent cited cancer research
with artemisinin.
The fact that artemisinin's direct antineoplastic effects closely resemble
that of high-dose intravenous vitamin C is intriguing. The potential benefit
of artemisinin in cancer treatment should be further explored because it is
simple, safe, well-understood, and capitalizes on the multifold weakness in
cancer cells to defend themselves against oxygen radicals. Enhancing the
oxidant activity with other oxidation agents (such as carnivora, ultraviolet
blood irradiation, H2O2, or higher oxygen tension itself) may add
significant synergism. Adding artemisinin to low dose chemotherapeutic
regimens inducing cytotoxicity via free radical mechanisms (such as
doxorubicin), may safely add to the effectiveness of such treatment.
Dr. Singh, in a personal communication to me, has shared that he has been
following a series of cancer patients with nearly universal improvement on
artemisinin or its derivatives. He believes artemisinin will prove to be the
most powerful, yet extremely inexpensive and safe, chemotherapeutic agent
yet found, and effective orally for home use. However, like myself, he and
the Hoang family of physicians, believes it should only be used in a
professional atmosphere together with complementary strategies employing
detoxification, diet, immune support, spiritual work, etc. This use of
complementary strategies and professional supervision cannot be emphasized
enough, especially since long term use of artemisinin and/or its derivatives
has had little study. The Hoang family has indicated to me a 50-60%
long-term remission in over 400 cancer patients utilizing artemisinin
together with a comprehensive cancer strategy, and with no observed
toxicity.
I gratefully acknowledge Drs. Lai and Singh in their pioneering work and
their personal assistance in providing me with the information needed to
work with artemisinin and its derivatives for the benefit of my patients.
Correspondence:
Robert Jay Rowen, MD
95 Montgomery Dr., Suite 220
Santa Rosa, California 95472 USA
Email: drrowen@xxxxxxxxx
Web site: www.doctorrowen.com
References
1. Klayman D. Qinghaosu (Artemisinin): Antimalarial Drug from China.
Science, 1985, Vol. 238, May 31, p.1049
2. China Cooperative Research Group on Qinghaosu and its Derivatives as
Antimalarials. J. Trad. Chin. Med 2, 17, 1982.
3. Keith Arnold, Tran Tinh Hien, Nguyen Tran Chin, et al. A randomized
comparative study of artemisinine suppositories and oral quinine in acute
falciparum Malaria.
4. Transactions of the Royal Society of Tropical Medicine and Hygiene (1990)
84:499-502.
5. Bharel S, Gulati M, Abdin P, Srivastava S. Structure biosynthesis and
functions of artemisinin. Fitoterapia Vol LXVII No 5, l996.
6. Gulati A, Bharel S, Srivastava M, Abdin MZ. Experimental Studies on
Artemisia, an herbal remedy for malaria. Fitoterapia Vol LXV11 No 5, 1996.
7. Hien T, White N. The Lancet 1993 Vol 341 March 6 p 603-651.
8. Personal communication from Dr. Hoang, M.D., 2002.
9. Ames JR, Ryan MD, Klayman DL. Charge transfer and oxy radicals in
antimalarial action. J. Free Rad Biol. Med 1985, 1:353-61.
10. Krungkrai SR, Yuthavong. The antimalarial action of Plasmodium
falciparum of qinghaosu and artesunate in combination with agents which
modulate oxidant stress. Trans. R Soc. Trop. Med Hyg 1987, 81:710-4.
11. Levander OA, Ager AL, Morris VC. Qinghaosu, dietary vitamin E, selenium
and cod liver oil: effect on susceptibility of mice to the malarial parasite
Plasmodium yoelii. Am. J. Clin. Nutr. 1989; 5:346-52.
12. Lai H., Narendra S. Cancer Letters, 91:41-46, 1995.
13. May WS. J Membr. Biol., 88:205-215, 1985.
14. Singh NP, Lai H. Life Sci Nov 21, 70(1):49-56, 2001.
15. Efferth T, Dunstan H, Sauerbrey A, Miyachi H, Chitambar CR. Antimalarial
artesunate is also active against cancer, Oncol. 2001, Apr;18(4):767-73.
16. Levine SA, Kidd PM. Antioxidant Adaptation: Its Role in Free Radical
Pathology. Allergy Research Group, San Leandro, California, 1985.
17. Journal of Orthomolecular Medicine, Special Edition, 1999.
.
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